{
"claim": "A Top-Down Mechanism for Sporadic ALS Initiated by Ocular Metal Dyshomeostasis and Retrograde Exosomal Transport along the Subcortical Visual Axis",
"timestamp": "2026-08-02T11:22:17.330Z",
"settings": {
"mode": "Social",
"library": "PubMed",
"format": "Preprint",
"length": "Standard",
"rigor": "Strict",
"tagCloud": "on",
"breadth": 50,
"depth": 5,
"runs": 1,
"evalsPerRun": 1,
"autoExplore": false,
"smartFollowUp": false
},
"prompt_settings": {
"research_veridical_check": {
"name": "Research Veridical Verification",
"purpose": "Audits the final research response after quotes pass to ensure absolute veridicality, logical consistency, and zero hallucinated external knowledge.",
"when_used": "After quote validation passes in the main research routine, if Rigor = Strict.",
"content": "You are a strict QA Audit AI. Your job is to verify the RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"assistant_veridical_check": {
"name": "Assistant Veridical Verification",
"purpose": "Audits the assistant's response to ensure absolute veridicality and rule adherence.",
"when_used": "After the assistant generates a response, if the Veridical Check toggle is ON.",
"content": "You are a strict QA Audit AI. Your job is to verify the ASSISTANT_RESPONSE and RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"custom_datapoints_directive": {
"name": "Custom Datapoints Directive",
"purpose": "Specifies custom keys and extraction rules for the AI to include in the JSON block.",
"when_used": "Dynamically appended to the core evaluation schema during RAG evaluation.",
"content": "### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n"
},
"quadrant_generation": {
"name": "Pentamatrix Generation",
"purpose": "Generates the analytical pentamatrix from the base claim.",
"when_used": "Beginning of the Semmelweis mode workflow.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes\n\nINITIAL EVALUATION: CLAIM vs. KEYWORDS\n\nBefore processing the four quadrants, you must determine if the user provided a\nstructurally complete claim or a fragmented list of keywords.\n\n - If Full Claim: Act as a strict transcription engine.\n - If Keyword List / Fragment: Act as a Speculative Synthesis Engine.\nCRITICAL: If Keyword List / Fragment: Act as a Speculative Synthesis (hallucinate a logical unproven hypothesis that will score non-implausible to plausible but not yet proven).\n\nQUADRANT CONSTRAINTS\n\n0. RAW USER TEXT\n1. ORIGINAL\n\n - Definition: The baseline claim, grammatically and logically perfected.\n - Rule for Full Claims: Transcribe exactly as stated. Your ONLY modification\n is to fix spelling, punctuation, and grammar. If the input is a question,\n convert it into a declarative claim.\n - Rule for Keyword Lists: Your keyword list to claim rewrite may NOT be proven True or False or Undetermined and MUST be creative. You MUST NOT summarize the keywords. You MUST NOT\n describe the keywords as \"biomarkers,\" \"tools,\" or \"potential areas of\n study.\" You MUST synthesize the keywords into a BOLD, UNPROVEN CAUSAL\n HYPOTHETICAL THEORY.\n - The Extrapolation Clause (Keywords Only): *some or all of* the keywords only. novel idea. \n\n2. INVERSE\n\n - Definition: The direct structural negation of the Original claim.\n - Rule: Directly negate the primary relationship. Do NOT introduce new\n variables. Flip the boolean state of the primary verb (e.g., \"promotes\"\n becomes \"does not promote\").\n\n3. ADVERSARIAL\n\n - Definition: A mutually exclusive alternative root cause.\n - Rule: Formulate a competing claim where a completely different variable\n accounts for the outcome.\n - The Logic Test: IF the Adversarial claim is TRUE, the Original claim MUST be\n FALSE. It must represent a conflict of causality.\n\n4. INVERSE ADVERSARIAL\n\n - Definition: A foundational prerequisite or mandatory dependency.\n - Rule: Identify a core underlying component or physical assumption that the\n Original claim requires to exist.\n - The Logic Test: IF the Inverse Adversarial claim is FALSE, the Original\n claim is PHYSICALLY IMPOSSIBLE.\n\nOUTPUT FORMAT\n\nReturn ONLY valid JSON. Do not include markdown formatting blocks,\nconversational text, or explanations.\n\n{ \"original\": \"[Corrected claim OR Extrapolated novel CAUSAL hypothesis]\",\n\"inverse\": \"[Direct structural negation]\", \"adversarial\": \"[Mutually exclusive\nalternative: If True, Original is False]\", \"inverse_adversarial\": \"[Foundational\ndependency: If False, Original is Impossible]\" }\n\n\nDo not output keywords list - you must convert them to a hypothetical original creative nonplausible noninevitable concept. Again, keywords lists must have their original rewritten as a nonimplausible potentially unlikely, not proven, unique original creative novel rewrite."
},
"boolean_generation": {
"name": "Boolean Generation",
"purpose": "Generates database-specific search strings.",
"when_used": "Stage 1 of each pentamatrix's evaluation loop.",
"content": "You are an expert librarian and systematic reviewer. Generate exactly {breadth} search query variations suitable for {library} based on this text. \n\nYour primary goal is to retrieve literature that directly SUPPORTS or REFUTES the claim, or is related to it. Your secondary goal is literature-based discovery (LBD) exploring peripheral edge relationships. Use OR to discover edges and overlooked abstracts.\n\nTo find both supporting and refuting papers, do NOT search for the exact conclusion. Instead, search for the intersection of the core variables (e.g., Variable A AND Variable B). USE \"OR\" for edge discovery.\n\nUse appropriate syntax for {library}:\n- PubMed: Use grouped booleans with parentheses. Group synonyms using OR (e.g., (\"Term 1\" OR \"Synonym 1\")). Connect distinct core concepts using AND. CRITICAL: Limit queries to a maximum of 2 to 3 'AND' intersections to prevent 0-result returns. Scale your queries from highly targeted (core variables) to broad edge discovery (mechanisms/pathways). Include MeSH terms.\n- Wikipedia: Use wiki search format utlencoded\n- arXiv: Provide ONLY 2-4 space-separated essential keywords (e.g., polar bear, skin, color). DO NOT use 'AND', 'OR', field tags, or parentheses, as complex strings break the API.\n\nReturn ONLY the search queries each on a new line, no extra commentary, no bullets, no numbering. \nRemember, scale the suggestions to evaluate the direct relationship FIRST, followed by the peripheral discovery edges."
},
"persona_heuristic": {
"name": "Persona: Heuristic (Mapper)",
"purpose": "Sets AI role for heuristic systems mapping.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Heuristic).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a heuristic logic mapper and researcher. You play the role of a Systems Architecht.\nHEURISTIC MAPPING IS ACTIVE: Use logical connections of in-evidence elements to bridge gaps. Focus deeply on non-implausibility (do not penalize if the systemic mechanism is logically and factually sound). Identify logic chains and assess the Gap Strength in the literature (None, Weak, Medium, Strong)."
},
"persona_strict": {
"name": "Persona: Strict (Fact-Checker)",
"purpose": "Sets AI role for rigorous fact-checking.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Strict).",
"content": "You are a strict, rigorous scientific fact-checker.\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes."
},
"format_preprint": {
"name": "Format: Preprint",
"purpose": "Defines the academic output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Preprint).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations. You must actually use the quotes you select within the conext of the preprint publication you write."
},
"format_clinical": {
"name": "Format: Clinical",
"purpose": "Defines the medical output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Clinical).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a clinical, medical-professional tone.\nFormat your readable response using these exact clinical headers:\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [CLINICAL BOTTOM-LINE / REWRITTEN CLAIM]\n(Scientific synthesis)\n### [RISK VS REWARD & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [PATIENT APPLICATION: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"format_standard": {
"name": "Format: Standard",
"purpose": "Defines the standard output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Standard).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nIf the user asked a question, you must first provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nThen use a friendly and appropriate tone and answer their intent based solely on the research provided.\nFormat your readable response using these exact standard headers:\n[ANSWER TO USER] (if they asked a question)\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [REWRITTEN CLAIM/PATHWAY]\n(Scientific synthesis based on evidence)\n### [JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [HIGHLIGHTS: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"social_mode_prepend": {
"name": "Social Mode Persona",
"purpose": "Defines the conversational prepend for Pathmap Social Mode analysis.",
"when_used": "When Analysis Mode = 'Pathmap Social' in Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###[FRIENDLY ANSWER TO USER INTENT]\nAddress the user intent directly at the very top. Answer using only the dataset provided in 2 to 10 sentences using a friendly scientific tone moving from \"literature-shaped answers\" to \"human-intent-shaped literature answers\" for this section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"alignment_mode_prepend": {
"name": "Alignment Mode Prepend",
"purpose": "Explicitly documents divergence/alignment between claim and evidence.",
"when_used": "When Analysis Mode = 'Alignment Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes. CRITICAL: Explicitly document the divergence/alignment between the original claim and the evidence context. Note any contradictions or supporting facts clearly."
},
"flexible_mode_eval": {
"name": "Flexible Mode Logic",
"purpose": "Logic used in Flexible Mode",
"when_used": "When Analysis Mode = 'Flexible Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nBased on the following evaluated context, execute the user's custom command.\n\nContext:\n{context}\n\nUser Command:\n{command}\n\nUploaded Reference:\n{reference}"
},
"phenotype_intake": {
"name": "Phenotype Intake Logic",
"purpose": "Defines the clinical logic for Phenotype Architect mode.",
"when_used": "When Analysis Mode = 'Phenotype Architect'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a clinical Phenotype Architect. Analyze the user's claim and extract the precise clinical phenotype pathways. Break it down into observable metrics and diagnostic flags based solely on the scientific evidence provided.\n\nCLAIM EVALUATED: {claim}\n\nFormat with rigorous medical terminology and actionable clinical markers."
},
"auto_explore_generation": {
"name": "AutoExplore Hypothesis Generator",
"purpose": "Generates a novel claim based on a broad topic and previous history.",
"when_used": "Beginning of each loop when AutoExplore is enabled.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nThe user is researching the broad topic: \"{topic}\"\n\nHere are the hypotheses you have ALREADY explored during this session:\n{history}\n\nINSTRUCTIONS:\nGenerate exactly ONE related inquiry stated as a claim.\n- It MUST be formatted as a declarative statement.\n- DO NOT wrap it in quotes.\n- DO NOT include conversational text or explanations.\n- Just return the simple claim."
},
"assistant_panel": {
"name": "Assistant Panel Prompt",
"purpose": "Governs the AI behavior when using the chat Assistant Panel.",
"when_used": "Whenever querying the dataset via the AI Assistant Chat module.",
"content": "You are an expert Data Scientist and Visualization Architect. Answer the user directly and truthfully. Do not introduce yourself.\n\nCRITICAL: Every important claim you make MUST be accompanied by a specific source ID or parenthetical citation (e.g., [ID: 12345]) if it is derived from the context.\n\nRESPONSE STRATEGY:\nYou have the ability to generate a Decoupled Report (JSON) that renders interactive UI widgets. Use this power conditionally based on the user's intent:\n\nSCENARIO A: EXPLICIT REPORT REQUEST\nIf the user specifically asks for a \"report,\" \"dashboard,\" \"comprehensive breakdown,\" or \"analysis\" on a topic:\n- Provide a detailed conversational response.\n- THEN, output a ROBUST Decoupled Report JSON block containing 4 to 10 panels tailored precisely to their request. (Include \"synthesis\" and \"pathmap\" as mandatory selections).\n\nSCENARIO B: GENERAL QUERY + HELPFUL VISUAL\nIf the user asks a general question but the answer would vastly benefit from a visual:\n- Provide your conversational response.\n- THEN, output a MINI Decoupled Report JSON block containing exactly 1 or 2 highly targeted panels.\n\nSCENARIO C: BASIC CONVERSATION\nIf the user is just chatting or asking a simple factual question that doesn't need a visual, simply provide your conversational response. Omit the JSON block entirely.\n\n================================================================\nDECOUPLED REPORT PROTOCOL (JSON)\n================================================================\nDo NOT generate raw HTML, CSS, or JS. Output ONLY valid JSON inside the fencing.\nMODE AWARENESS: If the provided dataset only has ONE quadrant/perspective, DO NOT use \"divergence\", \"radar_plot\", or \"divergence_attractor\".\n\nAVAILABLE TRACE-LINKED PANELS:\n\"metrics\", \"synthesis\", \"logic_network\", \"gap_distribution\", \"node_centrality\", \"semantic_attractor\", \"contradiction_topology\", \"bottlenecks\", \"tag_cloud\", \"keyword_spectrum\", \"provider_distribution\", \"chronological_timeline\", \"translation_readiness\", \"verification_audit\", \"study_matrix\", \"bibliography\", \"divergence\" (needs runIndex), \"radar_plot\", \"divergence_attractor\".\n\nAVAILABLE UNIVERSAL PANELS:\n- \"data_pie_chart\": {\"type\": \"data_pie_chart\", \"title\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"data_bar_chart\": {\"type\": \"data_bar_chart\", \"title\": \"...\", \"xAxisLabel\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"event_timeline\": {\"type\": \"event_timeline\", \"title\": \"...\", \"data\": [{\"date\": \"1990\", \"title\": \"...\", \"desc\": \"...\"}]}\n- \"comparison_matrix\": {\"type\": \"comparison_matrix\", \"title\": \"...\", \"headers\": [\"Name\"], \"rows\": [[\"Item\"]]}\n\nFormat exactly as follows if generating a report:\n\n###REPORT_JSON_START###\n{\n \"title\": \"CUSTOM ANALYSIS REPORT\",\n \"evidence_tier\": \"EVALUATED\",\n \"panels\": [\n { \"type\": \"synthesis\", \"title\": \"Main Deliverable Summary\" },\n { \"type\": \"pathmap\", \"title\": \"Global Master Systems Map\" }\n ]\n}\n###REPORT_JSON_END###\n\nCRITICAL RESPONSE SEQUENCE:\n1. First, provide your conversational response.\n2. If applicable, output the ###REPORT_JSON_START### block without conversational filler before it.\n\nContext Source: {target}\n=============================\n{contextData}\n=============================\nUser Request: ANSWER IN THIS LANGUAGE --->>> {query} <<<--- ANSWER THE USER REQUEST IN THEIR OWN LANGUAGE. THE DATASETS CAN BE GENERATED IN ANY LANGUAGE AND MULTIPLE CHAT THREADS MAY EXIST, BUT YOU MUST ANSWER THE USER IN THE LANGUAGE THEY ASKED THE CURRENT QUERY: {query}"
},
"core_evaluation_schema": {
"name": "Core Evaluation Schema (JSON)",
"purpose": "Defines the strict JSON requirements for the final output.",
"when_used": "Appended to every Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42512450\nTitle: Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.\nAbstract: Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-\u03b2 and tau aggregates in AD, \u03b1-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.\n\nID: 42487414\nTitle: Invited Commentary on: Gaebe et al's \"Effectiveness and Safety of Extracellular Vesicle-Based Therapies for Non-Surgical Facial Rejuvenation: A Systematic Review\": Extracellular Vesicles in Aesthetic Medicine: Promise Requires Proof.\nAbstract: \n\nID: 42458453\nTitle: Extracellular vesicles as a liquid biopsy for amyotrophic lateral sclerosis: a systematic review and meta-analysis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome diagnosed clinically using standardized criteria, with neuropathological confirmation of motor neuron loss and TDP-43 aggregates in postmortem brain tissue. Extracellular vesicles (EVs) have emerged as potential minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. Following PRISMA guidelines, we searched PubMed and EMBASE from inception to May 21st, 2026. Forty-one studies met inclusion criteria. Where published summary statistics were available, these were used directly; where they were not, data were reconstructed from figures or obtained from authors and re-analyzed to derive standardized effect sizes and exploratory diagnostic accuracy estimates. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. EV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in EVs from ALS vs. controls (SMD\u2009=\u20091.30) with high heterogeneity (I\u2009=\u200997.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC\u2009=\u20090.839). No publication bias was found across both meta-analyses. EV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. This work highlights the need for standardized protocols, transparent data sharing, and independent validation.\n\nID: 42436563\nTitle: Context of use matters: interpreting extracellular vesicle TDP-43 as a biomarker in ALS.\nAbstract: \n\nID: 42436372\nTitle: Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.\nAbstract: Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n\u2009=\u200921) and healthy controls (n\u2009=\u200916), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P\u2009=\u20090.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.\n\nID: 42430469\nTitle: Congenital blindness reduces myelination in human visual cortex.\nAbstract: Sensory experience is critical for cortical maturation, but the cellular consequences of its absence remain poorly understood in humans. Using in vivo sub-millimeter 3 T and 7 T MRI and ultra-high-gradient diffusion MRI, we investigated the effects of congenital blindness on the human early visual cortex. Blind individuals showed reduced R2* and MTsat-markers of iron and myelin-along with increased diffusivity, orientation dispersion, and reduced neurite density in the gray and superficial white matter. Cortical thickness was increased in blind individuals and associated with lower myelin and iron, questioning the long-standing assumption that increased thickness primarily reflects disrupted pruning. Our results provide no direct evidence for disrupted pruning. However, they suggest reduced myelination and oligodendrogenesis as key effects of congenital blindness and highlight the critical role of sensory input in shaping and stabilizing cortical circuits.\n\nID: 42391458\nTitle: Elevated urea levels in human frontotemporal dementia and amyotrophic lateral sclerosis post-mortem brain tissue: evidence of a multi-dementia pathogenic mechanism.\nAbstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent two neurodegenerative diseases on opposite sides of a movement disorder continuum. However, like many other neurodegenerative diseases, the molecular pathogenesis of FTD and ALS is not fully understood. Our group has previously reported evidence for a pervasive elevation of brain urea levels in five other dementia-causing diseases. However, brain urea levels have yet to be measured in ALS and FTD. Here, we employed ultra-high-performance liquid chromatography-tandem mass spectrometry to characterize brain urea differences between control (n\u2009=\u200914/12) and ALS/FTD (FTD: n\u2009=\u20098/9; ALS: n\u2009=\u200913/14) cases in post-mortem tissue from two brain regions with different levels of neuropathological burden (high versus low). Elevated urea levels were observed in both the frontal cortex (high neuropathological burden) and primary visual cortex (low neuropathological burden) in cases with FTD. Contrastingly, in cases with ALS, elevated urea was observed in the primary motor cortex (high neuropathological burden), but not the dentate nucleus (low neuropathological burden). These results not only suggest that elevated urea levels are also present in ALS and FTD but imply that elevated brain urea is linked to a multi-dementia pathogenic mechanism. In contrast to ALS, the observation of elevated urea in regions of both high and low neuropathological burden in FTD implies that this phenotype is likely widespread and, therefore, may play a larger role in the pathogenesis of disease. Such a mechanism could offer new directions for developing treatments targeting this underlying pathology.\n\nID: 42372734\nTitle: An open-label Phase 2a study of fasudil in amyotrophic lateral sclerosis: safety and exploratory endpoints.\nAbstract: The primary objective was to assess the safety of oral fasudil in amyotrophic lateral sclerosis (ALS) patients. Changes in serum neurofilament light (NfL) levels and the ratio of phosphorylated to total AKT (pAKT/tAKT) were exploratory endpoints. This was a multicenter, open-label study. Two 31-patient cohorts were sequentially enrolled and treated with either 180\u2009mg or 300\u2009mg per day of oral fasudil for 24\u2009weeks. The primary endpoint was safety. Secondary endpoints evaluated changes in the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity, and muscle strength. We also assessed changes in serum NfL and pAKT/tAKT ratios in plasma (neuron-derived) and CSF (total) extracellular vesicles (EVs). Eighty-one percent (25/31) and 71% (22/31) of patients completed 24\u2009weeks of treatment in the 180 and 300\u2009mg cohort, respectively. Fasudil was safe and well tolerated, with predominantly mild drug-related adverse events. Secondary endpoints, though not statistically significant, were directionally consistent with a treatment effect. Exploratory analyses showed a 15.4% reduction in serum NfL at 24\u2009weeks (p\u2009=\u20090.001) in the 180\u2009mg cohort, with no change in the 300\u2009mg cohort (-0.4%, p\u2009=\u20090.990). The NfL reduction was inversely correlated with ALSFRS-R decline (Spearman\u2009=\u2009-0.45, p\u2009=\u20090.028). Ratios of pAKT/tAKT, a pharmacodynamic marker of rho kinase (ROCK) inhibition, were significantly increased at 24\u2009weeks in plasma (neuron-derived) and CSF EVs. Oral fasudil is safe and well-tolerated in ALS patients. The reduction in NfL and demonstration of CNS target engagement, supports studying the 180\u2009mg dose in a double-blind placebo-controlled study.\n\nID: 42352907\nTitle: The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.\nAbstract: Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in the brain, with glial cell-derived EVs increasingly recognized for their roles in maintaining brain homeostasis and contributing to the progression of neurodegenerative diseases. By transferring a diverse cargo of bioactive molecules, including proteins, RNAs, and organelles, EVs influence recipient cell behavior and overall brain function. In neurodegenerative conditions, glial EVs can either propagate pathogenic signals or deliver neuroprotective and regenerative cues, depending on their cellular origin and molecular composition. This context-dependent heterogeneity highlights the need for physiologically relevant human models to investigate EVs biology. Human induced pluripotent stem cell (iPSC)-derived glial models provide a disease-relevant platform, as they recapitulate key pathological features of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). When further integrated with brain organoid platforms, these iPSC-based systems enable the generation of three-dimensional environments that closely resemble in vivo EVs dynamics. Importantly, glial EVs can modulate cellular pathways involved in neuronal survival and function. Indeed, their potential to interact with and, under specific experimental conditions, traverse the blood-brain barrier (BBB) has contributed to growing interest in their application for biomarker discovery and therapeutic development. Engineered and patient-specific EVs derived from iPSCs are emerging as promising tools for targeted, cell type-specific, therapeutic approaches, although their clinical applicability still requires further validation. This review discusses the emerging evidence supporting the dual role of iPSC-derived glial EVs in health and disease, underscores the translational potential of iPSC-based platforms for mechanistic studies, and outlines their promise as precision medicine tools for diagnostics and therapy.\n\nID: 42351263\nTitle: Dynamic integration of skeletal muscle signals via extracellular vesicles in motor neuron diseases.\nAbstract: Extracellular vesicles (EVs) are heterogenous lipid bilayer-enclosed particles secreted by virtually all cell types. They encapsulate a diverse array of bioactive molecules, including proteins, lipids, nucleic acids, and metabolites, which can be transferred to recipient cells, thereby modulating their function and phenotype. In recent years, skeletal muscle-derived EVs (SkM-EVs) have emerged as key players in the bidirectional communication between skeletal muscle and motor neurons, contributing to the establishment and maintenance of neuromuscular homeostasis. Disruptions in this intercellular signalling have been implicated in the pathophysiology of motor neuron diseases (MNDs) such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). In these contexts, SkM-EVs may contribute to disease progression by delivering pathogenic cargo, including misfolded proteins and aberrant RNAs, to motor neurons. A comprehensive understanding of SkM-EV biology, particularly their roles in neuromuscular communication, could offer critical insights into disease mechanisms and identify novel opportunities for biomarker discovery and therapeutic intervention. This review synthesizes current knowledge on the functional roles of SkM-EVs in motor neuron health and disease and evaluates their potential as diagnostic tools and therapeutic vectors in the context of MNDs.\n\nID: 42331016\nTitle: Imbalanced Trace Elements as Risk Factors in the Pathogenesis of Glaucoma.\nAbstract: Glaucoma, a neurodegenerative disease, is characterised by ocular pathogenic patterns, yet also by cerebral pathologies, particularly within the visual pathway. Oxidative stress is involved in glaucoma pathogenesis, similar to other neurodegenerative diseases, such as Alzheimer's disease. Trace elements can intervene within these molecular processes (e.\u200ag., via enzymes) and in the event of imbalances, also cause pathological changes. This review aims to provide an overview of the common features of glaucoma and other neurodegenerative diseases, focusing on the influence of imbalanced trace elements such as zinc, copper, iron and selenium, and oxidative stress. Das Glaukom weist als neurodegenerative Erkrankung neben den okul\u00e4ren Ver\u00e4nderungen, auch zerebrale Pathologien, vor allem innerhalb der Sehbahn auf. Gemeinsam mit anderen neurodegenerativen Krankheiten, wie z.\u200aB. dem Morbus Alzheimer, findet sich bei Glaukom eine Mitbeteiligung des oxidativen Stresses an der Pathogenese der Erkrankung. Spurenelemente verm\u00f6gen, via spezifische Enzyme, in diese molekularen Abl\u00e4ufe einzugreifen und im Falle einer Dysbalance, diese auch pathologisch zu ver\u00e4ndern. Der vorliegende \u00dcbersichtsartikel m\u00f6chte einen \u00dcberblick \u00fcber die gemeinsamen Features von Glaukom mit weiteren neurodegenerativen Erkrankungen geben \u2013 mit Fokus auf den Einfluss von dysbalancierten Spurenelementen, wie Zink, Kupfer, Eisen und Selen und oxidativem Stress.\n\nID: 42321919\nTitle: SMN deficiency contributes to osteoporosis in spinal muscular atrophy by impairing Snap23 meditated muscle-derived extracellular vesicle secretion.\nAbstract: Spinal muscular atrophy (SMA), caused by mutations in survival motor neuron 1 (SMN1), presents with severe muscle atrophy and prevalent osteoporosis. Transcriptomic profiling of patient muscle biopsies revealed enrichment of extracellular vesicle genes, yet the contribution of SMA-EVs to SMA-associated bone loss and their link to SMN deficiency remain undefined. Clinical CT/MRI images of SMA and control subjects were acquired to quantify osteoporosis and muscle atrophy. SMA model mice (Smn1hSMN2/hSMN2ROSA26hSMN2/+) were phenotyped at 6 weeks by micro-CT and histology. EVs were isolated from muscles, validated (western blot, transmission electron microscope, nano-flow cytometry, BCA protein assay), and compared between genotypes. DiL-labelled EV biodistribution was tracked in vivo; uptake by BMSCs/BMMs was confirmed by confocal microscopy. Cytotoxicity was assessed by live/dead staining. Dose-response experiments evaluated the osteogenic and anti-osteoclastic activity of SMA-EVs. Comparison of the effects of SMA-EVs and CON-EVs were performed with adequate doses in vitro and in vivo, followed by EV replenishment in SMA mice. Osteogenic and osteoclastogenic gene expression was quantified by qPCR; ALP activity by ELISA. Bone and cell parameters were assessed by HE staining, TRAP staining, COL-1 immunofluorescence staining, and micro-CT. RNA-seq data were validated by Western blot. Lentiviral shRNA and over-expression plasmids were used to generate muscle cells with stable SNAP23 knock-down or up-regulation, and AAV-mediated muscle-specific Snap23 over-expression was employed in mice to define the role of muscular SNAP23 in EV secretion and its impact on bone mass. Mice carrying extra SMN2 transgenic copies were analyzed to delineate the SMN-SNAP23 relationship. SMA patients and mice exhibited a significantly diminished capacity of skeletal muscle to secrete EVs, which were readily internalized by BMSCs and BMMs, dose-dependently promote osteogenic differentiation and suppress osteoclast formation. Adequate-dose SMA-EVs matched CON-EVs efficacy, and SMA-EVs supplementation effectively rescued the osteoporotic phenotype in SMA. Transcriptomics indicated impaired SNARE complex-mediated vesicle secretion pathway. We further demonstrated that deficiency of SMN protein drives downregulation of its downstream key SNARE component, SNAP23, thereby impairing the efficiency of SMA-EV secretion. Our work elucidates a novel disease-specific mechanism for SMA osteoporosis-dysfunction of the SMN-SNAP23-EVs axis-and highlights the therapeutic potential of replenishing SMA-EVs or targeting this axis, offering a promising strategy to improve skeletal health in SMA.\n\nID: 42196458\nTitle: The Molecular Basis of Partial Reversal or Significant Slowing of ALS, Parkinson's Disease, and Lewy Body Dementia by Mesenchymal Exosomes/Secretome.\nAbstract: Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson's disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up.\n\nID: 42178909\nTitle: Membrane ATG8ylation in secretory autophagy.\nAbstract: Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: A\u03b2, amyloid-\u03b2; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.\n\nID: 42070160\nTitle: miRNAs in Amyotrophic Lateral Sclerosis: Tiny Molecules, Tremendous Impact.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by progressive motor neuron degeneration, with diverse clinical manifestations and complex genetic and environmental triggers. The variability in disease progression underscores the necessity for tailored diagnostic and therapeutic approaches. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers and therapeutic targets in ALS. Dysregulation of specific miRNAs has been linked to mechanisms of ALS, including neuromuscular dysfunction, neuroinflammation, and neuronal survival/apoptosis. The potential of miRNA-based therapies, such as mimics and inhibitors, offers a more integrated approach by modulating entire disease networks, rather than targeting isolated pathways. However, challenges persist, particularly in delivering these therapies efficiently across the blood-brain barrier and minimizing off-target effects. Current delivery strategies involving nanoparticles, viral vectors, and exosome-based approaches require optimization for clinical use. This review synthesizes the latest research on miRNA-mediated mechanisms in ALS, evaluating their diagnostic, prognostic, and therapeutic potential, while highlighting the current limitations in clinical validation. It underscores the importance of standardized methodologies, multi-omics integration, and rigorous validation to facilitate the clinical translation of miRNA-based strategies. Standardized protocols and multicenter validation in large cohorts are essential to confirm the diagnostic accuracy of miRNAs, paving the way for their clinical application in ALS precision medicine.\n\nID: 41919473\nTitle: Long non-coding RNAs in neurodegenerative diseases - Molecular mechanisms, liquid biopsy biomarkers, and therapeutic targets: A review.\nAbstract: Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are age-related disorders characterized by progressive neuronal loss, cognitive decline, and limited options for disease-modifying treatments. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in neurodevelopment, neuronal homeostasis, and disease progression; however, their involvement in shared pathogenic pathways and clinical applications remains inadequately defined. This review consolidates recent experimental, transcriptomic, bioinformatic, and emerging clinical findings regarding the role of lncRNAs in NDDs. We examine how lncRNAs modulate common disease mechanisms, including protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, ferroptosis, synaptic failure, and aging-related neurodegenerative processes. These regulatory functions occur through various mechanisms, including epigenetic modifications, transcriptional regulation, post-transcriptional processes, and RNA-protein interactions, as well as novel mechanisms such as liquid-liquid phase separation (LLPS), peptide coding, and exosome-mediated intercellular communication.\u00a0Current evidence supports the potential of lncRNAs as minimally invasive liquid biopsy biomarkers, detectable in blood, cerebrospinal fluid (CSF), and extracellular vesicles. Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms. Overall, lncRNAs have emerged as central molecular regulators and promising candidates for translation in NDDs. Nonetheless, challenges related to specificity, validation, delivery across the blood-brain barrier, and clinical standardization must be addressed before their routine application in precision neurology.\n\nID: 41904071\nTitle: Platelet-derived and platelet secretome biotherapies for precision neuromedicine.\nAbstract: Platelet-derived biotherapies are emerging as innovative approaches for complex neurological disorders requiring multimodal interventions. Platelet-derived products, including lysates, platelet concentrate supernatants, secretome, extracellular vesicles, and fractionated components, represent a scalable and clinically accessible biotechnology platform for precision neuromedicine. Platelets provide a reservoir of trophic factors, cytokines, chemokines, lipids, antioxidants, and noncoding RNAs with demonstrated neuroprotective, anti-inflammatory, and antiferroptotic effects in models of neurodegeneration, trauma, and aging. Preclinical and patient-derived omics and neuroimaging data can help characterize mechanisms of action, identify biomarkers, and refine platelet secretome preparations toward indication-specific formulations. Combined with virus inactivation and purification technologies adapted from plasma protein manufacturing, these advances position platelet-derived biotherapies as a rational and versatile path toward future acellular therapeutics for brain disorders.\n\nID: 41894255\nTitle: Destabilized Soluble SOD1 Species as Potential Determinants of Disease Severity in Familial Amyotrophic Lateral Sclerosis.\nAbstract: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are linked to familial amyotrophic lateral sclerosis (ALS), yet the identity of the toxic molecular species remains unclear. We investigated the relationship between protein misfolding and pathogenicity by expressing GFP-tagged wild-type and mutant SOD1 (A4V, H46R, G93A) in mouse hippocampal HT22 cells. Western blotting under nonreducing conditions suggested that A4V, associated with rapid disease progression, was largely depleted of properly folded soluble SOD1 and instead produced highly destabilized soluble species. In contrast, H46R, associated with a milder phenotype, showed a moderate reduction in properly folded soluble SOD1 and generated partially folded/native-like conformers. G93A exhibited biochemical characteristics intermediate between those of A4V and H46R. A4V also showed a pronounced loss of GFP fluorescence, indicating severe structural destabilization; the extent of fluorescence loss in A4V, G93A, and H46R broadly correlated with clinical severity. Neither CuATSM nor ebselen\u2500targeting metal binding and disulfide formation, respectively\u2500rescued fluorescence, suggesting broader defects in SOD1 maturation. Nevertheless, both compounds inhibited ferroptosis, a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation, in HT22 cells, indicating alternative neuroprotective mechanisms. These findings identify destabilized soluble SOD1 species as a key toxic entity in ALS and highlight the utility of GFP-tagged constructs for evaluating folding status and screening therapeutic candidates.\n\nID: 41837970\nTitle: Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related mechanisms, including neuroinflammation, iron homeostasis, and dysregulated microRNAs. To evaluate the safety, tolerability, and potential efficacy of PrimeC in people living with ALS. This was a randomized, double-blind, placebo-controlled, phase 2b trial conducted at 4 ALS referral centers from May 2022 to November 2023 and followed by 12-month open-label extension. Adults with definite or probable ALS and disease duration of 30 months or less were eligible. Of 73 screened, 69 were randomized and 68 were included in the intent-to-treat population. Participants were randomized 2:1 to receive PrimeC or placebo for 6 months, followed by open-label extension PrimeC for all. The primary outcome was safety and tolerability. The prespecified primary biomarker outcome was plasma neuron-derived-exosomal TAR DNA-binding protein 43 (TDP-43) or prostaglandinJ2. Secondary outcomes included change in ALS Functional Rating Scale-Revised (ALSFRS-R) score at 6 and 18 months, survival, and time-to-composite events. Exploratory biomarkers included neurofilament light chains, iron-regulatory proteins, and circulating microRNAs. The 68 participants were well balanced in age at entry and sex. In the PrimeC group, the mean (SD) age was 59.1 (9.1) years, and 27 of 45 participants were male. In the placebo group, the mean (SD) age was 55.0 (13.0) years, and 14 of 23 participants were male. PrimeC was well tolerated, with a safety profile comparable to placebo (adverse event rate, 66.7% PrimeC vs 65.2% placebo). Drug-related adverse events were more frequent with PrimeC (20.0% vs 4.3%), mostly mild to moderate, and transient. At month 6, the mean ALSFRS-R difference was 2.23 points between PrimeC and placebo (95% CI, -0.61 to 5.07; P\u2009=\u2009.12). At month 18, ALSFRS-R scores in participants continuously treated with PrimeC maintained a difference (7.92 points; 95% CI, 2.25 to 13.60; P\u2009=\u2009.007), with significant bulbar difference (3.18 points; 95% CI, 1.32 to 5.04; P\u2009=\u2009.001). Continuous treatment was associated with lower risk of ALS complications, including hospitalization, respiratory failure, or death (HR, 0.36; 95% CI, 0.15-0.85; P\u2009=\u2009.02). In the double-blind period, transferrin levels were preserved with PrimeC (1.90 \u03bcmol/L difference; P\u2009=\u2009.03), the negative ferritin-ALSFRS-R correlation observed in placebo (\u03c1\u2009=\u2009-0.50; P\u2009=\u2009.02) was abolished, and ALS-associated microRNAs were downregulated (log2 fold change: miR-199a-3p, -1.87; false discovery rate [FDR] P\u2009=\u2009.004; miR-199a-5p, -2.23; FDR P\u2009<\u2009.001; miR-181a-5p: -1.89; FDR P\u2009=\u2009.001; miR-181b-5p, -1.62; FDR P\u2009=\u2009.005). Prespecified neuron-derived exosome TDP-43/PgJ2 analyses will be reported separately following completion of development and analyses. PrimeC was safe and well tolerated over 18 months. Although not powered for efficacy, functional and biomarker findings support a confirmatory trial. ClinicalTrials.gov Identifier: NCT05357950.\n\nID: 41776544\nTitle: Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with no established disease-modifying therapy. Mesenchymal stem/stromal cells (MSCs) have been reported to exert neuroprotective effects in models of injury and disease, acting primarily through release of small extracellular vesicles (sEVs). MSC-derived sEVs (MSC-sEVs) have therefore attracted attention as a potential cell-free therapeutic approach for treating neurological conditions such as ALS. Because MSC-sEVs can cross both the nasal epithelial barrier and blood-brain barrier to reach the central nervous system (CNS), intranasal administration represents an attractive approach for repeated delivery of MSC-sEVs for long-term administration. In this study, we administered bone marrow-derived MSC-sEVs or vehicle intranasally to a SOD1(G93A) transgenic mouse model of ALS; the large majority of the sEVs had surface markers for exosomes. Dosing was for three consecutive days per week beginning one day after onset of neurological symptoms and continuing until a moribund state. Neurological score and body weight were recorded daily. Although total survival time and post-onset survival duration were not significantly prolonged by MSC-sEV treatment, MSC-sEV treatment significantly delayed progression from a mild symptom phase (NeuroScore 1) to more severe symptoms (NeuroScore 2) compared with vehicle-treated controls and showed a trend toward slower weight loss. These findings indicate that intranasal administration of MSC-sEVs can delay functional deterioration and prolong the mild impairment stage in an ALS mouse model. If translatable to human patients, such preservation of neurological function could represent a clinically meaningful outcome.\n\nID: 41751374\nTitle: Mesenchymal Stem Cell-Based Therapies Applied in Neurological Diseases: A Systematic Review.\nAbstract: Background/Objectives: Neurodegenerative diseases (NDs) have a severe impact on patients' quality of life, and effective treatments remain limited. As the focus is on treating the symptoms, the root cause of the problem is commonly not addressed. Mesenchymal stem cells show an emerging potential due to the ability for self-renewal combined with their capability for differentiation into various cell lines, which makes them a strong candidate for regenerative therapies in general, and for application in neurological issues in particular. This article provides an overview of the safety, efficacy, and challenges associated with the use of mesenchymal stem cells (MSCs) and their derived secretome in clinical and preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Methods: A systematic search was conducted on PubMed to identify published studies providing clinical and preclinical evidence on the use of MSCs in neurodegenerative disorders. Results: Overall, the literature consistently indicates that MSCs and their derivatives exert disease-modifying effects across multiple NDs. Across AD, PD, HD and ALS, preclinical studies uniformly report improvements in behavioural outcomes, attenuation of neuroinflammation, and neuroprotective effects, largely mediated by MSCs' paracrine signalling rather than direct cell replacement. Clinical studies to date consistently support the safety and feasibility of MSC-based therapies, while efficacy signals remain modest, heterogeneous and predominantly short-term, highlighting the need for larger, well-controlled trials. Conclusions: Integration of genetic engineering, preconditioning, and EV technology may represent an emerging therapeutic approach that may complement existing neuroregeneration treatments, offering a scalable and minimally invasive frontier to improve long-term clinical outcomes in patients with AD, PD, HD, and ALS.\n\nID: 41686369\nTitle: Extracellular vesicles at the neuromuscular junction: messengers of synaptic health and disease.\nAbstract: Extracellular vesicles (EVs) have emerged as pivotal modulators of neuromuscular junction (NMJ) biology, reshaping our understanding of synaptic communication, maintenance, and degeneration. This review consolidates current insights into the roles of EVs derived from motor neurons, muscle fibers, and Schwann cells in regulating NMJ integrity. In healthy states, EVs deliver trophic factors, structural proteins, and regulatory RNAs that promote the clustering of acetylcholine receptors, presynaptic stability, and axonal growth. Motor neuron EVs carry Wnt7a, synaptophysin, and PGC-1\u03b1, while muscle-derived EVs deliver miR-206, agrin, and caveolin-3. Schwann cell EVs contribute neurotrophic support via NRG1 and GDNF. In contrast, diseased or aged NMJs exhibit EV cargo dysregulation, marked by the presence of misfolded proteins (e.g., SOD1, TDP-43), pro-inflammatory cytokines, and reduced regenerative miRNAs. These changes contribute to synaptic dismantling, neuroinflammation, and impaired repair in conditions such as ALS, SMA, MG, and sarcopenia. The review highlights the bidirectional nature of EV signalling and its dynamic regulation by neuronal activity and stress. Emerging therapeutic strategies include engineering EVs to deliver protective cargo, targeting them to NMJ components, and designing biomaterial-based depots for sustained release. Furthermore, EV signatures in blood and muscle hold promise as non-invasive biomarkers for early detection of NMJ decline in ALS, SMA, MG, and sarcopenia. Despite promising preclinical data, challenges remain in EV characterization, targeting specificity, and clinical translation. This review underscores a paradigm shift: EVs are not passive byproducts but active messengers of neuromuscular health and disease, with realistic applications in diagnostics, regenerative therapy, and personalized medicine.\n\nID: 41672113\nTitle: Superoxide dismutase impacts extracellular vesicle shedding and uptake.\nAbstract: Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play a critical role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and on the potential for EVs as diagnostic biomarkers, while the effects of pathogenic factors on EV release are poorly understood. Using a functional endogenous reporter, we showed that the key antioxidant enzyme superoxide dismutase 1 (SOD-1) is expressed in C. elegans EV-releasing neurons, localizes to the cytoplasm, and reduces levels of reactive oxygen species (ROS). We then defined how sod-1 mutations affect EV shedding from sensory neuron primary cilia into the environment, ciliary enrichment of proteins packaged into EVs, and glial uptake of EVs in vivo, by imaging C. elegans expressing fluorescent protein-tagged EV cargoes. Deletion of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different EV subpopulation that is shed from the ciliary base, without affecting release into the environment. These results demonstrate that SOD-1 has a subtype-specific effect on the release of EVs with distinct signaling potentials. Intriguingly, we discovered that exposure to paraquat, which increases mitochondrial ROS, reduced the shedding of both distal tip and ciliary base-derived EVs. These opposing effects of the sod-1 mutations and paraquat treatment on EV release suggest that ROS in distinct subcellular compartments may differentially impact ciliary EV shedding.\n\nID: 41651252\nTitle: Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, raising debate over whether ALS is a single disease or multiple disorders with similar symptoms. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are found in only 2-3% of ALS cases, yet misfolded SOD1 appears in both sporadic (sALS) and familial (fALS) patients. Furthermore, mutations in TDP-43 or FUS increase levels of misfolded SOD1 on extracellular vesicles (EVs). Small EVs isolated from ALS patient samples have been shown to cause death of wild-type motor neurons and myotubes, supporting the theory that EVs play a role in spreading disease. We hypothesize that the previously identified toxic trimeric SOD1 spreads via EVs in ALS and influences the distribution of other ALS-related proteins, suggesting a common mechanism. To test this, we isolate EVs from motor neuron-like cells expressing mutations that stabilize trimers. We then perform a sandwich enzyme-linked immunosorbent assay (ELISA) using a CD9 capture antibody to measure whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is affected by trimeric SOD1 using endocytosis and exocytosis inhibitors and analyze altered protein interaction pathways through co-immunoprecipitation and mass spectrometry proteomics. Our results show that VAPB, VCP, and Stathmin-2 increase on EVs when trimers are stabilized. The common pathway linking these ALS-associated proteins and SOD1 appears to involve multiple mechanisms, including the Caveolae endocytosis pathway, pointing to a novel hybrid EV release pathway in ALS. Overall, our findings show that trimeric SOD1 influences EV cargo and spread in ALS.\n\nID: 41638908\nTitle: TBK1 activity regulates the directionality of axonal transport of signalling endosomes.\nAbstract: The polarised and complex morphology of neurons poses massive challenges for efficient cargo delivery between the axon and soma, a process termed axonal transport. We have previously shown that the retrograde axonal transport of pro-survival, neurotrophic signalling endosomes relies on Rab7 in motor neurons, and that their trafficking is impaired in the early stages of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we report the effect of Rab7 phosphorylation on the transport of these signalling endosomes. We show that the ALS-linked kinase TBK1 phosphorylates Rab7 at S72 in neurons, altering its binding to cytoplasmic dynein adaptors. Accordingly, both TBK1 knockdown and the expression of a loss-of-function Rab7 mutant (S72E) induce aberrant bidirectional movement of signalling endosomes without modifying neuronal polarity or endosomal sorting. This alteration is specific for signalling endosomes, as axonal transport of lysosomes and mitochondria remains unaffected. We have therefore discovered a new TBK1 function that ensures the unidirectional transport of signalling endosomes, suggesting that reduced TBK1 activity determines retrograde transport dysfunctions and long-range signalling impairments.\n\nID: 41613186\nTitle: Dual role of exosomes in neurodegenerative diseases: a molecular bridge between neuroinflammation and transmission of pathological proteins.\nAbstract: Neurodegenerative diseases (NDDs) are complex disorders characterized by the progressive loss of neuronal function. Their pathological mechanisms involve multiple levels, including neuroinflammation, abnormal protein aggregation, and disrupted cell signaling. Diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis (MS), and prion diseases not only severely impact patients' quality of life but also pose significant challenges for medical research due to their complex pathogenesis and the lack of effective treatments. In recent years, extracellular vesicles (EVs), particularly exosomes, have garnered increasing attention for their critical role in cell-to-cell communication. Exosomes are membrane-enclosed nanovesicles approximately 30-150\u202fnm in diameter that can carry proteins, lipids, nucleic acids, and other bioactive molecules, influencing recipient cells through paracrine or distant signaling. This review aims to summarize the roles of exosomes as mediators of neuroinflammation and as vehicles for intercellular transmission of pathogenic proteins in neurodegenerative diseases.\n\nID: 41612503\nTitle: Diagnostic potential of cryptic exon-derived peptides in serum extracellular vesicles for sporadic amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration and loss of upper and lower motor neurons, with approximately 90% of cases being sporadic (sporadic ALS, SALS). A reliable diagnostic biomarker remains an unmet clinical need in SALS, with misdiagnosis and diagnostic delay hindering early management. The mislocalization of the RNA-binding protein TDP-43 (encoded by TARDBP), a pathological hallmark of SALS, could lead to aberrant splicing that produces transcripts with cryptic exons and, consequently, cryptic peptides. This study proposes cryptic peptides in serum extracellular vesicles as a novel candidate diagnostic biomarker of SALS. We included 10 healthy controls and 20 patients with SALS and quantified cryptic peptides predicted from cryptic exon sequences using mass spectrometry-based proteomics. Cryptic peptides from four proteins (RANBP1, IGLON5, ACTN1, ALPK2) were detected in participants, with the IGLON5 cryptic peptide detected significantly more frequently in SALS than in HC (adjusted P\u2009=\u20090.044). The number of detected cryptic peptides classified SALS and healthy controls with acceptable performance (area under the curve\u2009=\u20090.82). In conclusion, cryptic peptides could have diagnostic performance for SALS, warranting further validation.\n\nID: 41567979\nTitle: Brain-derived extracellular vesicles potentially mediate crosstalk with peripheral organs in neurodegenerative diseases.\nAbstract: Brain-Derived Extracellular vesicles (BDEVs) are emerging mediators of intra- and interorgan communication in neurodegenerative diseases (NDs) such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). A growing body of evidence suggests that BDEVs play an important role in modulating intercellular communication within the central nervous system in the pathogenesis of many NDs. By transporting non-coding RNAs (e.g., miRNAs) and important pathological proteins, BDEVs also influence peripheral organs and contribute to the progression of disease in the central nervous system (CNS). This review extends the understanding of NDs beyond solely brain dysfunction and gives a novel framework for the progression of these diseases, uniquely emphasizing the currently underexplored mechanisms by which BDEV-mediated communication exacerbates or potentially initiates peripheral dysfunction or complications. It maps and clarifies the specific and potential mechanisms by which CNS-originating EV activity proliferates systemic dysfunction, presenting new opportunities and areas for therapeutic and diagnostic treatments for NDs. These findings are contextualized across multiple NDs, including Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), by incorporating data on dysregulated BDEV miRNAs and toxic proteins to map the pathway of BDEV-mediated disease spread.\n\nID: 41546910\nTitle: Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.\nAbstract: Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.\n\nID: 41532955\nTitle: Unveiling the Proteomic Landscape of Extracellular Vesicles: Implications for Neurodegeneration and Neuroprotection.\nAbstract: Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to elucidate their roles in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and ischemic stroke. Across these conditions, EVs carry disease-relevant proteins that reflect and influence key pathological processes such as synaptic dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death. Proteomic profiling of brain- and biofluid-derived EVs has uncovered specific biomarkers and signaling pathways, ranging from tau and \u03b1-synuclein in AD and PD to mutant SOD1 in ALS and complement activation in stroke and TBI. Moreover, cell-type-specific EVs (e.g., from neurons, astrocytes, microglia, and stem cells) have been shown to exert either protective or deleterious effects, modulating apoptosis, axonal regeneration, and immune responses. Recent evidence highlights the translational potential of EVs as non-invasive biomarkers and therapeutic vectors across multiple disorders. By mapping shared and divergent proteomic signatures in EVs, we review the mechanistic relevance and clinical utility of EVs in neurodegeneration and CNS injury.\n\nID: 41397032\nTitle: Microglial Extracellular Vesicles Mediate C1q Deposition at the Pre-Synapse and Promote Synaptic Pruning.\nAbstract: C1q is released by microglia, localizes on weak synapses and acts as a tag for microglial synaptic pruning. However, how C1q tags synapses during the pruning period remains to be fully elucidated. Here, we report that C1q is delivered via extracellular vesicles by microglia to pre-synaptic sites that externalize phosphatidylserine. Using approaches to increase or reduce vesicles production in microglia, by C9orf72 knock out or pharmacological inhibition, respectively, we provided mechanistic evidence linking extracellular vesicle release to pre-synaptic remodelling in neuron-microglia cultures. In C9orf72 knockout mice, we confirmed larger production of microglial extracellular vesicles and showed augmented C1q presynaptic deposition associated with enhanced engulfment by microglia in the early postnatal hippocampus. Finally, we provide evidence that microglia physiologically release more vesicles during the period of postnatal circuit refinement. These findings implicate abnormal release of microglial extracellular vesicles in both neurodevelopmental and age-related disorders characterized by dysregulated microglia-mediated synaptic pruning.\n\nID: 41360752\nTitle: Anionic Liposomes as Optimal Membrane Fusion Carriers Enabling in Situ Multiplexed Detection of Extracellular Vesicle MicroRNAs.\nAbstract: Extracellular vesicle (EV) microRNAs (miRNAs) are promising liquid biopsy biomarkers for non-invasive diagnosis, monitoring, and therapeutic evaluation of cancer. However, sensitive EV miRNA detection is hindered by complex pre-analytical processing. Here, the authors present an anionic liposome (AL) assisted membrane fusion strategy enabling one-step multiplexed quantification of EV miRNAs directly from plasma without EV isolation or RNA extraction, termed EValarm (Anionic Liposome Assisted miRNAs Monitoring for Extracellular Vesicles). Liposomes encapsulating probes are prepared using a microfluidic chip, achieving catalytic signal amplification after target recognition of miRNA. Systematic lipid screening identified ALs as optimal carriers, exhibiting minimal background and superior sensitivity compared to cationic and neutral liposomes. The AL-based assay delivered accuracy comparable to quantitative PCR with a streamlined workflow. Applied to 106 clinical samples from lymphoma patients and healthy controls, integration with artificial intelligence achieved high accuracy (AUC > 0.99). In summary, this study demonstrates a platform enabling direct and sensitive plasma EV miRNA detection, offering strong potential for clinical translation in cancer liquid biopsy.\n\nID: 41328354\nTitle: Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation.\nAbstract: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS), are characterized by progressive neuronal dysfunction and limited therapeutic options, largely due to the restrictive nature of the blood-brain barrier (BBB). Exosomes, naturally occurring extracellular vesicles (EVs), have gained attention as innovative drug delivery vehicles owing to their intrinsic ability to cross the BBB, minimal immunogenicity, high biocompatibility, and capability to carry diverse therapeutic cargos such as proteins, nucleic acids, and small molecules. Furthermore, exosomes can be bioengineered to enhance drug-loading efficiency and targeting specificity, positioning them as a versatile and effective platform for treating NDDs. In this review, we summarize recent advances in exosome biogenesis, secretion, and engineering, with an emphasis on innovative strategies for exosome isolation, drug loading, and surface modification. We further explore their roles in modulating neuroinflammation, promoting neural regeneration, and enabling precise therapeutic delivery. Critical challenges associated with large-scale production, quality control, and regulatory compliance under Good Manufacturing Practices (GMP) are also discussed. Collectively, these developments underscore the transformative potential of engineered exosomes in advancing precision therapies for neurodegenerative disorders and offer strategic insights into their clinical translation.\n\nID: 41279722\nTitle: Superoxide dismutase impacts extracellular vesicle biogenesis and uptake.\nAbstract: Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play an important role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and the potential for EVs as diagnostic biomarkers, while the effect of pathogenic factors on EV release is less understood. Here, we defined how the key antioxidant enzyme superoxide dismutase 1 (SOD-1) affects EV shedding from sensory neuron primary cilia, enrichment of ciliary proteins packaged into EVs, and uptake of EVs by surrounding glia in vivo by imaging C. elegans expressing fluorescent protein-tagged EV cargos. We discovered that loss of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different cargo present in EVs shed from the ciliary base. Together, this suggests that redox balance has a subtype-specific effect on EV biogenesis, influencing neuron communication in vivo.\n\nID: 41278139\nTitle: Exosome-rich mesenchymal stem cell secretome improves strength in patients with amyotrophic lateral sclerosis, Kennedy disease, congenital myasthenic syndrome and Lewy body dementia.\nAbstract: Amyotrophic lateral sclerosis (ALS), Lewy Body dementia (LBD), Kennedy disease (KD), and Congenital Myasthenic Syndrome (CMS) are progressive motor disorders for which no disease modifying treatment exists. ALS and LBD are uniformly, and often rapidly, fatal. No treatment of any kind has ever resulted in actual improvement for ALS patients; the best that has been achieved is minor slowing of their progression. Forty-one preclinical studies of intra-nasal instillation of mesenchymal stem cell exosomes have, however, demonstrated complete safety and efficacy for models of a variety of neurocognitive and motor disorders. We hypothesized that intranasal exosomes treatment in humans would be completely safe and also effective for the treatment of motor disorders such as ALS, LBD, KD and CMS. 18 patients with ALS, Kennedy Disease, Congenital Myasthenic Syndrome, or Lewy Body Dementia had 32 AlloEx Exosome\u00ae treatments to assess safety, attenuation of disease, and increase in strength and motor function. The study was conducted under the clinical trial NCT07105371 found at clinicaltrials.gov/study/NCT07105371. There were no adverse events of any kind reported among these treatments. All patients, except for one, achieved some degree of clinical and strength improvement; the longest improvement was recorded at the 6-month follow-up. Intranasally-instilled AlloEx Exosomes\u00ae are completely safe, attenuate progression, and improve strength in ALS, Kennedy Disease, CMS, and LBD.\n\nID: 41256634\nTitle: LINE1 RNA dysregulation impairs chromatin accessibility in C9ORF72- and TDP-43-linked ALS/FTD.\nAbstract: The long interspersed element-1 (LINE1) retrotransposon RNAs are abnormally elevated in various neurodegenerative disorders, but their pathogenic roles remain unclear. Here we investigated the mechanism of LINE1 RNA accumulation and its function in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with C9ORF72 repeat expansion and TDP-43 loss-of-function, the leading causes of familial and sporadic forms of these neurodegenerative diseases. We show that LINE1 RNA is dysregulated due to an impaired nuclear exosome targeting (NEXT) degradation pathway. Its elevation epigenetically increases chromatin accessibility, enhancing global transcription via a retrotransposon-independent mechanism. Reducing LINE1 RNA mitigates chromosomal abnormalities and improves the survival of disease-relevant neurons. These findings uncover an essential noncoding RNA function and regulatory mechanism of LINE1 in neurons, providing insights into disease pathogenesis and highlighting potential therapeutic targets for neurodegenerative diseases.\n\nID: 41250892\nTitle: Co-localization of tau and TDP-43 after extracellular vesicle delivery to cells.\nAbstract: Perturbations in the metabolism of microtubule-associated protein tau (tau) underlie the pathology of a broad array of dementias, including chronic traumatic encephalopathy, amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) and approximately half of the dementias associated with frontotemporal lobar degeneration. We recently observed significantly increased hippocampal tau pathology in rats injected with pseudophosphorylated human tau (2N4R tauT175D) co-expressing an ALS-associated TAR DNA-binding protein 43 (TDP-43) mutant (TDP-43M337V) when compared to wild-type rats. To understand this mechanism, we examined whether the extracellular vesicles (EVs) derived from wild-type TDP-43 (wtTDP-43) or tau-expressing cells could transfer expression of these proteins to recipient cells, and whether co-localization of these proteins occurs. mCherry-wtTDP-43 or EGFP-tau constructs were expressed in HEK293 or SH-SY5Y cells. The secretome and EV fractions contained wtTDP-43 or 2N4R tau protein and RNA, and could transfer proteins into nontransfected cells. Co-localization was also detected in the cytosol of recipient cells. In silico modeling of tau and TDP-43 interactions suggests hydrogen bonding underlies this interaction. These studies further our understanding of the interaction between tau and TDP-43 by demonstrating their ability to co-aggregate and in providing a mechanism by which cell-cell transfer of either protein via extracellular vesicles can lead to these synergistic interactions.\n\nID: 41166771\nTitle: Cerebrospinal fluid-driven extracellular vesicle as a potential diagnostic biomarker for multiple system atrophy.\nAbstract: Given that Parkinsonian disorders, including Parkinson's disease (PD) and multiple system atrophy-parkinsonism (MSA-P), often have similar clinical presentations, making a clinical diagnosis can be challenging. In the present study, we extracted and analyzed extracellular vesicles (EVs) from the cerebrospinal fluid of individuals diagnosed with PD (N\u00a0=\u00a016), MSA-P (N\u00a0=\u00a016), and amyotrophic lateral sclerosis (ALS) (N\u00a0=\u00a016), with the latter serving as the control group. Transcriptomic analysis identified 7426 and 8003 differentially expressed RNAs between MSA and ALS, and MSA and PD, respectively. Four transcripts (RN7SL3, RN7SL1, MIR19B2, and SYF2P2) were among the top six transcripts upregulated in MSA-P compared with both ALS and PD. Proteomic analysis revealed notable changes in the levels of corneodesmosin, psoriasin (S100A7), and dystroglycan1 in MSA-P compared with ALS and PD. Notably, S100A7 mRNA levels were also significantly lower in MSA than in the other diseases examined. Furthermore, we found a positive correlation between S100A7 mRNA levels and the heart mean/mediastinum mean ratio on 123I-metaiodobenzylguanidine myocardial scintigraphy, whereas SYF2P2 mRNA levels were negatively correlated with both the asymmetry index on dopamine transporter scans and Mini Mental State Examination scores. A positive correlation was found between S100A7 levels and motor symptoms. In distinguishing MSA-P from PD, MIR19B2 exhibited the highest Area Under Curve (AUC) of 0.867, demonstrating 100\u00a0% sensitivity and 68.7\u00a0% specificity. Conversely, the results for CDSN showed an AUC value of 0.847, with 58.3\u00a0% sensitivity and 100\u00a0% specificity. These combined transcriptomic and proteomic biomarkers could serve as valuable diagnostic tools for MSA.\n\nID: 41057909\nTitle: Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch\u00ae 3-dimensional genomic regulatory immuno-genetic profiling.\nAbstract: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch\u00ae, that employs an algorithm-based CCs analysis. Using EpiSwitch\u00ae technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n\u2009=\u200947 patients with severe ME/CFS and n\u2009=\u200961 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch\u00aeCFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNF\u03b1, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.\n\nID: 41044342\nTitle: Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.\nAbstract: Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1G93A mice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression.\n\nID: 41028808\nTitle: Insights from meta-analysis and experimental validation identify exosomal miR-146a-5p as a potential biomarker for sporadic amyotrophic lateral sclerosis.\nAbstract: MicroRNAs (miRNAs) have emerged as key regulators in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite growing evidence that miRNAs exhibit altered expression profiles in ALS, their utility as a biomarker remains limited. To address this, we conducted a meta-analysis using the Robust Rank Aggregation package, incorporating 20 differential miRNA profiling studies. Among these, miR-146a-5p emerged as the most dysregulated and significant miRNA in ALS (P\u2009=\u20090.0000142, P-adj\u2009=\u20090.0096), particularly in extracellular vesicle-derived studies. To evaluate its diagnostic accuracy, we validated miR-146a-5p expression in serum-derived exosomes and observed a significant increase in sporadic ALS (sALS) patients (n\u2009=\u200922) as compared to healthy controls (n\u2009=\u200918). Moreover, higher levels of miR-146a-5p were strongly associated with longer survival (\u2265\u20095\u00a0years) (P\u2009=\u20090.0135), with a positive correlation between miR-146a-5p expression and survival duration (P\u2009=\u20090.0313) in sALS patients. Further, gene set enrichment analysis of miR-146a-5p target genes highlighted critical involvement of the Immune system and NF-kappa B signaling pathways in ALS pathophysiology. These findings highlight miR-146a-5p as a potential biomarker for ALS.\n\nID: 41024384\nTitle: Exosome Proteomics of SOD1D90A Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss. Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations. Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1D90A mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay. Father, Son, and Daughter are at different disease stages and carry the SOD1D90A mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1D90A mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA. Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.\n\nID: 41017972\nTitle: Akkermansia muciniphila in neurological disorders: mechanisms and therapeutic potential via the gut-brain axis.\nAbstract: In recent years, the role of Akkermansia muciniphila (A. muciniphila) in neurological diseases has attracted increasing attention. As a probiotic, A. muciniphila is closely associated with host health, metabolism, and immunity, demonstrating therapeutic potential in various conditions such as obesity, atherosclerosis, inflammatory bowel disease, diabetes, and liver disorders. In the context of neurological diseases, A. muciniphila significantly influences the host brain through the microbiota-gut-brain axis (MGBA). This review summarizes the roles and mechanisms of A. muciniphila and its active components (e.g., the outer membrane protein Amuc_1100, extracellular vesicles AmEVs, and short-chain fatty acids SCFAs) in various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), depression, cerebral palsy (CP), epilepsy (EP), autism spectrum disorder (ASD), and amyotrophic lateral sclerosis (ALS). It exerts protective effects by enhancing the intestinal barrier, regulating lipid metabolism, producing SCFAs, secreting neuroactive substances, and inhibiting neuroinflammation, thereby suggesting novel therapeutic avenues for neurological disorders. However, due to limited data from large-scale human clinical trials and the complexity of disease mechanisms and host-microbiota interactions, its clinical translation faces considerable challenges. Future efforts should focus on multicenter randomized controlled trials and in-depth mechanistic studies utilizing technologies such as metabolomics to facilitate evidence-based clinical application.\n\nID: 41004427\nTitle: MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis.\nAbstract: Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis and frontotemporal dementia with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice and patient-derived cells modelling TDP-43, SOD1 and C9ORF72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioural abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived extracellular vesicles that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.\n\nID: 40905633\nTitle: Targeting Amyotrophic Lateral Sclerosis with Gene Therapy: From Silencing Genes to Enhancing Neuroprotection.\nAbstract: Gene therapy is emerging as a transformative approach for treating amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease. While gene replacement has shown a groundbreaking success in spinal muscular atrophy, the complexity of ALS-due to frequent gain-of-function mutations and a heterogeneous etiology-presents significant challenges. Importantly, approximately 90% of ALS cases are sporadic, with unknown genetic mutation, further complicating patient stratification and therapeutic targeting. As a result, gene therapy strategies must often address multiple pathological mechanisms simultaneously. So far, current gene therapy strategies aim to either suppress toxic gene expression or promote neuroprotection, predominantly via viral-mediated delivery systems. This review will provide an overview of emerging preclinical and clinical gene therapy approaches for ALS, focusing on two main strategies: gene silencing and neuroprotection. Gene silencing techniques, including antisense oligonucleotides (ASOs), viral-mediated RNA interference, and gene editing, have demonstrated efficacy in reducing mutant gene expression, particularly in SOD1 and C9orf72 models, although clinical translation has so far yielded limited success. The recent Food and Drug Administration's approval of the ASO therapy Qalsody for SOD1-ALS underscores the clinical potential of these approaches. Neuroprotective strategies aim to enhance motor neuron survival through delivery of trophic factors, often targeting both central and peripheral tissues to harness retrograde transport mechanisms. We will discuss the advantages and limitations of various delivery vectors, targeting specificity, timing of intervention, and translational challenges, alongside current clinical trial data. This review aims to synthesize how these approaches may converge to address the multifaceted nature of ALS and guide the development of next-generation therapeutics.\n\nID: 40895800\nTitle: Boosting the Therapeutic Potential of Extracellular Vesicles Derived From Mesenchymal Stem Cells via Advanced Preconditioning for Neurodegenerative Disorders.\nAbstract: Acute and chronic neurodegenerative conditions (NDs) are major causes of disability and mortality worldwide. Acute NDs encompass conditions such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). On the other hand, chronic NDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Currently, no definitive cure exists for these diseases, and available therapies focus primarily on slowing the progression of symptoms. Mesenchymal stem cells (MSCs), due to their multilineage differentiation capacity, immunomodulatory abilities, and regenerative properties, have gained attention in regenerative medicine. In recent years, extracellular vesicles (EVs) derived from MSCs have shown great promise as a cell-free therapeutic approach, eliminating the risks associated with direct MSCs use, such as tumorigenicity and poor cell survival after transplantation. EVs have emerged as powerful mediators of intercellular communication and tissue repair, exhibiting immunomodulatory, anti-inflammatory, and proregenerative properties. However, limitations such as low EVs yield and reduced efficacy due to MSCs replicative senescence restrict their therapeutic potential. Preconditioning strategies, including hypoxia, 3D cultures, and biochemical priming, have been explored in other fields to enhance EVs properties, yet their specific application to NDs remains under-reported. This review aims to address this gap by analyzing the preconditioning methods used to boost the therapeutic potential of MSCs-derived EVs for neurodegenerative diseases. These preconditioning strategies may enhance EVs yield, functional cargo, and targeted therapeutic efficacy for treating acute and chronic NDs.\n\nID: 40891506\nTitle: TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.\nAbstract: TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development.\n\nID: 40868276\nTitle: Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS.\nAbstract: Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization-spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways-including PI3K-AKT-mTOR, MAPK, Wnt/\u03b2-catenin, and integrated stress response cascades-undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome-lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3-CR3 axis), and excitatory-inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network \"meaning-making\"-a collapse of coordinated signal interpretation, triage prioritization, and adaptive response-the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning-a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration.\n\nID: 40832743\nTitle: Neurochemical biomarkers of amyotrophic lateral sclerosis: recent developments.\nAbstract: To provide an overview of the recent developments in the field of neurochemical biomarkers of amyotrophic lateral sclerosis (ALS). Neurofilaments, especially NFL, have been confirmed to be good biomarkers for ALS. NFL may be diagnostically useful but its main role is as prognostic and pharmacodynamic biomarker. Inflammatory biomarkers, especially the chitinases, might also serve as pharmacodynamic biomarkers in treatment trials targeting neuroinflammation. GFAP could reflect cognitive-behavioural impairment. CSF dipeptides are diagnostic biomarkers for ALS caused by the C9ORF72 exanucleotide repeat expansion and may be used to confirm target engagement by experimental drugs. Levels of TDP-43 (virtually the ideal biomarker for ALS) in CSF and plasma have not been demonstrated to be consistently altered in ALS. However, promising advancements have been achieved in seed amplification assays for the protein, in its quantification in plasma extracellular vesicles, and in the measurement of CSF levels of a protein reflecting splicing dysfunction of TDP-43. Finally, blood phosphorylated tau has emerged as an ALS biomarker linked to lower motor neuron (or muscle) pathology. NFL is still the best neurochemical biomarker for ALS. However, substantial advances have been recently made, especially regarding detection of TDP-43 and blood phosphorylated tau.\n\nID: 40806377\nTitle: Small Extracellular Vesicles in Neurodegenerative Disease: Emerging Roles in Pathogenesis, Biomarker Discovery, and Therapy.\nAbstract: Neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, ALS, and Huntington's pose a growing global challenge due to their complex pathobiology and aging demographics. Once considered as cellular debris, small extracellular vesicles (sEVs) are now recognized as active mediators of intercellular signaling in NDD progression. These nanovesicles (~30-150 nm), capable of crossing the blood-brain barrier, carry pathological proteins, RNAs, and lipids, facilitating the spread of toxic species like A\u03b2, tau, TDP-43, and \u03b1-synuclein. sEVs are increasingly recognized as valuable diagnostic tools, outperforming traditional CSF biomarkers in early detection and disease monitoring. On the therapeutic front, engineered sEVs offer a promising platform for CNS-targeted delivery of siRNAs, CRISPR tools, and neuroprotective agents, demonstrating efficacy in preclinical models. However, translational hurdles persist, including standardization, scalability, and regulatory alignment. Promising solutions are emerging, such as CRISPR-based barcoding, which enables high-resolution tracking of vesicle biodistribution; AI-guided analytics to enhance quality control; and coordinated regulatory efforts by the FDA, EMA, and ISEV aimed at unifying identity and purity criteria under forthcoming Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines. This review critically examines the mechanistic roles, diagnostic potential, and therapeutic applications of sEVs in NDDs, and outlines key strategies for clinical translation.\n\nID: 40795306\nTitle: In vivo self-assembled SOD1-siRNAs mitigate muscle atrophy and denervation in amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the death of both upper and lower motor neurons. Approximately 20% of familial ALS cases are associated with mutations in the superoxide dismutase type 1 (SOD1) gene. Developing a specific strategy to characteristically silence the pathogenic SOD1 gene remains a crucial goal amidst significant challenges. In this study, we developed a synthetic biology strategy to reprogramme the liver as a tissue chassis for the in vivo self-assembly of small extracellular vesicles (sEVs)-encapsulated SOD1-siRNA, aiming to target spinal neurons and silence mutant SOD1 specifically in Tg(SOD1G93A) transgenic mice. We designed a cytomegalovirus (CMV) promoter-directed synthetic construct to encode a SOD1-siRNA along with a neuron-targeting rabies virus glycoprotein (RVG) tagged on the sEV surface. Theoretically, upon liver uptake, this construct reprogrammes liver cells to generate and self-assemble SOD1-siRNAs into RVG-tagged sEVs. Subsequently, the sEV-encapsulated SOD1-siRNAs are transported via the endogenous sEV circulation and guided by the RVG tag to the spinal neurons. Experimental results illustrated that intravenous administration of this synthetic construct effectively facilitated in vivo self-assembly of SOD1-siRNAs into circulating sEVs. The functional delivery of SOD1-siRNAs to the spinal cord and cerebral cortex was confirmed through in vivo tracking of sEVs and sEV-encapsulated siRNAs. Treatment of Tg(SOD1G93A) transgenic mice with this construct significantly reduced mutant SOD1 protein levels in the spinal cord and cerebral cortex. Consequently, the characteristic symptoms of ALS, including decreased body weight, shortened lifespan, compromised motor function, muscle atrophy, neuroinflammation, motor neuron loss and neuromuscular junction degeneration, were substantially ameliorated by the synthetic construct. Furthermore, an AAV-based strategy was devised for the enduring self-assembly of sEV-encapsulated SOD1-siRNA, whereby a single injection led to substantial and sustained inhibition of mutant SOD1 and significant symptom amelioration in transgenic mice. Overall, this study established an effective and convenient therapeutic approach for mitigating muscle atrophy and denervation in animal model, presenting a promising solution for future ALS treatment.\n\nID: 40750900\nTitle: Synergic action of MicroRNAs and Wnts delivered by motor neuron EVs in promoting AChR clustering.\nAbstract: The neuromuscular junction (NMJ) establishment occurs through complex communication events between motor neurons and muscle fibers; however, the molecular mechanisms leading to NMJ formation have yet to be fully elucidated. Little is known about the significance of extracellular vesicles (EVs) in mediating the interaction between motor neurons and muscle fiber in the NMJ establishment; this study investigates the role of motor neuron-derived EVs during the earliest stages of NMJ formation. NSC-34 cells have been used as a model of motor neurons; EVs have been isolated during neurite development using a serial ultracentrifugation protocol specifically adjusted to isolate large and small EVs. Isolated EVs were quantified through Nanoparticles Tracking Assay and characterized by Western Blot and TEM analyses. The microRNA (miRNA) cargo of EV subpopulations was identified by small-RNA sequencing and the predicted miRNA downstream targets were investigated. NGS analysis of small RNAs carried by NSC-34-derived EVs identified a total of 245 EV specific miRNAs, most of which are up-regulated in NSC-34 cells and EVs during neurite stretching. Target prediction analysis evidenced how these miRNAs synergically target the Wnt signaling pathway. Moreover, we found that NSC-34-derived EVs carry Wnt proteins, including Wnt11, Wnt4 and Wnt3a. Since several studies suggested a role for the Wnt-associated signaling network in NMJ formation, we investigated the potential role of NSC-34 EVs in NMJ development and demonstrated that EV administration to myotubes increases acetylcholine receptor (AChR) cluster formation, as revealed by immunofluorescence staining with \u03b1-bungarotoxin. Moreover, myotube treatment with NSC-34-derived EVs led to GSK3\u03b2 and JNK phosphorylation, followed by \u03b2-catenin nuclear translocation, suggesting that neuron-derived EVs can induce AChR clustering through Wnt pathway activation. These data demonstrate that EVs released from differentiated motor neurons carry multimodal signals, miRNAs, and Wnts, which can stimulate AChR clustering in myotubes, a fundamental preparatory stage for NMJ formation. These new data highlight that EVs may play a role in the NMJ establishment and function under physiological and pathological conditions, particularly neurodegenerative diseases.\n\nID: 40628227\nTitle: Reply to Scholz et al.\nAbstract: In our recent study1, we investigated the neural basis of attempts at forming voluntary visual imagery in individuals with aphantasia and found that although these individuals lack visual imagery experience, their early visual cortex exhibits stable, content-specific activation patterns during imagery attempts. Unlike in the neurotypicals, these neural representations, however, differ from those evoked during perception, as indicated by the failure of cross-decoding between imagery and perceptual tasks. In this response, we address Scholz et al.'s commentary2 on our findings and the broader implications for theories of unconscious imagery, emphasizing that while we do not claim the presence of unconscious imagery, our results suggest that early visual activity in aphantasia may reflect perceptual-like, but transformed or non-conscious, representations.\n\nID: 40620684\nTitle: Mesenchymal Stem Cell-Derived Extracellular Vesicles: Emerging Therapies for Neurodegenerative Diseases.\nAbstract: Neurodegenerative diseases are a group of chronic diseases characterized by a gradual loss of neurons that worsens over time and dysfunction. These diseases are extremely harmful, not only affecting the physical health of the patients, but also having a serious impact on their quality of life. They mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), etc. Their pathogenesis is complex, and it is difficult for the existing treatments to effectively slow down the progression of the disease. In recent years, Mesenchymal Stem Cells (MSCs) have received widespread attention for their anti-inflammatory, immunomodulatory and neuroprotective properties. In this context, MSC-derived Extracellular Vesicles (MSC-EVs) have demonstrated unique therapeutic potential as a cell-free therapeutic strategy. MSC-EVs are rich in bioactive substances such as proteins, lipids, mRNAs and miRNAs, which can pass through the blood-brain barrier and be targeted to the diseased area to regulate neuronal survival, synaptic plasticity and neuroinflammatory responses. In addition, compared with stem cell therapy, MSC-EVs have the advantages of low immunogenicity, easy storage and transportation, and avoiding ethical controversies. However, their clinical application still faces challenges: standardized isolation and purification techniques have not been unified, vesicle loading efficiency and targeting need to be further optimized, and long-term safety needs to be systematically evaluated. This review focuses on the role of MSC-EVs in the development of neurological diseases and explores their possible dual roles, both favorable and unfavorable, in the context of neurological diseases. In addition, this review provides a review of current studies on EVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases and provides a comprehensive review of the prospects and challenges of MSC-EVs in clinical applications.\n\nID: 40618341\nTitle: Integrated genomic and molecular insights into astrocyte- and oligodendrocyte-derived amyotrophic lateral sclerosis: focus on miRNAs and extracellular vesicles.\nAbstract: Motor neurons in the brain and spinal cord begin to die off in Amyotrophic lateral sclerosis (ALS), a disease that can be fatal. Molecular pathways in neurological disease, especially ALS, remain a challenge in the medical sciences. In this disease, a disorder in both astrocytes and oligodendrocytes can cause the disease to progress. This study aimed to investigate the molecular mechanisms and find key elements between these two cells in ALS with a bioinformatics perspective. In this study, using integrated and continuous bioinformatics analytics by various tools and databases, we investigated genes, protein products, and miRNAs between astrocytes and oligodendrocytes. The obtained data were involved in the Cellular senescence, actin cytoskeleton, and cell cycle signaling pathways. Then, after careful evaluation of the information, TP53, MDM2, KRAS, PTPRC, and GSK proteins were candidates, which are regulated by hsa-miR-564, hsa-miR-496-5p, hsa-miR-324-5p, hsa-miR-296-5p, and hsa-miR-4258-3p miRNAs. Finally, the four genes had a more robust and better relationship in this study between astrocyte and oligodendrocyte-derived ALS.\n\nID: 40580685\nTitle: Multifaceted roles of extracellular vesicles in the interplay of neuroinflammation and neurodegenerative diseases.\nAbstract: Despite advances in understanding neurodegenerative disease mechanisms, effective treatments remain elusive. Extracellular vesicles (EVs), key mediators of intercellular communication within the central nervous system (CNS), are increasingly recognized for their involvement in the pathogenesis of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's disease (HD). In vivo studies demonstrate EVs' crucial role in maintaining CNS homeostasis, modulating neuroinflammatory responses, and influencing tissue repair and regeneration following injury, thereby impacting disease progression and recovery. Their unique properties, including small size and ability to cross the blood-brain barrier (BBB), position them as promising candidates for both biomarkers and therapeutics in CNS diseases. This review delves into the significant impact of neuroinflammation on neurodegenerative conditions, specifically focusing on the multifaceted contributions of EVs and their intricate interplay with the inflammatory landscape. We explore EV biogenesis, cargo composition, diverse roles in neuroinflammation (including intercellular communication and neuroprotection), their potential as biomarkers and drug delivery vehicles across the BBB for diagnosis or treatment of neuroinflammation implemented neurodegenerative diseases.\n\nID: 40550228\nTitle: Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.\nAbstract: Exosomes, tiny extracellular vesicles, hold significant potential as biological nanocarriers for diverse therapeutic agents due to their exceptional ability to navigate through the barriers of biological systems. This comprehensive review delves into the capability of exosomes in the therapy of neurodegenerative disorders, concentrating on their potential for targeted drug delivery. It examines the complex processes involved in exosome-mediated drug delivery, including targeting, cellular uptake, intracellular trafficking, and therapeutic release. Insights from preclinical studies and clinical trials are exploited, highlighting the impactful applications of exosomes, particularly in the treatment of Parkinson's, Alzheimer's, ALS, and Huntington's diseases. The review also addresses challenges such as immunogenicity, scalability, and regulatory obstacles while exploring emerging technologies like advanced exosome engineering, personalized medicine, and the integration of nanotechnology. Overall, this review accentuates the potential impact of exosome-based treatments in biomedicine alongside the critical need to overcome existing barriers.\n\nID: 40498024\nTitle: Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis.\nAbstract: Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction.\n\nID: 40482989\nTitle: Knockdown of OPTN modulates miRNA-125b-5p expression via NF-\u03baB pathways in amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterized by severe dysfunction in upper and lower motor neurons. Previous studies have reported that the optineurin gene (OPTN) downregulation is one of the causative genetic factors for ALS, leading to the dysfunction of optineurin (OPTN), a multifunctional protein implicated in several cellular processes. Herein, we found that conditional knockout of the Optn gene in mouse microglia leads to activation of microglia. In subsequent studies, we also found that OPTN knockdown in BV2 cells leads to the activation of BV2 cells and promotes the apoptosis of co-cultured NSC34\u00a0cells via exosomes derived from BV2 cells in vitro. In contrast, OPTN knockdown in NSC34\u00a0cells did not cause apoptosis of the NSC34\u00a0cells themselves. It was suggested that microglia activation is involved in ALS initiation and development, but the nature of microglial-neuronal interactions remained elusive, requiring further exploration. Exosomes have been proven to be essential mediators. Notably, increased miRNA-125b-5p expression was uncovered in BV2 cells with the OPTN gene silenced, their derived exosomes, as well as the cocultured NSC34\u00a0cells. Interestingly, we proved that increased miRNA-125b-5p enhanced the apoptosis of NSC34\u00a0cells. We further noted that the overexpression of miRNA-125b-5p in BV2 cells can be regulated by an NF-\u03baB activator (LPS) or inhibitor (withaferin A). Altogether, this study showed that silencing the OPTN gene may overexpress miRNA-125b-5p levels via the classical NF-\u03baB pathway in BV2 cells. Up-regulated miRNA-125b-5p might be transmitted from exosomes to NSC34\u00a0cells, resulting in NSC34\u00a0cells apoptosis. Microglial-neuronal interactions mediated by exosomes were the crucial mechanism of OPTN gene downregulation leading to ALS, and this conclusion had been verified in cell models.\n\nID: 40435818\nTitle: Exosomal miR-574-3p from adipose-derived mesenchymal stem modulates CRIM1/BMPs signaling to restrain chondrocytes hypertrophy and inflammatory response in knee osteoarthritis.\nAbstract: Chondrocyte hypertrophy is an important feature of knee osteoarthritis (KOA) cartilage pathological damage, and existing evidence supports the potential therapeutic role of adipose-derived mesenchymal stem cells (ASCs) through exosomes. However, the differences of in exosome contents under different conditions and the mechanisms by which they affect the hypertrophic phenotype of chondrocytes remain unclear. Exosomes from ASCs with or without the stimulation of IL-1\u03b2 were extracted, identified by NTA, TEM, and membrane surface marker, stained with PKH26 to confirm the uptake by chondrocytes. Next, miRNA sequencing for these two types of exosomes were performed and miR-574-3p, significantly down-regulated in IL-1\u03b2 stimulated ACSs exosomes, was identified the most distinct miRNAs. Besides, RNA-seq on chondrocytes, KOA chondrocytes, and KOA chondrocytes under the intervention of exosomes derived from ASCs were conducted, and intersected the obtained differentially expressed genes with potential target genes of miR-574-3p known from miRNA database. Further on, exosomal miR-574-3p From ACSs modulated cysteine-rich motor neuron protein 1 (CRIM1)/bone morphogenetic proteins (BMPs) signaling to restrain chondrocytes hypertrophy and inflammatory response in KOA were verified. Exosomal miR-574-3p from ASCs was significantly down-regulated under inflammatory state. ASCs-derived exosomes could reduce inflammatory cell infiltration, cartilaginous surface rough and fractured, and collagen staining lost, via the regulation of CRIM1, BMP2, BMP6 and BMP9 expression level. This chondroprotective effect was further enhanced with miR-574-3p mimic, but disappeared with miR-574-3p inhibitor. Besides, CRIM1 siRNA interrupted the benign intervention of exosomes on inflammatory cell infiltration, surface cracking, and collagen loss in cartilage tissue, as well as the down-regulation of BMP2, BMP6 and BMP9, the down-regulation of chondrocyte hypertrophy markers ALP, RUNX2, MMP13, and inflammatory factors IL-1\u03b2 and TNF-\u03b1. Exosomal miR-574-3p from ASCs is significantly down-regulated under inflammatory state. Additionally, Exosomal miR-574-3p from ASCs modulates CRIM1/BMPs signaling to inhibit the chondrocytes hypertrophy and inflammatory response in KOA.\n\nID: 40388191\nTitle: Recent therapeutic advances in the treatment and management of amyotrophic lateral sclerosis: the era of regenerative medicine.\nAbstract: Despite decades of research, effective disease-modifying treatments for Amyotrophic Lateral Sclerosis (ALS) remain scarce. The emergence of regenerative medicine presents a new frontier for ALS treatment. This review is based on a comprehensive literature search using PubMed, Scopus and clinical trials databases on the recent therapeutic advancements in ALS, giving focus to regenerative medicine. The article includes coverage of stem cell-based therapies, including mesenchymal, neural and induced pluripotent stem cells; all of which may offer potential neuroprotective and immunomodulatory effects. Gene therapy, particularly antisense oligonucleotides targeting ALS-related mutations, has gained traction, with tofersen becoming the first FDA-approved genetic therapy for ALS. The article also covers emerging approaches such as extracellular vesicles, immune-modulating therapies, and bioengineering techniques, including CRISPR-based gene editing and cellular reprogramming, that hold promise for altering disease progression. While regenerative medicine provides hope for ALS patients, significant challenges remain. Biomarkers will play a crucial role in guiding personalized treatment strategies, ensuring targeted interventions. Future research should prioritize optimizing combinatory approaches, integrating different therapy strategies to maximize patient outcomes. Although regenerative medicine is still in its early clinical stages, its integration into ALS treatment paradigms could redefine disease management and alter its natural course.\n\nID: 40347374\nTitle: Exploring Exosome-Based Approaches for Early Diagnosis and Treatment of Neurodegenerative Diseases.\nAbstract: Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), present an increasingly significant global health burden, primarily due to the lack of effective early diagnostic tools and treatments. Exosomes-nano-sized extracellular vesicles secreted by nearly all cell types-have emerged as promising candidates for both biomarkers and therapeutic agents in NDs. This review examines the biogenesis, molecular composition, and diverse functions of exosomes in NDs. Exosomes play a crucial role in mediating intercellular communication. They are capable of reflecting the biochemical state of their parent cells and have the ability to cross the blood-brain barrier (BBB). In doing so, they facilitate the propagation of pathological proteins, such as amyloid-beta (A\u03b2), tau, and alpha-synuclein (\u03b1-syn), while also enabling the targeted delivery of neuroprotective compounds. Recent advancements in exosome isolation and engineering have opened up new possibilities for diagnostic and therapeutic strategies. These range from the discovery of non-invasive biomarkers to innovative approaches in gene therapy and drug delivery systems. However, challenges related to standardization, safety, and long-term effects must be addressed before exosomes can be translated into clinical applications. This review highlights both the promising potential and the obstacles that must be overcome to leverage exosomes in the treatment of NDs and the transformation of personalized medicine.\n\nID: 40319325\nTitle: Exosome-powered neuropharmaceutics: unlocking the blood-brain barrier for next-gen therapies.\nAbstract: The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods. This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions. By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.\n\nID: 40301571\nTitle: Cross-tissue MiRNA profiling of extracellular vesicles and PBMCs from amyotrophic lateral sclerosis patients.\nAbstract: RNA-mediated toxicity, which can be controlled by alteration of gene expression, is considered a key event in Amyotrophic Lateral Sclerosis (ALS). Transcriptomic deregulation of miRNAs expression can spread via \"horizontal\" RNA transfer through extracellular vesicles (EVs) to act in conjunction with proteins, leading to changes in mRNA, which can provide early signals to indicate forthcoming neuropathological changes in the brain. The aim of this work is to compare expression profiles (obtained by miRNA-seq) from different tissues to highlight commonly expressed and tissue-specific miRNAs. miRNA species from plasma EVs were correlated with miRNA profiles obtained from peripheral blood mononuclear cells (PBMCs). Each tissue from ALS patients was compared to controls, revealing 159 deregulated (DE) miRNAs in Exosomes (EXOs), 247 DE miRNAs in PBMCs and 162 DE miRNAs in Microvesicles (MVs). Next, data were filtered to include only miRNAs expressed in disease samples (not in healthy subjects), to reduce the number of tissue- and ALS- specific miRNAs (EXO n\u2009=\u200922, MV\u2009=\u200911, PBMCs n\u2009=\u20098). We identified specific miRNAs and pathways related to each tissue. Interestingly, in PBMCs we found mainly neuro-linked pathways, such as neurotransmitters, brain and neuron development, while in EXOs, we found miRNAs implicated in MAPK and ERB signaling. In contrast, the altered pathways in MVs were not specific. This study shows that the composition of small RNA differs significantly between blood cells and its respective EVs fraction. Differentially expressed miRNAs can target definite transcripts in different cellular and molecular fractions. It is evident that, in terms of miRNAs cargo, MVs are not specific to ALS. Therefore, future studies will focus on the interaction between cells and EXOs.\n\nID: 40291716\nTitle: Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, leading to controversy whether ALS is one disease or many diseases with a similar phenotype. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are only found in 2-3% of ALS cases, yet misfolded SOD1 is found in both sporadic (sALS) and familial (fALS) patients. Yet, mutations in TDP-43 or FUS increase the level of misfolded SOD1 on extracellular vesicles (EVs). Additionally, small EVs isolated from ALS patient samples caused cell death of wild type motor neurons and myotubules. The toxicity and protein alterations of ALS EVs have led to the theory that EVs are responsible for the spread of ALS. We hypothesize that previously-identified toxic trimeric SOD1 is spreading on EVs in ALS and altering the spread of other ALS-related proteins, linking them to a common mechanism. To test our hypothesis, we isolate EVs from motor neuron-like cells expressing trimer stabilizing mutations and perform a sandwich enzyme-linked immunoassay (ELISA) (CD9 capture antibody) to quantify whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is being affected by trimeric SOD1 utilizing endocytosis and exocytosis inhibitors, and determine if any specific EV-related proteins are altered with trimer stabilization. We establish that VAPB, VCP, and Stathmin-2 increase on EVs with trimer stabilization. The common pathway between SOD1 and three other ALS-associated proteins is affected by multiple pathways, including the Caveolae endocytosis pathway, suggesting a novel hybrid pathway of EV release present in ALS.\n\nID: 40136713\nTitle: Extracellular Vesicles from Regenerating Skeletal Muscle Mitigate Muscle Atrophy in an Amyotrophic Lateral Sclerosis Mouse Model.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor neuron degeneration and muscle atrophy, with no effective treatments available. Chronic inflammation, which impairs muscle regeneration and promotes proteolysis, is a key contributor to ALS-related muscle atrophy and a promising therapeutic target. Here, we applied extracellular vesicles (EVs) derived from regenerating skeletal muscles 14 days post-acute injury (CTXD14SkM-EVs), which possess a unique anti-inflammatory profile, to target muscle defects in ALS. We found that CTXD14SkM-EVs enhanced myoblast differentiation and fusion in a cellular muscle-wasting model induced by pro-inflammatory cytokine tumor necrosis factor alpha. Intramuscular administration of these EVs into an ALS mouse model mitigated muscle atrophy by promoting muscle regeneration, shifting macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 state, and suppressing the aberrant Nuclear Factor Kappa B (NF-\u03baB) signaling, a key driver of muscle protein degradation. These results underscore the therapeutic potential of regenerating muscle-derived EVs for combating muscle atrophy in ALS.\n\nID: 40095345\nTitle: Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.\nAbstract: Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.\n\nID: 40019378\nTitle: Accumulation of Damaging Lipids in the Arf1-Ablated Neurons Promotes Neurodegeneration through Releasing mtDNA and Activating Inflammatory Pathways in Microglia.\nAbstract: Lipid metabolism disorders in both neurons and glial cells have been found in neurodegenerative (ND) patients and animal models. However, the pathological connection between lipid droplets and NDs remains poorly understood. The recent work has highlighted the utility of a neuron-specific Arf1-knockout mouse model and corresponding cells for elucidating the nexus between lipid metabolism disorders and amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, it is found that Arf1 deficiency first induced surplus fatty acid synthesis through the AKT-mTORC1-SREBP1-FASN axis, which further triggered endoplasmic reticulum (ER)-mitochondrial stress cascade via calcium flux. The organelle stress cascade further caused mitochondrial DNA (mtDNA) to be released into cytoplasm. Concurrently, the FASN-driven fatty acid synthesis in the Arf1-deficient neurons might also induce accumulation of sphingolipids in lysosomes that caused dysfunction of autophagy and lysosomes, which further promoted lysosomal stress and mitochondria-derived extracellular vesicles (MDEVs)\u00a0release. The released MDEVs carried mtDNA into microglia to activate the inflammatory pathways and neurodegeneration. The studies on neuronal lipid droplets (LDs) and recent studies of microglial LDs suggest a unified pathological function of LDs in NDs: activating the inflammatory pathways in microglia. This finding potentially provides new therapeutic strategies for NDs.\n\nID: 39955442\nTitle: Extracellular vesicles efficiently deliver survival motor neuron protein to cells in culture.\nAbstract: Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron 1 (SMN1) gene, leading to a low quantity of SMN protein in cells. This depletion of SMN protein preferentially leads to death of motor neurons and, consequently, muscle atrophy, in addition to defects in many other peripheral tissues. SMN protein is naturally loaded into extracellular vesicles (EVs), which are sub-micron-sized, membrane-bound particles released from all cell types. The innate ability of EVs to deliver cargo to recipient cells has caused these vesicles to gain interest as therapeutic delivery vehicles. In this study, we show that adenovirus-mediated overexpression of SMN protein in HepG2 cells leads to the release of EVs loaded with high levels of SMN protein into conditioned medium. Application of this medium to recipient cells in tissue culture led to uptake of the SMN protein, which subsequently transited to the nucleus and co-localized with Gemin2 protein, forming nuclear gem-like structures similar to the native SMN protein. Overall, this work demonstrates that SMN protein can be delivered to cells through EVs, which holds promise as a potential therapy for patients with SMA.\n\nID: 39954940\nTitle: Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders.\nAbstract: Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-\u03b2 in AD and \u03b1-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.\n\nID: 42508418\nTitle: [Delayed Diagnosis of Primary Sj\u00f6gren's Syndrome presenting as Atypical Migraine - A Case Report].\nAbstract: Primary Sj\u00f6gren's Syndrome usually presents with Sicca symptoms but may initially manifest with non-specific neurological complaints such as migraine, paresthesia or dizziness. A 34-year-old woman reported recurrent headaches, dizziness, and a single episode of mild aphasia; she was initially diagnosed with migraine without aura. Despite stage-appropriate therapy, additional symptoms such as dry mouth and eyes as well as arthralgia developed. Cranial imaging was unremarkable. Orbital Doppler sonography revealed widened optic nerve sheaths. Autoimmune serology was positive for ANA, ENA, and Anti-SSA antibodies. Schirmer test, tear film break-up time, and salivary flow confirmed sicca syndrome. After diagnosis, treatment with prednisolone and hydroxychloroquine was initiated, leading to a significant improvement in neurological and extraglandular symptoms. Pilocarpine along with supportive eye and oral care improved the sicca symptoms. Non-specific neurological symptoms may represent early in Primary Sj\u00f6gren's Syndrome, highlighting the importance of early serological testing and interdisciplinary evaluation. Das prim\u00e4re Sj\u00f6gren-Syndrom zeigt meist Sicca-Symptome, kann aber fr\u00fch unspezifische neurologische Beschwerden wie Migr\u00e4ne, Par\u00e4sthesien oder Schwindel verursachen.Eine 34-j\u00e4hrige Patientin klagte \u00fcber rezidivierende Kopfschmerzen, Schwindel und einmalige leichte Aphasie; zun\u00e4chst wurde Migr\u00e4ne ohne Aura diagnostiziert. Trotz stadiengerechter Therapie traten zus\u00e4tzliche Symptome wie Mund- und Augentrockenheit sowie Arthralgien auf.Die kranielle Bildgebung war unauff\u00e4llig. In einer Orbita-Dopplersonografie zeigten sich verbreiterte Optikus-Nervenscheiden. Bei der Autoimmunserologie waren ANA, ENA und Anti-SSA positiv. Schirmer-Test, Tr\u00e4nenfilm-Break-Up-Time und Speichelfluss best\u00e4tigten ein Sicca-Syndrom.Nach der Diagnosestellung wurde eine Therapie mit Prednisolon und Hydroxychloroquin eingeleitet, wodurch sich die neurologischen und extraglandul\u00e4ren Beschwerden deutlich besserten. Pilocarpin und eine begleitende Tr\u00e4nen- und Mundpflege verbesserten die Sicca-Symptome.Unspezifische neurologische Symptome k\u00f6nnen Fr\u00fchmanifestationen eines prim\u00e4ren Sj\u00f6gren-Syndroms sein, weshalb eine fr\u00fche serologische Abkl\u00e4rung und interdisziplin\u00e4re Diagnostik entscheidend sind.\n\nID: 42505348\nTitle: Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.\nAbstract: Copper is an essential trace element required for numerous enzymatic processes in the brain, including mitochondrial metabolism, antioxidant defense, and gene expression regulation. Recent studies have further implicated copper in a newly defined form of regulated cell death termed cuproptosis, providing a mechanistic framework for copper-dependent cytotoxicity. Increasing evidence indicates that copper dyshomeostasis is a common feature of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), where it is associated with protein misfolding, redox imbalance, and neuronal vulnerability. Nevertheless, the mechanistic link between copper dysregulation and neuronal cell death remains incompletely defined. In this review, we systematically summarize the molecular mechanisms governing copper homeostasis and intracellular copper trafficking, while providing a timely, updated, and in-depth overview of the mechanistic basis and emerging biology of cuproptosis. We further comprehensively evaluate the current evidence linking copper dysregulation and cuproptosis-related pathways to neurodegenerative diseases, with particular emphasis on distinguishing mechanistic causation from pathological correlation. Importantly, we discuss current therapeutic strategies and emerging clinical efforts targeting copper metabolism, while highlighting the major challenges in defining the pathological significance and mechanistic contribution of cuproptosis in neurodegenerative diseases. Collectively, this review provides an updated framework for understanding the pathological significance and translational potential of cuproptosis in neurodegenerative diseases.\n\nID: 42332177\nTitle: Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.\nAbstract: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.\n\nID: 42156174\nTitle: COMMD1 Induces Copper Deficiency of SOD1 by Inhibiting the Palmitoylation of CCS in ALS.\nAbstract: Mutations in superoxide dismutase 1 (SOD1) compromise its metal-binding capacity, resulting in protein misfolding and aggregation, which ultimately induces cellular apoptosis in amyotrophic lateral sclerosis (ALS). Copper metabolism domain containing 1 (COMMD1), a gene implicated in copper homeostasis, has not been thoroughly characterized in the context of ALS pathogenesis. In this study, we identified elevated COMMD1 expression in ALS, potentially contributing to diminished copper incorporation into SOD1. Knockdown of COMMD1 enhanced palmitoylation of the copper chaperone for SOD1 (CCS), facilitating its membrane translocation and promoting copper loading into SOD1, thereby conferring neuroprotection in ALS. Mechanistically, we established that COMMD1 knockdown augments CCS palmitoylation via activation of the hypoxia-inducible factor 1 subunit alpha (HIF-1\u03b1)/fatty acid synthase (FASN) signaling axis. In vivo investigations utilizing male hSOD1G93A transgenic mice demonstrated that COMMD1 deficiency markedly ameliorated the deterioration of motor function and prolonged survival duration. These findings collectively suggest that COMMD1 represents a potential therapeutic target for ALS intervention.\n\nID: 42097486\nTitle: Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.\nAbstract: Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.\n\nID: 42034125\nTitle: Lead (Pb) exposure results in cell type specific changes in the mouse retina and optic nerve.\nAbstract: Chronic exposure to lead (Pb) is known to cause deficits in neuronal function across the nervous system, including the visual nervous system. Visual deficits have been observed in both humans and rodent models following Pb exposure. However, how Pb exposure causes visual deficits is poorly understood. In this study, we evaluated the effects of Pb toxicity on the retina and optic nerve of the mouse visual nervous system. We used C57BL/6 adult mice of both sexes and divided them into one of three different exposure groups. Adult mice received daily oral gavage of 108\u202fmg/kg Na-acetate (control), 54\u202fmg/kg Pb-acetate (low dose), or 108\u202fmg/kg Pb-acetate (high dose) for 4 weeks. At the end of Pb exposure, whole blood, retina, and optic nerve samples were collected for Pb quantification by atomic absorption spectroscopy and tissue immunohistochemical analyses. Cell type specific markers were used to quantify changes in cell density of retinal ganglion cells (RGCs), oligodendrocytes (OLs), oligodendrocyte precursor cells (OPCs), and myelin structure. Following Pb exposure, we observed a significant reduction in the cell density of RGCs in the retina. However, we found no significant changes in branch thickness or coverage of retinal vasculature following Pb exposure. In the optic nerve after Pb exposure, we found a significant reduction in the cell density of OLs and OPCs. Finally, using immunolabeling for Caspr and Nav1.6, we observed significant structural changes in nodes of Ranvier, suggesting a disruption in myelin structure. Our findings suggested that Pb toxicity may impair survival and maturation process of OLs, changes in myelin structures, and potential demyelination of the optic nerve. These results provide the foundation for future investigations into the molecular mechanisms of Pb-dependent changes in myelination and visual nervous system function.\n\nID: 41943905\nTitle: Letter to the Editor: Comment on Upadhyaya et al.'s \"Intravitreal Clindamycin as an Adjuvant Therapy in Congenital Toxoplasma Retinochoroiditis in a Neonate - A Case Report\".\nAbstract: The novel work by Upadhyaya et al. suggests a potential use of intravitreal clindamycin for treating congenital toxoplasma retinochoroiditis. We share our clinical experience of encountering a sudden spike in intraocular pressure (IOP) after administering intravitreal clindamycin (5\u2009mg/0.5\u2009mL) in a neonate. Intravitreal injections are known to cause an increase in IOP immediately, which reduces in a few minutes. However, a smaller vitreous volume in neonates can cause an exponential increase in IOP immediately post-injection, posing a risk of optic nerve damage and compromise in retinal perfusion. We suggest modifying the intravitreal preparation of clindamycin to 0.5\u2009mg/0.025\u2009mL when used in neonates to reduce this risk while maintaining therapeutic efficacy.\n\nID: 41783572\nTitle: Copper Homeostasis and Cuproptosis in Neurological Disorders.\nAbstract: Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development. Copper homeostasis imbalance plays a critical regulatory role in neurological disorders.Cuproptosis is a unique form of copper-mediated cell death that plays a key role in neuronal injury.Many key questions regarding the differences in copper homeostasis and cuproptosis mechanisms among various neurological disorders remain unresolved.The interplay between copper and other metal ions (such as iron and zinc) in maintaining homeostasis may have important implications in neurological disorders.\n\nID: 41781384\nTitle: Decreased metallothionein-3 expression in the human spinal cord is a common feature of amyotrophic lateral sclerosis and multiple sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are devastating adult-onset neurological diseases with distinct pathological manifestations. Although growing evidence implicates copper dysregulation in both diseases, our understanding of this connection remains incomplete. In this study, we investigated metallothionein-3 (MT3), which is a key regulator of copper metabolism in the central nervous system (CNS), and its relationship to copper in the ALS and MS spinal cord. Using combined quantitative mass spectrometry approaches and immunohistochemical observations, we found a significant decrease in ALS and MS spinal cord MT3 levels compared to controls. This was correlated with levels of copper and MT3-copper binding, highlighting a strong relationship between copper and MT3 levels. These findings demonstrate decreased MT3 expression alongside copper as a common feature of ALS and MS supporting previously reported evidence for copper dysregulation in these diseases.\n\nID: 41750213\nTitle: Color Vision Deficits and Binocular Vision Dysfunction in Parkinson's Disease.\nAbstract: Background/Objectives: Visual dysfunction is a common non-motor symptom in Parkinson's Disease (PD), as evidenced by deficits in color vision (CV) and binocular vision (BV). Computerized CV tests, such as the Cambridge Color Test (CCT), are underutilized in this patient population despite the known limitations of common CV tests. Methods: In total, 19 PD and 12 control participants underwent a comprehensive eye exam, including ocular motility testing and the CCT, utilizing thresholds obtained along 12 contrast vectors to fit a discrimination ellipse. Findings were compared across groups, and the association with disease severity was analyzed. Results: PD participants showed increases in ellipse area (p = 0.012) and short-axis length (p = 0.009). PD participants demonstrated convergence insufficiency type exotropia (p < 0.001) and impaired stereopsis (p = 0.006). No significant correlation with UPDRS scores was seen for either BV or CV. Conclusions: PD participants exhibited binocular vision dysfunction with selective changes in color vision. CV changes are more variable in PD, likely due to mixed parvocellular and cortical dysfunction. Convergence insufficiency type exotropia is more common in PD, likely due to combined cortical and subcortical neurodegeneration. Both BV and CV changes occur independently of motor severity, emphasizing the need for routine visual testing regardless of symptom progression.\n\nID: 41397557\nTitle: Differential binding of copper and zinc to a TDP-43 RNA recognition motif decapeptide and disulfide formation at residues C173/5 revealed by ESI-MS/MS.\nAbstract: Copper (Cu) and zinc (Zn) metal ions play important roles in the proper functioning and localization of neurological proteins, such as transactive response DNA-binding protein 43 (TDP-43), which is linked to amyotrophic lateral sclerosis (ALS). Previous experimental and computational studies have identified putative Zn-binding regions within the RNA recognition motif 1 (RRM1) of TDP-43. However, Cu-binding interactions have been less explored despite their redox activity in regulating thiol (C173/175) conversion to disulfide within the RRM1 domain, influencing protein structure and function. Herein, the structural characterization and fragmentation pattern analysis of a TDP-43 decapeptide (166-HMIDGRWCDC-175), within RRM1, coordinated to Cu(II) and Zn(II) ions using electrospray ionization tandem mass spectrometry (ESI-MS/MS) was conducted under non-denaturing conditions. Higher-energy collision dissociation (HCD) fragmentation analysis identified that Cu(II) prefers His/Met residues, while Zn(II) was weakly coordinated to various binding sites in the peptide, specifically His, Met, Glu, Cys, Trp and Asp residues. Computational modeling using a metal ion binding server (MIB2) confirmed the binding sites and coordination sphere of metal-peptide complexes. No significant coordination to C173 and C175 was observed with Cu or Zn, as identified by using a double Cys mutant peptide. A complete thiol-to-disulfide conversion was observed in the presence of Cu(II)/(I) only, which was confirmed by the comparison of a preformed intramolecular disulfide peptide. Overall, unique differential coordination environments were observed for each metal ion with the peptide. The study provides new insights into metal ion interactions with TDP-43 RRM1 peptide, leading to a greater understanding of metal homeostasis in TDP-43 protein biochemistry and neurodegeneration.\n\nID: 41237982\nTitle: The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-implications for the toxic gain of function observed in ALS.\nAbstract: A subset of familial cases of amyotrophic lateral sclerosis (fALS) are caused by mutations to copper, zinc superoxide dismutase (Cu, Zn SOD1). Over 200 mutations to SOD1 that have been associated with fALS and the majority of these mutations are dominantly inherited. Thus, individuals are heterozygous and express both wild-type SOD1 and the mutant form of the protein. Paradoxically, the motor neuron disease accelerates in rodent models that mimic the co-expression of wild-type SOD1 with mutant fALS SOD1. Previously, we have shown that the loss of zinc from SOD1 triggers motor neuron death in culture due to a gained, redox activity catalyzed by the active-site copper. Furthermore, motor neuron toxicity of zinc-deficient SOD1 is enhanced by wild-type Cu, Zn SOD1. Because SOD1 exists as a non-covalent dimer, the enhanced toxicity might result from stabilization of the heterodimeric interface between zinc-deficient SOD1 and Cu, Zn-SOD1. However, experimentation with the heterodimer is difficult because SOD1 subunits exchange in minutes. To better characterize the role of dimer stabilization on the enhanced toxicity of fALS mutant SOD1 by wild type SOD1, we genetically tethered a zinc-deficient SOD1 subunit with a Cu, Zn SOD1 subunit with a 16-residue linker. The x-ray structure of the tethered heterodimer showed that the zinc-deficient subunit adopts a wild-type-like conformation and is not misfolded. The heterodimer intermediate also produced peroxynitrite from nitric oxide, and the tethered SOD1 was strikingly toxic to primary cultures of motor neurons. This work supports the concept that zinc-deficient SOD1 is a likely toxic intermediate in ALS. Furthermore, the wild-type allele in human familial-SOD1 ALS patients may physically contribute to the dominant inheritance of SOD1 mutations through heterodimer formation.\n\nID: 41174080\nTitle: Novel and classic imaging signs of increased intracranial pressure.\nAbstract: The arachnoid bulk ratio was recently described by Berhanu et al. on ultrasonography (US) as a potentially useful surrogate for intracranial pressure (ICP). We aimed to evaluate this novel neuroimaging index using magnetic resonance imaging (MRI) and determine the accuracy of the novel and classic imaging signs to diagnose increased ICP. Patients with suspected increased ICP were recruited to undergo optic nerve US and MRI before invasive ICP measurement. We included a total of 23 participants and determined the correlation of the novel ratio with ICP, compared to the optic nerve sheath diameter (ONSD), and we assessed the diagnostic accuracy of the novel and classic imaging signs through receiver operating characteristic (ROC) curve analysis. The arachnoid bulk ratio and ONSD were significantly larger in individuals with increased ICP on MRI (36% and 16%,p\u2009<\u20090.001) and on US (39% and 13%,p\u2009<\u20090.001). The ratio correlated very strongly with ICP on MRI and US (rs\u2009=\u20090.89 and rs\u2009=\u20090.92), outperforming the ONSD (MRI:rs\u2009=\u20090.67 and US:rs\u2009=\u20090.63). The Berhanu et al.'s ratio predicted increased ICP with a sensitivity of 100% and a specificity of 91% on MRI. The classic imaging signs with highest accuracy were the transverse sinus stenosis and ONSD, with a sensitivity of 89% and 91% and specificity of 100% and 92%,respectively. This novel ratio, which selectively assesses the perineural fluid space, provides an accurate prediction of ICP on MRI. When combined with classic imaging signs, it serves as a useful non-invasive surrogate in the clinical approach to these patients.\n\nID: 41169217\nTitle: Retinal proteomics in neurodegeneration: Insights into ocular and brain disorders.\nAbstract: Dysregulated proteome in the retina represents a promising avenue for discovering novel therapeutic targets and noninvasive diagnostic biomarkers for neurodegenerative diseases with ocular manifestations. Advanced mass spectrometry-based proteomics techniques have shown considerable potential in investigating the retinal proteome in diseases such as glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, as well as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Recent proteomics innovations are overcoming challenges such as limited sample size and protein coverage that previously hindered comprehensive retinal proteome analysis. Notably, the incorporation of artificial intelligence-driven computational pipelines, including Graphics Processing Unit-accelerated deep learning architectures, has markedly enhanced the precision and effectiveness of retinal proteomics. These advances facilitate high-resolution identification of novel protein signatures within large-scale multi-omics datasets. Furthermore, the integration of advanced artificial intelligence with state-of-the-art big data infrastructures supports the early detection of biomarkers and therapeutic targets in neurodegenerative diseases with ocular involvement, offering unprecedented disease specificity and sensitivity. In addition to these computational strides, emerging complementary and alternative technologies continue to provide valuable tools for retinal analysis, expanding the potential for identifying biomarker and therapeutic targets in both ophthalmic and neurodegenerative disorders. This review summarizes recent advancements in retinal proteomics, with a particular focus on neurodegenerative and ocular diseases.\n\nID: 41109388\nTitle: Allosteric pathway connects Zn(II) loss from SOD1 to known pathogenic mechanisms.\nAbstract: Cu,Zn superoxide dismutase (SOD1) is one of the proteins with mutations linked to hereditary forms of the amyotrophic lateral sclerosis neurodegenerative disorder. The protein is known for its enzymatic activity, but it has been shown to also have regulatory functions, which could be related to its pathogenic potential. Seemingly unrelated to its regulatory roles, the most important hypothesis on SOD1 pathogenicity is related to misfolding of the protein, specifically centered on the region corresponding to its residues 28-38. The present work explores the structural and dynamical effect of Zn(II) removal from SOD1, which is known to influence its regulatory roles, with coarse-grained simulations of 450\u03bcs per system. In agreement with experiment, we see an increased solvent exposure of the regulatory region (residues 5-18). We also see an increased solvent exposure of the misfolding-critical 28-38 region. We unveil the mechanism and interactions connecting Zn(II) loss, and solvent exposure of both regions. The present work allows for an unified understanding of two different pathogenic mechanisms of SOD1.\n\nID: 41102382\nTitle: OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies.\nAbstract: Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-\u03baB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.\n\nID: 41099622\nTitle: Oxidative denaturation of Cu/Zn-superoxide dismutase associated with neurodegenerative diseases.\nAbstract: Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) is a well-established pathological feature of familial amyotrophic lateral sclerosis (ALS). While amino acid substitutions in mutant SOD1 destabilize its structure and promote misfolding, oxidation has also been implicated in the pathological alterations of wild-type SOD1, particularly in neurodegenerative diseases including sporadic ALS. However, the impact of oxidation on SOD1 folding remains to be fully elucidated. Here, we demonstrate that Cys111 is primarily oxidized to sulfonic acid upon exposure of apo-SOD1 to hydrogen peroxide, as confirmed by the quantitation of thiol groups and mass spectrometry. Molecular dynamics simulations showed that sulfonylation of Cys111 disrupts the dimer interface and promotes monomerization. This monomeric form then facilitates the subsequent oxidation of buried Cys6, leading to structural disruption, as evidenced by circular dichroism spectroscopy and loss of thiol groups. SOD1 denaturation triggered by Cys111 oxidation became evident when zinc binding was impaired due to pathological mutations and/or under zinc-deficient conditions. Given that increased oxidative stress is frequently associated with many neurodegenerative diseases, modulating Cys111 oxidation may offer a potential strategy for maintaining SOD1 structural stability and preventing its pathological misfolding.\n\nID: 41014556\nTitle: ER stress tolerance is regulated by copper-dependent PERK kinase activity.\nAbstract: Pancreatic/PKR-like endoplasmic reticulum (ER) kinase (PERK) is a kinase that, in response to ER stress, mediates dual homeostatic and pro-apoptotic signaling. Thus, intricate regulation is required for physiological function. Attempts to modulate PERK activity have shown that the determinants of adaptive vs. maladaptive signaling remain ambiguous. Here, with purified protein, we provide evidence that PERK binds copper, identifies residues required for interaction, and demonstrates that copper is necessary for kinase activity. Furthermore, cellular PERK activity can be modulated via copper availability, and this regulatory relationship can be manipulated to dictate ER stress tolerance. Critically, these phenomena translate to phenotypes in vivo, as C. elegans harboring a \"PERK-copper mutant\" exhibit exacerbated ER-stress sensitivity. The copper-PERK paradigm suggests that copper homeostasis, as a regulator of PERK, may constitute a critical factor in resolving the long-standing ambiguity in endeavors to therapeutically target PERK.\n\nID: 40994605\nTitle: Retinal vessel density alteration after FS-LASIK for myopia with different axial lengths.\nAbstract: To compare the effects of different types of negative pressure suction on the macular and optic disc retinal vessel density (VD) in myopic patients with different axial lengths (ALs) undergoing femtosecond laser-assisted excimer laser in situ keratomileusis (FS-LASIK) by optical coherence tomography angiography (OCTA). A prospective, nonrandomized, controlled study. Participants underwent FS-LASIK surgery were divided into the short AL group (SAL, 22\u2264AL<26 mm) and the long AL group (LAL, 26\u2264AL<28 mm) according to the different ALs. Further, the two groups were divided into subgroups according to the corneal flap using VisuMax or WaveLight FS200 femtosecond laser (FS) platform. All patients underwent OCTA before the surgery and 1-day/1-week/1-month after the surgery. ANOVA statistically analyzed data with two-factor repeated measurement in SPSS. Totally 108 participants (108 eyes, 18-35y) were divided into SAL group [22 patients (4 males and 18 females) were treated with VisuMax, and 24 (3 males and 21 females) were treated with WaveLight FS200] and LAL group [34 patients (4 males and 30 females) were treated with VisuMax, and 28 patients (6 males and 22 females) were treated with WaveLight FS200]. In the LAL group, there was no significant difference in macular superficial capillary plexuses vessel density (SCP-VD) in the fovea and perifovea region, but compared with the VisuMax subgroup, SCP-VD in the parafoveal region (t=2.647, P=0.010) and the whole area (t=2.030, P=0.047) in WaveLight FS200 subgroup decreased at one day after the operation and increased to a preoperative level at 1-week and 1-month after operation. There was no significant difference between SCP-VD in the two SAL subgroups, neither of deep capillary plexuses vessel density (DCP-VD) and optic nerve head vessel density (ONH-VD) in the SAL and LAL groups. With the increase of AL and suction intensity, a transient decrease of SCP-VD in the macular region is observed at 1d postoperatively during FS-LASIK, and it increases to preoperative level at 1-week and 1-month postoperatively. However, the AL and suction intensity do not affect the macular DCP-VD and ONH-VD.\n\nID: 40955291\nTitle: Prevalence of ocular and visual abnormalities following symptomatic and asymptomatic congenital CMV infection: a systematic review and meta-analysis.\nAbstract: Cytomegalovirus (CMV), the most common congenitally acquired infection, can result in visual disability in affected children. We aimed to estimate the burden of eye and vision disorders amongst children with symptomatic and asymptomatic congenital cytomegalovirus infection (cCMV), to inform the development of guidance for the provision of care. In this systematic review and meta-analysis, we searched PubMed, Embase, and CINAHL databases up to 6th Feb 2025 for studies reporting ocular disorders or visual impairment (VI) outcomes following cCMV diagnosis. We included longitudinal or cross-sectional studies which reported the frequency of visual or ophthalmic outcomes following an initial diagnosis of symptomatic or asymptomatic cCMV. Summary data, and individual patient level data where available, on the proportions of children noted to have visual impairment or ophthalmic disorders and the manifestation of these disorders, were extracted from published reports. Pooled prevalence of eye and vision outcomes were estimated through random effects models computed using Restricted Maximum Likelihood (REML) estimation. We included studies at lower risk of bias (assessed using the Joanna Briggs Institute tool) in meta-analyses of prevalence (random-effect models) and undertook subgroup analyses. The review protocol was registered with PROSPERO, CRD42021284678. We identified 4488 articles of which 28 were eligible for inclusion. Of these, 15 studies (total 858 children with symptomatic, 1176 with asymptomatic cCMV) were eligible for meta-analyses. Median follow up time from diagnosis of cCMV ranged from 6 to 156 months. Estimated pooled prevalence in symptomatic cCMV of visual impairment (VI) and ocular disorders 9% (95% CI, 5-14%, I 2 = 51.09%) and 14% (95% confidence interval, CI, 5-31%, I 2 = 93.2%) respectively. Cerebral visual impairment (i.e. VI due to neurological insult rather than ocular disease) was the most commonly reported visual disability, with an estimated pooled prevalence of 10% (95% CI, 6-15%, I 2 = 24.9). Prevalence of ocular disorders (most commonly chorioretinitis, and optic nerve and anterior segment anomalies) was higher in studies with greater proportions of pre-term birth, hearing impairment, and those undertaken prior to 2017. Estimated pooled prevalence of VI and ocular disorders was 1% and <1% (95% CI, 0-2%, I 2 = 0%) respectively in asymptomatic cCMV. Visual disability in cCMV is a strong marker of the broader neurological insult. Ocular disorders are prevalent in symptomatic disease, with consequent need for ongoing ophthalmic care. The low prevalence of sight-impactful disorders in asymptomatic disease suggests little benefit for ongoing ophthalmic surveillance, particularly in health settings with established programmes for whole population childhood eye and vision screening. This review is limited by the absence of information on the timing of diagnosis of the eye and vision disorders, data which would support the development of timeline pathways for ophthalmic surveillance. Wellcome Trust, National Institute for Health and Care Research (NIHR).\n\nID: 40894549\nTitle: Lead (Pb) exposure results in cell type specific changes in the mouse retina and optic nerve.\nAbstract: Chronic exposure to lead (Pb) is known to cause deficits in neuronal function across the nervous system, including the visual nervous system. Visual deficits have been observed in both humans and rodent models following Pb exposure. However, how Pb exposure causes visual deficits is poorly understood. In this study, we evaluated the effects of Pb toxicity on the retina and optic nerve of the mouse visual nervous system. We used C57BL/6 adult mice of both sexes and divided them into one of three different exposure groups. Adult mice received daily oral gavage of 108mg/kg Na-acetate (control), 54mg/kg Pb-acetate (low dose), or 108mg/kg Pb-acetate (high dose) for 4 weeks. At the end of Pb exposure, whole blood, retina, and optic nerve samples were collected for Pb quantification by atomic absorption spectroscopy and tissue immunohistochemical analyses. Cell type specific markers were used to quantify changes in cell density of retinal ganglion cells (RGCs), oligodendrocytes (OLs), oligodendrocyte precursor cells (OPCs), and myelin structure. Following Pb exposure, we observed a small, but significant reduction in the cell density of RGCs in the retina. However, we found no significant changes in branch thickness or coverage of retinal vasculature following Pb exposure. In the optic nerve after Pb exposure, we found a significant reduction in the cell density of OLs and OPCs. Finally, using immunolabeling for Caspr and Nav1.6, we observed significant structural changes in nodes of Ranvier, suggesting a disruption in myelin structure. Our findings suggested that Pb toxicity may impair survival and maturation process of oligodendrocytes, changes in myelin structures, and potential demyelination of the optic nerve. These results provide the foundation for future investigations into the molecular mechanisms of Pb-dependent changes in myelination and visual nervous system function.\n\nID: 40889423\nTitle: Oriented porous microtubules combined with CNTF-delivery directional guide axonal regeneration after traumatic optic neuropathy.\nAbstract: Neuroinflammation microenvironment and retinal ganglion cell (RGC) apoptosis are two critical barriers to axonal regeneration following traumatic optic neuropathy (TON). To overcome these challenges, we developed an innovative dual drug delivery strategy utilizing oriented porous nanofiber (OF) and ciliary neurotrophic factor (CNTF)-loaded delivery systems, aiming to promote axonal regeneration and restore RGC survival. Cerium oxide nanoparticles (Ce NPs) were physically mixed with poly(L-lactic acid)/polycaprolactone (PLA/PCL) solution to prepare oriented porous nanofibers (OF-Ce) via electrospinning and solvent evaporation techniques. The aligned porous nanofiber architecture supports drug loading, guides cell directional growth, and integrates Ce NPs properties to modulate the neuroinflammatory environment. Subsequently, neural stem cell-derived exosomes (NSC Exo) were applied onto the porous OF-Ce nanofiber microtubule (OF-Ce/Exo), stabilizing exosomes, improving hydrophilicity, and significantly reducing neuroinflammation while inhibiting glial scar formation. Importantly, these OF-Ce/Exo microtubules effectively guide the directional growth and migration in various cell types. Furthermore, CNTF was encapsulated into PEGylated mesoporous silica nanoparticles (PMSN-CNTF NPs) for sustained release, reducing PC12\u00a0cell apoptosis in inflammatory conditions. Notably, in situ implantation of OF-Ce/Exo microtubules, coupled with intravitreal injection of PMSN-CNTF NPs, significantly promoted axonal regeneration and alleviated RGC death in a rat optic crush model, highlighting their potential for treating TON.\n\nID: 40698100\nTitle: Ganglion Cell Layer Thickness as a Biomarker for Amyotrophic Lateral Sclerosis Functional Outcome: An OCT study.\nAbstract: This study aims to evaluate various optical coherence tomography (OCT) parameters in patients diagnosed with amyotrophic lateral sclerosis (ALS). Assessment of BCVA was done using Snellen charts, and subjective refraction was done to achieve a BCVA for distance and near. Measurement of intraocular pressure (IOP) was done with Goldman applanation tonometry. Stereoscopic fundus examination was performed using a 90D lens to assess the status of the optic nerve and retina, ruling out any ocular pathology. The patients were then subjected to OCT scanning to measure optic nerve head and macular parameters. Optical coherence tomography was performed using CIRRUS\u2122 HD OCT (500-21822) (version 8.0.0.518) (Carl Zeiss Meditec, Dublin, CA, USA). The analyzed area was centered manually, and the absence of segmentation errors was confirmed for each scan. RE Avg RNFL and LE Avg RNFL showed weak correlations with ALSFRS, indicated by Pearson Correlation coefficients of 0.073 and -0.026, respectively. The p-values (0.637 and 0.86) suggested that these correlations were not statistically significant. RE Avg GCL and LE Avg GCL, on the other hand, exhibited moderate positive correlations with ALSFRS scores, with correlation coefficients of 0.337 (RE) and 0.389 (LE). These correlations were statistically significant, as indicated by p-values of 0.021 and 0.006, respectively, suggesting a substantial association between GCL thickness and ALS functional outcomes. All patients in our study were clinically diagnosed cases of ALS, as per the El Escorial criteria. Age group-wise analysis showed statistically significant thinning overall as well as quadrant-wise RNFL parameters in patients less than 50 years compared to age-matched controls, indicating that the pathological process occurring in larger motor neurons in ALS might also be happening in smaller sensory neurons of the retina, causing thinning, which was not due to age-related process. Although GCIPL thinning was occurring in our cases, though statistically not significant compared to control, the significant positive correlation observed between GCIPL and ALS functional outcome and between RNFL and GCIPL measurements highlighted the fact that though the axonal degeneration in retinal neurons might not be translating to the same extent in ganglion cells in ALS, the subtle thinning of GCIPL correlated strongly with functional disability in patients with ALS, implying better functional scores with higher values of GCIPL parameters. In summary, GCL measurements in both eyes showed a notable relationship with ALSFRS, whereas RNFL did not appear to correlate significantly.\n\nID: 40692425\nTitle: Comparison of the Peripapillary Structure-Vessel Density Relationship Before and After Axial Length Magnification Correction Using Different Methods.\nAbstract: To evaluate changes in OCTA-derived structural and vascular parameters before and after axial length (AL) magnification correction using two different formulas, and to explore their correlations with vessel density (VD). This study included 45 high myopic eyes and 45 age- and gender-matched controls. Both 6\u2009\u00d7\u20096\u2009mm2 optic nerve head imaging and biological measurement were performed using OCTA. Magnification correction was performed using both the Bennett formula and the device's built-in algorithm. Parameters analysed included retinal nerve fibre layer (RNFL) thickness, superficial vascular complex (SVC) VD, deep vascular complex (DVC) VD, and choroidal VD. In long AL eyes, uncorrected values underestimated RNFL thickness and SVC VD but overestimated DVC VD and choroidal VD; discrepancies increased with AL. The opposite pattern was observed in shorter eyes. After correction, all vascular parameters except DVC VD showed significant changes in the high myopia group, while non-high myopic eyes showed no significant differences. The two correction methods showed strong agreement across all layers. RNFL thickness correlated strongly with SVC VD, and choroidal thickness (CT) with choroidal VD, both before and after correction. Post-correction, AL was no longer associated with RNFL thickness or SVC VD, while its correlation with CT and choroidal VD persisted. Mediation analysis showed AL fully mediated the CT-choroidal VD relationship, with a stronger effect post-correction. Magnification correction is crucial in high myopic eyes. Both formulas showed high consistency. Correction eliminated AL's confounding effects on RNFL and SVC VD, while emphasising its mediating role between CT and choroidal VD.\n\nID: 40607673\nTitle: [Focus on MS - visual loss as a cardinal symptom of multiple sclerosis].\nAbstract: Visual disturbances are a common presenting symptom of multiple sclerosis (MS), often caused by optic neuritis. This acute inflammation of the optic nerve leads to pain during eye movements, visual impairment and colour vision defects. Optic neuritis can be idiopathic, MS-associated or occur in the context of other diseases such as NMOSD or MOGAD. Diagnosis is based on clinical findings, imaging and visual evoked potentials. Early high-dose corticosteroid treatment can support recovery and improve long-term prognosis. Blickpunkt MS \u2013 Sehst\u00f6rungen als Leitsymptom der Multiplen Sklerose. Sehst\u00f6rungen sind h\u00e4ufig ein fr\u00fches Leitsymptom der Multiplen Sklerose (MS), oft verursacht durch eine Optikusneuritis. Diese akute Entz\u00fcndung des Sehnervs f\u00fchrt zu Schmerzen bei Augenbewegungen, Visusminderung und Farbsinnst\u00f6rungen. Die Optikusneuritis kann idiopathisch, MS-assoziiert oder im Rahmen anderer Erkrankungen wie NMOSD oder MOGAD auftreten. Die Diagnose st\u00fctzt sich auf klinische Befunde, Bildgebung und visuell evozierte Potenziale. Eine fr\u00fchzeitige, hoch dosierte Kortikosteroidtherapie kann die Genesung unterst\u00fctzen und die Langzeitprognose verbessern. Schl\u00fcsselw\u00f6rter: Optikusneuritis, Sehst\u00f6rungen, Multiple Sklerose (MS), Demyelinisierung, Kortikosteroidtherapie.\n\nID: 40517843\nTitle: Response to: Commentary on Maja Guberina et al.'s study of dose response relation for optic nerve atrophy at low-dose rate brachytherapy of uveal melanoma.\nAbstract: \n\nID: 40517842\nTitle: Commentary on Maja Guberina et al.'s study of dose response relation for optic nerve atrophy at low-dose rate brachytherapy of uveal melanoma.\nAbstract: \n\nID: 40428407\nTitle: Pontocerebellar Hypoplasia Type 1 and Associated Neuronopathies.\nAbstract: Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders.\n\nID: 40389143\nTitle: COMM domain containing 4 inhibits hephaestin and ferroportin to enhance neuronal ferroptosis by disturbing the Cu-Fe balance in amyotrophic lateral sclerosis.\nAbstract: Dysregulation of copper and iron homeostasis contributes to the progression of amyotrophic lateral sclerosis (ALS), but the role and mechanism of COMM domain containing 4 (COMMD4) in ALS remains unclear. In this research, we showed that the expression of COMMD4 was upregulated in ALS cells and animal models. The increased COMMD4 induced neuronal ferroptosis by disrupting the Cu-Fe balance. Mechanistic studies indicated that COMMD4 inhibited ferroportin (FPN)-mediated neuronal iron efflux by inhibiting intracellular copper and hephaestin (HEPH). Our findings demonstrated that COMMD4 depletion exerts neuroprotective effects on ALS by increasing intracellular copper and activating HEPH/FPN pathway, rather than affecting the interaction between HEPH and FPN. Targeting COMMD4 and its downstream signaling pathways may offer potential therapeutic avenues for ALS.\n\nID: 40346885\nTitle: Progressive Thalamo-Cortical Disconnection in Amyotrophic Lateral Sclerosis Genotypes: Structural Degeneration and Network Dysfunction of Thalamus-Relayed Circuits.\nAbstract: The thalamus is a key subcortical hub of numerous corticobasal and corticocortical circuits mediating a wealth of cognitive, behavioural, sensory and motor processes. While thalamic pathology is increasingly recognised in amyotrophic lateral sclerosis, its degeneration is often assessed in isolation instead of adopting a network-wise perspective and assessing the integrity of its rich cortical projections. A prospective imaging study was conducted in a cohort of genetically stratified patients to assess the structural and functional integrity of thalamo-cortical circuits and volumetric alterations longitudinally. The white matter integrity of thalamic projections to the anterior cingulate cortex, cerebellum, dorsolateral prefrontal cortex (DLPFC), Heschl's gyrus, medial frontal gyrus (MFG), orbitofrontal cortex, parietal cortex, postcentral gyrus and precentral gyrus (PreCG) is affected at baseline in ALS, which is more marked in C9orf72 hexanucleotide repeat carriers. Precentral gyrus and cerebellar grey matter volumes are also reduced, particularly in C9orf72. Longitudinal analyses capture progressive disconnection between the thalamus and frontal regions (DLPFC and MFG) in both C9orf72 positive and sporadic patients and progressive thalamo-PreCG disconnection in the sporadic C9orf72 negative cohort. Functional connectivity analyses revealed increasing thalamo-cerebellar connectivity in sporadic ALS and increasing thalamo-DLPFC connectivity in intermediate-length CAG repeat expansion carriers in ATXN2 over time. Our data provide evidence of extensive thalamo-cortical connectivity alterations in ALS. Corticobasal circuits mediating extrapyramidal, somatosensory, cognitive and behavioural functions are increasingly affected as the disease progresses. The degeneration of thalamic projections support the conceptualisation of ALS as a 'network disease' and the notion of 'what wires together degenerates together'.\n\nID: 40204975\nTitle: Distinct patterns of cerebral and spinal pathology along the spectrum of ATXN2-related disorders.\nAbstract: The ATXN2 gene contains a polymorphic CAG-rich region encoding a polyglutamine tract in ataxin- 2. Normal alleles have fewer than 27 CAG repeats, 27-34 repeats pose a risk for ALS (ATXN2-ALS), and >\u200934 repeats cause spinocerebellar ataxia type 2 (SCA2). The striking phenotypic differences between these two ATXN2-related conditions are not yet fully understood. To characterize and compare the distinguishing radiological signatures of ATXN2-ALS, SCA2, sporadic ALS (sALS) and healthy controls in vivo using quantitative computational neuroimaging techniques. Four groups were defined: healthy controls (n\u2009= 34), sALS (n\u2009= 17), ATXN2-ALS (n\u2009= 16), and SCA2 (n\u2009= 17). Cortical, subcortical, brainstem, cerebellar and spinal regions were segmented based on T1-weighted data using validated segmentation tools and their volumes estimated. Group-specific morphometric data were correlated with cerebral ATXN2 expression maps from the Allen Human Brain Atlas. Study groups were age and sex-matched. sALS, ATXN2-ALS and SCA2 have distinct structural CNS signatures, with disease burden restricted to the precentral gyri in the sALS group, to the spinal cord and brainstem in the ATXN2-ALS group and more diffusely distributed in the subcortical structures in the SCA2 group. Brain ATXN2 expression correlated with the structural signature of SCA2, but not with that of ATXN2-ALS. Neuroimaging signatures differ in ATXN2-ALS and SCA2, indicating distinct mechanisms of ATXN2-mediated neurodegeneration. sALS and ATXN2-ALS also exhibit distinct patterns of CNS involvement. The unique imaging signatures and clinical profiles along the spectrum of ATXN2-related disorders raise important questions regarding the pathophysiology of the disease and have practical clinical ramifications.\n\nID: 40184864\nTitle: Copper in human health: From COVID 19 to neurodegenerative diseases.\nAbstract: Copper (Cu) exists in two oxidation states Cu+I and Cu+II yielding formation of enzymes involved in biological processes. In higher concentrations, by oxidative process and ROS production, Cu is toxic towards plants, humans and animals livers as observed in Wilson disease or sheep scrapie. Fighting according to the Fenton reaction against bacteria and viruses, has been proposed as a mean of combatting nosocomial diseases and complementary to COVID19 vaccination. In humans, Cu is stocked in liver, muscle or bound to brain protein as \u00df-APP, tau-protein, \u03b1-synuclein, ubiquitin or prion which present antioxidant properties when Cu-bonded. In abnormal \u00df-sheet conformation, they can trigger neurodegenerative diseases such as Alzheimer(AD), Parkinson(PD) and ALS. In these diseases, blood copper increase correlated with brain copper decrease has been described. In AD, abnormal D-serine has been detected in blood and cerebrospinal fluid. D-glutamate and D-alanine blood levels have been found in AD and could also be controlled with Cu and ceruloplasmin in a possible disease screening test. This abnormal D-conformation might result from epimerization of physiologically L-conformation brain peptides into protease-resistant D-enantiomers. This has previously been experimentally demonstrated for Bovine Spongiform Encephalopathy in a free Cu reductive medium with UV-induced free radicals. The Cu brain protective effect against free radicals was restored with cupric addition in oxidizing medium. Cupric supplementation in the brain, might restore Cu protection and slow down neurodegenerative processes. To lower side effects, Cu amino-acid complexes able to cross the blood brain barrier might be suggested for a Cu transfer to the brain.\n\nID: 40075889\nTitle: Cornea Oculomics: A Clinical Blueprint for Extending Corneal Diagnostics and Artificial Intelligence in Systemic Health Insights.\nAbstract: Oculomics is an emerging field that leverages ophthalmic imaging data to identify biomarkers of systemic disease, facilitating early diagnosis and risk stratification. Despite its growing recognition, gaps remain in the literature regarding the clinical applications of oculomics. Various systemic diseases-including metabolic disorders (e.g., diabetes mellitus), infectious diseases (e.g., COVID-19), neurodegenerative diseases (e.g., dementia), hematologic disorders (e.g., thalassemia), autoimmune conditions (e.g., rheumatoid arthritis), and genetic syndromes (e.g., Fabry disease)-exhibit ocular manifestations detectable through in vivo confocal microscopy and anterior segment optical coherence tomography, among other imaging modalities. Increasing evidence supports the role of corneal imaging in identifying systemic disease biomarkers, a process further enhanced by artificial intelligence-driven analyses. This review synthesizes the current findings on corneal biomarkers of systemic disease, their ophthalmic imaging correlates, and the expanding role of corneal oculomics in translational medicine. Additionally, we explore future directions for integrating oculomics into clinical practice and biomedical research.\n\nID: 39979261\nTitle: Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.\nAbstract: Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN\u2206C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.\n\nID: 39930076\nTitle: Improved image reconstruction from brain activity through automatic image captioning.\nAbstract: Significant progress has been made in the field of image reconstruction using functional magnetic resonance imaging (fMRI). Certain investigations reconstructed images with visual information decoded from brain signals, yielding insufficient accuracy and quality. The combination of semantic information in the reconstruction was recommended to improve performance. However, this issue continues to come across numerous difficulties. To address such problems, we proposed an approach that combines semantically complex details with visual details for reconstruction. Our proposed method consists of two main modules: visual reconstruction and semantic reconstruction. In the visual reconstruction module, visual information is decoded from brain data using a decoder. This module employs a deep generator network (DGN) to produce images and utilizes a VGG19 network to extract visual features from the generated images. Image optimization is performed iteratively to minimize the error between features decoded from brain data and features extracted from the generated image. In the semantic reconstruction module, two models BLIP and LDM are employed. Using the BLIP model, we generate 10 captions for each training image. The semantic features extracted from the image captions, along with brain data obtained from training sessions, are used to train a decoder. The trained decoder is then utilized to decode semantic features from human brain activity. Finally, the reconstructed image from the visual reconstruction module is used as input to the LDM model, while the semantic features decoded from brain activity are provided as conditional input for semantic reconstruction. Including decoded semantic features improves reconstruction quality, as confirmed by our ablation study. Our strategy is superior both qualitatively and quantitatively to Shen et al.'s method, which utilizes a similar dataset. Our methodology achieved an accuracy of 0.812 and 0.815 for the inception and contrastive language-image pre-training (CLIP) metrics, respectively, which are excellent for the quantitative evaluation of semantic content. We achieved an accuracy of 0.328 in the structural similarity index measure (SSIM), indicating superior performance as a low-level metric. Moreover, our proposed approach for semantic reconstruction of artificial shapes and imagined images achieved acceptable success, attaining accuracies of 0.566 and 0.627 based on the CLIP metric, and 0.671 and 0.565 based on the SSIM metric, respectively.\n\nID: 39894843\nTitle: Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.\nAbstract: As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.\n\nID: 39761853\nTitle: Regulation of sod1 mRNA and protein abundance by zinc in fission yeast is dependent on the CCR4-NOT complex.\nAbstract: Zinc is an essential micronutrient that serves as a cofactor in a wide variety of enzymes, including Cu-Zn Superoxide Dismutase 1 (Sod1). We have discovered in Schizosaccharomyces pombe that Sod1 mRNA and protein levels are regulated in response to cellular zinc availability. We demonstrate that lower levels of sod1 mRNA and protein accumulate under low zinc conditions and that this regulation does not require the sod1 promoter or known factors that regulate the transcription of sod1 in response to zinc and other environmental stresses. Further analyses using yeast deletion strains and an inactive allele of Caf1 revealed that the reduced accumulation of sod1 mRNA and protein under low zinc conditions depends on the Caf1 and Ccr4 deadenylases of the CCR4-NOT complex. We also found that Caf1 and Ccr4 are both required for growth under zinc-limiting conditions. To gain additional mechanistic insight we used immunoblot analysis to map the regions required for the regulation of the Sod1 protein by zinc. We found that the sod1 ORF and 3'UTR are both necessary and sufficient for the zinc-dependent changes in Sod1 protein abundance. Our studies reveal a novel mechanism of altering mRNA and protein abundance in response to zinc status, which depends on the CCR4-NOT complex.\n\nID: 39596915\nTitle: Neuronal Intranuclear Inclusion Disease with a Corneal Disorder: A Case Report.\nAbstract: Background: Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder characterized by the formation of intranuclear inclusions in cells. Adult-type NIID usually develops in elderly patients with various clinical manifestations and is sometimes accompanied by ocular symptoms. A case of adult-onset NIID with early and unique manifestations, including a progressive corneal defect and retinal changes, which are concerning at a young age, is reported. Case Presentation: A 29-year-old woman with adult sporadic NIID presented to our department with a progressive corneal disorder. Her neurological symptoms started at the age of 22 years, and she was diagnosed with NIID by skin biopsy and genetic testing. Ocular examination revealed bilateral corneal superficial punctate keratitis, right corneal opacity, decreased vision, nocturnal lagophthalmos, and early retinal changes. Corneal nerve fiber atrophy was detected by in vivo confocal microscopy. With a Cochet-Bonnet aesthesiometer, the progression of NIID and decreased corneal sensation were confirmed. Findings consistent with neurotrophic keratitis and keratoconjunctivitis due to nocturnal lagophthalmos were both suggested as being complications of her underlying NIID. Treatment with punctal plugs, sodium hyaluronate eye drops, diquafosol sodium eye drops, systemic and local antivirals, and local steroid medications resulted in the gradual improvement in the irregularity and opacity of the epithelium. Conclusions: NIID may lead to neurotrophic keratopathy due to impairment of the corneal sensory nerves. Nocturnal lagophthalmos is a remarkable finding in a case of NIID. The findings in the present case highlight the complex and multifaceted nature of NIID, with neurological and ocular manifestations requiring a multidisciplinary approach to management.\n\nID: 39494632\nTitle: Lack of habituation in somatosensory cortex but not in visual cortex of ALS patients.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a multisystem degenerative disease with extra-motor components. In ALS, there is also hyperexcitability of extra-motor areas. Habituation is defined as ''a response decrement\" caused by repeated stimulations. Studies on evoked potential habituation can be conducted to detect cortical excitability. This study aimed to explore lack of habituation in non-motor cortical structures in ALS. Twenty-one ALS patients and 14 controls were enrolled. Recordings were obtained in 3 and 10 consecutive blocks (each containing 100 responses) during right median somatosensory evoked potential (SEP) and bilateral visual evoked potential (VEP), respectively. \"Habituation\" and \"lack of habituation\" were defined as the amount of increase or decrease in the average N20 or N75-P100 amplitude of the last blocks compared to the first blocks, respectively. Comparative analyses were performed between patient and control groups, as well as the first and last block within groups. Paired sample t-test showed that in control group N20 peak amplitude of last blocks were significantly lower than first block values (p\u2009=\u20090.025) that indicate the physiological habituation as expected. On the other hand, there was not such a difference in ALS group (p\u2009=\u20090.239) which indicated lack of habituation. Our study results suggest somatosensory hyperexcitability in line with cortical reorganization in ALS patients.\n\nID: 39462586\nTitle: MicroRNA-5572 Is Associated with Endoplasmic Reticulum Stress Responses in Low Zinc Treated and SOD1 G85R-Transfected HEK293 Cells.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease. The mechanism of sporadic ALS onset remains unclarified in detail. Disruption of zinc homeostasis could be related to sporadic ALS. Previously, we first reported miR-5572 as a microRNA (miRNA) among those identified in the spinal cords of patients with sporadic ALS. However, since its function in ALS remained unknown, this study further examined the role of miR-5572 in low-zinc status and ALS model cells which transfected with causative gene, Cu/Zn superoxide dismutase 1 (SOD1) G85R mutant vector. The miR-5572 level was increased by low-zinc condition accompanied by increase of endoplasmic reticulum (ER) stress. In addition, increase of miR-5572 enhanced the cellular toxicity induced by low-zinc treatment. The expression of miR-5572 was also increased, which was accompanied by an increase of ER stress markers associated with SOD1 aggregation formation. Cell death and ER stress makers levels induced by tunicamycin treatment were further increased in miR-5572 mimic-transfected cells. This study showed that miR-5572 exacerbated ER stress toxicity associated with low-zinc status and mutant SOD1 aggregates in ALS.\n\nID: 39251386\nTitle: Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.\nAbstract: Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice. Congruent with the CNS being relatively susceptible to disrupted copper availability, brain and spinal cord tissue from Slc31a1+/- mice contained significantly less copper than wild-type littermates, even though copper levels in other tissues were unaffected. Slc31a1+/- mice had less spinal cord \u03b1-motor neurons compared to wild-type littermates, but they did not develop any overt physical signs of motor impairment. By contrast, ALS model SOD1G37R mice had fewer \u03b1-motor neurons than control mice and exhibited clear signs of motor function impairment. With the expression of Slc31a1 notwithstanding, spinal cord expression of genes related to copper handling revealed only minor differences between Slc31a1+/- and wild-type mice. This contrasted with SOD1G37R mice where changes in the expression of copper handling genes were pronounced. Similarly, the expression of genes related to toxic glial activation was unchanged in spinal cords from Slc31a1+/- mice but highly upregulated in SOD1G37R mice. Together, results from the Slc31a1+/- mice and SOD1G37R mice indicate that although depleted CNS copper has a significant impact on spinal cord motor neuron numbers, the manifestation of overt ALS-like motor impairment requires additional factors.\n\nID: 39225106\nTitle: Amyotrophic Lateral Sclerosis and swim training affect copper metabolism in skeletal muscle in a mouse model of disease.\nAbstract: Swim training and regulation of copper metabolism result in clinical benefits in amyotrophic lateral sclerosis (ALS) mice. Therefore, the study aimed to determine whether swim training improves copper metabolism by modifying copper metabolism in the skeletal muscles of ALS mice. SOD1G93A mice (n\u2009=\u20096 per group) were used as the ALS model, and wild-type B6SJL (WT) mice as controls (n\u2009=\u20096). Mice with ALS were analyzed before the onset of ALS (ALS BEFORE), at baseline ALS (first disease symptoms, trained and untrained, ALS ONSET), and at the end of ALS (last stage disease, trained and untrained, ALS TERMINAL). Copper concentrations and the level of copper metabolism proteins in the skeletal muscles of the lower leg were determined. ALS disease caused a reduction in the copper concentration in ALS TERMINAL untrained mice compared with the ALS BEFORE (10.43\u2009\u00b1\u20091.81 and 38.67\u2009\u00b1\u200911.50\u2009\u03bcg/mg, respectively, p\u2009=\u2009.0213). The copper chaperon for SOD1 protein, which supplies copper to SOD1, and ATPase7a protein (copper exporter), increased at the terminal stage of disease by 57% (p\u2009=\u2009.0021) and 34% (p\u2009=\u2009.0372), while the CTR1 protein (copper importer) decreased by 45% (p\u2009=\u2009.002). Swim training moderately affected the copper concentration and the concentrations of proteins responsible for copper metabolism in skeletal muscles. The results show disturbances in skeletal muscle copper metabolism associated with ALS progression, which is moderately affected by swim training. From a clinical point of view, exercise in water for ALS patients should be an essential element of rehabilitation for maintaining quality of life.\n\nID: 39117623\nTitle: Mass spectrometry imaging of SOD1 protein-metal complexes in SOD1G93A transgenic mice implicates demetalation with pathology.\nAbstract: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the central nervous system (CNS). Mutations in the metalloenzyme SOD1 are associated with inherited forms of ALS and cause a toxic gain of function thought to be mediated by dimer destabilization and misfolding. SOD1 binds two Cu and two Zn ions in its homodimeric form. We have applied native ambient mass spectrometry imaging to visualize the spatial distributions of intact metal-bound SOD1G93A complexes in SOD1G93A transgenic mouse spinal cord and brain sections and evaluated them against disease pathology. The molecular specificity of our approach reveals that metal-deficient SOD1G93A species are abundant in CNS structures correlating with ALS pathology whereas fully metalated SOD1G93A species are homogenously distributed. Monomer abundance did not correlate with pathology. We also show that the dimer-destabilizing post-translational modification, glutathionylation, has limited influence on the spatial distribution of SOD1 dimers.\n\nID: 39050823\nTitle: Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.\nAbstract: The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.\n\nID: 38922402\nTitle: [Graves' orbitopathy as the cause of diplopia in old age-Differences between young and old].\nAbstract: Endocrine orbitopathy (EO) is an autoimmune disease mostly associated with a disease of the thyroid gland, which leads to inflammation, adipogenesis and fibrosis. The severity of EO can vary greatly between individuals, which makes it difficult to exactly predict the natural course of the disease; however, this is important to be able to individually adapt the treatment. The aim of this study was to compare the clinical features, course, treatment and prognosis for patients with EO under 50 years old with older patients. The results of the study with a focus on motility are presented in this special issue. The hospital records of a randomly selected sample of 1000 patients from the EO databank in Essen (GODE), which includes 4260 patients, were analyzed. The patients were divided into two groups: group 1 \u226450 years and group 2 >50 years. Only patients with complete data sets were included in the statistical analyses. Younger patients (n\u202f=\u2009484) presented significantly more frequently with milder EO (53% vs. 33%, p\u202f<\u20090.0001), whereas older patients (n\u202f=\u2009448) more frequently suffered from moderate or severe forms (44% vs. 64%, p\u202f<\u20090.0001). Older patients showed more severe strabismus, motility and clinical activity scores (5.9 vs. 2.3 prism diopters, PD/310\u00b0 vs. 330\u00b0, both p\u202f<\u20090.0001, CAS 2.1 vs. 1.7, p\u202f=\u20090.001). Proptosis and the occurrence of optic nerve compression showed no significant differences between the groups (3% each). Multiple logistic regression showed that the necessity for a second eye muscle surgery was most strongly associated with a previous decompression (OR\u202f=\u20090.12, 95\u202f% CI 0.1-0.2, p\u202f<\u20090.0001), followed by orbital irradiation and age. In summary, younger patients with EO presented with milder clinical features, such as a lower rate of restrictive motility disorders and weaker expression of signs of inflammation. Therefore, older patients needed steroids, irradiation, eyelid and eye muscle surgery more frequently; however, the risk of dysthyroid optic neuropathy and the necessity of a second eye surgery were not or only slightly associated with age. HINTERGRUND: Die endokrine Orbitopathie (EO) ist eine Autoimmunerkrankung, meist mit einer Schilddr\u00fcsenerkrankung assoziiert, die zu Entz\u00fcndungen, Adipogenese und Fibrose f\u00fchrt. Die Schwere der EO kann zwischen Individuen stark variieren, was es schwierig macht, den nat\u00fcrlichen Verlauf der Erkrankung genau vorherzusagen. Dies ist jedoch wichtig, um die Behandlung individuell anpassen zu k\u00f6nnen. Ziel dieser Studie war es, die klinischen Merkmale, den Verlauf, die Behandlung und die Prognose von EO-Patienten unter 50\u00a0Jahren mit \u00e4lteren Patienten zu vergleichen. F\u00fcr dieses Sonderheft wurden dabei die Ergebnisse der Arbeit mit Schwerpunkt auf die Motilit\u00e4t reproduziert. Analysiert wurden die Krankenakten einer zuf\u00e4llig ausgew\u00e4hlten Stichprobe von 1000 Patienten aus unserer EO-Datenbank in Essen (GODE), die 4260 Patienten umfasst. Die Patienten wurden in 2\u00a0Gruppen unterteilt: Gruppe\u00a01 (\u2264\u202f50\u00a0Jahre) und Gruppe\u00a02 (>\u202f50\u00a0Jahre). Nur Patienten mit vollst\u00e4ndigen Datens\u00e4tzen wurden in die weitere statistische Analyse einbezogen. J\u00fcngere Patienten (n\u202f=\u2009484) waren signifikant h\u00e4ufiger mit milder EO (53\u202f% vs. 33\u202f%, p\u202f<\u20090,0001) vorstellig, w\u00e4hrend \u00e4ltere Patienten (n\u202f=\u2009448) h\u00e4ufiger an moderaten bis schweren Formen litten (44\u202f% vs. 64\u202f%, p\u202f<\u20090,0001). \u00c4ltere Patienten zeigten schwerwiegendere Strabismus\u2011, Motilit\u00e4ts- und klinische Aktivit\u00e4tsscores (5,9 vs. 2,3 PD/310\u00b0 vs. 330\u00b0, beide p\u202f<\u20090,0001, CAS: 2,1 vs. 1,7, p\u202f=\u20090,001). Proptosis und das Auftreten einer Optikuskompression zeigten keinen signifikanten Unterschied zwischen den Gruppen (jeweils 3\u202f%). Die multiple logistische Regression ergab, dass der Bedarf an einer zweiten Augenmuskeloperation am st\u00e4rksten mit einer vorherigen Dekompression assoziiert war (OR\u202f=\u20090,12, 95\u202f% CI: 0,1\u20130,2, p\u202f<\u20090,0001), gefolgt von orbitaler Bestrahlung und Alter. Zusammenfassend pr\u00e4sentieren sich j\u00fcngere EO-Patienten mit milderen klinischen Merkmalen wie einer geringeren Rate an restriktiven Motilit\u00e4tsst\u00f6rungen und weniger ausgepr\u00e4gten Entz\u00fcndungszeichen. \u00c4ltere Patienten ben\u00f6tigen daher h\u00e4ufiger Steroide, Bestrahlung sowie Lid- und Augenmuskeloperationen. Das Risiko f\u00fcr eine Optikuskompression und die Notwendigkeit einer zweiten Augenmuskeloperation sind jedoch nicht bzw. nur geringf\u00fcgig mit dem Alter assoziiert.\n\nID: 38891791\nTitle: MS785-MS27 Reactive Misfolded/Non-Native Zn-Deficient SOD1 Species Exhibit Cytotoxicity and Adopt Heterozygous Conformations in Motor Neurons.\nAbstract: Misfolding of superoxide dismutase-1 (SOD1) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) with SOD1 mutations. The development of antibodies specific for misfolded SOD1 deepens our understanding of how the protein participates in ALS pathogenesis. Since the term \"misfolding\" refers to various disordered conformers other than the natively folded one, which misfolded species are recognized by specific antibodies should be determined. Here, we molecularly characterized the recognition by MS785-MS27, an antibody cocktail experimentally confirmed to recognize over 100 ALS-linked SOD1 mutants. Indirect ELISA revealed that the antibody cocktail recognized Zn-deficient wild-type and mutated SOD1 species. It also recognized conformation-disordered wild-type and mutated SOD1 species, such as unfolded and oligomeric forms, but had less affinity for the aggregated form. Antibody-reactive SOD1 exhibited cytotoxicity to a motor neuron cell model, which was blocked by Zn treatment with Zn-deficient SOD1. Immunohistochemistry revealed antibody-reactive SOD1 mainly in spinal motor neurons of SOD1G93A mice throughout the disease course, and the distribution after symptomatic stages differed from that of other misfolded SOD1 species. This suggests that misfolded/non-native SOD1 species exist as heterogeneous populations. In conclusion, MS785-MS27 recognizes various conformation-disordered SOD1 species lacking the Zn ion.\n\nID: 38788796\nTitle: TMEM119-positive microglia were increased in the brains of patients with amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has been reported to be affected by inflammatory cells, such as microglia and macrophages, through the concept of non-cell autonomous neuronal death. Resident microglia in the human brain and monocyte-derived macrophages (MoDM) infiltrating in tissues are difficult to distinguish. Therefore, the effects of microglia and MoDMs in ALS remain poorly understood. This study aimed to investigate the role of resident microglia and MoDMs in the pathogenesis of ALS using postmortem brain and spinal cord samples. The samples used for immunohistochemical analysis included 11 cases of sporadic ALS and 11 age-matched controls. We stained the cells with TMEM119 to detect resident microglia and CCR2 to detect MoDMs. In ALS cases, TMEM119-immunopositive resident microglia were abundant in the motor cortex and subcortical white matter (SWM) of the motor area, whereas CCR2-immunopositive MoDM was similar to control cases. In addition, the mean density of CD68-immunopositive cells in the SWM significantly correlated with the mean density of pTDP-43-positive GCIs. These results suggest that resident microglial activation plays an important role in the cerebral pathogenesis of ALS and may provide novel therapeutic strategies to target excessive activation of resident microglia in ALS.\n\nID: 38617277\nTitle: Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.\nAbstract: Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We found that OPTN C-terminus truncation (OPTN\u2206C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a striking decrease of axonal mitochondria. Surprisingly, we discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Encouragingly, overexpressing OPTN/TRAK1/KIF5B reverses not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes striking ON regeneration. Therefore, in addition to generating new animal models for NTG and ALS, our results establish OPTN as a novel facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.\n\nID: 38593618\nTitle: A dynamic regulatory switch for phase separation of FUS protein: Zinc ions and zinc finger domain.\nAbstract: Zinc is an important trace element in the human body, and its homeostasis is closely related to amyotrophic lateral sclerosis (ALS). Cytoplasmic FUS proteins from patients with ALS aggregate their important pathologic markers. Liquid-liquid phase separation (LLPS) of FUS can lead to its aggregation. However, whether and how zinc homeostasis affects the aggregation of disease-associated FUS proteins in the cytoplasm remains unclear. Here, we found that zinc ion enhances LLPS and promotes the aggregation in the cytoplasm for FUS protein. In the FUS, the cysteine of the zinc finger (ZnF), recognizes and binds to zinc ions, reducing droplet mobility and enhancing protein aggregation in the cytoplasm. The mutation of FUS cysteine disrupts the dynamic regulatory switch of zinc ions and ZnF, resulting in insensitivity to zinc ions. These results suggest that the dynamic regulation of LLPS by binding with zinc ions may be a widespread mechanism and provide a new understanding of neurological diseases such as ALS and other ZnF protein-related diseases.\n\nID: 38511674\nTitle: Engineering a monobody specific to monomeric Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis.\nAbstract: Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) has been implicated in familial form of amyotrophic lateral sclerosis (ALS). A natively folded SOD1 forms a tight homodimer, and the dimer dissociation has been proposed to trigger the oligomerization/aggregation of SOD1. Besides increasing demand for probes allowing the detection of monomerized forms of SOD1 in various applications, the development of probes has been limited to conventional antibodies. Here, we have developed Mb(S4) monobody, a small synthetic binding protein based on the fibronectin type III scaffold, that recognizes a monomeric but not dimeric form of SOD1 by performing combinatorial library selections using phage and yeast-surface display methods. Although Mb(S4) was characterized by its excellent selectivity to the monomeric conformation of SOD1, the monomeric SOD1/Mb(S4) complex was not so stable (apparent Kd\u2009~\u2009\u03bcM) as to be detected in conventional pull-down experiments. Instead, the complex of Mb(S4) with monomeric but not dimeric SOD1 was successfully trapped by proximity-enabled chemical crosslinking even when reacted in the cell lysates. We thus anticipate that Mb(S4) binding followed by chemical crosslinking would be a useful strategy for in vitro and also ex vivo detection of the monomeric SOD1 proteins.\n\nID: 38467696\nTitle: Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS.\nAbstract: The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~\u20092% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.\n\nID: 38234062\nTitle: Resting-state fMRI functional connectome of C9orf72 mutation status.\nAbstract: The resting-state functional connectome has not been extensively investigated in amyotrophic lateral sclerosis (ALS) spectrum disease, in particular in relationship with patients' genetic status. Here we studied the network-to-network connectivity of 19 ALS patients carrying the C9orf72 hexanucleotide repeat expansion (C9orf72+), 19 ALS patients not affected by C9orf72 mutation (C9orf72-), and 19 ALS-mimic patients (ALSm) well-matched for demographic and clinical variables. When compared with ALSm, we observed greater connectivity of the default mode and frontoparietal networks with the visual network for C9orf72+ patients (P\u2009=\u20090.001). Moreover, the whole-connectome showed greater node degree (P\u2009<\u20090.001), while sensorimotor cortices resulted isolated in C9orf72+. Our results suggest a crucial involvement of extra-motor functions in ALS spectrum disease. In particular, alterations of the visual cortex may have a pathogenic role in C9orf72-related ALS. The prominent feature of these patients would be increased visual system connectivity with the networks responsible of the functional balance between internal and external attention.\n\nID: 38037913\nTitle: Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.\nAbstract: Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.\n\nID: 38009843\nTitle: Primary visual cortex pathology in ALS patients with C9ORF72 expansion.\nAbstract: Poly-GA and poly-GP immunofluorescence studies show conspicuous dipeptide repeat pathology in layers IV and II of primary visual cortex in C9ALS patients.\n\nID: 37573553\nTitle: Computational study of the mechanical behavior of the astrocyte network and axonal compartments in the mouse optic nerve head.\nAbstract: Glaucoma is a blinding disease characterized by the degeneration of the retinal ganglion cell (RGC) axons at the optic nerve head (ONH). A major risk factor for glaucoma is the intraocular pressure (IOP). However, it is currently impossible to measure the IOP-induced mechanical response of the axons of the ONH. The objective of this study was to develop a computational modeling method to estimate the IOP-induced strains and stresses in the axonal compartments in the mouse astrocytic lamina (AL) of the ONH, and to investigate the effect of the structural features on the mechanical behavior. We developed experimentally informed finite element (FE) models of six mouse ALs to investigate the effect of structure on the strain responses of the astrocyte network and axonal compartments to pressure elevation. The specimen-specific geometries of the FE models were reconstructed from confocal fluorescent images of cryosections of the mouse AL acquired in a previous study that measured the structural features of the astrocytic processes and axonal compartments. The displacement fields obtained from digital volume correlation in prior inflation tests of the mouse AL were used to determine the displacement boundary conditions of the FE models. We then applied Gaussian process regression to analyze the effects of the structural features on the strain outcomes simulated for the axonal compartments. The axonal compartments experienced, on average, 6 times higher maximum principal strain but 1800 times lower maximum principal stress compared to those experienced by the astrocyte processes. The strains experienced by the axonal compartments were most sensitive to variations in the area of the axonal compartments. Larger axonal compartments that were more vertically aligned, closer to the AL center, and with lower local actin area fraction had higher strains. Understanding the factors affecting the deformation in the axonal compartments will provide insights into mechanisms of glaucomatous axonal damage.\n\nID: 36900043\nTitle: Deep Learning Algorithms for Screening and Diagnosis of Systemic Diseases Based on Ophthalmic Manifestations: A Systematic Review.\nAbstract: Deep learning (DL) is the new high-profile technology in medical artificial intelligence (AI) for building screening and diagnosing algorithms for various diseases. The eye provides a window for observing neurovascular pathophysiological changes. Previous studies have proposed that ocular manifestations indicate systemic conditions, revealing a new route in disease screening and management. There have been multiple DL models developed for identifying systemic diseases based on ocular data. However, the methods and results varied immensely across studies. This systematic review aims to summarize the existing studies and provide an overview of the present and future aspects of DL-based algorithms for screening systemic diseases based on ophthalmic examinations. We performed a thorough search in PubMed\u00ae, Embase, and Web of Science for English-language articles published until August 2022. Among the 2873 articles collected, 62 were included for analysis and quality assessment. The selected studies mainly utilized eye appearance, retinal data, and eye movements as model input and covered a wide range of systemic diseases such as cardiovascular diseases, neurodegenerative diseases, and systemic health features. Despite the decent performance reported, most models lack disease specificity and public generalizability for real-world application. This review concludes the pros and cons and discusses the prospect of implementing AI based on ocular data in real-world clinical scenarios.\n\nID: 36686537\nTitle: Case report: Motor neuron disease phenotype associated with symptomatic copper deficiency: Challenging diagnosis and treatment.\nAbstract: Copper deficiency is an acquired condition that can lead to neurologic dysfunctions, such as myelopathy, motor neuron impairment, polyneuropathy, cognitive impairment, and optic nerve neuropathy. Associated biological findings are low serum copper and ceruloplasmin levels with low copper urinary excretion. We report the case of a previously healthy 59-year-old man who presented a complex neurological picture starting with symptoms and radiological signs consistent with degenerative myelopathy in the presence of persisting low serum copper and ceruloplasmin despite oral and intravenous copper supplementation. Over time, his symptoms evolved into a motor neuron disease evocating an amyotrophic lateral sclerosis (ALS) phenotype. The potential role of copper deficiency is discussed, together with the difficulties in biomonitoring copper supplementation.\n\nID: 36454509\nTitle: Functional characterization of SLC39 family members ZIP5 and ZIP10 in overexpressing HEK293 cells reveals selective copper transport activity.\nAbstract: Zinc is the second most prevalent metal element present in living organisms, and control of its concentration is pivotal to physiology. The amount of zinc available to the cell cytoplasm is regulated by the activity of members of the SLC39 family, the ZIP proteins. Selectivity of ZIP transporters has been the focus of earlier studies which provided a biochemical and structural basis for the selectivity for zinc over other metals such as copper, iron, and manganese. However, several previous studies have shown how certain ZIP proteins exhibit higher selectivity for metal elements other than zinc. Sequence similarities suggest an evolutionary basis for the elemental selectivity within the ZIP family. Here, by engineering HEK293 cells to overexpress ZIP proteins, we have studied the selectivity of two phylogenetic clades of ZIP proteins, that is ZIP8/ZIP14 (previously known to be iron and manganese transporters) and ZIP5/ZIP10. By incubating ZIP over-expressing cells in presence of several divalent metals, we found that ZIP5 and ZIP10 are high affinity copper transporters with greater selectivity over other elements, revealing a novel substrate signature for the ZIP5/ZIP10 clade.\n\nID: 36364128\nTitle: Native Mass Spectrometry Coupled to Spectroscopic Methods to Investigate the Effect of Soybean Isoflavones on Structural Stability and Aggregation of Zinc Deficient and Metal-Free Superoxide Dismutase.\nAbstract: The deficiency or wrong combination of metal ions in Cu, Zn-superoxide dismutase (SOD1), is regarded as one of the main factors causing the aggregation of SOD1 and then inducing amyotrophic lateral sclerosis (ALS). A ligands-targets screening process based on native electrospray ionization ion mobility mass spectrometry (ESI-IMS-MS) was established in this study. Four glycosides including daidzin, sophoricoside, glycitin, and genistin were screened out from seven soybean isoflavone compounds and were found to interact with zinc-deficient or metal-free SOD1. The structure and conformation stability of metal-free and zinc-deficient SOD1 and their complexes with the four glycosides was investigated by collision-induced dissociation (CID) and collision-induced unfolding (CIU). The four glycosides could strongly bind to the metal-free and copper recombined SOD1 and enhance the folding stability of these proteins. Additionally, the ThT fluorescence assay showed that these glycosides could inhibit the toxic aggregation of the zinc-deficient or metal-free SOD1. The competitive interaction experiments together with molecular docking indicate that glycitin, which showed the best stabilizing effects, binds with SOD1 between \u03b2-sheet 6 and loop IV. In short, this study provides good insight into the relationship between inhibitors and different SOD1s.\n\nID: 36224351\nTitle: Structural analysis of the overoxidized Cu/Zn-superoxide dismutase in ROS-induced ALS filament formation.\nAbstract: Eukaryotic Cu, Zn-superoxide dismutase (SOD1) is primarily responsible for cytotoxic filament formation in amyotrophic lateral sclerosis (ALS) neurons. Two cysteine residues in SOD1 form an intramolecular disulfide bond. This study aims to explore the molecular mechanism of SOD1 filament formation by cysteine overoxidation in sporadic ALS (sALS). In this study, we determined the crystal structure of the double mutant (C57D/C146D) SOD1 that mimics the overoxidation of the disulfide-forming cysteine residues. The structure revealed the open and relaxed conformation of loop IV containing the mutated Asp57. The double mutant SOD1 produced more contagious filaments than wild-type protein, promoting filament formation of the wild-type SOD1 proteins. Importantly, we further found that HOCl treatment to the wild-type SOD1 proteins facilitated their filament formation. We propose a feasible mechanism for SOD1 filament formation in ALS from the wild-type SOD1, suggesting that overoxidized SOD1 is a triggering factor of sALS. Our findings extend our understanding of other neurodegenerative disorders associated with ROS stresses at the molecular level.\n\nID: 36168806\nTitle: Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates in primary neurons.\nAbstract: Splicing factor proline- and glutamine-rich (SFPQ) is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating centre (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a second zinc-binding site revealed by the 1.83 \u00c5 crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.\n\nID: 35900338\nTitle: Cells Overexpressing ALS-Associated SOD1 Variants Are Differentially Susceptible to CuATSM-Associated Toxicity.\nAbstract: CuATSM has repeatedly demonstrated to be therapeutically effective in SOD1 mouse models of amyotrophic lateral sclerosis (ALS), leading to current clinical trials. CuATSM acts to stabilize ALS-associated mutant SOD1 protein by supplying copper. However, in vitro work has demonstrated that CuATSM is only therapeutic for wild-type-like SOD1 mutants, not metal-binding-region mutants, suggesting that CuATSM may have genotype-specific effects. Furthermore, relatively high doses of CuATSM have been shown to produce adverse events in humans and mice. Here, we investigated the genotype-specific therapeutic window of CuATSM. NSC-34 cells transiently expressing copper-binding or non-binding mutations of SOD1 were treated with a broad range of CuATSM concentrations and examined for survival via time-lapse microscopy. Determination of the no-observed-adverse-effect level and the LC50 suggest that CuATSM-associated toxicity is dependent on the amount of copper-depleted SOD1 available as well as the mutant's ability to bind copper. Our results suggest that the particular variant of SOD1 mutant is crucial in not only determining the level of efficacy achieved but also potential adverse events.\n\nID: 35844238\nTitle: A Strength Endurance Exercise Paradigm Mitigates Deficits in Hypoglossal-Tongue Axis Function, Strength, and Structure in a Rodent Model of Hypoglossal Motor Neuron Degeneration.\nAbstract: The tongue plays a crucial role in the swallowing process, and impairment can lead to dysphagia, particularly in motor neuron diseases (MNDs) resulting in hypoglossal-tongue axis degeneration (e.g., amyotrophic lateral sclerosis and progressive bulbar palsy). This study utilized our previously established inducible rodent model of dysphagia due to targeted degeneration of the hypoglossal-tongue axis. This model was created by injecting cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue base for retrograde transport to the hypoglossal (XII) nucleus via the hypoglossal nerve, which provides the sole motor control of the tongue. Our goal was to investigate the effect of high-repetition/low-resistance tongue exercise on tongue function, strength, and structure in four groups of male rats: (1) control + sham exercise (n = 13); (2) control + exercise (n = 10); (3) CTB-SAP + sham exercise (n = 13); and (4) CTB-SAP + exercise (n = 12). For each group, a custom spout with adjustable lick force requirement for fluid access was placed in the home cage overnight on days 4 and 6 post-tongue injection. For the two sham exercise groups, the lick force requirement was negligible. For the two exercise groups, the lick force requirement was set to \u223c40% greater than the maximum voluntary lick force for individual rats. Following exercise exposure, we evaluated the effect on hypoglossal-tongue axis function (via videofluoroscopy), strength (via force-lickometer), and structure [via Magnetic Resonance Imaging (MRI) of the brainstem and tongue in a subset of rats]. Results showed that sham-exercised CTB-SAP rats had significant deficits in lick rate, swallow timing, and lick force. In exercised CTB-SAP rats, lick rate and lick force were preserved; however, swallow timing deficits persisted. MRI revealed corresponding degenerative changes in the hypoglossal-tongue axis that were mitigated by tongue exercise. These collective findings suggest that high-repetition/low-resistance tongue exercise in our model is a safe and effective treatment to prevent/diminish signs of hypoglossal-tongue axis degeneration. The next step is to leverage our rat model to optimize exercise dosing parameters and investigate corresponding treatment mechanisms of action for future translation to MND clinical trials.\n\nID: 35657595\nTitle: Determining Copper and Zinc Content in Superoxide Dismutase Using Electron Capture Dissociation Under Native Spray Conditions.\nAbstract: Localizing metal binding to specific sites in proteins remains a challenging analytical problem in vitro and in vivo. Although metal binding can be maintained by \"native\" electrospray ionization with intact proteins for quantitation by mass spectrometry, subsequent fragmentation of proteins with slow-heating methods like collision-induced dissociation (CID) can scramble and detach metals. In contrast, electron capture dissociation (ECD) fragmentation produces highly localized bond cleavage that is well known to preserve posttranslational modifications. We show how a newly available ECD tool that can be retrofitted on standard QTOF mass spectrometers allows the sites of copper and zinc binding to be localized in the antioxidant enzyme Cu, Zn superoxide dismutase (SOD1). The loss of zinc from Cu, Zn SOD1 has been shown to induce motor neuron death and could have a causal role in the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The methods described enable copper loss to be distinguished from zinc using distinct ECD fragments of SOD1 and are broadly applicable to other metalloproteins.\n\nID: 35630637\nTitle: Evaluation of Zn2+- and Cu2+-Binding Affinities of Native Cu,Zn-SOD1 and Its G93A Mutant by LC-ICP MS.\nAbstract: The tight binding of Cu and Zn ions to superoxide dismutase 1 (SOD1) maintains the protein stability, associated with amyotrophic lateral sclerosis (ALS). Yet, the quantitative studies remain to be explored for the metal-binding affinity of wild-type SOD1 and its mutants. We have investigated the demetallation of Cu,Zn-SOD1 and its ALS-related G93A mutant in the presence of different standard metal ion chelators at varying temperatures by using an LC-ICP MS-based approach and fast size-exclusion chromatography. Our results showed that from the slow first-order kinetics both metal ions Zn2+ and Cu2+ were released simultaneously from the protein at elevated temperatures. The rate of the release depends on the concentration of chelating ligands but is almost independent of their metal-binding affinities. Similar studies with the G93A mutant of Cu,Zn-SOD1 revealed slightly faster metal-release. The demetallation of Cu,Zn-SOD1 comes always to completion, which hindered the calculation of the KD values. From the Arrhenius plots of the demetallation in the absence of chelators \u0394H\u2021 = 173 kJ/mol for wt and 191 kJ/mol for G93A mutant Cu,Zn-SOD1 was estimated. Obtained high \u0394H values are indicative of the occurrence of protein conformational changes before demetallation and we concluded that Cu,Zn-SOD1 complex is in native conditions kinetically inert. The fibrillization of both forms of SOD1 was similar.\n\nID: 35472603\nTitle: Neuro-ophthalmological manifestations of Wolfram syndrome: Case series and review of the literature.\nAbstract: Wolfram Syndrome (WS) is a rare progressive hereditary neurodegenerative disease with hallmark features of diabetes mellitus, optic atrophy, and hearing loss. Its other clinical manifestations may include diabetes insipidus, urological, neurological, and psychiatric abnormalities. We review systemic and ocular manifestations of WS as well as its pathophysiology, diagnostic approach, and treatment options. We then describe a case series of 5 patients (ages 15-38, 60% male) with WS. All had significant progressive visual loss. 3/5 patients had type 1 DM and 4/5 had hearing loss. Other neuro-ophthalmological findings included convergence impairment and end-gaze nystagmus. This case series highlights the variability in clinical presentations of patients with WS, reminding clinicians to maintain high suspicion for this diagnosis in order to allow for prompt diagnosis and genetic counselling for patients and their families.\n\nID: 35352678\nTitle: Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy.\nAbstract: Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: (1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. (2) Even with possible access for 'local refrigeration', cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4 \u00b0C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas. Hypothermic therapy is a radical type of treatment that involves cooling a person\u2019s core body temperature several degrees below normal to protect against brain damage. Lowering body temperature slows blood flow, which reduces inflammation, and eases metabolic demands, similar to hibernation. It can also reduce lasting damage to the brain and aid recovery when used to treat people who have gone into cardiac arrest, where their heart suddenly stops beating. Recently, there has been renewed interest in using hypothermic therapy to treat people who have sustained traumatic brain injuries, which can cause brain swelling, and other nerve injuries. However, its use remains controversial because clinical trials have failed to show that inducing mild hypothermia provides any benefit for people with severe nerve injuries. This might be because cooling cells to near-freezing temperatures can damage their internal structural supports, called microtubules, thwarting any therapeutic benefit. Traumatic optical neuropathy is a type of injury in which the optic nerve \u2013 the nerve that connects the eyes to the brain \u2013 is damaged or severed, causing vision loss. There is currently no clinically proven treatment for this condition, nor is there a system that can test local treatments in large animals as a prior test to using the treatment in the clinic. Therefore, Zhang et al. wanted to establish such a animal model and test whether local hypothermic therapy could help protect the optic nerve. Zhang et al. used a surgical tool guided by an endoscope (a thin plastic tube with a light and camera attached to it) to injure the optic nerves of goats, and then deliver hypothermic therapy. To cool the surgically-injured nerves to a chilly 4C, Zhang et al. applied a deep-cooling agent, using a second reagent (a cocktail of protease inhibitors) to protect the cells\u2019 microtubules from cold-induced damage, an insight gained from a previous study of hibernating animals. This was critical, as the hypothermic therapy was only effective when the secondary protective agent was applied. The combination therapy developed by Zhang et al. relieved some aspects of nerve degeneration at the injury site and activated an anti-inflammatory response in cells, but did not restore vision. To simplify surgical techniques, Zhang et al. also developed a computer program which generates virtual surgical paths for up-the-nose endoscopic procedures based on brain scans of an animal\u2019s skull. This program was successfully applied in a range of large animals, including goats and macaque monkeys. Zhang et al.\u2019s work establishes a method to study treatments for traumatic optical neuropathy using large animals, including hypothermic therapy. The methods developed could also be useful to study other optic nerve disorders, such as optic neuritis or ischemic optic neuropathy.\n\nID: 35320105\nTitle: Review: Emerging Eye-Based Diagnostic Technologies for Traumatic Brain Injury.\nAbstract: The study of ocular manifestations of neurodegenerative disorders, Oculomics, is a growing field of investigation for early diagnostics, enabling structural and chemical biomarkers to be monitored overtime to predict prognosis. Traumatic brain injury (TBI) triggers a cascade of events harmful to the brain, which can lead to neurodegeneration. TBI, termed the \"silent epidemic\" is becoming a leading cause of death and disability worldwide. There is currently no effective diagnostic tool for TBI, and yet, early-intervention is known to considerably shorten hospital stays, improve outcomes, fasten neurological recovery and lower mortality rates, highlighting the unmet need for techniques capable of rapid and accurate point-of-care diagnostics, implemented in the earliest stages. This review focuses on the latest advances in the main neuropathophysiological responses and the achievements and shortfalls of TBI diagnostic methods. Validated and emerging TBI-indicative biomarkers are outlined and linked to ocular neuro-disorders. Methods detecting structural and chemical ocular responses to TBI are categorised along with prospective chemical and physical sensing techniques. Particular attention is drawn to the potential of Raman spectroscopy as a non-invasive sensing of neurological molecular signatures in the ocular projections of the brain, laying the platform for the first tangible path towards alternative point-of-care diagnostic technologies for TBI.\n\n\n\nID: 35065969\nTitle: A copper chaperone-mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons progressively and rapidly degenerate, eventually leading to death. The first protein found to contain ALS-associated mutations was copper/zinc superoxide dismutase 1 (SOD1), which is conformationally stable when it contains its metal ligands and has formed its native intramolecular disulfide. Mutations in SOD1 reduce protein folding stability via disruption of metal binding and/or disulfide formation, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS; however, the results have been mixed. Here, we utilize a small-molecule polytherapy of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuATSM) and ebselen to mimic the metal delivery and disulfide bond promoting activity of the cellular chaperone of SOD1, the \"copper chaperone for SOD1.\" Using microscopy with automated image analysis, we find that polytherapy using CuATSM and ebselen is highly effective and acts in synergy to reduce inclusion formation in a cell model of SOD1 aggregation for multiple ALS-associated mutants. Polytherapy reduces mutant SOD1-associated cell death, as measured by live-cell microscopy. Measuring dismutase activity via zymography and immunoblotting for disulfide formation showed that polytherapy promoted more effective maturation of transfected SOD1 variants beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may merit more study as an effective method of treating SOD1-associated ALS.\n\nID: 34785624\nTitle: Is pseudoexfoliation glaucoma a neurodegenerative disorder?\nAbstract: Pseudoexfoliation (PEX) is a systemic age-related progressive disorder with ocular manifestations. The earlier stage of the disease, pseudoexfoliation syndrome (PEXS) involves deposition of white fibrillar aggregates on anterior and posterior eye tissues. It is also the cause of most common form of secondary glaucoma known as pseudoexfoliation glaucoma (PEXG). Studies in the past decade highlight the role of many genetic and environmental factors as the underlying cause of PEX pathogenesis. Latest research findings by various researchers and us present the view of PEX as a type of neurodegenerative disorder. Epidemiological studies have shown association of PEX with different forms of neurodegenerative diseases like Alzheimer's, agerelated macular degeneration and open angle glaucoma. Also, sharing of common genetic risk factors, abnormal protein aggregation and most importantly, progressive degeneration of neurons with age are some of the identifiable features seen in both PEX and other neurodegenerative diseases. In this review, we have compared the pathological symptoms and factors involved in the disease manifestation of PEXG with various forms of neurodegenerative disorders and categorized PEXG as a progressive neurodegenerative disorder.\n\nID: 34779338\nTitle: Impact of Alzheimer's Disease in Ocular Motility and Visual Perception: A Narrative Review.\nAbstract: Alzheimer's disease (AD) is a neurodegenerative disease generating a progressive neuronal loss as well as cognitive deficiencies. This disease can be accompanied by ocular manifestations, including alterations in ocular motility and visual perception. The aim of the current review article was to collect all the information about these alterations and to analyze if there is scientific evidence supporting the potential use of these changes as biomarkers of the disease. A bibliographic search was performed using two different databases, Pubmed and Google Scholar, as well as a search of material in non-peer reviewed journals about Alzheimer's and Neurology. A total of 227 articles were found in the initial search, but only 76 were included considering their relevance according to the purpose of the reviewResults: This narrative review describes the findings obtained in this area to this date, confirming that deficiencies in saccades is the most common condition among AD patients. Furthermore, other visual alterations have also been reported in these patients, including a compromise of visual acuity and contrast sensitivity, fluctuations of colour vision, stereopsis impairment and visual field losses. Likewise, other complex visuo-spatial and visuo-perceptual impairments can be present. More studies are still needed to understand better what type of changes occurs in ocular alignment, binocularity, and fixation pattern in AD patients. AD is associated to visual perception and ocular motility alterations. All the scientific information found in this review should be considered as a guide for designing future studies and to define adequate clinical protocols for the visual evaluation of patients with AD, considering the cognitive limitations that are normally present in this type of patients.\n\nID: 34660270\nTitle: Metal-Regulatory Transcription Factor-1 Targeted by miR-148a-3p Is Implicated in Human Hepatocellular Carcinoma Progression.\nAbstract: Metal-regulatory transcription factor-1 (MTF-1) is of importance in maintaining metal homeostasis. Copper exposure considerably stimulates the proliferation of hepatocellular carcinoma (HCC) cells with enhanced MTF-1 expression. However, the underlying molecular mechanisms have not been completely elucidated. In this study, we utilized different approaches to investigate the potential role of MTF-1 involved in HCC progression. The expression levels of MTF-1 and miR-148a-3p were determined using real-time polymerase chain reaction (PCR), Western blotting, and immunohistochemistry. The interaction of MTF-1 with apurinic apyrimidinic endonuclease/redox effector factor 1 (APE/Ref-1) or miR-148a-3p was determined using immunoprecipitation or dual-luciferase reporter assay, respectively. Cell viability and metastatic ability were evaluated using colony formation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound scratch, and Transwell assays, and apoptotic cells were detected by flow cytometry. The biological functions of MTF-1 and miR-148a-3p were also determined using a xenograft mouse model. MTF-1 expression was upregulated in HCC cells and was associated with poor survival and recurrence. MTF-1 overexpression enhanced the proliferation and metastatic potential of HCC cells. Further mechanistic analyses demonstrated that MTF-1 bound to APE/Ref-1 and that MTF-1 is a direct target of miR-148-3p, which inversely regulated MTF-1 transcription activity. MiR-148a-3p overexpression effectively inhibited HCC cell proliferation and metastasis stimulated by MTF-1, with increased apoptosis. There was a decrease in miR-148a-3p expression in exosomes isolated from the plasma of patients with HCC and HCC cell culture supernatants. Co-incubation of HCC cells with exosomes from hepatocyte-conditioned media inhibited cell migration and caused apoptosis. The in vivo study revealed slow growth of MTF-1-knockdown and miR-148a-3p-overexpressing Hep3B-derived xenografts, with reduced tumor volume and weight compared with the control group. Collectively, these findings implicate MTF-1 as a modulator of HCC tumorigenesis and progression. Selective targeting towards exosomal miR-148a-3p, which might contribute to the negative regulation of MTF-1 at least partially in HCC, demonstrates therapeutic benefits for patients with HCC.\n\nID: 34511130\nTitle: Disruption of the white matter structural network and its correlation with baseline progression rate in patients with sporadic amyotrophic lateral sclerosis.\nAbstract: There is increasing evidence that amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting large-scale brain networks. However, it is still unclear which structural networks are associated with the disease and whether the network connectomics are associated with disease progression. This study was aimed to characterize the network abnormalities in ALS and to identify the network-based biomarkers that predict the ALS baseline progression rate. Magnetic resonance imaging was performed on 73 patients with sporadic ALS and 100 healthy participants to acquire diffusion-weighted magnetic resonance images and construct white matter (WM) networks using tractography methods. The global and regional network properties were compared between ALS and healthy subjects. The single-subject WM network matrices of patients were used to predict the ALS baseline progression rate using machine learning algorithms. Compared with the healthy participants, the patients with ALS showed significantly decreased clustering coefficient Cp (P\u2009=\u20090.0034, t\u2009=\u20092.98), normalized clustering coefficient \u03b3 (P\u2009=\u20090.039, t\u2009=\u20092.08), and small-worldness \u03c3 (P\u2009=\u20090.038, t\u2009=\u20092.10) at the global network level. The patients also showed decreased regional centralities in motor and non-motor systems including the frontal, temporal and subcortical regions. Using the single-subject structural connection matrix, our classification model could distinguish patients with fast versus slow progression rate with an average accuracy of 85%. Disruption of the WM structural networks in ALS is indicated by weaker small-worldness and disturbances in regions outside of the motor systems, extending the classical pathophysiological understanding of ALS as a motor disorder. The individual WM structural network matrices of ALS patients are potential neuroimaging biomarkers for the baseline disease progression in clinical practice.\n\nID: 34502369\nTitle: Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer's Disease.\nAbstract: The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer's disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased A\u03b2 generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-A\u03b2 cross-linking and up-regulation of RAGE expression. Moreover, A\u03b2 glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and A\u03b2, as well as inhibiting AGE accumulation and metal-induced neurotoxicity.\n\nID: 34494975\nTitle: Ophthalmic manifestations of dementing disorders.\nAbstract: Dementia is a term for loss of memory, language, problem-solving, and other thinking abilities, which significantly interferes with daily life. Certain dementing conditions may also affect visual function. The eye is an accessible window to the brain that can provide valuable information for the early diagnosis of people who suffer from Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies as well as from more rare causes of dementias, such as Creutzfeldt-Jacob and Huntington's diseases. Herein, we present the ocular manifestations of neurocognitive disorders focusing on the neuro-ophthalmic ones and further discuss potential ocular biomarkers that could help in early detection of these disorders. Ophthalmic examination along with the recent developments in in-vivo testing have provided a strong foundation of useful knowledge about brain disorder in neurodegenerative diseases without the need for invasive studies. Currently, a number of visual measures, such as visual acuity, contrast sensitivity, pupil response, and saccades in addition to various ophthalmic tests, such as electroretinogram, visual evoked potential, optical coherence tomography (OCT), and OCT-angiography have been widely used and evaluated as potential biomarkers for different stages of dementia. Ophthalmologic and neuro-ophthalmic evaluation is evolving as an important part of the early diagnosis and management of people with dementia. A particular focus on ocular biomarkers in dementing illnesses has arisen over the past few years and there are several promising measures and imaging tools that have been proposed as potential biomarkers for these diseases.\n\nID: 34171378\nTitle: Emerging role of tumor microenvironment derived exosomes in therapeutic resistance and metastasis through epithelial-to-mesenchymal transition.\nAbstract: The tumor microenvironment (TME) constitutes multiple cell types including cancerous and non-cancerous cells. The intercellular communication between these cells through TME derived exosomes may either enhance or suppress the tumorigenic processes. The tumor-derived exosomes could convert an anti-tumor environment into a pro-tumor environment by inducing the differentiation of stromal cells into tumor-associated cells. The exosomes from tumor-associated stromal cells reciprocally trigger epithelial-to-mesenchymal transition (EMT) in tumor cells, which impose therapeutic resistance and metastasis. It is well known that these exosomes contain the signals of EMT, but how these signals execute chemoresistance and metastasis in tumors remains elusive. Understanding the significance and molecular signatures of exosomes transmitting EMT signals would aid in developing appropriate methods of inhibiting them. In this review, we focus on molecular signatures of exosomes that shuttle between cancer cells and their stromal populations in TME to explicate their impact on therapeutic resistance and metastasis through EMT. Especially Wnt signaling is found to be involved in multiple ways of exosomal transport and hence we decipher the biomolecules of Wnt signaling trafficked through exosomes and their potential in serving as therapeutic targets.\n\nID: 34106804\nTitle: Ocular Manifestations of Neuronal Ceroid Lipofuscinoses.\nAbstract: Neuronal ceroid lipofuscinoses (NCLs) are a group of rare neurodegenerative storage disorders associated with devastating visual prognosis, with an incidence of 1/1,000,000 in the United States and comparatively higher incidence in European countries. The pathophysiological mechanisms causing NCLs occur due to enzymatic or transmembrane defects in various sub-cellular organelles including lysosomes, endoplasmic reticulum, and cytoplasmic vesicles. NCLs are categorized into different types depending upon the underlying cause i.e., soluble lysosomal enzyme deficiencies or non-enzymatic deficiencies (functions of identified proteins), which are sub-divided based on an axial classification system. In this review, we have\u00a0evaluated the current evidence in the literature and reported the incidence rates, underlying mechanisms and currently available management protocols for these rare set of neuroophthalmological disorders. Additionally, we also highlighted the potential therapies under development that can expand the treatment of these rare disorders beyond symptomatic relief.\n\nID: 34076319\nTitle: Free energy calculations of ALS-causing SOD1 mutants reveal common perturbations to stability and dynamics along the maturation pathway.\nAbstract: With over 150 heritable mutations identified as disease-causative, superoxide dismutase 1 (SOD1) has been a main target of amyotrophic lateral sclerosis (ALS) research and therapeutic efforts. However, recent evidence has suggested that neither loss of function nor protein aggregation is responsible for promoting neurotoxicity. Furthermore, there is no clear pattern to the nature or the location of these mutations that could suggest a molecular mechanism behind SOD1-linked ALS. Here, we utilize reliable and accurate computational techniques to predict the perturbations of 10 such mutations to the free energy changes of SOD1 as it matures from apo monomer to metallated dimer. We find that the free energy perturbations caused by these mutations strongly depend on maturational progress, indicating the need for state-specific therapeutic targeting. We also find that many mutations exhibit similar patterns of perturbation to native and non-native maturation, indicating strong thermodynamic coupling between the dynamics at various sites of maturation within SOD1. These results suggest the presence of an allosteric network in SOD1 which is vulnerable to disruption by these mutations. Analysis of these perturbations may contribute to uncovering a unifying molecular mechanism which explains SOD1-linked ALS and help to guide future therapeutic efforts.\n\nID: 34014900\nTitle: ASYMPTOMATIC OCULAR MANIFESTATIONS OF ACERULOPLASMINEMIA IN TWO ADULT WHITE SIBLINGS: A MULTIMODAL IMAGING APPROACH.\nAbstract: To report ocular manifestations of aceruloplasminemia in two adult White siblings. The ocular findings were investigated using a multimodal imaging approach including color fundus photography, fluorescein angiography, autofluorescence imaging, and spectral-domain optical coherence tomography. A 43-year-old woman and a 39-year-old man were diagnosed with aceruloplasminemia based on clinical symptoms, laboratory tests, liver biopsy, and genetic examination of the ceruloplasmin gene confirming the homozygotic mutation G708S. Both patients had no ophthalmologic symptoms, unremarkable anterior segment, and visual acuity of 20/20 in both eyes. Indirect ophthalmoscopy of the fundus revealed subtle yellowish color with punctate inhomogeneous pigmentation in the whole retina. The autofluorescence images demonstrated remarkable punctate hyperfluorescence involving the central and peripheral retina. Spectral-domain optical coherence tomography images showed normal retinal structure in the macular area with intact outer retinal layers. Fluorescein angiography showed a slightly inhomogeneous pattern of hypofluorescence and hyperfluorescence from the early until late angiography phase. We describe two adult cases of ocular manifestations of a rare hereditary condition with systemic iron overload. Retinal degeneration in aceruloplasminemia might be overlooked on a routine ophthalmic examination and requires at least an autofluorescence image because initial damage at the level of retinal pigment epithelium is not always visible on ophthalmoscopy.\n\nID: 33825682\nTitle: The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model.\nAbstract: Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, amyotrophic lateral sclerosis (ALS). Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid-induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a 'co-factor derived membrane association model' wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association-mediated toxic aggregation and survival time scale after ALS diagnosis. Amyotrophic lateral sclerosis, or ALS, is an incurable neurodegenerative disease in which a person slowly loses specialized nerve cells that control voluntary movement. It is not fully understood what causes this fatal disease. However, it is suspected that clumps, or aggregates, of a protein called SOD1 in nerve cells may play a crucial role. More than 140 mutations in the gene for SOD1 have been linked to ALS, with varying degrees of severity. But it is still unclear how these mutations cause SOD1 aggregation or how different mutations influence the survival rate of the disease. The protein SOD1 contains a copper ion and a zinc ion, and it is possible that mutations that affect how these two ions bind to SOD1 influences the severity of the disease. To investigate this, Sannigrahi, Chowdhury, Das et al. genetically engineered mutants of the SOD1 protein which each contain only one metal ion. Experiments on these mutated proteins showed that the copper ion is responsible for the protein\u2019s role in neutralizing harmful reactive molecules, while the zinc ion stabilizes the protein against aggregation. Sannigrahi et al. found that when the zinc ion was removed, the SOD1 protein attached to a structure inside the cell called the mitochondria and formed toxic aggregates. Sannigrahi et al. then used these observations to build a computational model that incorporated different mutations that have been previously associated with ALS. The model suggests that mutations close to the site where zinc binds to the SOD1 protein increase disease severity and shorten survival time after diagnosis. This model was then experimentally validated using two disease variants of ALS that have mutations close to the sites where zinc or copper binds. These findings still need to be tested in animals and humans to see if these mechanisms hold true in a multicellular organism. This discovery could help design new ALS treatments that target the zinc binding site on SOD1 or disrupt the protein\u2019s interactions with the mitochondria.\n\nID: 33577819\nTitle: Zn2+ modulates in vitro phase separation of TDP-432C and mutant TDP-432C-A315T C-terminal fragments of TDP-43 protein implicated in ALS and FTLD-TDP diseases.\nAbstract: TDP-43 proteinopathy is implicated in the neurodegenerative diseases, ALS and FTLD-TDP. Metal ion dyshomeostasis is observed in neurodegenerative diseases including ALS. Previously, mice expressing A315T familial ALS TDP-43 mutant showed elevated spinal cord Zn2+ levels. Recently, Zn2+ was observed to modulate the in vitro amyloid-like aggregation of the TDP-43's RRM12 domains. As a systematic knowledge of the TDP-43's interaction with Zn2+ is lacking, we in silico predicted potential Zn2+ binding sites in TDP-43 and estimated their relative solvent accessibilities. Zn2+ binding sites were predicted in the TDP-43's N-terminal domain, in the linker region between RRM1 and RRM2 domain, within RRM2 domain and at the junction of the RRM2 and C-terminal domain (CTD), but none in the 311-360 region of CTD. Furthermore, we found that Zn2+ promotes the in vitro thioflavin-T-positive aggregations of C-terminal fragments (CTFs) termed TDP-432C and TDP-432C-A315T that encompass the RRM2 and CTD domains. Also, while the Alexa-fluor fluorescently labelled TDP-432C and TDP-432C-A315T proteins manifested liquid-like spherical droplets, Zn2+ caused a solid-like phase separation that was not ameliorated even by carboxymethylation of the free cysteines thereby implicating the other Zn2+-binding residues. The observed Zn2+-promoted TDP-43 CTF's solid-like phase separation can be relevant to the Zn2+ dyshomeostasis in ALS and FTLD-TDP.\n\nID: 33443392\nTitle: Reduced Occipital Cortex Excitability in Amyotrophic Lateral Sclerosis.\nAbstract: In addition to motor cortex involvement, sensory abnormalities have been demonstrated in amyotrophic lateral sclerosis (ALS), including structural and metabolic alterations in the occipital cortex. The aim of this study was to examine occipital excitability changes in ALS. Twenty-one patients with ALS and 16 healthy subjects were enrolled into the study. Phosphene experience and phosphene threshold were studied to assess occipital excitability. Cognitive function was evaluated in both groups by means of Montreal Cognitive Assessment and Addenbrooke's Cognitive Examination-Revised visuospatial score tests. Phosphene was experienced in 13 (81.3%) healthy subjects and 9 (42.9%) patients with ALS ( P = 0.04). The mean phosphene threshold was not significantly different between the two groups. No correlation existed between phosphene threshold and motor cortical excitability parameters, ALS Functional Rating Scale Revised, Montreal Cognitive Assessment, and Addenbrooke's Cognitive Examination-Revised scores. Visual cortex is affected, and the occipital excitability is reduced in ALS, without any relation to motor cortical excitability changes, providing another clue suggestive of sensory involvement in ALS.\n\nID: 33408125\nTitle: TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy.\nAbstract: Mislocalization of the TAR DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm is a common feature of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The downstream in vivo cellular effects of this mislocalization are not well understood. To investigate the impact of mislocalized TDP-43 on neuronal cell bodies, axons and axonal terminals, we utilized the mouse visual system to create a new model of TDP-43 proteinopathy. Mouse (C57BL/6J) retinal ganglion cells (RGCs) were transduced with GFP-tagged human wildtype TDP-43 (hTDP-WT-GFP) and human TDP-43 with a mutation in the nuclear localization sequence (hTDP-\u0394NLS-GFP), to cause TDP-43 mislocalization, with \u223c60% transduction efficiency achieved. Expression of both hTDP-WT-GFP and hTDP-\u0394NLS-GFP resulted in changes to neurofilament expression, with cytoplasmic TDP-43 being associated with significantly (p<0.05) increased neurofilament heavy expression in the cell soma, and both forms of altered TDP-43 leading to significantly (p<0.05) decreased numbers of neurofilament-positive axons within the optic nerve. Alterations to neurofilament proteins were associated with significantly (p<0.05) increased microglial density in the optic nerve and retina. Furthermore expression of hTDP-WT-GFP was associated with a significant (p<0.05) increase in pre-synaptic input into RGCs in the retina. The current study has developed a new model allowing detailed examination of alterations to TDP-43 and will contribute to the knowledge of TDP-43-mediated neuronal alterations and degeneration.\n\nID: 33359139\nTitle: The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease.\nAbstract: Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65\u00a0year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7AM1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7AM1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7AM1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7AM1311V fibroblasts. iPSC-MNs harboring the ATP7AM1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7AM1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7AM1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7AM1311V. Taken together, these observations suggest that ATP7AM1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology.\n\nID: 33220280\nTitle: A novel hypothesis on metal dyshomeostasis and mitochondrial dysfunction in amyotrophic lateral sclerosis: Potential pathogenetic mechanism and therapeutic implications.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunctions resulting from the loss of upper (UMNs) and lower (LMNs) motor neurons. While ALS symptoms are coincidental with pathological changes in LMNs and UMNs, the causal relationship between the two is unclear. For example, research on the extra-motor symptoms associated with this condition suggests that an imbalance of metals, including copper, zinc, iron, and manganese, is initially induced in the sensory ganglia due to a malfunction of metal binding proteins and transporters. It is proposed that the resultant metal dyshomeostasis may promote mitochondrial dysfunction in the satellite glial cells of these sensory ganglia, causing sensory neuron disturbances and sensory symptoms. Sensory neuron hyperactivation can result in LMN impairments, while metal dyshomeostasis in spinal cord and brain stem parenchyma induces mitochondrial dysfunction in LMNs and UMNs. These events could prompt intracellular calcium dyshomeostasis, pathological TDP-43 formation, and reactive microglia with neuroinflammation, which in turn activate the apoptosis signaling pathways within the LMNs and UMNs. Our model suggests that the degeneration of LMNs and UMNs is incidental to the metal-induced changes in the spinal cord and brain stem. Over time psychiatric symptoms may appear as the metal dyshomeostasis and mitochondrial dysfunction affect other brain regions, including the reticular formation, hippocampus, and prefrontal cortex. It is proposed that metal dyshomeostasis in combination with mitochondrial dysfunction could be the underlying mechanism responsible for the initiation and progression of the pathological changes associated with both the motor and extra-motor symptoms of ALS.\n\nID: 33206086\nTitle: Manganese-induced neurotoxicity in cerebellar granule neurons due to perturbation of cell network pathways with potential implications for neurodegenerative disorders.\nAbstract: Manganese (Mn) is essential for living organisms, playing an important role in nervous system function. Nevertheless, chronic and/or acute exposure to this metal, especially during early life stages, can lead to neurotoxicity and dementia by unclear mechanisms. Thus, based on previous works of our group with yeast and zebrafish, we hypothesized that the mechanisms mediating manganese-induced neurotoxicity can be associated with the alteration of protein metabolism. These mechanisms may also depend on the chemical speciation of manganese. Therefore, the current study aimed at investigating the mechanisms mediating the toxic effects of manganese in primary cultures of cerebellar granule neurons (CGNs). By exposing cultured CGNs to different chemical species of manganese ([[2-[(dithiocarboxy)amino]ethyl]carbamodithioato]](2-)-kS,kS']manganese, named maneb (MB), and [[1,2-ethanediylbis[carbamodithioato]](2-)]manganese mixture with [[1,2-ethanediylbis[carbamodithioato]](2-)]zinc, named mancozeb (MZ), and manganese chloride (MnCl2)), and using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, we observed that both MB and MZ induced similar cytotoxicity (LC50\u223c 7-9 \u03bcM), which was higher than that of MnCl2 (LC50\u223c 27 \u03bcM). Subsequently, we applied systems biology approaches, including metallomics, proteomics, gene expression and bioinformatics, and revealed that independent of chemical speciation, for non-cytotoxic concentrations (0.3-3 \u03bcM), Mn-induced neurotoxicity in CGNs is associated with metal dyshomeostasis and impaired protein metabolism. In this way, we verified that MB induced more post-translational alterations than MnCl2, which can be a plausible explanation for cytotoxic differences between both chemical species. The metabolism of proteins is one of the most energy consuming cellular processes and its impairment appears to be a key event of some cellular stress processes reported separately in other studies such as cell cycle arrest, energy impairment, cell signaling, excitotoxicity, immune response, potential protein accumulation and apoptosis. Interestingly, we verified that Mn-induced neurotoxicity shares pathways associated with the development of Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, and Parkinson's disease. This has been observed in baker's yeast and zebrafish suggesting that the mode of action of Mn may be evolutionarily conserved.\n\nID: 33071739\nTitle: Amyotrophic Lateral Sclerosis: A Neurodegenerative Motor Neuron Disease With Ocular Involvement.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes degeneration of the lower and upper motor neurons and is the most prevalent motor neuron disease. This disease is characterized by muscle weakness, stiffness, and hyperreflexia. Patients survive for a short period from the onset of the disease. Most cases are sporadic, with only 10% of the cases being genetic. Many genes are now known to be involved in familial ALS cases, including some of the sporadic cases. It has also been observed that, in addition to genetic factors, there are numerous molecular mechanisms involved in these pathologies, such as excitotoxicity, mitochondrial disorders, alterations in axonal transport, oxidative stress, accumulation of misfolded proteins, and neuroinflammation. This pathology affects the motor neurons, the spinal cord, the cerebellum, and the brain, but recently, it has been shown that it also affects the visual system. This impact occurs not only at the level of the oculomotor system but also at the retinal level, which is why the retina is being proposed as a possible biomarker of this pathology. The current review discusses the main aspects mentioned above related to ALS, such as the main genes involved, the most important molecular mechanisms that affect this pathology, its ocular involvement, and the possible usefulness of the retina as a biomarker.\n\nID: 33029965\nTitle: Shape Analysis of the Subcortical Nuclei in Amyotrophic Lateral Sclerosis without Cognitive Impairment.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the pyramidal motor system. However, recent studies have suggested that degeneration of the extramotor system plays a role in the disability experienced by patients with ALS. We investigated the local shape changes and mean volumes of the subcortical nuclei in sporadic ALS patients with preserved cognition. The participants comprised 32 patients with ALS and 43 age- and sex-matched healthy controls. Three-dimensional T1-weighted structural images were acquired. Surface-based vertex analysis was performed with fully automated segmentation of both amygdalae, hippocampi, caudate nuclei, nuclei accumbens, putamina, pallida, and thalami, and the brainstem. The scalar distances from the mean surfaces of the individual subcortical nuclei were compared between groups, and correlations of the local shape distances with initial Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALS-FRS-R) scores and the delta FRS-R and with the disease duration were analyzed. ALS patients showed regional shape contractions on the lateral surfaces of both pallida, the lateroposterior surface of the right putamen, and the anterior basal surface of the right accumbens. Delta FRS-R scores were negatively correlated with local shape distances in the right hippocampus and the putamina. However, the initial ALS-FRS-R score and disease duration were not correlated with local shape distances. Subcortical gray-matter structures are involved in the neurodegenerative process of ALS before cognitive impairment becomes evident.\n\nID: 32794552\nTitle: Molecular and pharmacological chaperones for SOD1.\nAbstract: The efficacy of superoxide dismutase-1 (SOD1) folding impacts neuronal loss in motor system neurodegenerative diseases. Mutations can prevent SOD1 post-translational processing leading to misfolding and cytoplasmic aggregation in familial amyotrophic lateral sclerosis (ALS). Evidence of immature, wild-type SOD1 misfolding has also been observed in sporadic ALS, non-SOD1 familial ALS and Parkinson's disease. The copper chaperone for SOD1 (hCCS) is a dedicated and specific chaperone that assists SOD1 folding and maturation to produce the active enzyme. Misfolded or misfolding prone SOD1 also interacts with heat shock proteins and macrophage migration inhibitory factor to aid folding, refolding or degradation. Recognition of specific SOD1 structures by the molecular chaperone network and timely dissociation of SOD1-chaperone complexes are, therefore, important steps in SOD1 processing. Harnessing these interactions for therapeutic benefit is actively pursued as is the modulation of SOD1 behaviour with pharmacological and peptide chaperones. This review highlights the structural and mechanistic aspects of a selection of SOD1-chaperone interactions together with their impact on disease models.\n\nID: 32745677\nTitle: Methods for quantitative susceptibility and R2* mapping in whole post-mortem brains at 7T applied to amyotrophic lateral sclerosis.\nAbstract: Susceptibility weighted magnetic resonance imaging (MRI) is sensitive to the local concentration of iron and myelin. Here, we describe a robust image processing pipeline for quantitative susceptibility mapping (QSM) and R2* mapping of fixed post-mortem, whole-brain data. Using this pipeline, we compare the resulting quantitative maps in brains from patients with amyotrophic lateral sclerosis (ALS) and controls, with validation against iron and myelin histology. Twelve post-mortem brains were scanned with a multi-echo gradient echo sequence at 7T, from which susceptibility and R2* maps were generated. Semi-quantitative histological analysis for ferritin (the principal iron storage protein) and myelin proteolipid protein was performed in the primary motor, anterior cingulate and visual cortices. Magnetic susceptibility and R2* values in primary motor cortex were higher in ALS compared to control brains. Magnetic susceptibility and R2* showed positive correlations with both myelin and ferritin estimates from histology. Four out of nine ALS brains exhibited clearly visible hyperintense susceptibility and R2* values in the primary motor cortex. Our results demonstrate the potential for MRI-histology studies in whole, fixed post-mortem brains to investigate the biophysical source of susceptibility weighted MRI signals in neurodegenerative diseases like ALS.\n\nID: 32438517\nTitle: Early life metal dysregulation in amyotrophic lateral sclerosis.\nAbstract: Deficiencies and excess of essential elements and toxic metals are implicated in amyotrophic lateral sclerosis (ALS), but the age when metal dysregulation appears remains unknown. This study aims to determine whether metal uptake is dysregulated during childhood in individuals eventually diagnosed with ALS. Laser ablation-inductively coupled plasma-mass spectrometry was used to obtain time series data of metal uptake using biomarkers in teeth from autopsies or dental extractions of ALS (n\u00a0=\u00a036) and control (n\u00a0=\u00a031) participants. Covariate data included sex, smoking, occupational exposures, and ALS family history. Case-control differences were identified in temporal profiles of metal uptake for individual metals using distributed lag models. Weighted quantile sum (WQS) regression was used for metals mixture analyses. Similar analyses were performed on an ALS mouse model to further verify the relevance of dysregulation of metals in ALS. Metal levels were higher in cases than in controls: 1.49 times for chromium (1.11-1.82; at 15\u00a0years), 1.82 times for manganese (1.34-2.46; at birth), 1.65 times for nickel (1.22-2.01; at 8\u00a0years), 2.46 times for tin (1.65-3.30; at 2\u00a0years), and 2.46 times for zinc (1.49-3.67; at 6\u00a0years). Co-exposure to 11 elements indicated that childhood metal dysregulation was associated with ALS. The mixture contribution of metals to disease outcome was likewise apparent in tooth biomarkers of an ALS mouse model, and differences in metal distribution were evident in ALS mouse brains compared to brains from littermate controls. Overall, our study reveals direct evidence that altered metal uptake during specific early life time windows is associated with adult-onset ALS.\n\nID: 42533344\nTitle: Ethical challenges in treatment-goal transitions in invasively ventilated ALS: a case-based topical review.\nAbstract: In advanced amyotrophic lateral sclerosis (ALS), eye movements often represent the last channel for intentional communication. While oculomotor function has traditionally been considered relatively preserved, emerging evidence indicates progressive impairment in long-term survivors on tracheostomy-invasive ventilation (TIV). As a result, eye-based communication may become increasingly unreliable before complete loss, challenging clinical decision-making and advance care planning (ACP). We conducted a case-based topical review integrating clinical observation and literature to examine the trajectory of oculomotor decline, its impact on communication, and implications for treatment decisions. Three patients with ALS receiving TIV in a home-care setting illustrate key clinical and ethical challenges. Across cases and literature, oculomotor decline followed a gradual trajectory from effective eye-tracking communication to a complete locked-in syndrome. We identify a transitional phase of communicative ambiguity, in which residual ocular signals persist but can no longer be reliably attributed to intentional, patient-controlled communication. This phase is characterized by increasing inconsistency of signals and a divergence between observable responses and their interpretive certainty, creating uncertainty in assessing patient preferences. Communicative ambiguity represents a clinically underrecognized but critical threshold in advanced ALS, marking the transition from direct patient autonomy to interpretative and surrogate-based decision-making. Failure to recognize this phase risks misinterpretation of patient intent and may undermine goal-concordant care. Timely and iterative ACP, initiated before communication becomes unreliable, is essential. We further propose four clinical pathways for treatment goal conversations, highlighting their differing implications for timing, symptom burden, and ethical decision-making.\n\nID: 42530644\nTitle: [Cogan syndrome as a\u00a0rare cause of deafness].\nAbstract: Cogan syndrome is a\u00a0rare systemic disease characterized by the occurrence of audiovestibular and ocular symptoms. We present the case of a\u00a062-year-old female patient who received a\u00a0cochlear implant after unilateral deafness. Despite successful implantation, the disease progressed with chronic headache, recurrent otitis, fluctuating intracochlear impedances, and slowly progressing hearing loss in the contralateral ear. Through interdisciplinary collaboration, the diagnosis of Cogan syndrome was established, and biological therapy was initiated. Das Cogan-I-Syndrom ist eine seltene Systemerkrankung, die sich durch das Auftreten audiovestibul\u00e4rer und okul\u00e4rer Symptome auszeichnet. Wir pr\u00e4sentieren den Fall einer 62-j\u00e4hrigen Patientin, die nach einseitiger Ertaubung ein Cochleaimplantat erhielt. Trotz regelrechter Implantation kam es zu einem protrahierten Verlauf mit chronischer Zephalgie, wiederkehrender Otitis, schwankenden intracochle\u00e4ren Impedanzen sowie langsam progredientem H\u00f6rverlust der Gegenseite. In interdisziplin\u00e4rer Zusammenarbeit wurde die Diagnose des Cogan-I-Syndroms gestellt und eine Biologikatherapie eingeleitet.\n\nID: 42526365\nTitle: A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS. A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I2 statistic. A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD\u00a0=\u00a0-0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD\u00a0=\u00a0-0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant. This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder. PROSPERO identifier CRD420251076035.\n\nID: 42512084\nTitle: Retinal Thickness and Vascular Density Changes in Amyotrophic Lateral Sclerosis Assessed by Optical Coherence Tomography Angiography.\nAbstract: Background: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder involving neurovascular dysfunction. The retina allows in vivo assessment of neurovascular changes. This study evaluated retinal structural and microvascular alterations in ALS using optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A). Methods: This cross-sectional study included 46 participants with ALS and 19 healthy controls. Retinal thickness and vascular density in the superficial and deep retinal capillary plexuses and the choriocapillaris were quantified using OCT and OCT-A. Group comparisons and logistic regression analyses were performed to assess associations with ALS. Subgroup analyses were conducted according to clinical phenotype. Results: In total, 124 eyes were analyzed. ALS was associated with increased average retinal thickness (p = 0.023) and reduced vascular density in the superficial retinal capillary plexus (p = 0.005), deep retinal capillary plexus (p < 0.001), and choriocapillaris (p = 0.004). In logistic regression analyses, retinal thickness was positively associated with ALS status (OR = 1.42, p = 0.023), whereas higher vascular density in the superficial plexus, deep plexus, and choriocapillaris was associated with lower odds of ALS. No significant differences were observed between bulbar- and spinal-onset ALS phenotypes. Conclusions: ALS is associated with structural and microvascular retinal alterations detectable by OCT and OCT-A. These findings support the presence of systemic neurovascular dysfunction and highlight retinal imaging as a promising, non-invasive approach for investigating disease mechanisms and developing potential biomarkers.\n\nID: 42509340\nTitle: [Prepapillary vitreous exudate as the first ocular manifestation of Beh\u00e7et's disease: A case report].\nAbstract: Beh\u00e7et's disease is a systemic inflammatory disorder that frequently presents with ocular involvement in the form of non-granulomatous panuveitis and retinal vasculitis. A prepapillary inflammatory vitreous infiltrate represents a rare but potentially characteristic manifestation. We report the case of a 29-year-old female patient presenting with acute, painless visual loss in the right eye. Clinical examination revealed non-granulomatous anterior uveitis with bilateral vitritis and a prepapillary inflammatory vitreous infiltrate in the right eye. Optical coherence tomography (OCT) demonstrated a typical mushroom-shaped prepapillary infiltrate associated with serous macular detachment. Fluorescein angiography revealed optic disc and peripheral leakage. Infectious causes were excluded. In the context of recurrent oral and genital aphthous ulcers, the patient fulfilled the diagnostic criteria for Beh\u00e7et's disease. Following intravenous high-dose corticosteroid pulse therapy, treatment with adalimumab was initiated. This resulted in significant functional and anatomical improvement, with regression of the prepapillary inflammatory vitreous infiltrate and the serous retinal detachment. A prepapillary inflammatory vitreous infiltrate is a rare but important diagnostic sign of ocular Beh\u00e7et's disease and may be a key finding, particularly in patients presenting with initial ocular involvement. Early diagnosis and prompt initiation of immunosuppressive therapy are essential for visual prognosis. HINTERGRUND: Der Morbus Beh\u00e7et ist eine systemische entz\u00fcndliche Erkrankung, die sich h\u00e4ufig mit okul\u00e4rer Beteiligung in Form einer nichtgranulomat\u00f6sen Panuveitis und retinalen Vaskulitis manifestiert. Ein pr\u00e4papill\u00e4res entz\u00fcndliches Glask\u00f6rperinfiltrat stellt eine seltene, jedoch potenziell charakteristische Manifestation dar. Wir berichten \u00fcber eine 29-j\u00e4hrige Patientin mit akut aufgetretener, schmerzloser Visusminderung am rechten Auge. Klinisch zeigte sich eine nichtgranulomat\u00f6se anteriore Uveitis mit beidseitiger Vitritis sowie eine pr\u00e4papill\u00e4re Glask\u00f6rperverdichtung am rechten Auge. Die optische Koh\u00e4renztomographie (OCT) zeigte ein typisches \u201echampignonf\u00f6rmiges\u201c pr\u00e4papill\u00e4res Infiltrat mit begleitender ser\u00f6ser Makulaabhebung. Die Fluoreszenzangiographie ergab eine papill\u00e4re und periphere Leckage. Infekti\u00f6se Ursachen wurden ausgeschlossen. In Zusammenschau mit rezidivierenden oralen und genitalen Aphthen erf\u00fcllte die Patientin die Kriterien f\u00fcr Morbus Beh\u00e7et. Nach einer intraven\u00f6sen hochdosierten Kortikosteroidsto\u00dftherapie wurde eine Behandlung mit Adalimumab eingeleitet. Darunter kam es zu einer deutlichen funktionellen und morphologischen Besserung mit R\u00fcckbildung des pr\u00e4papill\u00e4ren Infiltrats und der ser\u00f6sen Netzhautabhebung. Das pr\u00e4papill\u00e4re entz\u00fcndliche Glask\u00f6rperinfiltrat ist ein seltenes, aber wichtiges diagnostisches Zeichen einer okul\u00e4ren Manifestation des Morbus Beh\u00e7et und kann insbesondere bei initialer okul\u00e4rer Pr\u00e4sentation wegweisend sein. Eine fr\u00fchzeitige Diagnose und rasche Einleitung einer immunsuppressiven Therapie sind entscheidend f\u00fcr die Visusprognose.\n\nID: 42420060\nTitle: Development of a target product profile for artificial intelligence in diabetic eye screening in England: a modified Delphi consensus study.\nAbstract: Artificial intelligence (AI) health-care technologies offer a means of addressing the growing gap between health-care capacity and demand. However, few technologies have met the complex requirements of health-care systems for adoption. Diabetic eye screening (DES) in England exemplifies the difficulty of understanding these requirements and translating them into real-world implementation decisions. This Review responds to a recognised policy need to develop a target product profile (TPP) for a DES AI system for use in England. The TPP outlines the requirements of the English health-care system for such a device and was developed using a modified Delphi consensus process involving interviews, surveys, and a consensus meeting. Participants included people living with diabetes, health-care professionals, health-care managers and leaders, regulators and policy makers, and developers. Thirty-five product specifications were agreed upon, covering areas such as clinical validity, utility, and environmental sustainability. Our TPP establishes clear criteria for DES AI development and deployment in England, and this TPP development process can serve as a template for initiatives to create TPPs for other AI health technologies and settings.\n\nID: 42362968\nTitle: Longitudinal cognitive outcomes in two progressive supranuclear palsy clinical trials.\nAbstract: Progressive supranuclear palsy (PSP) causes executive dysfunction, fluency deficits, and behavioral changes. We examined longitudinal changes in PSP cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Using the RBANS and executive function and fluency tests from 486 and 377 participants in the PASSPORT (NCT03068468) and tilavonemab (NCT02985879) clinical trials, we assessed linear mixed models of cognitive subtest score change, controlling for disease duration, age, sex, and treatment group. The greatest declines occurred in subtests assessing visuospatial (figure copy, figure recall), executive function (Color Trails, coding), and fluency (primarily semantic fluency), although controlling for motor and ocular motor disability reduced the magnitude of score decline. Subtests assessing immediate and delayed memory (story recall, story memory, list recall, list recognition) declined slowly or not at all. Cognition in PSP is characterized by declines in executive, visuospatial function, and fluency, with relative preservation of memory.\n\nID: 42334608\nTitle: [Calculating IOL\u00a0power - principles, development and current challenges].\nAbstract: The formulae for calculating intraocular lens (IOL) power have undergone considerable development. In recent years in particular, novel approaches based on artificial intelligence (AI) have been incorporated into the calculation models. The aim is to discuss both classical and new principles of IOL calculation, to present the current classification, to explain new approaches and to compare the performance of the formulae based on current reviews and meta-analyses. This article is a\u00a0narrative review without any claim to completeness. The literature selection was based on relevant publications identified through medical databases and specialist journals. Initial publications on the formulae and articles on classification systems were identified and analyzed, followed by an evaluation of current reviews and meta-analyses to compare the performance capabilities. The spectrum of IOL formulae ranges from historical refraction-based and regression-based approaches, classical vergence and ray tracing to modern AI-based methods. Many of the contemporary formulae used integrate multiple methodologies. In recent years there has been a\u00a0clear trend towards reducing prediction errors with the advent of newer formulae, particularly in short eyes. Modern IOL formulae are preferable to traditional ones and outdated guidelines regarding formula selection should be updated. Many modern formulae are universally applicable and yield similarly good results. Further developments will reduce the number of outliers but will likely never eliminate them entirely. HINTERGRUND: Die Berechnung der Intraokularlinsenst\u00e4rke hat sich zunehmend weiterentwickelt. Insbesondere in den letzten Jahren haben KI-basierte Ans\u00e4tze Einzug in die Berechnungsmodelle gefunden. Ziel ist es, klassische und neue Prinzipien der IOL-Berechnung zu diskutieren, die aktuelle Klassifikation darzustellen, neue Ans\u00e4tze zu erl\u00e4utern und die Leistungsf\u00e4higkeit der Formeln anhand aktueller Reviews und Metaanalysen zu vergleichen. Es handelt sich um einen narrativen Review ohne Anspruch auf Vollst\u00e4ndigkeit. Die Literaturauswahl erfolgte auf Basis relevanter Publikationen aus medizinischen Datenbanken und Fachzeitschriften. Erstpublikationen zu den Formeln sowie Arbeiten zur Klassifikation wurden identifiziert und analysiert. Anschlie\u00dfend erfolgte eine Auswertung aktueller Reviews und Metaanalysen zum Vergleich der Leistungsf\u00e4higkeit. Das Spektrum der Intraokularlinsenformeln reicht von historischen refraktions- und regressionsbasierten Ans\u00e4tzen \u00fcber klassische Vergenz- und Raytracing- bis hin zu modernen KI-basierten Formeln. Viele der aktuell verwendeten Formeln integrieren mehrere Ans\u00e4tze. In den letzten Jahren zeigt sich ein deutlicher Trend zur Verringerung des Vorhersagefehlers mit dem Aufkommen neuerer Formeln, insbesondere bei kurzen Augen. Moderne Formeln sind den klassischen vorzuziehen, und veraltete Leitlinien zur Formelwahl sollten aktualisiert werden. Viele der modernen Formeln sind universell einsetzbar und zeigen \u00e4hnlich gute Ergebnisse. Weiterentwicklungen werden die Anzahl von Ausrei\u00dfern reduzieren, aber vermutlich nie g\u00e4nzlich eliminieren.\n\nID: 42331015\nTitle: Malnutrition as a Risk Factor for Cerebral and Glaucomatous Neurodegeneration - Mechanisms and Therapeutic Strategies.\nAbstract: BACKGROUND: Neurodegenerative diseases are an increasing challenge for healthcare systems in the context of demographic change. They affect the central nervous system, including the brain-manifesting, for example, as dementia-as well as the retina, as seen in glaucoma or age-related macular degeneration. Malnutrition-defined as quantitative or qualitative under- or overnutrition-affects key mechanisms that contribute to neuronal and retinal neurodegeneration. OBJECTIVE: The aim of this study is to systematically present the pathophysiological mechanisms of malnutrition-related neurodegeneration, to evaluate the current evidence on dietary patterns and cognitive health, and to derive practical clinical strategies for nutritional optimization. METHODS: Narrative literature review based on peer-reviewed publications from the fields of nutritional medicine, geriatrics, neurology, ophthalmology, and public health. RESULTS: Malnutrition promotes oxidative stress, mitochondrial dysfunction, chronic neuroinflammation, and vascular dysregulation, and it influences neurotransmitter synthesis. These mechanisms are relevant to both cerebral and ocular neurodegenerative processes. The Mediterranean diet and the MIND diet are associated with a significantly reduced risk of cognitive impairment; for ocular diseases, interventional studies in age-related macular degeneration in particular demonstrate protective effects of antioxidant supplementation, whereas evidence for glaucoma is currently based predominantly on observational data. Screening approaches and micronutrient diagnostics enable early identification of at-risk individuals. Building on this, individualised dietary interventions and targeted supplementation of selected nutrients could be potentially preventive and stabilising therapeutic strategies. CONCLUSION: Malnutrition is a key modifiable risk factor for neurodegenerative diseases of the brain and retina. More intense integration of nutritional diagnostics and therapy into neurological, geriatric, and ophthalmological care structures appears warranted. Neurodegenerative Erkrankungen stellen angesichts des demografischen Wandels eine zunehmende Herausforderung f\u00fcr das Gesundheitswesen dar. Sie betreffen das zentrale Nervensystem, einschlie\u00dflich des Gehirns, etwa in Form von Demenz, sowie die Retina, wie beim Glaukom oder bei der altersabh\u00e4ngigen Makuladegeneration. Fehlern\u00e4hrung \u2013 verstanden als quantitative oder qualitative Unter- bzw. \u00dcberversorgung \u2013 beeinflusst zentrale Mechanismen, die zur neuronalen und retinalen Neurodegeneration beitragen. Ziel dieser Arbeit ist es, die pathophysiologischen Mechanismen fehlern\u00e4hrungsbedingter Neurodegeneration systematisch darzustellen, die aktuelle Evidenzlage zu Ern\u00e4hrungsmustern und kognitiver Gesundheit zu bewerten sowie praxisnahe klinische Strategien zur Ern\u00e4hrungsoptimierung abzuleiten. Narrative Literatur\u00fcbersicht basierend auf Publikationen mit Peer-Review-Verfahren aus den Bereichen Ern\u00e4hrungsmedizin, Geriatrie, Neurologie, Ophthalmologie und Public Health. Fehlern\u00e4hrung f\u00f6rdert oxidativen Stress, mitochondriale Dysfunktion, chronische Neuroinflammation sowie vaskul\u00e4re Dysregulation und beeinflusst die Neurotransmittersynthese. Diese Mechanismen sind sowohl f\u00fcr zerebrale als auch f\u00fcr okul\u00e4re Neurodegenerationsprozesse relevant. Mediterrane Ern\u00e4hrung und MIND-Di\u00e4t sind mit einem signifikant reduzierten Risiko kognitiver Beeintr\u00e4chtigung assoziiert; f\u00fcr okul\u00e4re Erkrankungen zeigen insbesondere Interventionsstudien bei AMD protektive Effekte antioxidativer Supplementierung, w\u00e4hrend f\u00fcr das Glaukom bislang vorwiegend beobachtende Daten vorliegen. Screening-Ans\u00e4tze und Mikron\u00e4hrstoffdiagnostik erm\u00f6glichen die fr\u00fchzeitige Identifikation von Risikopersonen. Darauf aufbauend stellen individualisierte di\u00e4tetische Ma\u00dfnahmen sowie die gezielte Supplementierung ausgew\u00e4hlter N\u00e4hrstoffe potenziell pr\u00e4ventive und stabilisierende therapeutische Strategien dar. Fehlern\u00e4hrung ist ein zentraler, modifizierbarer Risikofaktor neurodegenerativer Erkrankungen des Gehirns und der Retina. Eine st\u00e4rkere Integration ern\u00e4hrungsmedizinischer Diagnostik und Therapie in neurologischen, geriatrischen und ophthalmologischen Versorgungsstrukturen erscheint sinnvoll.\n\nID: 42304926\nTitle: Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.\nAbstract: Age-related macular degeneration (AMD) is caused by the degeneration of photoreceptors and retinal pigment epithelium (RPE) along with drusen deposition and is the leading cause of vision loss in older adults. Both these structures within the central nervous system (CNS) utilize common neuro-inflammatory mechanisms because the retina is an outgrowth of the brain. Like the brain, the eye has its own physical characteristics and surface molecules as well as a tendency towards specific immune reactions. Numerous distinct neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Frontotemporal dementia (FTD) that impact the brain present as eye symptoms, and the conventional diagnosis of these neurodegenerative disorders (NDs) is often preceded by ocular symptoms. Furthermore, several eye-specific disorders have characteristics in common with other CNS disorders. NDs and AMD share common key features, such as tau and amyloid-\u03b2 deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and m\u00fcller glia. Common pathological mechanisms include complement activation, amyloid aggregation, neuroinflammation, vascular impairment, and cell death, providing a basis for a convergent neuroimmune axis between retinal and cerebral degeneration. Comparing these age-related diseases will facilitate the identification of shared risk factors, convergent molecular pathways, and potential cross-applicable therapeutic strategies, such as anti-inflammatory, anti-complementary, anti-apoptotic, and anti-VEGF-based approaches. This knowledge may enhance understanding of neurodegenerative diseases, help identify early biomarker development for diagnosis, and enable the design of targeted therapeutic strategies.\n\nID: 42304076\nTitle: Multi-omic analysis of deep learning-derived phenotypes links ophthalmic imaging to cardiovascular and neurological traits.\nAbstract: The eye is a recognized source of biomarkers for cardiovascular and neurodegenerative disease risk. Here we characterize the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integrating physiological, radiomic, metabolomic and genomic information. We trained retinal adversarial autoencoders to represent optical coherence tomography images and color fundus photographs as 256-dimensional embeddings. Retinal adversarial autoencoder-derived embeddings were associated with a range of cardiovascular and neurodegenerative diseases, including ischemic heart disease, cerebrovascular disease, Parkinson's disease and dementia. Examining associations across diverse omics datasets, we provide evidence linking ophthalmic imaging features to neurological and cardiovascular anatomy and function, lipid metabolism and gene sets associated with neurodegenerative pathology. Collectively, our findings show that ophthalmic features reflect complex, multisystem biological processes and reinforce the role of the eye as a composite indicator of systemic health.\n\nID: 42231162\nTitle: The roles of cytoplasmic dynein complex in various ocular disorders.\nAbstract: The cytoplasmic dynein complex mediates retrograde transport of various intracellular components and plays a critical role in mitosis, nuclear migration, organelle positioning, vesicle trafficking, misfolded protein clearance, and intercellular signaling. Mutations in human cytoplasmic dynein subunits and regulators have been directly linked to various neurological diseases and are increasingly recognized as contributors to ocular degenerative diseases. However, the precise mechanisms underlying ocular morphogenesis and degeneration remain poorly understood. Various animal models, including Drosophila, mouse, and zebrafish, have been established to investigate the pathogenesis of cytoplasmic dynein complex-related ocular disorders. Findings from these models indicate that dynein complex-related ocular pathologies often involve endoplasmic reticulum stress, impaired Notch signaling, and disrupted Sonic Hedgehog pathways. Systematically integrating gene functional data and molecular mechanism clues derived from different models can help refine the \"gene-phenotype-mechanism\" correlation network and may ultimately advance precision diagnosis and targeted therapy. Emerging evidence has highlighted the cytoplasmic dynein complex as a key factor in ocular development and disease. Integrating findings across model systems may enable more precise diagnosis and the development of targeted interventions for dynein-related ocular disorders.\n\nID: 42121359\nTitle: Development of an Optical Defocus-Induced Myopia Model for Guinea Pigs Using Rigid Gas Permeable Contact Lenses.\nAbstract: Guinea pigs are a widely used mammalian model for studies of myopia and early ocular growth regulation more generally. The study reported here covers the development of rigid gas permeable (RGP) contact lenses (CLs) for guinea pigs, as an alternative to spectacle lenses for imposing optical defocus, recognized as an important modulator of eye elongation in young animals. New Zealand pigmented guinea pigs ( Cavia porcellus ) were used in this study, with the RGP lens design based on developmental corneal shape profiles derived from anterior segment optical coherence tomography data collected across a range of ages, as typically encountered in such studies. The validity of this CL-based approach was examined in a follow-up study, in which the ocular effects of -10, 0, and +5 diopters [D] RGP lenses, applied as continuous monocular optical defocus treatments, were tracked over 2 weeks, with the fellow untreated eyes of experimental animals serving as contralateral controls. Pretreatment baseline spherical equivalent refractive errors (RE) and axial length (AL) of both eyes were measured, along with follow-up weekly measurements over the wearing period. There were no differences in any of the ocular parameters between the three groups at baseline, while after two weeks of lens wear, there were significant differences between the -10 D group compared with 0 D and +5 D groups in both RE ( P <0.001) and AL ( P <0.05). Importantly, myopia was observed in all of the guinea pigs fitted with -10 D lenses, and overall, eyes fitted with -10 D lenses showed increased ALs and relative myopia compared with their fellows, while those fitted with +5 D lenses showed reduced ALs and relative hyperopia; the plano lens group fell in between (treated-fellow eyes: -10, 0, and +5 D lenses: -8.25, -1.0, and +0.5 D, and +0.16, +0.08, and -0.02 mm, respectively). Also importantly, no significant CL-related adverse ocular effects were observed. This study provides proof of principle that defocusing RGP CLs are a feasible alternative to spectacle lenses for studies of eye growth regulation in young guinea pigs and experimental myopia specifically, with potential application in investigations into novel approaches for controlling myopia progression and underlying mechanisms.\n\nID: 41976821\nTitle: Speculum-Induced Intraocular Pressure Elevation During Cataract Surgery and Its Association with Axial Length: A Retrospective Clinical Study.\nAbstract: Background/Objectives: This study aimed to characterize eyelid speculum-induced intraocular pressure (IOP) elevation during cataract surgery and identify ocular biometric factors that stratify susceptibility to this pressure response. This study was conducted at Zengyo Suzuki Eye Clinic, Kanagawa, Japan. Methods: In this retrospective observational study, we analyzed 100 eyes that underwent routine cataract surgery. IOP was measured immediately before and within 10 s of speculum opening in the seated position using a rebound tonometer. The eyelid speculum was opened to a maximal opening position, and the opening width was recorded. Biometric parameters included axial length (AL), central corneal thickness, white-to-white distance, anterior chamber depth, and temporal angle-opening distance. Associations between IOP elevation and biometric factors were analyzed. IOP elevation rate was quantified as the percentage increase from baseline. The discriminatory performance of axial length was evaluated using receiver operating characteristic (ROC) analysis. Results: Overall, 100 patients (100 eyes) were included in the analysis. Mean IOP increased significantly from 15.75 \u00b1 2.77 mmHg before speculum placement to 21.42 \u00b1 5.54 mmHg after placement. The mean IOP elevation rate was 36.0 \u00b1 27.4%. Shorter AL was consistently associated with a greater proportional IOP elevation. ROC analysis demonstrated consistent stratification of IOP elevation susceptibility by AL (area under the curve [AUC] = 0.645), with eyes shorter than 23.84 mm showing greater pressure elevation (sensitivity, 73.1%; specificity, 56.0%). Eyes in the upper quartile of the IOP elevation rate exhibited relatively greater pressure elevation. Conclusions: Eyelid speculum placement imposes a clinically meaningful IOP load during cataract surgery, with shorter ALs making eyes more biomechanically susceptible to IOP elevation.\n\nID: 41907197\nTitle: Hereditary transthyretin amyloidosis mimicking ALS: First genetically proven case report from Saudi Arabia.\nAbstract: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder that may mimic motor neuron disease (MND), leading to misdiagnosis and delayed access to disease-modifying therapies. We report the first genetically confirmed case of ATTRv mimicking amyotrophic lateral sclerosis (ALS) in Saudi Arabia. A 47-year-old male presented with progressive right-sided limb weakness (proximal > distal) and dysarthria over 18\u00a0months. Neurological examination revealed fasciculations, distal atrophy, and brisk reflexes with normal muscle tone and no spasticity. Electrophysiological studies demonstrated a length-dependent sensorimotor axonal neuropathy with widespread denervation changes involving bulbar, cervical, and lumbosacral regions. Brain and spine MRI, along with whole-body CT, excluded structural or paraneoplastic causes. Genetic testing identified a pathogenic heterozygous variant in the TTR gene: NM_000371.4:c.424G\u00a0>\u00a0A (p.Val142Ile). Transthoracic echocardiography revealed mild concentric left ventricular hypertrophy. There was no clinical evidence of autonomic, renal, or ocular involvement. This case underscores the importance of considering ATTRv in patients presenting with atypical MND, particularly when clinically significant sensory symptoms, absent upper motor neuron signs, or unexplained cardiac abnormalities are present. Early diagnosis enables access to targeted therapies such as TTR stabilizers and gene-silencing agents, which can alter disease trajectory.\n\nID: 41860208\nTitle: Intravitreal Anti-vascular Endothelial Growth Factor in Retinopathy of Prematurity: A Bibliometric Analysis.\nAbstract: Retinopathy of prematurity (ROP) is one of the leading cause of blindness in premature infants. A bibliometric analysis on intravitreal anti-vascular endothelial growth factor (VEGF) in ROP was conducted. A comprehensive search of the article on the Scopus database was conducted with the terms related to \"anti-vascular endothelial growth factor and retinopathy of prematurity.\" Only original research and review articles published in the English language were considered. VOSviewer version 1.6.20 was used for the visualization and analysis of the data. Publication trend, productive countries, researchers' details, commonly cited documents, source and influential journals, and keyword occurrence were analyzed. A total of 329 studies were considered, of which 270 were original articles and 59 were review articles. The highest numbers of publications were seen in the year 2022. The United States, China, Turkey, India, and Taiwan were the top 5 countries that published research on the use of anti-VEGF in ROP. The most documents were published by Wei-Chi Wu (22) and Chi-Chun Lai (14), and Falavarjani et al's article had the most citations (737). A total of 2,504 keywords were identified. All keyword analysis revealed the occurrence of \"retinopathy of prematurity\" and \"human\" as a keyword was 290 and 286 times, respectively. Most articles and citations were found in Retina. The use of anti-VEGF in ROP is constantly evolving and bibliometric analysis highlights a research trend and influential authors and journals that have published significant work on it. This article can serve as a guide to conduct a literature review for future researchers.\n\nID: 41854827\nTitle: Nonlinear and Asymmetric Refractive Sensitivity to Effective Lens Position Errors in Pseudophakic Eye Models.\nAbstract: To perform a theoretical analysis of refractive sensitivity to effective lens position (ELP) errors in pseudophakic eyes using an explicit vergence-based optical model, and to quantify how this sensitivity depends on axial length (AL) and corneal power across a wide biometric range. A paraxial two-lens thin-lens model of the pseudophakic eye was developed, explicitly parameterised by AL, total corneal power (TCP), intraocular lens (IOL) power and effective lens position (ELP). Refraction was calculated at the corneal plane using vergence propagation. For a fixed reference ELP, the emmetropic IOL power was derived analytically for each combination of AL and TCP, and subsequently held constant while ELP was perturbed by \u00b11.0\u2009mm. Simulations were performed for ALs from 19 to 31\u2009mm and corneal powers from 38 to 50 dioptres. Refractive changes were approximated using families of quadratic regression models as functions of AL. Refractive sensitivity to ELP errors was dominated by AL. Short eyes exhibited large refractive changes per millimetre of ELP error, whereas long eyes showed markedly reduced sensitivity. The relationship between refractive error and ELP displacement was nonlinear, resulting in asymmetric refractive effects for equal-magnitude anterior and posterior ELP deviations. TCP continuously modulated refractive sensitivity indirectly through its influence on the emmetropic IOL power required for a given optical configuration. Refractive sensitivity to ELP errors in pseudophakic eye models is inherently nonlinear and asymmetric. This sensitivity is primarily governed by AL, with TCP acting as a secondary but systematic modulator through its effect on emmetropic IOL power. By explicitly separating optical sensitivity from ELP prediction, this vergence-based framework provides a physical basis for understanding ELP-related refractive variability across the biometric spectrum.\n\nID: 41843090\nTitle: [Imaging: new techniques for imaging of the vitreous body].\nAbstract: This review article addresses the central problem that although the vitreous body constitutes approximately 80% of the ocular volume, it can often only be insufficiently clinically assessed due to its transparency. This article therefore emphasizes the necessity for improved diagnostic methods to be able to make a better assessment of the actual role of the vitreous body in health and disease. Diese \u00dcbersichtsarbeit adressiert das zentrale Problem, dass der Glask\u00f6rper \u2013\u00a0obwohl er rund 80\u202f% des okul\u00e4ren Volumens ausmacht\u00a0\u2013 aufgrund seiner Transparenz klinisch oft nur unzureichend beurteilt werden kann. Diese Arbeit hebt damit die Notwendigkeit verbesserter diagnostischer Methoden hervor, um die tats\u00e4chliche Rolle des Glask\u00f6rpers in Gesundheit und Krankheit besser erfassen zu k\u00f6nnen.\n\nID: 41818823\nTitle: Effect of G4C2repeat expansions on the motion of lysosomes inside neurites.\nAbstract: The G4C2hexanucleotide repeat expansion (HRE) in the c9orf72 locus is a mutation associated with amyotrophic lateral sclerosis. Recent evidence suggests a link with disrupted axonal trafficking in neurons. Here, using a neuronal-like cell line without or transfected with G4C2repeats, we characterize the motion of lysosomes inside neurites. The neurites grew either aligned to patterned lines, or oriented freely on a 2D-substrate. Implementing time-resolved (local) mean squared displacement analysis lysosome trajectories were split into sub-diffusive, diffusive, and super-diffusive parts. Our results suggest that in the presence of the G4C2repeats, lysosome trafficking is hampered, exhibiting overall decreased mean squared displacement and speed, more prominently inside aligned neurites. Moreover, a prominent effect in the super-diffusive drift velocity and diffusive motion diffusion coefficient was evident when the motion occurred inside aligned neurites. Trajectories which included super-diffusive motion, exhibited a varied ratio of anterograde/retrograde/neutral for both neurite geometries in the presence of G4C2repeats but a similar velocity decrease for both directions in each neurite geometry. Our findings support the hypothesis that impaired axonal trafficking emerges in the presence of the G4C2HRE, and demonstrate that this effect is more prominent when the neurites are aligned.\n\nID: 41813079\nTitle: OCT-based myopic index: a biological predictor for the progression of high myopia.\nAbstract: The growth of axial length (AL) can lead to high myopia and ocular deformation, especially causing microstructural changes in the fundus, which cannot be fully quantified by AL alone. We propose an optical coherence tomography (OCT)-based modified AL (Myopic Index) to represent the extent of fundus deformation caused by AL elongation and to explore its clinical significance in myopic progression prediction. A deep learning model was trained using 27\u2009539 cases of OCT images and referred ocular biometric data to evaluate the Myopic Index. By comparing the Myopia Index with the Measured AL, the difference of two AL indices (DAL) was calculated. We further prospectively employed 2866 cases of OCT images, which were categorised into short AL (Measured AL<22\u2009mm), normal AL (22 mm\u2264Measured AL<26\u2009mm) and long AL (\u226526\u2009mm), to evaluate the model ability of myopic progression prediction. The attention regions of images were also analysed. The Myopia Index was closely correlated with Measured AL (all p<0.001, R\u00b2=0.804 in all eyes). Specifically, the Myopia Index was closer to the Measured AL in eyes with long ALs, whereas in eyes with short and normal axial lengths, the Myopia Index clustered around 23-24\u2009mm. The visualisation model demonstrated that for eyes with short and normal ALs, attention regions were primarily concentrated on the retina; conversely, for eyes with long ALs, the choroidal layer and the retinal pigment epithelium layer received more attention. Moreover, DAL was significantly correlated with AL increment (p=0.038). The Myopia Index reflects the real status of fundus microstructures through fundus microstructures, with a particular focus on the choroid. The Myopia Index demonstrates good predictive capabilities for high myopia progression.\n\nID: 41796748\nTitle: Accuracy of sixteen axial length adjusted intraocular lens power calculation formulas in long Caucasian eyes.\nAbstract: To compare the accuracy of sixteen intraocular lens (IOL) power calculation formulas incorporating targeted adjustments or regression-based modifications of axial length (AL) in eyes longer than 26.00\u202fmm. Retrospective observational study. The data of myopic patients with cataract who underwent uneventful phacoemulsification with in-the-bag implantation of a PARTIAL-RoF narrow IOL between January 2020 and June 2025 were reviewed. Preoperative IOL power was calculated using the IOLMaster 700 with six formulas: Barrett Universal II (BU II), Haigis, Hoffer Q, Holladay 1, Holladay 2, and SRK/T. The implanted IOL power was selected from BU II or SRK/T recommendations. Refraction was measured three months postoperatively. Postoperative IOL power predictions were generated using the following formulas or formula variants: K6, PEARL-DGS, Castrop, Eom, VRF CMAL; Holladay 1 with Wang-Koch 2 center optimization (WK2), modified Wang-Koch (MWK), non-linear regression (NLR), and Fam-adjusted method (F2); SRK/T WK2, SRK/T MWK, SRK/T F2; Holladay 2 NLR; Hoffer Q WK2; Haigis WK2; and Barrett True AL. The primary outcome measures were root mean square absolute error (RMSAE) and the percentage of eyes with prediction error (PE) within \u00b1 0.25 D, \u00b1 0.50 D, \u00b1 0.75 D, and \u00b1 1.00 D. One hundred sixty-four eyes with ALs ranging from 26.04\u202fmm to 29.72\u202fmm were included. RMSAE values across the sixteen formulas ranged from 0.393 (Holladay 1 NLR and SRK/T WK2) to 0.803 (Haigis WK2). The percentage of eyes with PE within \u00b10.50 D ranged from 35.98% (Haigis WK2) to 81.1% (Holladay 1 NLR). Holladay 1 NLR-followed by SRK/T WK2, Holladay 1 MWK, VRF CMAL, PEARL-DGS, and Eom-demonstrated significantly higher accuracy than most other formulas. Haigis WK2 and Hoffer Q WK2 were the least accurate. Certain modified third-generation formulas (Holladay 1 NLR, SRK/T WK2) achieve accuracy comparable to that of new-generation formulas (PEARL-DGS, K6, VRF CMAL) in IOL power calculations for long eyes. However, some third- and fourth-generation formulas-even after AL-based modification (Hoffer Q WK2, Haigis WK2)-continue to yield suboptimal results in this anatomical range.\n\nID: 41788972\nTitle: Tolcapone Interferes With Key Pathological Features in Alzheimer's Disease.\nAbstract: Tolcapone, a clinically approved drug for the treatment of Parkinson's disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid-\u03b2 aggregation and toxicity, which are hallmark features of Alzheimer's disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age-related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid-\u03b2 and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal-amyloid-\u03b2 species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper-free amyloid-\u03b2 and copper-associated amyloid-\u03b2 complexes, using a combination of techniques including UV-vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid-\u03b2 monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid-\u03b2 for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal-free and metal aggregation pathways by preventing metal coordination to amyloid-\u03b2 or disrupting preformed amyloid-\u03b2-metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.\n\nID: 41785987\nTitle: Spectrum of Colopathy and Severe Polyposis Associated With Pentosan Polysulfate Sodium Maculopathy: A Retrospective Case Series.\nAbstract: To expand the spectrum of gastrointestinal (GI) manifestations associated with pentosan polysulfate sodium (PPS) maculopathy. Retrospective case series. Eight patients (16 eyes) diagnosed with PPS maculopathy who also underwent GI evaluation between 2019 and 2025. Electronic medical records were reviewed for demographics, PPS dosage and duration, ocular findings, GI history, diagnostic presentation, and histopathology. Multimodal imaging included fundus photography, fundus autofluorescence, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography. Colonoscopy was performed in all patients with histopathologic analysis in selected cases. PPS maculopathy was staged according to Wang et al.'s classification system. Genetic testing was obtained in selected cases to exclude any form of inherited maculopathy or familial adenomatous polyposis. Clinical and imaging features of PPS maculopathy and GI pathological diagnosis, including polyposis, dysplasia, and inflammatory bowel disease. The cohort included 6 women and 2 men (median age: 68.5 years). Median PPS exposure was 25.4 years with a median cumulative dose of 2899 grams. At presentation, 62.5% of eyes were stage 1, 31.3% stage 2, and 6.3% stage 3. At final follow-up, 25% of eyes were stage 1, 50% stage 2, and 25% stage 3. Overall, 37.5% of eyes showed progression of maculopathy stage, and cRORA was present in 75% of eyes at last follow-up. Additional findings included acquired vitelliform lesions, outer retinal tubulations, epiretinal membranes, and type 2 macular neovascularization. Colonoscopy revealed severe adenomatous polyposis in 6 of the 8 patients (75%), with 3 requiring partial or total colectomy and 2 undergoing endoscopic resection. One patient developed ulcerative colitis, and 2 additional patients were diagnosed with Crohn's disease or microscopic colitis. The median latency to GI diagnosis was 10 years after PPS initiation. This study expands the recognized systemic toxicity of PPS, demonstrating that PPS maculopathy patients are at risk of concomitant colonic disease, including severe polyposis and dysplasia. The frequent detection of asymptomatic polyposis underscores the importance of colonoscopy screening in exposed patients, even in the absence of GI symptoms. Heightened interdisciplinary awareness and long-term surveillance are warranted to mitigate the vision- and life-threatening consequences of PPS toxicity.\n\nID: 41784766\nTitle: The Impact of Myopia Control Spectacle Lens Designs on Visual Function.\nAbstract: To profile the immediate effect of defocus-modulating and contrast-modulating myopia control spectacle lens interventions on visual function. Healthy myopic (mean spherical equivalent (MSE) -4.25 to -0.50\u2009D) young adults, corrected with contact lenses, wore diffusion optics technology (DOT), defocus incorporated multiple segments (DIMS), highly aspherical lenslets (HAL) and standard single vision (SV) plano trial spectacle lenses, in a prospective, single-visit, double-blind, four-way randomised crossover study. Distance and near high- and low-contrast visual acuity (VA), contrast sensitivity, reading performance, accommodative facility, visual search task and accommodative accuracy were assessed foveally through the central zone (CZ) and/or peripheral zone (PZ) of the lenses. Twenty participants (16\u2009female) were recruited, with a mean (\u00b1SD) age of 22.4 (\u00b12.72) years and MSE -2.21 (\u00b11.10)\u2009D. VAs through the PZ differed significantly between myopia control lenses and SV, with the HAL and DIMS exhibiting lower VA across all testing conditions (all p\u2009<0.05) and DOT demonstrating equivalence to SV with high contrast letters. Contrast sensitivity was similarly reduced for all lenses through the CZ, while HAL and DIMS performed worse than both SV and DOT through the PZ (p\u2009<0.01). Near acuity threshold, reading speed and critical print size through the PZ were comparable for SV, DOT and HAL (all p\u2009>0.05), whereas DIMS exhibited worse near acuity threshold and critical print size (p\u2009<0.001). No significant differences emerged for error score (p\u2009=\u20090.53), accommodative facility refocusing cycles (all p\u2009>0.05) or visual search duration (CZ: p\u2009=\u20090.68; PZ: p\u2009=\u20090.35). Accommodative response was similar across lenses (all p\u2009>0.05); however, SV had lower variability at distance through the PZ than DOT, HAL and DIMS (p\u2009<0.001). All three myopia control lenses exhibited visual performance comparable to standard SV lenses through the CZ. Clinicians should note differences in visual performance, especially VA and reading speed through the lens periphery and their relative testing.\n\nID: 41739160\nTitle: [On the urgency of treating ophthalmic emergencies].\nAbstract: In emergencies in ophthalmology a\u00a0distinction must be made between systemic emergency situations that manifest in the eye and purely ocular emergencies. The latter threaten vision to varying degrees and therefore require differentiated treatment and care by the ophthalmologist. This requires considerable responsibility and high expertise as all subdisciplines of ophthalmology can be affected. Due to demographic developments and other factors, the number of emergency patients is increasing, which requires adaptation in resources and clinical management of patients. Bei Notf\u00e4llen in der Augenheilkunde ist zwischen systemischen Notfallsituationen, die sich am Auge manifestieren, und rein okul\u00e4ren Notf\u00e4llen zu unterscheiden. Letztere bedrohen das Sehverm\u00f6gen in ganz unterschiedlichem Ausma\u00df und bed\u00fcrfen daher ophthalmologischerseits einer differenzierten Betrachtung und Versorgung. Diese erfordert besondere Verantwortung und gro\u00dfe Kompetenz, da alle Subdisziplinen der Augenheilkunde betroffen sein k\u00f6nnen. Nicht zuletzt wegen der demografischen Entwicklung nimmt die Anzahl der Notfallpatienten zu, was eine bessere Steuerung der Patienten erfordert.\n\nID: 41702277\nTitle: Trace metal signatures in cerebrospinal fluid (CSF): Insights from an amyotrophic lateral sclerosis (ALS) hotspot on Mount Etna (Sicily, Italy).\nAbstract: Chronic exposure to trace metals has been increasingly recognized as a possible factor influencing the risk of amyotrophic lateral sclerosis (ALS). In the province of Catania, on the eastern slopes of Mount Etna, epidemiological investigations have highlighted the presence of a high-incidence cluster of the disease. Against this backdrop, the present study was designed to explore whether the concentrations of trace elements in cerebrospinal fluid (CSF) differ between ALS patients residing in this high-incidence area (In-Cluster) and those living in regions with lower incidence (Out-Cluster). For trace element analysis, CSF was analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Fourteen metals (Al, V, Mn, Co, Ni, Cu, Zn, As, Cd, Hg, Pb, Fe, Se, Mg) were quantified in standard and KED modes. No single metal concentration differed significantly between In-Cluster and Out-Cluster groups. However, In-Cluster patients frequently showed higher upper quartiles for Al, Mn, As, Hg, and Se, suggesting broader variability. Ratio analysis highlighted significant differences between groups, with higher Al/Cu ratios observed in In-Cluster patients. Sex-stratified analysis further revealed increased Mn-based ratios in females, with a significantly elevated Mn/Pb ratio. These patterns indicate possible dysregulation of trace metal homeostasis linked to environmental exposure. In conclusion, although statistical significance was limited, our findings suggest that chronic volcanic ash exposure may contribute to subtle imbalances between neurotoxic and neuroprotective elements in CSF, potentially influencing ALS susceptibility. Further studies integrating environmental monitoring, speciation analysis, and larger cohorts are needed to clarify the role of trace metals in ALS pathogenesis.\n\nID: 41665722\nTitle: Recombinant AMPs (Epinecidin-1 and its Variants): A New Hope against Invasive Fungal Infections against Candida spp. and Aspergillus flavus.\nAbstract: To enhance stability and antimicrobial efficacy of antimicrobial peptide (AMP) epinecidin-1, we previously engineered three variants - GK-epi-1, Variant-1 and Variant-2-by substituting alanine and histidine residues with lysine. Our current study focuses on the antifungal capabilities of Epinecidin-1 and its variants against the clinical isolates of Candida spp. (Candida albicans, C. tropicalis, C. krusei & C. glabrata) and Aspergillus flavus. Computational docking studies are evidenced, the peptides had strong affinity against all fungal receptor examined which indicates their efficacy to interact with the Candida cell membrane receptors (Exo-B-(1,3)-Glucanase, Secreted aspartic proteinase (SAP) 1 & N-terminal domain adhesin: Als 9\u2009-\u20092). Minimum Inhibitory Concentration (MIC), Minimum Fungicidal Concentration (MFC) and antibiofilm assays revealed its potent antifungal activity, particularly in disrupting biofilm formation. Effects of peptides on hyphal growth inhibition activity and Scanning Electron Microscopy (SEM) confirmed that the mechanism of action involves pore formation, hyphal disruption and induction of reactive oxygen species in Candida cell membrane. The antifungal spectrum was extended to A. flavus, a known ocular pathogen, where combination therapy using sub-inhibitory concentrations of Epinecidin-1 and its variant peptides with Amphotericin B and Miconazole showed enhanced synergistic effects, reducing required dosages for effective pathogen control.\n\nID: 41652471\nTitle: Large-scale mapping of the MCH network in ALS mice reveals the vulnerability of dopaminergic and GABAergic neurons in zona incerta.\nAbstract: Weight loss and hypermetabolism are early and prognostically significant features of amyotrophic lateral sclerosis (ALS) and are associated with hypothalamic atrophy and degeneration of melanin-concentrating hormone (MCH) neurons that regulate energy balance. To investigate whether MCH vulnerability arises from upstream network dysfunction, we performed whole-brain retrograde rabies tracing in SOD1G93A mice. We identified an early, selective loss of monosynaptic inputs from the zona incerta (ZI), a dopaminergic (DA)/gamma-aminobutyric acid (GABA)ergic nucleus that preceded MCH neuron degeneration. Neurochemical profiling confirmed the DA/GABAergic identity of these ZI input neurons, and ZI/DAergic neurons later degenerated. ALS-related pathology emerged early in the ZI, paralleling pathology in the motor cortex, while anterograde mapping revealed that motor cortical projections preferentially targeted the ZI, linking vulnerable motor and metabolic networks. Loss of ZI/DAergic neurons was observed in conjunction with weight loss in non-SOD1 ALS models. These findings identify the ZI as an early-affected node within hypothalamic networks and suggest that disruption of DA/GABAergic inputs to MCH neurons is associated with subsequent MCH and DA neuronal vulnerability, degeneration and metabolic imbalance in ALS.\n\nID: 41621861\nTitle: Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice.\nAbstract: Methylmercury (MeHg) is a global pollutant that readily crosses the blood-brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the effect of fetal exposure remains poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90-120 (P90-120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes (n = 4/group) in multiple pathways associated with neurodegeneration, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation.\n\nID: 41598508\nTitle: Surgical Outcomes and Differences in Values of Ocular Parameters Following Vitrectomy for Macular Hole over a 10-Year Period.\nAbstract: Background/Objectives: We aimed to compare the surgical outcomes of macular hole (MH) cases and evaluate how the axial length (AL) affected the outcomes. Methods: Six hundred and sixty-three eyes with MHs that underwent vitrectomy over the past 10 years were reviewed. The changes in AL were compared to those of 1948 eyes with idiopathic epiretinal membranes (ERMs) operated on during the same period. The MH cases for the 5 years from 2014 to 2018 were designated as the MH2014 group, and those from 2019 to 2023 as the MH2019 group. The ERM cases were divided similarly into the ERM2014 and ERM2019 groups. The clinical characteristics of the cases and surgical outcomes were compared. Results: The MH diameter, closure rate, and baseline and postoperative visual acuity were not significantly different. The use of the inverted internal limiting membrane flap technique was significantly higher in the MH2019 group (58%) than in the MH2014 group (24%, p < 0.001). The mean AL was significantly longer in the MH2019 group (25.2 \u00b1 2.4 mm) than in the MH2014 group (24.6 \u00b1 2.1 mm, p = 0.004). The incidence of myopic MHs with AL \u2265 26 mm and AL \u2265 30 mm was higher in the MH2019 group (30.9%, p = 0.008, 6.4%, p = 0.017, respectively). There was a significant trend for longer ALs over 10 years in the MH group (p = 0.002), but not in the ERM group. Conclusions: The increased AL and the rising proportion of eyes with myopic MHs indicate that the patient profile of eyes with MHs has changed over the past decade.\n\nID: 41517507\nTitle: Evolution of Retinal Morphology Changes in Amyotrophic Lateral Sclerosis.\nAbstract: Background/Objectives: To compare changes in the thickness of retinal layers between patients with amyotrophic lateral sclerosis (ALS) and healthy controls using optical coherence tomography. Amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motoneurons with a rapidly progressive course, but non-motor symptoms such as decreased ocular motility and reduced visual acuity have also been reported. Specific biomarkers or surrogate parameters assessing neurodegeneration in ALS are of interest. Methods: In a retrospective, longitudinal study using optic coherence tomography of the retinal layers, we compared changes in the thickness of the layers between patients with ALS and healthy controls. Correlations to clinical scores, such as the modified ranking scale, were analyzed. Results: In our cohort of patients with early ALS (disease duration 5.15 \u00b1 21.4 months at baseline), we neither observed differences in retinal layer thickness at baseline nor did the thickness changes in any retinal layer differ in comparison to healthy controls at baseline. Moreover, we observed no significant thickness changes over the course of the observational period in our patients with ALS. However, a correlation analysis revealed a negative association of the thickness change rates in the complex of ganglion cell and inner plexiform layer and the inner nuclear layer with a higher modified Rankin scale at follow-up. Conclusions: This study adds to the notion that OCT may not be a suitable tool to monitor atrophy and disease progression in ALS. However, further longitudinal studies with longer follow-up times and larger cohorts are warranted.\n\nID: 41463293\nTitle: Human Mutant Dynactin Subunit 1 Causes Profound Motor Neuron Disease Consistent with Possible Mechanisms Involving Axonopathy, Mitochondriopathy, Protein Nitration, and T-Cell-Mediated Cytolysis.\nAbstract: Mutations in the gene encoding the p150 subunit of the dynactin complex (DCTN1) are linked to amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Perry syndrome. These neurodegenerative diseases can cause muscle weakness and atrophy, parkinsonian-like symptoms, and paralysis. To examine the evolution of neuropathology caused by a mutation in DCTN1 and cellular mechanisms of disease for therapeutic discovery, we characterized mice expressing either human wildtype or mutant (G59S) DCTN1. Neuron-specific expression of mutant, but not wildtype, DCTN1 caused fatal age-related paralytic disease and motor neuron (MN) degeneration in the spinal cord with axonopathy and chromatolysis without apoptotic morphology. MNs became positive for cleaved caspase-3, cleaved caspase-8, and nitrated Hsp90. Mitochondria accumulated and appeared fragmented and dysmorphic and then were lost. This pathology was accompanied by invasion of CD95- and CD8-positive mononuclear T cells into the ventral horn and accumulation of TNF\u03b1 and IL9. Administration of the mitochondrial division inhibitor-1 (Mdivi-1) protected MNs and extended the lifespan of G59S-DCTN1 mice. A mitochondrial permeability transition pore inhibitor also extended lifespan. Thus, mutant DCTN1 causes degeneration of MNs associated with axonopathy, mitochondriopathy, nitrative stress, and caspase activation. It appears as retrograde neurodegeneration and inflammatory T-cell-like cytolysis. Mitochondria are possible therapeutic targets in DCTN1-linked neurodegenerative disorders.\n\nID: 41457335\nTitle: Letter to the Editor: Comment on Palmieri et al.'s \"Uveitis Following Intravitreal Injections of Faricimab: A Case Report\".\nAbstract: The article provides valuable insight on presentation and management of isolated anterior uveitis and with vitritis following intravitreal (IVT) faricimab. We highlight additional points. First sterile intraocular inflammation (IOI) onset ranges from 1-35 days; however, two patterns have been described: acute onset within 5 days and delayed onset at approximately 14 days following a mean of four IVT injections, although it may occur after the first. Sterile IOI may be recognised by delayed onset, suggestive of a type IV hypersensitivity reaction rather than infectious causes and by absence of hypopyon, although may present in severe cases. Second, faricimab's dual inhibition may alter ocular immune surveillance, potentially facilitating herpes simplex virus reactivation. Increased vigilance for dendritic ulcers is therefore warranted, and antiviral therapy should be initiated prior to corticosteroids. Finally, management should be guided by severity, with anterior or vitreous tap considered to exclude exogenous endophthalmitis. Resolution typically occurs within 15 days.\n\nID: 41334909\nTitle: Herpes simplex virus 1 strain 17+ with R2 mutation in UL37 has residual retrograde transport.\nAbstract: Herpes simplex virus 1 (HSV-1) causes lifelong recurrent infections. Following primary infection of the oral or genital mucosa, HSV-1 travels retrogradely through axons and establishes latency in the cell body of ganglionic neurons of the peripheral nervous system. Periodic reactivation in neurons and anterograde transport of virions back to peripheral regions cause oral or genital ulcerations. Many host and viral factors implicated in retrograde and anterograde transport of HSV-1 have been identified. In particular, studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate retrograde transport of HSV-1 strain F. Here, we introduced the same R2 mutations in the highly neurovirulent HSV-1 strain 17+. We show that this R217 virus is highly attenuated in mice and acts as a potent vaccine that protects mice against acute HSV-1 infection. However, we report that the R217 virus has residual retrograde transport. We show that R217 can establish latency in mouse models of ocular and vaginal infection and reactivate. These results contradict published evidence and show that the R2 mutation is not sufficient to fully prevent retrograde transport of HSV-1. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen without a cure or vaccine. HSV-1 travels through nerves between the oral and genital mucosa and the peripheral nervous system, where it establishes lifelong latency. Studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate the retrograde transport of HSV-1 strain F from the mucosa to the nervous system. Here, we present contradictory findings. We report that an HSV-1 virus from strain 17+ with the same R2 mutation has residual retrograde transport. This shows that the R2 mutation is not sufficient to fully prevent the retrograde transport of HSV-1 in all settings. This finding may be particularly relevant for assessing the safety of prospective live-attenuated vaccines that include the R2 mutation.\n\nID: 41214888\nTitle: Comparison of ocular biometry and refractive outcome between a new and classic optical biometer.\nAbstract: To compare the ocular biometry and refractive outcome between 2 optical biometers. Zhongshan Ophthalmic Center, Guangzhou, China. Prospective observational study. 953 patients with cataract underwent preoperative biometry including ZW-30 sum-of-segments (SOS) method (ZW SM ), ZW-30 composite method (ZW CM ), and IOLMaster 700. Agreement of axial length (AL), with or without Cooke-modified AL (CMAL) adjustment, was analyzed using Bland-Altman 95% limits of agreement (LoA). Subgroup analysis was used based on ALs (short eyes: AL <22 mm; normal eyes: 22 mm \u2264 AL <26 mm; long eyes: AL \u226526 mm). Refractive prediction accuracy was evaluated using the Emmetropia verifying optical (EVO) 2.0 formula and its SOS-optimized version (EVO 2.0 SOS ). In short and normal eyes, narrow 95% LoAs (<0.2 mm) were identified among 3 ALs. However, AL obtained by ZW SM was lower compared with this obtained by ZW CM and IOLMaster 700 (95% LoA -0.39 to 0.01 mm; -0.38 to 0.04 mm) in long eyes. CMAL adjustment enhanced the agreement of AL between ZW SM and ZW CM (95% LoA -0.01 mm to 0.02 mm), ZW SM and IOLMaster 700 (95% LoA -0.10 mm to 0.07 mm) in long eyes. Myopic prediction errors (PE) have been identified in the use of ocular biometric parameters obtained from ZW SM (mean PE [ME]: EVO 2.0, -0.19 diopters [D]; EVO 2.0 SOS , -0.18 D). After adjusting ME to zero, no difference was observed in PE calculated using any combination of formulas based on biometric measurements from 3 devices. This new segmented biometer demonstrated excellent agreement with IOLMaster 700 in short and normal eyes. However, ALs obtained by IOLMaster 700 are not interchangeable with the SOS method and require CMAL adjustment in long eyes. The application of the SOS method's ocular biometric parameters in refractive prediction led to myopic errors, which suggests constant optimization.\n\nID: 41213652\nTitle: Letter to the Editor: Comment on Ku\u010d et al.'s \"Smoking and Risk of Uveitis: A Systematic Review and Meta-Analysis\".\nAbstract: \n\nID: 41145518\nTitle: Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model.\nAbstract: Selective neuronal vulnerability is a defining feature of neurodegenerative disorders, exemplified by motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The nature of motor neurons underlying this selectivity remains unresolved. Here, by monitoring autophagy at single-cell resolution across the translucent zebrafish spinal cord, we identify motor neurons as the cell population with the highest autophagic flux. Large spinal motor neurons (SMNs), most susceptible to ALS, exhibit higher flux compared to smaller SMNs and ALS-resistant ocular motor neurons. Notably, large SMNs accelerates both autophagy and proteasome-mediated degradation, which are further augmented by TDP-43 loss. Additionally, acceleration of multiple unfolded protein response pathways indicates their innate tendency to accumulate misfolded proteins. Enhanced cellular degradation in large SMNs is neuroprotective as its inhibition halts axon outgrowth. These findings propose that cell size-associated degradation load underlies selective neuronal vulnerability in ALS, highlighting the alleviation of catabolic stress as a target of therapy and prevention.\n\nID: 41092899\nTitle: Neurovascular dynamics in the spinal cord from development to pathophysiology.\nAbstract: The vasculature is increasingly recognized as an active regulator of homeostasis and repair, beyond conventional roles in nutrient delivery. In the central nervous system, vascular cells adopt region-specific traits tailored to the distinct demands of the brain, retina, and spinal cord. Despite long-standing interest in the spinal cord as a model for neural development and injury, its vascular organization and properties remain understudied. The assumption that spinal cord and brain neurovascular systems are built and function in the same way has limited progress. Here, we challenge this view by examining specific properties underlying spinal cord vascular development, physiology, and pathology. We highlight unique angioarchitecture and homeostatic mechanisms, and discuss how neurovascular disruption contributes to spinal disorders and regenerative failure after injury. Identifying critical knowledge gaps, we aim to stimulate new research in spinal cord neurovascular biology, redefining its importance for health and disease.\n\nID: 41029500\nTitle: Correlation between refractive errors and ocular biometric parameters at Al-Mustaqbal University, Iraq.\nAbstract: To establish the relationship between ocular biometry and refractive errors in young adult Iraqis by analyzing three critical biometric ocular parameters, including axial length (AL), corneal radius (CR), and central corneal thickness (CCT). A cross-sectional study was conducted on individuals aged 18-33 years at Al-Mustaqbal University, Iraq, including 1841 participants (3682 eyes). Quantitative measurements of AL, CR, and CCT were obtained using an Auto Kerato-Refractometer, IOL Master, and pachymetry techniques. Statistical analyses included Pearson correlation, multiple linear regression, one-way ANOVA, and independent samples t-tests to compare biometric parameters between refractive error groups. Generalized Estimating Equations (GEE) were applied to account for the correlation between fellow eyes. The overall mean AL was 24.45\u2009\u00b1\u20091.10\u00a0mm, mean CR was 7.37\u2009\u00b1\u20090.77\u00a0mm, and mean CCT was 555.83\u2009\u00b1\u200950.83\u00a0\u03bcm. Myopic participants had a significantly longer AL (25.11\u2009\u00b1\u20090.42\u00a0mm) compared to hyperopic participants (22.71\u2009\u00b1\u20090.65\u00a0mm; p\u2009<\u20090.001). Likewise, myopic eyes had significantly thicker corneas (CCT: 565.62\u2009\u00b1\u200912.68\u00a0\u03bcm) than hyperopic eyes (495.42\u2009\u00b1\u200918.74\u00a0\u03bcm; p\u2009<\u20090.001), as determined by independent samples t-tests. Females exhibited slightly longer ALs than males across both myopic and hyperopic groups (p\u2009<\u20090.0001). Regression analysis showed that AL was the strongest predictor of spherical equivalent (SE), followed by CR and CCT. The regression model including AL and CR explained 94.5% of the variance in SE (R\u00b2 = 0.945). The findings confirm that AL and CCT are strongly associated with refractive errors, with AL being a primary determinant. This study highlights the role of gender differences in biometric ocular parameters and provides valuable insights into the prevalence of refractive errors in young adults in Iraq. These results can inform future public health initiatives aimed at addressing refractive errors in this population.\n\nID: 41021147\nTitle: Iron and Ferritin Dyshomeostasis Intersect with Sex, Age, and Disease Severity in Amyotrophic Lateral Sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor neurons. Due to heterogeneity in both cause and clinical phenotype, accuracy of diagnosis and efficacy of treatment remain challenging. An evolving body of evidence point to the importance of the \"gene-time-environment\" hypothesis in ALS onset and progression. Despite extensive research, understanding of the complex environmental risk factors remains fragmented. In this study, we comprehensively analyzed the associations between trace elements, biochemical signatures, and modifiable risk factors among ALS patients stratified by age, sex, type of onset, disease severity, and progression. Specifically, we investigated blood concentrations of cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), and iron (Fe) levels in 121 participants. Moreover, we examined the associations between trace metals, biochemical indicators including serum ferritin (SF), blood glucose, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), cerebrospinal fluid (CSF) cell count, CSF total protein, as well as history of hypertension, hazardous chemical exposure, drinking, and smoking in ALS patients. Specifically, we report that high Fe levels were found in male and spinal-onset patients. Moreover, high serum ferritin was positively associated with age of onset, blood iron and glucose, as well as high disease severity. Results from this study highlight the complex characteristics of ALS and provide new insight for understanding the intricate relationship between disease phenotype, metal homeostasis, and modifiable risk factors.\n\nID: 41004400\nTitle: Atypical features including acquired oculomotor apraxia in C9orf72-associated familial primary lateral sclerosis.\nAbstract: The phenotypic variability of C9orf72-associated disease is broadening, including atypical and non-motor presentations. C9orf72-associated neurodegeneration has only rarely been associated with primary lateral sclerosis (PLS), and even more rarely with ocular motor apraxia. Describe a family with C9orf72 mutation presenting with frontotemporal dementia (FTD) and atypical PLS phenotypes and discuss the implications regarding 1) where PLS lies on the ALS-FTD spectrum, and 2) how C9orf72 mutations influence PLS clinically. Chart review. A 52-year-old male experiencing 4 months of progressive right lower leg spasticity with a family history of FTD was referred to us. Within 15 months, he was anarthric and required a powered wheelchair. He developed acquired ocular motor apraxia, consistent with supranuclear ophthalmoplegia. He later developed laryngeal dystonia which led to his death. Ten years later, his 67-year-old brother presented with 8 months of progressive spastic dysarthria, hyperreflexia, right foot drop, and right facial weakness. Genetic testing revealed heterozygous C9orf72 hexanucleotide repeat expansion. This family's presentation expands on sparse reports of C9orf72-associated PLS. The proband showcases a severity of ocular motor deficits not yet reported in PLS, extending ocular motor findings in MND. These deficits also provide clinical evidence of degeneration outside the motor cortex/spinal cord in PLS. The symptomatology (laryngeal dystonia, rapid progression) clinically overlaps with ALS/FTD, suggesting PLS may lie on the ALS-FTD spectrum. The severity and atypicality of this case also support suggestions that C9orf72 mutations amplify the spectrum/severity of disease observed in TDP-43 proteinopathies.\n\nID: 40986613\nTitle: Theoretical influence of segmented axial length on intraocular lens power calculation in short eyes.\nAbstract: To compare the segmented axial length (AL) provided by the Argos with the traditional AL provided by the IOLMaster 700 in short eyes and assess their impact on intraocular lens (IOL) power calculation. IRCCS Bietti Foundation, Rome, Italy. Retrospective case series. Patients undergoing cataract or refractive surgery preoperative examinations were enrolled if their AL was <22.0 mm with the IOLMaster 700. The ALs given by the 2 biometers were compared. Using the formulas included in the ESCRS IOL calculator, the IOL power for a schematic eye was calculated with both AL measurements. In 78 eyes, the traditional mean AL (21.22 \u00b1 0.54 mm) was shorter than the segmented AL (21.29 \u00b1 0.51 mm, P < .0001) with a proportional bias (r2 = 0.3312, P < .0001). The difference decreased with thicker lenses (r2 = 0.4941, P < .0001). Based on the IOL power calculated when the traditional AL was entered and the first negative refractive value was aimed at, the predicted refraction was more myopic with the Argos AL (P < .0001). The difference ranged from -0.18 \u00b1 0.13 D (Cooke K6) to -0.24 \u00b1 0.18 D (Barrett Universal II). The same IOL power would have been recommended by the ESCRS IOL calculator in only 40% to 50% of eyes, irrespective of formula used. The difference was minimized when the sum-of-segments option was used. AL measurements provided by the Argos and IOLMaster 700 are not interchangeable for IOL power calculation in short eyes <22.0 mm.\n\nID: 40971912\nTitle: Intraocular lens power calculation formula accuracy in 1178 eyes with short axial length: systematic review and network meta-analysis.\nAbstract: To systematically review the literature and conduct a comprehensive quantitative analysis to compare the accuracy of different intraocular lens (IOL) calculation formulas in eyes with short axial lengths (ALs). The precision of the IOL formulas decreases when applied in eyes with short AL (AL <22 mm), and many new formulas for calculating IOL power have been proposed in the past few decades. However, the accuracy of these formulas has not been systematically compared when applied in eyes with short AL. This study systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases to collect relevant research literature published between January 2003 and September 2023. Included were prospective or retrospective clinical studies involving cataract patients with short AL (AL <22 mm) and reporting the following outcomes: mean absolute error, median absolute error (MedAE), and percentage of eyes with a prediction error (PE) within \u00b10.25 diopters (D), \u00b10.50 D, and \u00b11.00 D. A network meta-analysis was performed using R software (v. 4.2.1). 15 prospective or retrospective studies involving 1178 eyes and 12 calculation formulas were included in this study. The network meta-analysis showed that compared with the widely used Haigis formula, the Kane formula had a higher percentage of eyes with PE within the range of \u00b10.25 D, \u00b10.50 D, and \u00b11.00 D (all odds ratio >1, but P > .05). In addition, based on the surface under the cumulative ranking area (SUCRA), the Kane formula had the highest probability of predicting the PE of the eyes within the range of \u00b10.25 D, with its SUCRA value of 95.74%, followed by Haigis formula (94.79%) and Olsen Standalone formula (84.04%). The Kane and Olsen Standalone formulas had the lowest MedAE. The Kane, Haigis, and Olsen Standalone formulas may perform better than other formulas in calculating the IOLs power in eyes with short AL. Nonetheless, significant uncertainty remains in this area. The accuracy of these formulas in patients with short AL needs to be verified by large multicenter registry studies.\n\nID: 40971256\nTitle: Comment on: Changes in Aqueous Humor Cytokines and Metabolomics in Contralateral Eye After Unilateral Cataract Surgery.\nAbstract: We extend Li et al.'s investigation of aqueous humor (AH) metabolomics in sequential cataract surgery by referencing our prior study on interocular symmetry/asymmetry in AH metabolomic profiles from simultaneous bilateral cataract surgery in emmetropic patients, which demonstrated similar AH compositions in fellow eyes. We also illustrate variability with 2 sequential-surgery cases and highlight the most and least variable metabolites across 6 biochemical classes. Taken together with Li et al., these observations support careful attribution of second-eye changes to surgery versus biology. To extend the findings of Li et al. on AH metabolomics in sequential cataract surgery by incorporating reference data on interocular symmetry/asymmetry in AH metabolomic profiles and illustrating variability in sequential cases. We drew on our prior study of simultaneous bilateral cataract surgery in emmetropic patients, which demonstrated high interocular similarity, and examined AH metabolomic variability in 2 patients undergoing sequential cataract surgery. Baseline interocular comparisons highlight metabolic symmetry in the AH among patients undergoing simultaneous cataract surgery. In 2 additional cases, we identified the most and least variable metabolites across 6 biochemical classes among patients undergoing sequential cataract surgery, complementing the observations of Li et al.Conclusion:Our reference data help contextualize Li et al.'s results. Although based on limited cases, our findings emphasize the need for caution when interpreting AH metabolomics in sequential surgery to distinguish true intra- and inter-individual biological variability from potential surgical effects on the second eye. Multimodal approaches integrating metabolomic and vascular metrics may improve biomarker selection and inform surgical timing.\n\nID: 40838943\nTitle: Choroidal Thickness Distribution and Its Association With Axial Length and Spherical Equivalent in Schoolchildren Assessed by Wide-Field Swept-Source Optical Coherence Tomography.\nAbstract: The purpose of this study was to evaluate the distribution of choroidal thickness (ChT) in schoolchildren using wide-field swept-source optical coherence tomography (SS-OCT) and to investigate its association with axial length (AL) and spherical equivalent (SE). This prospective study included 176 eyes from 88 healthy Japanese schoolchildren aged 6 to 15 years (mean age = 9.9 \u00b1 2.4 years). Wide-field SS-OCT was used to measure ChT across a 57 degrees \u00d7 57 degrees fundus area. After excluding poor-quality images, 169 eyes were included in the final analysis. The ChT distribution was evaluated by dividing the obtained images into a 3 \u00d7 3 grid comprising 9 sections. ChT measurements were performed automatically with custom-designed software. ChT values were compared among the nine regions, and correlations with AL and SE were assessed for each grid section. Additionally, the findings in schoolchildren were compared with historical data from adults. Mean ChT values across the 9 regions ranged from 172 \u00b1 29 \u00b5m in the nasal-inferior region to 307 \u00b1 39 \u00b5m in the temporal region. The choroid was thicker in the temporal and macular regions and thinner around the optic disc and inferior regions. Significant negative correlations were found between ChT and AL across all regions (R = -0.50 to -0.23, P < 0.05), indicating that longer ALs were associated with thinner choroids. Similarly, significant positive correlations were observed between ChT and SE (R = 0.19 to 0.55, P < 0.05), demonstrating that higher degrees of myopia were associated with thinner choroids. Moreover, ChT in schoolchildren was generally thicker compared to that in adults. This study provides a detailed analysis of ChT distribution in schoolchildren, revealing regional variability and a generally thicker choroid compared with adults. The significant correlations between ChT, AL, and SE across all regions suggest a potential role for ChT in ocular growth and myopia progression. These findings underscore the need for longitudinal studies to investigate causal relationships between ChT distribution and myopia development. Wide-field choroidal mapping identifies early structural biomarkers for pediatric myopia progression and control.\n\nID: 40819701\nTitle: Ocular manifestations in Dengue Fever: A Systematic Review and Meta-Analysis.\nAbstract: Ocular manifestations in dengue fever remain underrecognized despite reports of vision-threatening complications. This systematic review and meta-analysis aimed to determine the pooled prevalence of ocular manifestations in dengue patients, characterizing their spectrum, frequency, and clinical significance. Dengue fever affects millions globally, predominantly in tropical regions. While systemic complications are well documented, ophthalmic involvement remains poorly defined, with variable prevalence estimates and unclear risk factors. Early recognition is crucial for timely intervention, particularly in endemic areas where clinical suspicion is low. A comprehensive search was conducted in PubMed, CINAHL, and LILACS. Eligible studies included observational studies reporting the prevalence of ocular manifestations in dengue patients. Risk of bias was assessed using Hoy et al.'s tool for prevalence studies. Pooled prevalence estimates were calculated using a random-effects model, and heterogeneity was assessed using I2 statistics. A total of 32 studies, including 11,426 patients, were included. The pooled prevalence of ocular manifestations, calculated from 16 studies, was 0.32 (95% CI: 0.22-0.45, I2 = 91.8%). Retro-ocular pain had a pooled prevalence of 0.20 (95% CI: 0.10-0.37, I2 = 99.6%), while blurred vision was reported in 0.11 (95% CI: 0.05-0.23, I2 = 92.8%). Among structural manifestations, subconjunctival hemorrhage had a prevalence of 0.18 (95% CI: 0.10-0.30, I2 = 94.1%), retinal hemorrhage 0.08 (95% CI: 0.05-0.12, I2 = 77.8%), maculopathy 0.04 (95% CI: 0.02-0.08, I2 = 91.6%), and uveitis 0.05 (95% CI: 0.01-0.24, I2 = 97.4%). Significant heterogeneity was observed across studies, likely due to differences in diagnostic criteria, study populations, and disease severity. This study highlights a substantial prevalence of ocular manifestations in dengue patients, emphasizing the need for increased clinical awareness, particularly in endemic regions. Given the heterogeneity in reported prevalence, future research should focus on prospective, standardized ophthalmologic assessments to improve early diagnosis and management.\n\nID: 40777082\nTitle: Investigation of early axonal phenotypes in an iPSC-derived ALS cellular model using a microfluidic device.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of upper and lower motor neurons. Mutations in the FUS/TLS gene have been reported as the second most common mutation in Japanese patients with familial ALS. In recent years, lower motor neurons (LMNs) differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients have been widely used to analyze the mechanisms of neuronal cell death and degeneration. In this study, we developed a microfluidic device designed to observe axonal growth, morphology, and trafficking at high resolution in neurons derived from induced pluripotent stem cells (iPSCs) and tested whether our microfluidic device effectively evaluates neurodegenerative phenotypes. We used iPSCs carrying homozygous FUS/TLS mutations (FUS_H517D) to induce LMNs by expressing NEUROG2, ISL1, and LHX3 under the control of the tetracycline regulation system. After seven days of in vitro differentiation (DIV7), we confirmed that over 95% of iPSCs differentiated into HB9-positive LMNs. Notably, the cell viability of FUS_H517D LMNs was comparable to that of LMNs differentiated from iPSCs without the FUS/TLS mutation at DIV7. However, by DIV14 and DIV21, the viability of FUS_H517D LMNs was notably lower than that of control LMNs, indicating degeneration of FUS_H517D LMNs after differentiation. Using our microfluidic device, we assessed axonal phenotypes in FUS_H517D LMNs. Under oxidative stress conditions, we observed that the axonal length of FUS_H517D LMNs was significantly shorter than that of control cells as early as DIV7, with this axonal growth restriction becoming more pronounced by DIV11. This suggests that axonal growth restriction is an early detectable phenotype in degenerating neurons. Additionally, we examined mitochondrial trafficking within axons in our device, which is often disrupted in degenerative neurons. Our results showed a significant increase in the number of motile mitochondria in FUS_H517D LMNs, with retrograde transport accounting for a large portion of trafficking. Our microfluidic device-based culture and evaluation system using FUS_H517D LMNs offers a valuable ALS cellular model focused on early axonal phenotypes. This approach contributes to the study of molecular mechanisms underlying axonal degeneration in ALS.\n\nID: 40755069\nTitle: Improvement in Patient-Reported Symptoms of Generalised Myasthenia Gravis With Rozanolixizumab in the Randomised Phase 3 MycarinG Study Using the MG Symptoms PRO.\nAbstract: In the Phase 3 MycarinG study (NCT03971422), rozanolixizumab improved myasthenia gravis (MG)-specific outcomes versus placebo in patients with generalised MG, including those measured by the five independent MG Symptoms patient-reported outcome (PRO) scales: Muscle Weakness Fatigability (MWF), Physical Fatigue (PF) and Bulbar Muscle Weakness (BMW) as secondary endpoints and Ocular Muscle Weakness and Respiratory Muscle Weakness (exploratory endpoints). This research aimed to provide further insights into these improvements. Post hoc analyses evaluated correlation (Pearson coefficient) between MG Symptoms PRO and subdomain scores of MG Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) at baseline. Proportions of responders reaching clinically meaningful thresholds and analyses at the item level (observed mean change and Rasch modelling of predicted change from baseline) are reported for MWF, PF, and BMW with rozanolixizumab versus placebo at Day 43. Correlation coefficients between MG Symptoms PRO and MG-ADL were strong (\u2265\u20090.7) for ocular and bulbar scores and moderate (0.5 to <\u20090.7) for other scores. Correlations with clinician-assessed QMG scores were generally weak (<\u20090.5). For MWF, PF, and BMW, greater proportions of responders were observed with rozanolixizumab 7\u2009mg/kg (46.9%, 31.3% and 26.6%, respectively) or 10\u2009mg/kg (56.5%, 48.4% and 32.3%) versus placebo (28.1%, 26.6% and 10.9%). Item-level analyses demonstrated rozanolixizumab benefit at a symptom-specific level. MG Symptoms PRO scales correlate well with concepts in MG-ADL while assessing additional concepts, such as PF and MWF. Results from the MG Symptoms PRO in MycarinG reflected improvements from baseline in patient-relevant symptoms, including fatigue, with rozanolixizumab.\n\nID: 40736059\nTitle: Effect of Defocus Incorporated Multiple Segments (Fog Vision +0.50 D) Combined With 0.01% Atropine on the Preclinical and Early Stages of Myopia in Children.\nAbstract: To retrospectively analyze the efficacy of multi-zone positive optical defocus lenses (DIMS) + fog vision + 0.01% atropine for the treatment of children with preclinical and early stages of myopia. The axial length (AL) and refraction were analyzed at baseline and after 12 months of follow-up in 192 eyes treated with combined therapy. The success of treatment was defined as an annual AL growth rate within the physiological growth range and myopia progression of -0.50 diopters (D)/year or greater. Subgroup analysis was performed to investigate the percentage of treatment success in the overall population compared to the subgroups based on baseline AL and age. Overall, the success rates were 87% and 93% for AL control and myopia control, respectively. Compared to before combined therapy, there was an increase in AL after treatment (boys: P < .001; girls: P < .001). The change in spherical equivalent (SE) was consistent with the change in AL, with both boys and girls showing an increase in SE after treatment, with a statistically significant difference in girls (boys: P = .059; girls: P = .001). There was no statistically significant difference in the percentage of treatment success in either boys or girls based on baseline AL and age subgroups compared to the overall population. The treatment regimen of DIMS + fog vision + 0.01% atropine demonstrated significant control effects on myopia in preclinical and early stages of myopia in children across different genders, baseline ALs, and ages. Timely intervention is recommended once a tendency toward myopia is observed in children.\n\nID: 40721761\nTitle: Accuracy of 7 intraocular lens power calculation formulas in primary angle-closure glaucoma eyes, according to axial length and anterior chamber depth.\nAbstract: To assess the impact of Axial Length (AL) and anterior chamber depth (ACD) on the performance of the Kane, EVO 2.0, Barrett Universal II (BU II), SRK/T, Haigis, Holladay 2 and Hoffer Q formulas when calculating intraocular lens power in primary angle-closure glaucoma (PACG) patients. Eye hospital, Wen Zhou Medical University, Zhejiang, China. Retrospective, consecutive case series. Patients who underwent cataract surgery diagnosed with PACG or not were included. The main outcome measures comprised mean prediction error (ME), mean absolute refractive error (MAE), median absolute refractive error (MedAE). Additionally, the proportions of eyes with postoperative refractive errors within \u00b1\u20090.25 diopter (D), \u00b1\u20090.50 D, \u00b1\u20090.75 D, and \u00b1\u20091.00 D were calculated. Subgroup analyses were conducted based on AL and ACD. A total of 116 eyes were included, with 66 in the PACG group and 50 in the control group. The PACG group showed significantly larger MAEs compared to the control group. In PACG eyes, the BUII formula tends to cause negative residual refractive errors, while the Kane, EVO, and Holladay 2 formulas often lead to positive ones (P\u2009<\u20090.01). Notably, the SRK/T and Haigis formulas demonstrated better predictability for ME (P\u2009<\u20090.01). PACG patients with an AL under 22\u00a0mm or an ACD under 2.5\u00a0mm have lower IOL power calculation predictability (P\u2009<\u20090.05). Subgroup analysis shows that PACG eyes with both AL under 22\u00a0mm and ACD under 2.5\u00a0mm have the lowest predictability and are most prone to significant prediction errors (P\u2009<\u20090.05). A negative correlation was found between postoperative prediction error and AL. PACG eyes showed lower prediction accuracy, especially in short ALs and shallow ACD cases. SRK/T and Haigis formulas had better ME predictability. The study stresses optimizing IOL power calculation formulas for PACG eyes, considering AL and ACD effects.\n\nID: 40704719\nTitle: Ophthalmic Quality of Life and Its Association With Visual Function, Accommodative and Binocular Vision Performance in Keratoconus Patients: A Study Using Rasch Analysis\u200f.\nAbstract: To investigate the relationship between ophthalmic quality of life with visual function and accommodative/binocular vision performance in patients with keratoconus (KCN), using the Keratoconus Outcomes Research Questionnaire (KORQ). Seventy patients with KCN were recruited in this study (average age: 27.04 \u00b1 5.60). A Persian adaptation of the KORQ was developed, and its psychometric properties were evaluated through Rasch analysis. The associations between study variables and the KORQ subscales, activity limitations (AL-S) and symptoms (S-S), were evaluated through linear regression models. The Persian KORQ demonstrated good psychometric properties after removing items 5 and 8 from the AL-S and items 4 and 5 from the S-S. The analysis showed a statistically significant direct association between the AL-S score and age (\u03b2: 0.280, P < 0.05). In addition, there was a statistically significant direct relationship between the AL-S score with best-corrected visual acuity in the better eye (\u03b2: 0.279, P = 0.048), binocular contrast sensitivity (\u03b2: 0.319, P = 0.033), and steep keratometry in the better eye (\u03b2: 0.409, p-0.007). The near negative fusional vergence parameters-blur (\u03b2: -0.460, P = 0.012), break (\u03b2: -0.403, P = 0.027), and recovery (\u03b2: -0.391, P = 0.033)-showed a statistically significant inverse association with the S-S score. The Persian KORQ is a reliable tool for assessing ophthalmic quality of life in Persian-speaking patients with KCN. The KCN-related AL-S are primarily influenced by age, basic visual functions, and the severity of KCN in the better eye. Deficits in certain binocular vision metrics, particularly a diminished near negative fusional vergence amplitude, may contribute to the symptoms reported by patients with KCN.\n\nID: 40691358\nTitle: [Assessment of myopia progression].\nAbstract: The global increase in myopia prevalence and associated secondary complications necessitates adequate monitoring of myopia progression. This review highlights the advantages and disadvantages of the most commonly used target parameters for assessing myopia progression: refractive error and axial length. Although refractive error is essential for the diagnosis and optical correction of myopia, axial length proves to be a\u00a0more reliable and clinically relevant parameter for monitoring progression and guiding preventive interventions. Axial length correlates more strongly with the risk of ocular complications and is less susceptible to diurnal variations and interventions that alter the eye's refractive power. Assessing myopia progression under preventive measures requires consideration of age-dependent physiological changes in axial length. Standardized comparison parameters, such as the cumulative absolute reduction in axial elongation (CARE) can facilitate the objective evaluation of the efficacy of the intervention. Regular monitoring of refraction and axial length should also be performed in young adults with risk factors, as myopia onset and progression can occur even at this age. Die globale Zunahme der Myopiepr\u00e4valenz und damit einhergehender Sekund\u00e4rkomplikationen erfordert eine ad\u00e4quate \u00dcberwachung der Myopieprogression. Diese \u00dcbersichtsarbeit beleuchtet die Vor- und Nachteile der gebr\u00e4uchlichsten Zielparameter zur Beurteilung der Myopieprogression: Refraktionsfehler und Achsenl\u00e4nge. Obwohl der Refraktionsfehler f\u00fcr die Diagnose und optische Korrektur der Myopie unerl\u00e4sslich ist, erweist sich die Achsenl\u00e4nge als zuverl\u00e4ssigerer und klinisch relevanterer Parameter zur \u00dcberwachung der Progression und zur Steuerung von Pr\u00e4ventionsma\u00dfnahmen. Die Achsenl\u00e4nge korreliert st\u00e4rker mit dem Risiko okul\u00e4rer Komplikationen und ist weniger anf\u00e4llig f\u00fcr tageszeitliche Schwankungen und Interventionen, die die Brechkraft des Auges ver\u00e4ndern. Die Beurteilung der Myopieprogression unter Pr\u00e4ventionsma\u00dfnahmen erfordert die Ber\u00fccksichtigung altersabh\u00e4ngiger physiologischer Ver\u00e4nderungen der Achsenl\u00e4nge. Standardisierte Vergleichsparameter wie CARE (\u201ecumulative absolute reduction in axial elongation\u201c) k\u00f6nnen die objektive Beurteilung der Wirksamkeit von Interventionen erleichtern. Auch bei jungen Erwachsenen mit Risikofaktoren sollte eine regelm\u00e4\u00dfige \u00dcberwachung von Refraktion und Achsenl\u00e4nge erfolgen, da eine Myopisierung auch in diesem Alter auftreten kann.\n\nID: 40675818\nTitle: Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations.\nAbstract: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) that innervate skeletal muscles. However, certain MN groups including ocular MNs, are relatively resilient. To reveal key drivers of resilience versus vulnerability in ALS, we investigate the transcriptional dynamics of four distinct MN populations in SOD1G93A ALS mice using LCM-seq and single-molecule fluorescent in situ hybridization. We find that resilient ocular MNs regulate few genes in response to disease. Instead, they exhibit high baseline gene expression of neuroprotective factors, including En1, Pvalb, Cd63, and Gal, some of which vulnerable MNs upregulate during disease. Vulnerable MN groups upregulate both detrimental and regenerative responses to ALS and share pathway activation, indicating that breakdown occurs through similar mechanisms across vulnerable neurons, albeit with distinct timing. Meta-analysis across four rodent mutant Sod1 MN transcriptome data sets identify a shared vulnerability code of 39 genes, including Atf4, Nupr1, Ddit3, and Penk, involved in apoptosis, as well as a proregenerative and antiapoptotic signature consisting of Atf3, Vgf, Ina, Sprr1a, Fgf21, Gap43, Adcyap1, and Mt1 Machine learning using genes upregulated in SOD1G93A spinal MN predicts disease in human stem cell-derived SOD1E100G MNs and shows that dysregulation of VGF, INA, and PENK is a strong disease predictor across species and SOD1 mutations. Our study reveals MN population-specific gene expression and temporal disease-induced regulation that together provide a basis to explain ALS selective vulnerability and resilience and that can be used to predict disease.\n\nID: 40667132\nTitle: Herpes simplex virus 1 strain 17+ with R2 mutation in UL37 has residual retrograde transport.\nAbstract: Herpes simplex virus 1 (HSV-1) causes lifelong recurrent infections. Following primary infection of the oral or genital mucosa, HSV-1 travels retrogradely through axons and establishes latency in the cell body of ganglionic neurons of the peripheral nervous system. Periodic reactivation in neurons and anterograde transport of virions back to peripheral regions causes oral or genital ulcerations. Many host and viral factors implicated in retrograde and anterograde transport of HSV-1 have been identified. In particular, studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate retrograde transport of HSV-1 strain F. Here, we introduced the same R2 mutations in the highly neurovirulent HSV-1 strain 17+. We report that this R217 virus has residual retrograde travel. We show that R217 can establish latency in mouse models of ocular and vaginal infection and reactivate. These results contradict published evidence and show that the R2 mutation is not sufficient to fully prevent retrograde transport of HSV-1.\n\nID: 40625857\nTitle: A Novel Retinal Nerve Fiber Layer Biomarker of Amyotrophic Lateral Sclerosis (ALS) Identified Using Longitudinal in vivo Ocular Imaging.\nAbstract: Like motor neurons, retinal ganglion cells (RGCs) have long axons and high metabolic demands, making them vulnerable to disruption of axonal transport. Unlike motor neurons, the RGC axons are accessible to high-resolution non-invasive optical imaging in their intraocular portion. A non-invasive in vivo retinal imaging biomarker can be valuable for amyotrophic lateral sclerosis (ALS) diagnosis and monitoring. We aim to assess the presence of inner retinal pathology in a mouse model of ALS and its possible progression with age. Transgenic SOD1G93A mice (n=8, 4M/4F) and age-matched controls (n=8, 4M/4F) underwent in vivo retinal imaging with confocal scanning laser ophthalmoscopy (cSLO) coupled with optical coherence tomography (OCT) at 20\u00a0weeks of age. Another group of SOD1G93A mice (n=20, 6M/14F) and age-matched controls (n=20, 6M/14F) underwent longitudinal in vivo retinal imaging with the same device. Each retinal imaging session included infrared reflectance (IR) and blue reflectance (BR) cSLO coupled with OCT. Hyperreflective puncta located in the retinal nerve fiber layer (RNFL) were counted in a blinded fashion in ALS and control mice. The number of puncta at 20\u00a0weeks of age in ALS mice was compared with controls using Wilcoxon test. The rates of increase of puncta number were analyzed using a Generalized Linear Mixed-Effect Model (GLMM) for genotype, time, and sex. IR-cSLO coupled with OCT revealed hyperreflective puncta located in the RNFL of ALS mice. IR-cSLO fundus imaging at the age of 20\u00a0weeks showed ALS mice had significantly higher number of puncta compared to controls (2.1\u00b12.3 vs 0.5\u00b10.8; (mean\u00b1SD), respectively, p=0.036). GLMM analysis showed both ALS mutation and age were significantly associated with the rate of increase of puncta number (p=0.000232 and p=0.000366, respectively). In addition, female ALS mice had a steeper increase of puncta compared to male ALS mice (0.21\u00b10.04 log number puncta/week vs 0.16\u00b10.04, respectively; p=0.037). Our findings demonstrate distinct inner retinal nerve fiber layer pathology, detected using cSLO coupled with OCT, which worsens over time. These findings support the potential of retinal imaging as a translationally relevant, non-invasive biomarker for ALS diagnosis or disease monitoring in humans.\n\nID: 40616089\nTitle: D-optimal candexch algorithm-enhanced machine learning UV-spectrophotometry for five-analyte determination in novel anti-glaucoma formulations and ocular fluids: four-color sustainability framework with NQS assessment and UN-SDG integration.\nAbstract: The novel anti-glaucoma ophthalmic preparation containing latanoprost, netarsudil, and benzalkonium chloride has posed a significant challenge due to its complexity and the lack of environmentally sustainable quantification methods, with only a single published method available for its quantification that lacks environmental consideration. This study aims to address this crucial gap by presenting a novel and sustainable approach using machine learning-enhanced UV-spectrophotometric chemometric models for the concurrent quantification of latanoprost, netarsudil, benzalkonium chloride, and two related compounds in ophthalmic preparations and aqueous humour. A strategic multi-level, multi-factor experimental design creates a 25-mixture calibration set for four models (PLS, GA-PLS, PCR, and MCR-ALS). The key novelty was using the D-optimal design generated by MATLAB's candexch algorithm to construct a robust validation set, overcoming random data splitting limitations in machine learning chemometric methods and ensuring unbiased evaluation across concentrations. The optimized MCR-ALS model outperforms in predictive ability, with recovery percentages of 98-102%, low root mean square errors of calibration and prediction, favorable bias-corrected mean square error of prediction, relative root mean square error within acceptable limits, and adequate limits of detection for pharmaceutical analysis. The Greenness Index Spider Charts and the Green Solvents Selection Tool were applied to replace hazardous solvents. A total of seven advanced evaluation tools were employed to assess the method's greenness, blueness, violetness, and whiteness, highlighting its eco-friendly profile, practical relevance, and innovation potential. Additionally, the method's environmental and societal benefits were further validated using the Need, Quality, Sustainability (NQS) index. Overall, this machine learning-based framework contributes meaningfully to ten United Nations Sustainable Development Goals (UN-SDGs), underscoring its value for future-oriented pharmaceutical research.\n\nID: 40602557\nTitle: Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1G93A mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.\nAbstract: Amyotrophic Lateral Sclerosis (ALS) is a prevalent condition characterized by motor neuron loss and skeletal muscle paralysis. Despite being associated to mutations in over 40 genes, its etiology remains elusive without a cure or effective treatment. ALS, historically considered a motor neuron disease, is defined today as a multisystem disorder involving non-neuronal cell types, including early muscle pathology independent of motor neuron degeneration (dying back hypothesis), thus skeletal muscle actively contributes to disease pathology, making it a viable therapeutic target for ALS. Our previous research has shown that boron transporter NaBC1 (encoded by the SLC4A11 gene), after activation co-localizes with integrins and growth factor receptors synergistically enhancing muscle repair. Here we investigate the effects of injectable alginate-based hydrogels for controlled local borax release in Amyotrophic Lateral Sclerosis muscle. Treated mice showed improved motor function, prolonged survival, and activation of essential muscle metabolic pathways, leading to enhanced muscle repair and reduced atrophy and inflammation. Interestingly, local muscle repair activation provided retrograde neuroprotection by preserving motor neurons and reducing neuro-inflammation. This study highlights the role of muscle tissue in ALS pathology, supporting its targeting with NaBC1-based therapies for muscle regeneration.\n\nID: 40581291\nTitle: Comparison of axial length measurements of myopic eyes from ocular biometers versus axial length estimator.\nAbstract: To compare axial length (AL) estimates of myopic eyes obtained using an axial length estimator (ALE) and AL measurements made with the IOLMaster 700 in India and the Lenstar 900 in Vietnam. This multicenter retrospective cross-sectional study analyzed masked data of both eyes from myopic children (<18 years of age). Estimated AL was derived from mean keratometry and refraction values using ALE. Differences between actual and estimated ALs and their correlation were assessed using Bland-Altman plots and intraclass correlation coefficients (ICCs). A total of 237 myopic children (474 eyes) aged 5-16 years were included: 90 Indian and 147 Vietnamese children. ALE estimates on average exceeded actual AL measurements, with mean differences of -0.26 mm (95% limits of agreement, -1.25 to 0.73 mm) for ALE formula, and -0.21 mm (95% limits of agreement, -1.14 to 0.71 mm) for ALE data input. ICCs showed strong agreement: 0.90 (95% CI, 0.83-0.93) for actual AL versus ALE data input and 0.89 (95% CI, 0.78-0.93) for actual AL versus ALE formula. Indian children had shorter actual AL than Vietnamese children (24.56 \u00b1 0.90 vs 24.91 \u00b1 0.86 mm [P < 0.001]) and exhibited slightly smaller differences between actual and estimated AL (-0.13 vs -0.27 mm for ALE data input; -0.17 vs -0.31 mm for ALE formula). In our cohorts, ALE demonstrated strong agreement with IOLMaster 700 and Lenstar 900 AL measurements in myopic children. ALE may be a useful clinical tool for this population when direct measurements of AL are unavailable.\n\nID: 40560963\nTitle: Analysis of retinal markers and incident amyotrophic lateral sclerosis: An optical coherence tomography-based cohort study.\nAbstract: Biomarkers are widely recognized as crucial breakthroughs in tackling amyotrophic lateral sclerosis (ALS). Among them, retina markers may hold promise due to the close retina-brain connection and non-invasive, portable detection methods. Thus, using optical coherence tomography (OCT), we investigated the link between baseline cell-level retinal features and future ALS risk. Participants from the UK Biobank underwent OCT scans to assess retinal layers, macula, and optic disc parameters. Follow-up commenced two years after the baseline period (2006-2010), during which ALS cases were identified using International Classification of Diseases (ICD) codes from medical and assessment records. Cox proportional hazards models were applied to examine the relationship between retinal markers and incident ALS. Over a median follow-up of 14.11 years, 70 ALS cases occurred among 53,824 participants (incidence 10.58 per 100,000 person-years). Most participants were White (94.6%), 44.8% male, with a median age of 58 years. After adjusting for demographics and comorbidities affecting the retina, a standard deviation (SD) decrease of 15.19 \u00b5m in photoreceptor layer (PRL) thickness was associated with a 19% (95% confidence interval [7, 29]; p\u2009=\u20090.002) increased risk of ALS, while a SD increase of 26.11 \u00b5m in retinal pigment epithelium (RPE) thickness corresponded to a 20% (95% CI [7, 34]; p\u2009=\u20090.002) higher risk. Sensitivity analyses excluding follow-ups of less than 4 and 6 years yielded consistent results. Subgroup analyses showed these findings were more pronounced in smokers. The main limitation of this study is its single time point observational design. A thinner PRL and thicker RPE may precede the clinical diagnosis of ALS, offering potential clues for early diagnosis and insights into the disease's pathogenesis.\n\nID: 40554439\nTitle: Bidirectional Causal Relationship Between Myopia and Neurodegenerative Diseases: Two-Sample Mendelian Randomization Analyses.\nAbstract: Aims/Background Myopia is highly prevalent in certain neurodegenerative diseases (NDDs), and both conditions demonstrate genetic susceptibility. This study investigated the potential bidirectional causal relationships between myopia and four NDDs, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), using Mendelian randomization (MR). We aimed to determine whether myopia contributes to the risk of NDDs and vice versa. Methods We analyzed data from two independent, large-scale genome-wide association study (GWAS) cohorts on myopia, comprising 212,571 participants in the first cohort (finn-b-H7_MYOPIA) and 95,619 in the second (GCST009521). GWAS summary statistics for the four NDDs, encompassing 589,439 samples, were also incorporated. Bidirectional MR was employed to investigate causal relationships between myopia and each of the four NDDs. The inverse variance-weighted (IVW) method served as the primary analytical approach. Sensitivity analyses, including MR-Egger regression, weighted median, weighted mode, and simple mode, were conducted to assess the robustness of the findings. Horizontal pleiotropy was evaluated using the MR-Egger regression intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, while heterogeneity was assessed via Cochran's Q test. Leave-one-out analyses were conducted to evaluate the influence of individual single nucleotide polymorphisms (SNPs). Odds ratios (ORs) with 95% confidence intervals (CIs) were reported, and statistical significance was set at p < 0.05. Results MR analyses identified no evidence of a causal relationship between myopia and refractive error and increased risk of any of the four NDDs (all p > 0.05). Similarly, none of the NDDs were associated with an increased risk of myopia or refractive error (all p > 0.05). Sensitivity analyses revealed no SNPs with significant influence on the causal associations (all p > 0.05), supporting the robustness of the findings. Conclusion This study provides no evidence of a bidirectional causal relationship between myopia and the four NDDs among individuals of European ancestry. Future research should extend beyond direct causal inference to investigate potential mediating biological mechanisms.\n\nID: 40455211\nTitle: [Ocular alterations in pseudoxanthoma elasticum : The eye as a window to diagnosing a systemic disease].\nAbstract: Pseudoxanthoma elasticum (PXE) is an autosomal-recessive multisystem disease characterized by elastic fiber calcification in the skin, the cardiovascular system, and eyes. PXE is caused by biallelic mutations in the ABCC6\u00a0gene on chromosome\u00a016, resulting in low inorganic pyrophosphate plasma levels. Typical ocular manifestations result from calcification of Bruch's membrane and include peau d'orange, angioid streaks, and comet-tail lesions. Advances in multimodal imaging have significantly improved the detection of these features. Ocular complications in PXE include the development of secondary neovascularization, which can be treated with anti-vascular endothelial growth factor (VEGF) injections. In cases of suspected PXE, genetic testing and genetic counseling should be performed for diagnostic confirmation. Early referral to a\u00a0specialized center is essential. Interdisciplinary care and management of complications, particularly in collaboration with angiologists, are crucial for treating this multisystem disorder. Although no approved causal therapy for PXE currently exists to date, accurate and early diagnosis using phenotypic characteristics is critical. Early identification of other affected family members and timely treatment of secondary complications allow for better disease management and offer patients the opportunity to participate in ongoing clinical trials. Promising therapeutic options are currently emerging and may significantly improve management and prognosis in the future. Pseudoxanthoma elasticum (PXE) ist eine autosomal-rezessiv vererbte Multisystemerkrankung, die sich durch charakteristische Ver\u00e4nderungen an der Haut, im arteriellen Gef\u00e4\u00dfsystem und an den Augen manifestiert. Die Erkrankung wird durch biallelische Mutationen im ABCC6-Gen auf Chromosom\u00a016 verursacht, die zu einer pathologischen Kalzifizierung von elastischen Fasern f\u00fchren. Typische okul\u00e4re Manifestationen, die fundoskopisch sichtbar sind, umfassen die sog. Peau d\u2019orange, angioide Streifen und Kometenschweifl\u00e4sionen und sind auf eine Kalzifizierung der Bruch-Membran zur\u00fcckzuf\u00fchren. Fortschritte in der multimodalen Bildgebung haben die Erkennung dieser Charakteristika erheblich verbessert. Okul\u00e4re Komplikationen bei PXE umfassen die Entwicklung von sekund\u00e4ren Neovaskularisationen, die mit Anti-\u201evascular endothelial growth factor\u201c (VEGF)-Injektionen behandelt werden k\u00f6nnen. Bei Verdacht auf PXE sollten zur Diagnosesicherung eine molekulargenetische Untersuchung sowie eine humangenetische Beratung erfolgen, und eine rechtzeitige Anbindung an ein spezialisiertes Zentrum sollte eingeleitet werden. Eine interdisziplin\u00e4re Betreuung und Therapie von Komplikationen, insbesondere in Zusammenarbeit mit der Angiologie, sind f\u00fcr die Behandlung dieser Multisystemerkrankung unerl\u00e4sslich. Obwohl derzeit noch keine zugelassene kausale Therapie f\u00fcr PXE existiert, ist eine korrekte und fr\u00fche Diagnosestellung anhand ph\u00e4notypischer Charakteristika entscheidend. Neben der fr\u00fchzeitigen Erkennung weiterer betroffener Familienmitglieder sowie einer rechtzeitigen Behandlung von Sekund\u00e4rkomplikationen erm\u00f6glicht sie den Patienten zudem eine potenzielle Teilnahme an laufenden klinischen Studien. Mehrere laufende oder geplante klinische Studien sind aussichtsreich und k\u00f6nnten bei Erfolg zu einer verbesserten Versorgung und Prognose der Patienten f\u00fchren.\n\nID: 40451408\nTitle: TFOS DEWS III: Diagnostic Methodology.\nAbstract: A standard approach to the diagnosis of dry eye disease across eye care practitioners is critical to reassuring the patient, providing consistency between practitioners and informing governments as to the true prevalence and resulting healthcare needs. The Tear Film & Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) III has reviewed the evidence-base since their previous reports published in 2017 and revised the definition to \"Dry eye is a multifactorial, symptomatic disease characterized by a loss of homeostasis of the tear film and/or ocular surface, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities are etiological factors.\" Key features from the definition include that dry eye disease is multifactorial, is a disease and not a syndrome and is always symptomatic. Differential diagnosis and ocular examination guidance is given along with the risk factors that should be discussed with the patient. The recommended screening questionnaire is the OSDI-6 with a cut-off score \u22654. A positive result together with a non-invasive breakup time <10s or alternatively tear film hyperosmolarity (\u2265308mOsm/L in either eye or an interocular difference >8mOsm/L) or alternatively >5 corneal fluorescein and/or >9 conjunctival lissamine green punctate spots and/or lid margin lissamine green staining of \u22652mm length & \u226525 % width, gives a diagnosis of dry eye. Subclassification was separated into tear film deficiencies (lipid, aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid margin) and ocular surface abnormalities (anatomical misalignment, neural dysfunction, ocular surface cell damage/disruption and primary inflammation/oxidative stress) components, with appropriate clinical tests and cut-offs provided to identify these etiological drivers in an individual, to inform appropriate management and therapy.\n\nID: 40444312\nTitle: Validation of ocular trauma score (OTS) in open- and closed-globe injuries in Indian patients.\nAbstract: To validate the predictive value of the ocular trauma score (OTS) in open- and closed-globe eye injuries in the Indian context. Prospective interventional case series. This study, conducted at a tertiary healthcare institute from January 2018 to June 2019, included 150 eyes of 150 patients with open- and closed-globe injuries. Inclusion criteria were patients with globe injuries who provided informed consent and had complete OTS data. Exclusion criteria included electric, chemical, and thermal injuries, prior surgery, pre-existing poor visual acuity (VA), and severe systemic injuries. There was no randomization. Demographic details, initial and final VA, injury type, and OTS variables were recorded. Patients were classified into OTS categories preoperatively based on Kuhn et al.'s system, and VA distribution was compared with the original study. The main outcome was to assess the correlation between the final BCVA at 6 months post-intervention and the predicted VA based on the OTS category. A total of 150 patients (72% open globe, 28% closed globe) were included, with a male-to-female ratio of 4.5:1. The mean age \u00b1 SD was 29.34 \u00b1 17.49 years. OTS classification showed 6% in OTS 1, 17% in OTS 2, 67% in OTS 3, 4% in OTS 4, and 6% in OTS 5. Final VA was \u226420/40 (41%), 20/50-20/200 (20%), 20/200-1/200 (15%), HM/PL (15%), and NLP (9%). Final VA post-treatment correlated with predicted VA as per the OTS category (Spearman's r = 0.53, P < 0.001). OTS provides reliable prognostic information and has fair predictive value for final VA in open- and closed-globe injuries.\n\nID: 40429496\nTitle: Exploring the Risk: Peripheral Retinal Degenerations in Young Australian Adults.\nAbstract: Background/Objectives: Peripheral retinal degenerations (PRDs) are structural anomalies in the outer regions of the retina, typically emerging in adolescence and early adulthood. Early detection is crucial, as some PRDs can lead to sight-threatening complications, such as retinal detachment, if left unmanaged. Due to a paucity of research regarding PRDs and their association with axial length (AL) and refractive error (RE) in young Australian adults, this study aimed to investigate the prevalence of PRDs in this population and establish whether AL and RE could help predict the likelihood of PRD occurrence. Methods: A cross-sectional study was conducted on a mixed population (n = 221) of Australian adults aged 18 to 40. Demographic data, RE, AL, and a series of ultra-widefield (UWF) retinal images were obtained from participants' undilated eyes using the Zeiss ClarusTM 500. Results: The overall PRD prevalence was 8.15% (n = 442 eyes). Binary logistic regression revealed that a longer AL was a more significant factor in increasing the risk of PRD development across all myopia classifications compared to emmetropia than RE. The likelihood of a PRD was 50% at an AL of 26.9 mm and -6.50D of myopia, and 95% at 29.6 mm and -11.00D. Conclusions: PRD prevalence was lower than reported in other global studies, perhaps reflecting the diverse ethnic makeup of the cohort. While our study supports the conventional understanding that longer ALs, and high myopia are key risk factors for developing a PRD, it also provides new insights into the likelihood of detecting a PRD at a given AL or RE in a mixed population. This information is crucial for eye care practitioners, enabling early identification of at-risk individuals and screening for PRDs that may increase the risk of retinal detachment.\n\nID: 40350723\nTitle: [Oculomotor disorders in patients with amyotrophic lateral sclerosis].\nAbstract: Oculomotor disorders are not typical manifestations of amyotrophic lateral sclerosis (ALS). Occasionally, this disease is associated with vertical gaze paresis, presenting a distinct type as \u00abALS+progressive supranuclear palsy\u00bb. Studies using eye-tracking methods have revealed a variety of subclinical oculomotor disorders in this disease. These disorders can manifest as changes in reflex and voluntary saccades, antisaccades, smooth tracking eye movements, and fixations. A significant association between oculomotor disorders and clinical manifestations of ALS was reported. The occurrence of oculomotor disorders indicates the involvement of broader neuroanatomical structures, including the prefrontal cortex and basal ganglia. 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\u043e\u0433\u0440\u0430\u043d\u0438\u0447\u0435\u043d\u043d\u043e\u0435 \u043a\u043e\u043b\u0438\u0447\u0435\u0441\u0442\u0432\u043e \u043f\u043e\u0434\u0447\u0435\u0440\u043a\u0438\u0432\u0430\u044e\u0442 \u043d\u0435\u043e\u0431\u0445\u043e\u0434\u0438\u043c\u043e\u0441\u0442\u044c \u0434\u0430\u043b\u044c\u043d\u0435\u0439\u0448\u0438\u0445 \u0438\u0441\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u0439 \u0432 \u044d\u0442\u043e\u0439 \u043e\u0431\u043b\u0430\u0441\u0442\u0438.\n\nID: 40340620\nTitle: Exploring oculomotor challenges in amyotrophic lateral sclerosis: a comprehensive review.\nAbstract: Traditionally understood as a motor neuron disease, amyotrophic lateral sclerosis (ALS) is now recognized to involve broader neurodegenerative processes, including the oculomotor system. This narrative review summarizes current evidence on oculomotor dysfunction in ALS, with a focus on its relationship to disease-related motor and cognitive impairments. Specifically, the review examines key eye-tracking (ET) metrics, including saccades, smooth pursuit, and fixation, highlighting their potential to reflect both motor and extramotor degeneration. Notably, patients with bulbar-onset ALS exhibit more pronounced oculomotor impairments. By synthesizing findings on the connection between oculomotor dysfunction and cognitive decline, this review underscores the potential of ET as a noninvasive tool for assessing ALS progression. Oculomotor metrics, as part of a broader understanding of ALS's impact on multiple neural networks, may offer valuable insights to refine patient assessment and care strategies, particularly in advanced disease stages.\n\nID: 40330963\nTitle: The Effect of Axial Length on Macular Vascular Density in Eyes with High Myopia.\nAbstract: To evaluate the relationship between optical coherence tomography angiography (OCTA) findings and axial length (AL) in eyes with high myopia. A total of 122 eyes from 78 patients were included. Seventy-five eyes with an AL ranging between 26.00 and 27.49 mm comprised Group 1, and 47 with an AL of \u2265 27.50 mm comprised Group 2. Spectral-domain OCT was performed to measure the central macular thickness, subfoveal choroidal thickness (SCT) and swept-source OCTA was utilized to obtain the data on foveal avascular zone (FAZ) and vascular density (VD) values at the superficial and deep capillary plexuses (SCP and DCP), outer retina (OuR), and choriocapillaris (CC) segments. While no significant differences were found in terms of the mean superficial-FAZ and deep-FAZ areas (p=0.284 and p=0.952, respectively), there were significant differences between the groups in terms of the mean foveal VD in the SCP (p=0.001), the mean total VD (p=0.045) and foveal VD in the DCP (p<0.001), the mean foveal VD (p=0.019) and superior parafoveal VD in the OuR (p=0.008), the mean total (p=0.005), temporal parafoveal (p=0.034), inferior parafoveal (p=0.029), and nasal parafoveal VDs in the CC segments (p=0.005). The findings of the present study highlight the complex interplay between axial elongation and retinal microvasculature, suggesting that factors beyond mechanical stretching may contribute to these alterations. The variability in the existing literature on this topic arises from inconsistencies in the definition of high myopia, the use of different OCTA devices, and heterogeneous study populations. By including eyes with myopic maculopathy and employing axial length-based classification, this study provides a broad representation of high myopia. However, its retrospective design, single-center setting, and monoracial cohort represent limitations. Future large-scale, prospective studies involving diverse populations are needed to elucidate further the pathophysiology of high myopia and its impact on retinal and choroidal microcirculation. Our study revealed that high-myopic eyes with longer ALs exhibited increased total VD in the DCP and increased foveal VD in the SCP, DCP, and OuR segments, while they showed decreased total VD and temporal, inferior, and nasal parafoveal VDs in the CC segment compared to high-myopic eyes with shorter ALs.\n\nID: 40306255\nTitle: Retinal alterations induced by amyotrophic lateral sclerosis: An analysis using optical coherence tomography.\nAbstract: In this study, we aimed to investigate retinal changes in a large cohort of amyotrophic lateral sclerosis (ALS) patients and healthy controls (HCs) to further elucidate their relationship with ALS. This was a cross-sectional observational study. We evaluated retinal layer thickness in 134 ALS patients and 66 HCs using optical coherence tomography (OCT). Particularly, we focused on the macular region and peripapillary retinal nerve fiber layer (p-RNFL). The examination of retinal layers in ALS patients revealed a significant change in the inner nuclear layer (INL), with a pattern of initial thickening followed by thinning, which correlated with disease stages, most notably in the inner nasal quadrant. Moreover, the p-RNFL in the temporal quadrant was thinner in ALS patients compared to HCs. In addition, ALS patients who developed bulbar symptoms exhibited marginally thinner p-RNFL in the temporal quadrant compared to those without bulbar symptoms. Interestingly, a thinner p-RNFL in the temporal quadrant did not correlate with faster disease progression. This study reveals notable changes in the INL and p-RNFL thickness in ALS patients, highlighting the intricate relationship between retinal changes and ALS progression. Despite these retinal alterations, no correlation with disease progression rate was observed. These findings suggest that while OCT shows potential in monitoring ALS, its role in predicting disease course requires further investigation with long-term longitudinal studies and diverse patient cohorts.\n\nID: 40209696\nTitle: Clinical Features, Diagnostic Implications, and Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review.\nAbstract: Objective: This review aimed to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision. Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included. Forty-two cases were categorized into four groups as follows: the first group had 26 cases with MG onset (age range 26-82 years) preceding ALS (age range 46-83 years). The second group had 9 cases with ALS onset (age range 34-89 years) preceding MG (age range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments. The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.
.\n\nID: 40163087\nTitle: [Ocular graft versus host disease].\nAbstract: Ocular graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) is predominantly an inflammatory and destructive ocular surface disease with increasing incidence. It not only leads to a\u00a0reduced quality-of-life but can also impair vision and in severe cases lead to blindness. The occurrence of GVHD can lead to a\u00a0severe, often refractory disorders of the ocular surface, which is associated with chronic inflammation. The occurrence of corneal involvement is a\u00a0major problem. The establishment of comprehensive care structures and individually adapted stage-appropriate treatment in interdisciplinary collaboration with colleagues in hemato-oncology is therefore of particular importance. Die okul\u00e4re Graft-versus-Host-Erkrankung (\u201egraft-versus-host disease\u201c [GVHD]) nach allogener h\u00e4matopoetischer Stammzelltransplantation (HSCT) stellt \u00fcberwiegend eine entz\u00fcndliche und destruierende Augenoberfl\u00e4chenerkrankung mit zunehmender Inzidenz dar. Sie f\u00fchrt nicht nur zu einer reduzierten Lebensqualit\u00e4t, sondern kann auch die Sehf\u00e4higkeit beeintr\u00e4chtigen und in schweren F\u00e4llen zur Erblindung f\u00fchren. Die GVHD kann zu einer schweren, oft therapierefrakt\u00e4ren Benetzungsst\u00f6rung der Augenoberfl\u00e4che f\u00fchren, die mit chronischer Entz\u00fcndung einhergeht. Ein gro\u00dfes Problem stellt das Auftreten kornealer Affektionen dar. Die Etablierung von fl\u00e4chendeckenden Versorgungsstrukturen sowie eine individuell angepasste stadiengerechte Therapie in interdisziplin\u00e4rer Zusammenarbeit mit den h\u00e4matoonkologischen Kollegen ist daher von besonderer Bedeutung.\n\nID: 40152605\nTitle: EPG-5 regulates TGFB/TGF-\u03b2 and WNT signalling by modulating retrograde endocytic trafficking.\nAbstract: The Vici syndrome protein EPG5 acts as a tethering factor determining the fusion specificity of autophagosomes with late endosomes/lysosomes. Here we demonstrated that during C. elegans development, EPG-5 modulates SMA and MAB TGFB/TGF-\u03b2 signaling in controlling body size and also WNT signaling in regulating cell migration. EPG-5 is required for retrograde trafficking of the TGFB receptor SMA-6 and WLS/Wntless homolog MIG-14. In epg-5 mutants, SMA-6 and MIG-14 are trapped within hybrid endosomal structures, which colocalize with SNX-1- and SNX-3-labeled vesicles, respectively. Basolateral recycling processes of transmembrane cargos H.s.TFR/hTfR and H.s.IL2RA/hTAC are also defective in epg-5 mutants. Depletion of EPG-5 causes defective RAB-5 and RAB-7, and RAB-5 and RAB-10 conversion, leading to the formation of these hybrid vesicles. The defects in endocytic trafficking and autophagy in epg-5 mutants are ameliorated by knocking down components of the HOPS complex. Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.Abbreviations: ALM: anterior lateral microtubule; ATG: autophagy related; AVM: anterior ventral microtubule; CORVET: class C core vacuole/endosome tethering; DAF-4: abnormal dauer formation 4; DIC: differential interference contrast; EPG: ectopic PGL granules; EPG-5: ectopic P granules 5; GAP: GTPase activating protein; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; H.s.IL2RA/hTAC: human interleukin 2 receptor subunit alpha; H.s.TFR/hTfR: human transferrin receptor; L1/L4: the first/fourth larval; mCh: mCherry; MIG-14: abnormal cell migration 14; PLM: posterior lateral microtubule; PVM: posterior ventral microtubule; RAB: ras-related protein; RFP: red fluorescent protein; RME-1: receptor mediated endocytosis 1; SMA-6: small 6; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNX: sorting nexin; TBC-2: TBC1 (Tre-2/Bub2/Cdc16) domain family 2; TGFB/TGF-\u03b2: transforming growth factor beta; TGN: trans-Golgi network; VPS: related to yeast vacuolar protein sorting factor; WT: wild type.\n\nID: 40012679\nTitle: TDP-43 as a potential retinal biomarker for neurodegenerative diseases.\nAbstract: TDP-43 proteinopathies are a spectrum of neurodegenerative diseases (NDDs) characterized by the pathological cytoplasmic aggregation of the TDP-43 protein. These include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and others. TDP-43 in the eye shows promise as a biomarker for these NDDs. Several studies have identified cytoplasmic TDP-43 inclusions in retinal layers of donors with ALS, FTLD, AD, CTE, and other conditions using immunohistochemistry. Our findings suggest that pathological aggregates of TDP-43 in the human retina are most prevalent in FTLD-TDP, ALS, and CTE, suggesting these diseases may provide the most reliable context for studying the potential of TDP-43 as a retinal biomarker. Animal model studies have been pivotal in exploring TDP-43's roles in the retina, including its nuclear and cytoplasmic localization, RNA binding properties, and interactions with other proteins. Despite these advances, more research is needed to develop therapeutic strategies. A major limitation of human autopsy studies is the lack of corresponding brain pathology assessments to confirm TDP-43 proteinopathy diagnosis and staging. Other limitations include small sample sizes, lack of antemortem eye pathology and clinical histories, and limited comparisons across multiple NDDs. Future directions for the TDP-43 as a retinal biomarker for NDDs include retinal tracers, hyperspectral imaging, oculomics, and machine learning development.\n\nID: 39957197\nTitle: Clinical prognostic factors in progressive supranuclear palsy: Implications for clinical trials.\nAbstract: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with diverse clinical phenotypes, prompting the development of new diagnostic criteria known as the MDS-PSP classification. However, little is known about the prognostic value of this classification in order to better stratify patients for the clinical trials. To assess the impact of the different clinical phenotypes according to the MDS-PSP classification on prognosis using the clinical milestones of death, severe dysphagia, institutionalization, and need for walking aid. A prospective cohort of 205 PSP patients from Lille University Hospital was analyzed retrospectively. Patients were classified into different MSD-PSP phenotypes according to their clinical presentation after 3 years of follow-up. The milestones of death, severe dysphagia, institutionalization, and need for walking aid were recorded, and a survival analysis was performed to describe the prognosis of each disease presentation. Median survival time was 6.4 (interquartile range (IQR): 4.8-8.6) years and mean diagnostic delay from symptom onset was 38.1\u2009\u00b1\u200922.5 months. PSP Richardson Syndrome (PSP-RS) had a poorer survival rate and a higher occurrence of severe dysphagia and need for walking aid compared to PSP variants such as PSP Parkinsonism (PSP-P), PSP postural instability without ocular motor dysfunction (PSP-PI), and other rare phenotypes. PSP-RS has a less favorable prognosis compared to PSP variants stratified according to the MDS-PSP classification. This classification could assist in selecting patients for clinical trials and help design outcomes that account for the disease heterogeneity. Progressive supranuclear palsy (PSP) is a rare and debilitating neurodegenerative disease marked by diverse combination of motor and cognitive symptoms. No treatment is currently available to slow down disease progression. The multiple clinical presentations of PSP compromise clinical trials. Thus, we aimed to study the differential prognosis of the different forms of the disease. We showed that PSP-Richardson Syndrome (PSP-RS), which is the most frequent presentation, seems to have a poorer prognosis than other variants on survival and other disability criteria such as severe dysphagia occurrence. This study suggests that these differences should account to improve the design of future clinical trials.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 20 quotes\" then there must be at least 20 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH Objective: This review aimed to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision. Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included. Forty-two cases were categorized into four groups as follows: the first group had 26 cases with MG onset (age range 26-82 years) preceding ALS (age range 46-83 years). The second group had 9 cases with ALS onset (age range 34-89 years) preceding MG (age range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments. The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.
.",
"40291716": "ID: 40291716\nTitle: Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, leading to controversy whether ALS is one disease or many diseases with a similar phenotype. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are only found in 2-3% of ALS cases, yet misfolded SOD1 is found in both sporadic (sALS) and familial (fALS) patients. Yet, mutations in TDP-43 or FUS increase the level of misfolded SOD1 on extracellular vesicles (EVs). Additionally, small EVs isolated from ALS patient samples caused cell death of wild type motor neurons and myotubules. The toxicity and protein alterations of ALS EVs have led to the theory that EVs are responsible for the spread of ALS. We hypothesize that previously-identified toxic trimeric SOD1 is spreading on EVs in ALS and altering the spread of other ALS-related proteins, linking them to a common mechanism. To test our hypothesis, we isolate EVs from motor neuron-like cells expressing trimer stabilizing mutations and perform a sandwich enzyme-linked immunoassay (ELISA) (CD9 capture antibody) to quantify whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is being affected by trimeric SOD1 utilizing endocytosis and exocytosis inhibitors, and determine if any specific EV-related proteins are altered with trimer stabilization. We establish that VAPB, VCP, and Stathmin-2 increase on EVs with trimer stabilization. The common pathway between SOD1 and three other ALS-associated proteins is affected by multiple pathways, including the Caveolae endocytosis pathway, suggesting a novel hybrid pathway of EV release present in ALS.",
"40301571": "ID: 40301571\nTitle: Cross-tissue MiRNA profiling of extracellular vesicles and PBMCs from amyotrophic lateral sclerosis patients.\nAbstract: RNA-mediated toxicity, which can be controlled by alteration of gene expression, is considered a key event in Amyotrophic Lateral Sclerosis (ALS). Transcriptomic deregulation of miRNAs expression can spread via \"horizontal\" RNA transfer through extracellular vesicles (EVs) to act in conjunction with proteins, leading to changes in mRNA, which can provide early signals to indicate forthcoming neuropathological changes in the brain. The aim of this work is to compare expression profiles (obtained by miRNA-seq) from different tissues to highlight commonly expressed and tissue-specific miRNAs. miRNA species from plasma EVs were correlated with miRNA profiles obtained from peripheral blood mononuclear cells (PBMCs). Each tissue from ALS patients was compared to controls, revealing 159 deregulated (DE) miRNAs in Exosomes (EXOs), 247 DE miRNAs in PBMCs and 162 DE miRNAs in Microvesicles (MVs). Next, data were filtered to include only miRNAs expressed in disease samples (not in healthy subjects), to reduce the number of tissue- and ALS- specific miRNAs (EXO n\u2009=\u200922, MV\u2009=\u200911, PBMCs n\u2009=\u20098). We identified specific miRNAs and pathways related to each tissue. Interestingly, in PBMCs we found mainly neuro-linked pathways, such as neurotransmitters, brain and neuron development, while in EXOs, we found miRNAs implicated in MAPK and ERB signaling. In contrast, the altered pathways in MVs were not specific. This study shows that the composition of small RNA differs significantly between blood cells and its respective EVs fraction. Differentially expressed miRNAs can target definite transcripts in different cellular and molecular fractions. It is evident that, in terms of miRNAs cargo, MVs are not specific to ALS. Therefore, future studies will focus on the interaction between cells and EXOs.",
"40306255": "ID: 40306255\nTitle: Retinal alterations induced by amyotrophic lateral sclerosis: An analysis using optical coherence tomography.\nAbstract: In this study, we aimed to investigate retinal changes in a large cohort of amyotrophic lateral sclerosis (ALS) patients and healthy controls (HCs) to further elucidate their relationship with ALS. This was a cross-sectional observational study. We evaluated retinal layer thickness in 134 ALS patients and 66 HCs using optical coherence tomography (OCT). Particularly, we focused on the macular region and peripapillary retinal nerve fiber layer (p-RNFL). The examination of retinal layers in ALS patients revealed a significant change in the inner nuclear layer (INL), with a pattern of initial thickening followed by thinning, which correlated with disease stages, most notably in the inner nasal quadrant. Moreover, the p-RNFL in the temporal quadrant was thinner in ALS patients compared to HCs. In addition, ALS patients who developed bulbar symptoms exhibited marginally thinner p-RNFL in the temporal quadrant compared to those without bulbar symptoms. Interestingly, a thinner p-RNFL in the temporal quadrant did not correlate with faster disease progression. This study reveals notable changes in the INL and p-RNFL thickness in ALS patients, highlighting the intricate relationship between retinal changes and ALS progression. Despite these retinal alterations, no correlation with disease progression rate was observed. These findings suggest that while OCT shows potential in monitoring ALS, its role in predicting disease course requires further investigation with long-term longitudinal studies and diverse patient cohorts.",
"40319325": "ID: 40319325\nTitle: Exosome-powered neuropharmaceutics: unlocking the blood-brain barrier for next-gen therapies.\nAbstract: The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods. This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions. By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.",
"40330963": "ID: 40330963\nTitle: The Effect of Axial Length on Macular Vascular Density in Eyes with High Myopia.\nAbstract: To evaluate the relationship between optical coherence tomography angiography (OCTA) findings and axial length (AL) in eyes with high myopia. A total of 122 eyes from 78 patients were included. Seventy-five eyes with an AL ranging between 26.00 and 27.49 mm comprised Group 1, and 47 with an AL of \u2265 27.50 mm comprised Group 2. Spectral-domain OCT was performed to measure the central macular thickness, subfoveal choroidal thickness (SCT) and swept-source OCTA was utilized to obtain the data on foveal avascular zone (FAZ) and vascular density (VD) values at the superficial and deep capillary plexuses (SCP and DCP), outer retina (OuR), and choriocapillaris (CC) segments. While no significant differences were found in terms of the mean superficial-FAZ and deep-FAZ areas (p=0.284 and p=0.952, respectively), there were significant differences between the groups in terms of the mean foveal VD in the SCP (p=0.001), the mean total VD (p=0.045) and foveal VD in the DCP (p<0.001), the mean foveal VD (p=0.019) and superior parafoveal VD in the OuR (p=0.008), the mean total (p=0.005), temporal parafoveal (p=0.034), inferior parafoveal (p=0.029), and nasal parafoveal VDs in the CC segments (p=0.005). The findings of the present study highlight the complex interplay between axial elongation and retinal microvasculature, suggesting that factors beyond mechanical stretching may contribute to these alterations. The variability in the existing literature on this topic arises from inconsistencies in the definition of high myopia, the use of different OCTA devices, and heterogeneous study populations. By including eyes with myopic maculopathy and employing axial length-based classification, this study provides a broad representation of high myopia. However, its retrospective design, single-center setting, and monoracial cohort represent limitations. Future large-scale, prospective studies involving diverse populations are needed to elucidate further the pathophysiology of high myopia and its impact on retinal and choroidal microcirculation. Our study revealed that high-myopic eyes with longer ALs exhibited increased total VD in the DCP and increased foveal VD in the SCP, DCP, and OuR segments, while they showed decreased total VD and temporal, inferior, and nasal parafoveal VDs in the CC segment compared to high-myopic eyes with shorter ALs.",
"40340620": "ID: 40340620\nTitle: Exploring oculomotor challenges in amyotrophic lateral sclerosis: a comprehensive review.\nAbstract: Traditionally understood as a motor neuron disease, amyotrophic lateral sclerosis (ALS) is now recognized to involve broader neurodegenerative processes, including the oculomotor system. This narrative review summarizes current evidence on oculomotor dysfunction in ALS, with a focus on its relationship to disease-related motor and cognitive impairments. Specifically, the review examines key eye-tracking (ET) metrics, including saccades, smooth pursuit, and fixation, highlighting their potential to reflect both motor and extramotor degeneration. Notably, patients with bulbar-onset ALS exhibit more pronounced oculomotor impairments. By synthesizing findings on the connection between oculomotor dysfunction and cognitive decline, this review underscores the potential of ET as a noninvasive tool for assessing ALS progression. Oculomotor metrics, as part of a broader understanding of ALS's impact on multiple neural networks, may offer valuable insights to refine patient assessment and care strategies, particularly in advanced disease stages.",
"40346885": "ID: 40346885\nTitle: Progressive Thalamo-Cortical Disconnection in Amyotrophic Lateral Sclerosis Genotypes: Structural Degeneration and Network Dysfunction of Thalamus-Relayed Circuits.\nAbstract: The thalamus is a key subcortical hub of numerous corticobasal and corticocortical circuits mediating a wealth of cognitive, behavioural, sensory and motor processes. While thalamic pathology is increasingly recognised in amyotrophic lateral sclerosis, its degeneration is often assessed in isolation instead of adopting a network-wise perspective and assessing the integrity of its rich cortical projections. A prospective imaging study was conducted in a cohort of genetically stratified patients to assess the structural and functional integrity of thalamo-cortical circuits and volumetric alterations longitudinally. The white matter integrity of thalamic projections to the anterior cingulate cortex, cerebellum, dorsolateral prefrontal cortex (DLPFC), Heschl's gyrus, medial frontal gyrus (MFG), orbitofrontal cortex, parietal cortex, postcentral gyrus and precentral gyrus (PreCG) is affected at baseline in ALS, which is more marked in C9orf72 hexanucleotide repeat carriers. Precentral gyrus and cerebellar grey matter volumes are also reduced, particularly in C9orf72. Longitudinal analyses capture progressive disconnection between the thalamus and frontal regions (DLPFC and MFG) in both C9orf72 positive and sporadic patients and progressive thalamo-PreCG disconnection in the sporadic C9orf72 negative cohort. Functional connectivity analyses revealed increasing thalamo-cerebellar connectivity in sporadic ALS and increasing thalamo-DLPFC connectivity in intermediate-length CAG repeat expansion carriers in ATXN2 over time. Our data provide evidence of extensive thalamo-cortical connectivity alterations in ALS. Corticobasal circuits mediating extrapyramidal, somatosensory, cognitive and behavioural functions are increasingly affected as the disease progresses. The degeneration of thalamic projections support the conceptualisation of ALS as a 'network disease' and the notion of 'what wires together degenerates together'.",
"40347374": "ID: 40347374\nTitle: Exploring Exosome-Based Approaches for Early Diagnosis and Treatment of Neurodegenerative Diseases.\nAbstract: Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), present an increasingly significant global health burden, primarily due to the lack of effective early diagnostic tools and treatments. Exosomes-nano-sized extracellular vesicles secreted by nearly all cell types-have emerged as promising candidates for both biomarkers and therapeutic agents in NDs. This review examines the biogenesis, molecular composition, and diverse functions of exosomes in NDs. Exosomes play a crucial role in mediating intercellular communication. They are capable of reflecting the biochemical state of their parent cells and have the ability to cross the blood-brain barrier (BBB). In doing so, they facilitate the propagation of pathological proteins, such as amyloid-beta (A\u03b2), tau, and alpha-synuclein (\u03b1-syn), while also enabling the targeted delivery of neuroprotective compounds. Recent advancements in exosome isolation and engineering have opened up new possibilities for diagnostic and therapeutic strategies. These range from the discovery of non-invasive biomarkers to innovative approaches in gene therapy and drug delivery systems. However, challenges related to standardization, safety, and long-term effects must be addressed before exosomes can be translated into clinical applications. This review highlights both the promising potential and the obstacles that must be overcome to leverage exosomes in the treatment of NDs and the transformation of personalized medicine.",
"40350723": "ID: 40350723\nTitle: [Oculomotor disorders in patients with amyotrophic lateral sclerosis].\nAbstract: Oculomotor disorders are not typical manifestations of amyotrophic lateral sclerosis (ALS). Occasionally, this disease is associated with vertical gaze paresis, presenting a distinct type as \u00abALS+progressive supranuclear palsy\u00bb. Studies using eye-tracking methods have revealed a variety of subclinical oculomotor disorders in this disease. These disorders can manifest as changes in reflex and voluntary saccades, antisaccades, smooth tracking eye movements, and fixations. A significant association between oculomotor disorders and clinical manifestations of ALS was reported. The occurrence of oculomotor disorders indicates the involvement of broader neuroanatomical structures, including the prefrontal cortex and basal ganglia. 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"40388191": "ID: 40388191\nTitle: Recent therapeutic advances in the treatment and management of amyotrophic lateral sclerosis: the era of regenerative medicine.\nAbstract: Despite decades of research, effective disease-modifying treatments for Amyotrophic Lateral Sclerosis (ALS) remain scarce. The emergence of regenerative medicine presents a new frontier for ALS treatment. This review is based on a comprehensive literature search using PubMed, Scopus and clinical trials databases on the recent therapeutic advancements in ALS, giving focus to regenerative medicine. The article includes coverage of stem cell-based therapies, including mesenchymal, neural and induced pluripotent stem cells; all of which may offer potential neuroprotective and immunomodulatory effects. Gene therapy, particularly antisense oligonucleotides targeting ALS-related mutations, has gained traction, with tofersen becoming the first FDA-approved genetic therapy for ALS. The article also covers emerging approaches such as extracellular vesicles, immune-modulating therapies, and bioengineering techniques, including CRISPR-based gene editing and cellular reprogramming, that hold promise for altering disease progression. While regenerative medicine provides hope for ALS patients, significant challenges remain. Biomarkers will play a crucial role in guiding personalized treatment strategies, ensuring targeted interventions. Future research should prioritize optimizing combinatory approaches, integrating different therapy strategies to maximize patient outcomes. Although regenerative medicine is still in its early clinical stages, its integration into ALS treatment paradigms could redefine disease management and alter its natural course.",
"40389143": "ID: 40389143\nTitle: COMM domain containing 4 inhibits hephaestin and ferroportin to enhance neuronal ferroptosis by disturbing the Cu-Fe balance in amyotrophic lateral sclerosis.\nAbstract: Dysregulation of copper and iron homeostasis contributes to the progression of amyotrophic lateral sclerosis (ALS), but the role and mechanism of COMM domain containing 4 (COMMD4) in ALS remains unclear. In this research, we showed that the expression of COMMD4 was upregulated in ALS cells and animal models. The increased COMMD4 induced neuronal ferroptosis by disrupting the Cu-Fe balance. Mechanistic studies indicated that COMMD4 inhibited ferroportin (FPN)-mediated neuronal iron efflux by inhibiting intracellular copper and hephaestin (HEPH). Our findings demonstrated that COMMD4 depletion exerts neuroprotective effects on ALS by increasing intracellular copper and activating HEPH/FPN pathway, rather than affecting the interaction between HEPH and FPN. Targeting COMMD4 and its downstream signaling pathways may offer potential therapeutic avenues for ALS.",
"40428407": "ID: 40428407\nTitle: Pontocerebellar Hypoplasia Type 1 and Associated Neuronopathies.\nAbstract: Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders.",
"40429496": "ID: 40429496\nTitle: Exploring the Risk: Peripheral Retinal Degenerations in Young Australian Adults.\nAbstract: Background/Objectives: Peripheral retinal degenerations (PRDs) are structural anomalies in the outer regions of the retina, typically emerging in adolescence and early adulthood. Early detection is crucial, as some PRDs can lead to sight-threatening complications, such as retinal detachment, if left unmanaged. Due to a paucity of research regarding PRDs and their association with axial length (AL) and refractive error (RE) in young Australian adults, this study aimed to investigate the prevalence of PRDs in this population and establish whether AL and RE could help predict the likelihood of PRD occurrence. Methods: A cross-sectional study was conducted on a mixed population (n = 221) of Australian adults aged 18 to 40. Demographic data, RE, AL, and a series of ultra-widefield (UWF) retinal images were obtained from participants' undilated eyes using the Zeiss ClarusTM 500. Results: The overall PRD prevalence was 8.15% (n = 442 eyes). Binary logistic regression revealed that a longer AL was a more significant factor in increasing the risk of PRD development across all myopia classifications compared to emmetropia than RE. The likelihood of a PRD was 50% at an AL of 26.9 mm and -6.50D of myopia, and 95% at 29.6 mm and -11.00D. Conclusions: PRD prevalence was lower than reported in other global studies, perhaps reflecting the diverse ethnic makeup of the cohort. While our study supports the conventional understanding that longer ALs, and high myopia are key risk factors for developing a PRD, it also provides new insights into the likelihood of detecting a PRD at a given AL or RE in a mixed population. This information is crucial for eye care practitioners, enabling early identification of at-risk individuals and screening for PRDs that may increase the risk of retinal detachment.",
"40435818": "ID: 40435818\nTitle: Exosomal miR-574-3p from adipose-derived mesenchymal stem modulates CRIM1/BMPs signaling to restrain chondrocytes hypertrophy and inflammatory response in knee osteoarthritis.\nAbstract: Chondrocyte hypertrophy is an important feature of knee osteoarthritis (KOA) cartilage pathological damage, and existing evidence supports the potential therapeutic role of adipose-derived mesenchymal stem cells (ASCs) through exosomes. However, the differences of in exosome contents under different conditions and the mechanisms by which they affect the hypertrophic phenotype of chondrocytes remain unclear. Exosomes from ASCs with or without the stimulation of IL-1\u03b2 were extracted, identified by NTA, TEM, and membrane surface marker, stained with PKH26 to confirm the uptake by chondrocytes. Next, miRNA sequencing for these two types of exosomes were performed and miR-574-3p, significantly down-regulated in IL-1\u03b2 stimulated ACSs exosomes, was identified the most distinct miRNAs. Besides, RNA-seq on chondrocytes, KOA chondrocytes, and KOA chondrocytes under the intervention of exosomes derived from ASCs were conducted, and intersected the obtained differentially expressed genes with potential target genes of miR-574-3p known from miRNA database. Further on, exosomal miR-574-3p From ACSs modulated cysteine-rich motor neuron protein 1 (CRIM1)/bone morphogenetic proteins (BMPs) signaling to restrain chondrocytes hypertrophy and inflammatory response in KOA were verified. Exosomal miR-574-3p from ASCs was significantly down-regulated under inflammatory state. ASCs-derived exosomes could reduce inflammatory cell infiltration, cartilaginous surface rough and fractured, and collagen staining lost, via the regulation of CRIM1, BMP2, BMP6 and BMP9 expression level. This chondroprotective effect was further enhanced with miR-574-3p mimic, but disappeared with miR-574-3p inhibitor. Besides, CRIM1 siRNA interrupted the benign intervention of exosomes on inflammatory cell infiltration, surface cracking, and collagen loss in cartilage tissue, as well as the down-regulation of BMP2, BMP6 and BMP9, the down-regulation of chondrocyte hypertrophy markers ALP, RUNX2, MMP13, and inflammatory factors IL-1\u03b2 and TNF-\u03b1. Exosomal miR-574-3p from ASCs is significantly down-regulated under inflammatory state. Additionally, Exosomal miR-574-3p from ASCs modulates CRIM1/BMPs signaling to inhibit the chondrocytes hypertrophy and inflammatory response in KOA.",
"40444312": "ID: 40444312\nTitle: Validation of ocular trauma score (OTS) in open- and closed-globe injuries in Indian patients.\nAbstract: To validate the predictive value of the ocular trauma score (OTS) in open- and closed-globe eye injuries in the Indian context. Prospective interventional case series. This study, conducted at a tertiary healthcare institute from January 2018 to June 2019, included 150 eyes of 150 patients with open- and closed-globe injuries. Inclusion criteria were patients with globe injuries who provided informed consent and had complete OTS data. Exclusion criteria included electric, chemical, and thermal injuries, prior surgery, pre-existing poor visual acuity (VA), and severe systemic injuries. There was no randomization. Demographic details, initial and final VA, injury type, and OTS variables were recorded. Patients were classified into OTS categories preoperatively based on Kuhn et al.'s system, and VA distribution was compared with the original study. The main outcome was to assess the correlation between the final BCVA at 6 months post-intervention and the predicted VA based on the OTS category. A total of 150 patients (72% open globe, 28% closed globe) were included, with a male-to-female ratio of 4.5:1. The mean age \u00b1 SD was 29.34 \u00b1 17.49 years. OTS classification showed 6% in OTS 1, 17% in OTS 2, 67% in OTS 3, 4% in OTS 4, and 6% in OTS 5. Final VA was \u226420/40 (41%), 20/50-20/200 (20%), 20/200-1/200 (15%), HM/PL (15%), and NLP (9%). Final VA post-treatment correlated with predicted VA as per the OTS category (Spearman's r = 0.53, P < 0.001). OTS provides reliable prognostic information and has fair predictive value for final VA in open- and closed-globe injuries.",
"40451408": "ID: 40451408\nTitle: TFOS DEWS III: Diagnostic Methodology.\nAbstract: A standard approach to the diagnosis of dry eye disease across eye care practitioners is critical to reassuring the patient, providing consistency between practitioners and informing governments as to the true prevalence and resulting healthcare needs. The Tear Film & Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) III has reviewed the evidence-base since their previous reports published in 2017 and revised the definition to \"Dry eye is a multifactorial, symptomatic disease characterized by a loss of homeostasis of the tear film and/or ocular surface, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities are etiological factors.\" Key features from the definition include that dry eye disease is multifactorial, is a disease and not a syndrome and is always symptomatic. Differential diagnosis and ocular examination guidance is given along with the risk factors that should be discussed with the patient. The recommended screening questionnaire is the OSDI-6 with a cut-off score \u22654. A positive result together with a non-invasive breakup time <10s or alternatively tear film hyperosmolarity (\u2265308mOsm/L in either eye or an interocular difference >8mOsm/L) or alternatively >5 corneal fluorescein and/or >9 conjunctival lissamine green punctate spots and/or lid margin lissamine green staining of \u22652mm length & \u226525 % width, gives a diagnosis of dry eye. Subclassification was separated into tear film deficiencies (lipid, aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid margin) and ocular surface abnormalities (anatomical misalignment, neural dysfunction, ocular surface cell damage/disruption and primary inflammation/oxidative stress) components, with appropriate clinical tests and cut-offs provided to identify these etiological drivers in an individual, to inform appropriate management and therapy.",
"40455211": "ID: 40455211\nTitle: [Ocular alterations in pseudoxanthoma elasticum : The eye as a window to diagnosing a systemic disease].\nAbstract: Pseudoxanthoma elasticum (PXE) is an autosomal-recessive multisystem disease characterized by elastic fiber calcification in the skin, the cardiovascular system, and eyes. PXE is caused by biallelic mutations in the ABCC6\u00a0gene on chromosome\u00a016, resulting in low inorganic pyrophosphate plasma levels. Typical ocular manifestations result from calcification of Bruch's membrane and include peau d'orange, angioid streaks, and comet-tail lesions. Advances in multimodal imaging have significantly improved the detection of these features. Ocular complications in PXE include the development of secondary neovascularization, which can be treated with anti-vascular endothelial growth factor (VEGF) injections. In cases of suspected PXE, genetic testing and genetic counseling should be performed for diagnostic confirmation. Early referral to a\u00a0specialized center is essential. Interdisciplinary care and management of complications, particularly in collaboration with angiologists, are crucial for treating this multisystem disorder. Although no approved causal therapy for PXE currently exists to date, accurate and early diagnosis using phenotypic characteristics is critical. Early identification of other affected family members and timely treatment of secondary complications allow for better disease management and offer patients the opportunity to participate in ongoing clinical trials. Promising therapeutic options are currently emerging and may significantly improve management and prognosis in the future. Pseudoxanthoma elasticum (PXE) ist eine autosomal-rezessiv vererbte Multisystemerkrankung, die sich durch charakteristische Ver\u00e4nderungen an der Haut, im arteriellen Gef\u00e4\u00dfsystem und an den Augen manifestiert. Die Erkrankung wird durch biallelische Mutationen im ABCC6-Gen auf Chromosom\u00a016 verursacht, die zu einer pathologischen Kalzifizierung von elastischen Fasern f\u00fchren. Typische okul\u00e4re Manifestationen, die fundoskopisch sichtbar sind, umfassen die sog. Peau d\u2019orange, angioide Streifen und Kometenschweifl\u00e4sionen und sind auf eine Kalzifizierung der Bruch-Membran zur\u00fcckzuf\u00fchren. Fortschritte in der multimodalen Bildgebung haben die Erkennung dieser Charakteristika erheblich verbessert. Okul\u00e4re Komplikationen bei PXE umfassen die Entwicklung von sekund\u00e4ren Neovaskularisationen, die mit Anti-\u201evascular endothelial growth factor\u201c (VEGF)-Injektionen behandelt werden k\u00f6nnen. Bei Verdacht auf PXE sollten zur Diagnosesicherung eine molekulargenetische Untersuchung sowie eine humangenetische Beratung erfolgen, und eine rechtzeitige Anbindung an ein spezialisiertes Zentrum sollte eingeleitet werden. Eine interdisziplin\u00e4re Betreuung und Therapie von Komplikationen, insbesondere in Zusammenarbeit mit der Angiologie, sind f\u00fcr die Behandlung dieser Multisystemerkrankung unerl\u00e4sslich. Obwohl derzeit noch keine zugelassene kausale Therapie f\u00fcr PXE existiert, ist eine korrekte und fr\u00fche Diagnosestellung anhand ph\u00e4notypischer Charakteristika entscheidend. Neben der fr\u00fchzeitigen Erkennung weiterer betroffener Familienmitglieder sowie einer rechtzeitigen Behandlung von Sekund\u00e4rkomplikationen erm\u00f6glicht sie den Patienten zudem eine potenzielle Teilnahme an laufenden klinischen Studien. Mehrere laufende oder geplante klinische Studien sind aussichtsreich und k\u00f6nnten bei Erfolg zu einer verbesserten Versorgung und Prognose der Patienten f\u00fchren.",
"40482989": "ID: 40482989\nTitle: Knockdown of OPTN modulates miRNA-125b-5p expression via NF-\u03baB pathways in amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterized by severe dysfunction in upper and lower motor neurons. Previous studies have reported that the optineurin gene (OPTN) downregulation is one of the causative genetic factors for ALS, leading to the dysfunction of optineurin (OPTN), a multifunctional protein implicated in several cellular processes. Herein, we found that conditional knockout of the Optn gene in mouse microglia leads to activation of microglia. In subsequent studies, we also found that OPTN knockdown in BV2 cells leads to the activation of BV2 cells and promotes the apoptosis of co-cultured NSC34\u00a0cells via exosomes derived from BV2 cells in vitro. In contrast, OPTN knockdown in NSC34\u00a0cells did not cause apoptosis of the NSC34\u00a0cells themselves. It was suggested that microglia activation is involved in ALS initiation and development, but the nature of microglial-neuronal interactions remained elusive, requiring further exploration. Exosomes have been proven to be essential mediators. Notably, increased miRNA-125b-5p expression was uncovered in BV2 cells with the OPTN gene silenced, their derived exosomes, as well as the cocultured NSC34\u00a0cells. Interestingly, we proved that increased miRNA-125b-5p enhanced the apoptosis of NSC34\u00a0cells. We further noted that the overexpression of miRNA-125b-5p in BV2 cells can be regulated by an NF-\u03baB activator (LPS) or inhibitor (withaferin A). Altogether, this study showed that silencing the OPTN gene may overexpress miRNA-125b-5p levels via the classical NF-\u03baB pathway in BV2 cells. Up-regulated miRNA-125b-5p might be transmitted from exosomes to NSC34\u00a0cells, resulting in NSC34\u00a0cells apoptosis. Microglial-neuronal interactions mediated by exosomes were the crucial mechanism of OPTN gene downregulation leading to ALS, and this conclusion had been verified in cell models.",
"40498024": "ID: 40498024\nTitle: Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis.\nAbstract: Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction.",
"40517842": "ID: 40517842\nTitle: Commentary on Maja Guberina et al.'s study of dose response relation for optic nerve atrophy at low-dose rate brachytherapy of uveal melanoma.\nAbstract: ",
"40517843": "ID: 40517843\nTitle: Response to: Commentary on Maja Guberina et al.'s study of dose response relation for optic nerve atrophy at low-dose rate brachytherapy of uveal melanoma.\nAbstract: ",
"40550228": "ID: 40550228\nTitle: Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.\nAbstract: Exosomes, tiny extracellular vesicles, hold significant potential as biological nanocarriers for diverse therapeutic agents due to their exceptional ability to navigate through the barriers of biological systems. This comprehensive review delves into the capability of exosomes in the therapy of neurodegenerative disorders, concentrating on their potential for targeted drug delivery. It examines the complex processes involved in exosome-mediated drug delivery, including targeting, cellular uptake, intracellular trafficking, and therapeutic release. Insights from preclinical studies and clinical trials are exploited, highlighting the impactful applications of exosomes, particularly in the treatment of Parkinson's, Alzheimer's, ALS, and Huntington's diseases. The review also addresses challenges such as immunogenicity, scalability, and regulatory obstacles while exploring emerging technologies like advanced exosome engineering, personalized medicine, and the integration of nanotechnology. Overall, this review accentuates the potential impact of exosome-based treatments in biomedicine alongside the critical need to overcome existing barriers.",
"40554439": "ID: 40554439\nTitle: Bidirectional Causal Relationship Between Myopia and Neurodegenerative Diseases: Two-Sample Mendelian Randomization Analyses.\nAbstract: Aims/Background Myopia is highly prevalent in certain neurodegenerative diseases (NDDs), and both conditions demonstrate genetic susceptibility. This study investigated the potential bidirectional causal relationships between myopia and four NDDs, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), using Mendelian randomization (MR). We aimed to determine whether myopia contributes to the risk of NDDs and vice versa. Methods We analyzed data from two independent, large-scale genome-wide association study (GWAS) cohorts on myopia, comprising 212,571 participants in the first cohort (finn-b-H7_MYOPIA) and 95,619 in the second (GCST009521). GWAS summary statistics for the four NDDs, encompassing 589,439 samples, were also incorporated. Bidirectional MR was employed to investigate causal relationships between myopia and each of the four NDDs. The inverse variance-weighted (IVW) method served as the primary analytical approach. Sensitivity analyses, including MR-Egger regression, weighted median, weighted mode, and simple mode, were conducted to assess the robustness of the findings. Horizontal pleiotropy was evaluated using the MR-Egger regression intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, while heterogeneity was assessed via Cochran's Q test. Leave-one-out analyses were conducted to evaluate the influence of individual single nucleotide polymorphisms (SNPs). Odds ratios (ORs) with 95% confidence intervals (CIs) were reported, and statistical significance was set at p < 0.05. Results MR analyses identified no evidence of a causal relationship between myopia and refractive error and increased risk of any of the four NDDs (all p > 0.05). Similarly, none of the NDDs were associated with an increased risk of myopia or refractive error (all p > 0.05). Sensitivity analyses revealed no SNPs with significant influence on the causal associations (all p > 0.05), supporting the robustness of the findings. Conclusion This study provides no evidence of a bidirectional causal relationship between myopia and the four NDDs among individuals of European ancestry. Future research should extend beyond direct causal inference to investigate potential mediating biological mechanisms.",
"40560963": "ID: 40560963\nTitle: Analysis of retinal markers and incident amyotrophic lateral sclerosis: An optical coherence tomography-based cohort study.\nAbstract: Biomarkers are widely recognized as crucial breakthroughs in tackling amyotrophic lateral sclerosis (ALS). Among them, retina markers may hold promise due to the close retina-brain connection and non-invasive, portable detection methods. Thus, using optical coherence tomography (OCT), we investigated the link between baseline cell-level retinal features and future ALS risk. Participants from the UK Biobank underwent OCT scans to assess retinal layers, macula, and optic disc parameters. Follow-up commenced two years after the baseline period (2006-2010), during which ALS cases were identified using International Classification of Diseases (ICD) codes from medical and assessment records. Cox proportional hazards models were applied to examine the relationship between retinal markers and incident ALS. Over a median follow-up of 14.11 years, 70 ALS cases occurred among 53,824 participants (incidence 10.58 per 100,000 person-years). Most participants were White (94.6%), 44.8% male, with a median age of 58 years. After adjusting for demographics and comorbidities affecting the retina, a standard deviation (SD) decrease of 15.19 \u00b5m in photoreceptor layer (PRL) thickness was associated with a 19% (95% confidence interval [7, 29]; p\u2009=\u20090.002) increased risk of ALS, while a SD increase of 26.11 \u00b5m in retinal pigment epithelium (RPE) thickness corresponded to a 20% (95% CI [7, 34]; p\u2009=\u20090.002) higher risk. Sensitivity analyses excluding follow-ups of less than 4 and 6 years yielded consistent results. Subgroup analyses showed these findings were more pronounced in smokers. The main limitation of this study is its single time point observational design. A thinner PRL and thicker RPE may precede the clinical diagnosis of ALS, offering potential clues for early diagnosis and insights into the disease's pathogenesis.",
"40580685": "ID: 40580685\nTitle: Multifaceted roles of extracellular vesicles in the interplay of neuroinflammation and neurodegenerative diseases.\nAbstract: Despite advances in understanding neurodegenerative disease mechanisms, effective treatments remain elusive. Extracellular vesicles (EVs), key mediators of intercellular communication within the central nervous system (CNS), are increasingly recognized for their involvement in the pathogenesis of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's disease (HD). In vivo studies demonstrate EVs' crucial role in maintaining CNS homeostasis, modulating neuroinflammatory responses, and influencing tissue repair and regeneration following injury, thereby impacting disease progression and recovery. Their unique properties, including small size and ability to cross the blood-brain barrier (BBB), position them as promising candidates for both biomarkers and therapeutics in CNS diseases. This review delves into the significant impact of neuroinflammation on neurodegenerative conditions, specifically focusing on the multifaceted contributions of EVs and their intricate interplay with the inflammatory landscape. We explore EV biogenesis, cargo composition, diverse roles in neuroinflammation (including intercellular communication and neuroprotection), their potential as biomarkers and drug delivery vehicles across the BBB for diagnosis or treatment of neuroinflammation implemented neurodegenerative diseases.",
"40581291": "ID: 40581291\nTitle: Comparison of axial length measurements of myopic eyes from ocular biometers versus axial length estimator.\nAbstract: To compare axial length (AL) estimates of myopic eyes obtained using an axial length estimator (ALE) and AL measurements made with the IOLMaster 700 in India and the Lenstar 900 in Vietnam. This multicenter retrospective cross-sectional study analyzed masked data of both eyes from myopic children (<18 years of age). Estimated AL was derived from mean keratometry and refraction values using ALE. Differences between actual and estimated ALs and their correlation were assessed using Bland-Altman plots and intraclass correlation coefficients (ICCs). A total of 237 myopic children (474 eyes) aged 5-16 years were included: 90 Indian and 147 Vietnamese children. ALE estimates on average exceeded actual AL measurements, with mean differences of -0.26 mm (95% limits of agreement, -1.25 to 0.73 mm) for ALE formula, and -0.21 mm (95% limits of agreement, -1.14 to 0.71 mm) for ALE data input. ICCs showed strong agreement: 0.90 (95% CI, 0.83-0.93) for actual AL versus ALE data input and 0.89 (95% CI, 0.78-0.93) for actual AL versus ALE formula. Indian children had shorter actual AL than Vietnamese children (24.56 \u00b1 0.90 vs 24.91 \u00b1 0.86 mm [P < 0.001]) and exhibited slightly smaller differences between actual and estimated AL (-0.13 vs -0.27 mm for ALE data input; -0.17 vs -0.31 mm for ALE formula). In our cohorts, ALE demonstrated strong agreement with IOLMaster 700 and Lenstar 900 AL measurements in myopic children. ALE may be a useful clinical tool for this population when direct measurements of AL are unavailable.",
"40602557": "ID: 40602557\nTitle: Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1G93A mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.\nAbstract: Amyotrophic Lateral Sclerosis (ALS) is a prevalent condition characterized by motor neuron loss and skeletal muscle paralysis. Despite being associated to mutations in over 40 genes, its etiology remains elusive without a cure or effective treatment. ALS, historically considered a motor neuron disease, is defined today as a multisystem disorder involving non-neuronal cell types, including early muscle pathology independent of motor neuron degeneration (dying back hypothesis), thus skeletal muscle actively contributes to disease pathology, making it a viable therapeutic target for ALS. Our previous research has shown that boron transporter NaBC1 (encoded by the SLC4A11 gene), after activation co-localizes with integrins and growth factor receptors synergistically enhancing muscle repair. Here we investigate the effects of injectable alginate-based hydrogels for controlled local borax release in Amyotrophic Lateral Sclerosis muscle. Treated mice showed improved motor function, prolonged survival, and activation of essential muscle metabolic pathways, leading to enhanced muscle repair and reduced atrophy and inflammation. Interestingly, local muscle repair activation provided retrograde neuroprotection by preserving motor neurons and reducing neuro-inflammation. This study highlights the role of muscle tissue in ALS pathology, supporting its targeting with NaBC1-based therapies for muscle regeneration.",
"40607673": "ID: 40607673\nTitle: [Focus on MS - visual loss as a cardinal symptom of multiple sclerosis].\nAbstract: Visual disturbances are a common presenting symptom of multiple sclerosis (MS), often caused by optic neuritis. This acute inflammation of the optic nerve leads to pain during eye movements, visual impairment and colour vision defects. Optic neuritis can be idiopathic, MS-associated or occur in the context of other diseases such as NMOSD or MOGAD. Diagnosis is based on clinical findings, imaging and visual evoked potentials. Early high-dose corticosteroid treatment can support recovery and improve long-term prognosis. Blickpunkt MS \u2013 Sehst\u00f6rungen als Leitsymptom der Multiplen Sklerose. Sehst\u00f6rungen sind h\u00e4ufig ein fr\u00fches Leitsymptom der Multiplen Sklerose (MS), oft verursacht durch eine Optikusneuritis. Diese akute Entz\u00fcndung des Sehnervs f\u00fchrt zu Schmerzen bei Augenbewegungen, Visusminderung und Farbsinnst\u00f6rungen. Die Optikusneuritis kann idiopathisch, MS-assoziiert oder im Rahmen anderer Erkrankungen wie NMOSD oder MOGAD auftreten. Die Diagnose st\u00fctzt sich auf klinische Befunde, Bildgebung und visuell evozierte Potenziale. Eine fr\u00fchzeitige, hoch dosierte Kortikosteroidtherapie kann die Genesung unterst\u00fctzen und die Langzeitprognose verbessern. Schl\u00fcsselw\u00f6rter: Optikusneuritis, Sehst\u00f6rungen, Multiple Sklerose (MS), Demyelinisierung, Kortikosteroidtherapie.",
"40616089": "ID: 40616089\nTitle: D-optimal candexch algorithm-enhanced machine learning UV-spectrophotometry for five-analyte determination in novel anti-glaucoma formulations and ocular fluids: four-color sustainability framework with NQS assessment and UN-SDG integration.\nAbstract: The novel anti-glaucoma ophthalmic preparation containing latanoprost, netarsudil, and benzalkonium chloride has posed a significant challenge due to its complexity and the lack of environmentally sustainable quantification methods, with only a single published method available for its quantification that lacks environmental consideration. This study aims to address this crucial gap by presenting a novel and sustainable approach using machine learning-enhanced UV-spectrophotometric chemometric models for the concurrent quantification of latanoprost, netarsudil, benzalkonium chloride, and two related compounds in ophthalmic preparations and aqueous humour. A strategic multi-level, multi-factor experimental design creates a 25-mixture calibration set for four models (PLS, GA-PLS, PCR, and MCR-ALS). The key novelty was using the D-optimal design generated by MATLAB's candexch algorithm to construct a robust validation set, overcoming random data splitting limitations in machine learning chemometric methods and ensuring unbiased evaluation across concentrations. The optimized MCR-ALS model outperforms in predictive ability, with recovery percentages of 98-102%, low root mean square errors of calibration and prediction, favorable bias-corrected mean square error of prediction, relative root mean square error within acceptable limits, and adequate limits of detection for pharmaceutical analysis. The Greenness Index Spider Charts and the Green Solvents Selection Tool were applied to replace hazardous solvents. A total of seven advanced evaluation tools were employed to assess the method's greenness, blueness, violetness, and whiteness, highlighting its eco-friendly profile, practical relevance, and innovation potential. Additionally, the method's environmental and societal benefits were further validated using the Need, Quality, Sustainability (NQS) index. Overall, this machine learning-based framework contributes meaningfully to ten United Nations Sustainable Development Goals (UN-SDGs), underscoring its value for future-oriented pharmaceutical research.",
"40618341": "ID: 40618341\nTitle: Integrated genomic and molecular insights into astrocyte- and oligodendrocyte-derived amyotrophic lateral sclerosis: focus on miRNAs and extracellular vesicles.\nAbstract: Motor neurons in the brain and spinal cord begin to die off in Amyotrophic lateral sclerosis (ALS), a disease that can be fatal. Molecular pathways in neurological disease, especially ALS, remain a challenge in the medical sciences. In this disease, a disorder in both astrocytes and oligodendrocytes can cause the disease to progress. This study aimed to investigate the molecular mechanisms and find key elements between these two cells in ALS with a bioinformatics perspective. In this study, using integrated and continuous bioinformatics analytics by various tools and databases, we investigated genes, protein products, and miRNAs between astrocytes and oligodendrocytes. The obtained data were involved in the Cellular senescence, actin cytoskeleton, and cell cycle signaling pathways. Then, after careful evaluation of the information, TP53, MDM2, KRAS, PTPRC, and GSK proteins were candidates, which are regulated by hsa-miR-564, hsa-miR-496-5p, hsa-miR-324-5p, hsa-miR-296-5p, and hsa-miR-4258-3p miRNAs. Finally, the four genes had a more robust and better relationship in this study between astrocyte and oligodendrocyte-derived ALS.",
"40620684": "ID: 40620684\nTitle: Mesenchymal Stem Cell-Derived Extracellular Vesicles: Emerging Therapies for Neurodegenerative Diseases.\nAbstract: Neurodegenerative diseases are a group of chronic diseases characterized by a gradual loss of neurons that worsens over time and dysfunction. These diseases are extremely harmful, not only affecting the physical health of the patients, but also having a serious impact on their quality of life. They mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), etc. Their pathogenesis is complex, and it is difficult for the existing treatments to effectively slow down the progression of the disease. In recent years, Mesenchymal Stem Cells (MSCs) have received widespread attention for their anti-inflammatory, immunomodulatory and neuroprotective properties. In this context, MSC-derived Extracellular Vesicles (MSC-EVs) have demonstrated unique therapeutic potential as a cell-free therapeutic strategy. MSC-EVs are rich in bioactive substances such as proteins, lipids, mRNAs and miRNAs, which can pass through the blood-brain barrier and be targeted to the diseased area to regulate neuronal survival, synaptic plasticity and neuroinflammatory responses. In addition, compared with stem cell therapy, MSC-EVs have the advantages of low immunogenicity, easy storage and transportation, and avoiding ethical controversies. However, their clinical application still faces challenges: standardized isolation and purification techniques have not been unified, vesicle loading efficiency and targeting need to be further optimized, and long-term safety needs to be systematically evaluated. This review focuses on the role of MSC-EVs in the development of neurological diseases and explores their possible dual roles, both favorable and unfavorable, in the context of neurological diseases. In addition, this review provides a review of current studies on EVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases and provides a comprehensive review of the prospects and challenges of MSC-EVs in clinical applications.",
"40625857": "ID: 40625857\nTitle: A Novel Retinal Nerve Fiber Layer Biomarker of Amyotrophic Lateral Sclerosis (ALS) Identified Using Longitudinal in vivo Ocular Imaging.\nAbstract: Like motor neurons, retinal ganglion cells (RGCs) have long axons and high metabolic demands, making them vulnerable to disruption of axonal transport. Unlike motor neurons, the RGC axons are accessible to high-resolution non-invasive optical imaging in their intraocular portion. A non-invasive in vivo retinal imaging biomarker can be valuable for amyotrophic lateral sclerosis (ALS) diagnosis and monitoring. We aim to assess the presence of inner retinal pathology in a mouse model of ALS and its possible progression with age. Transgenic SOD1G93A mice (n=8, 4M/4F) and age-matched controls (n=8, 4M/4F) underwent in vivo retinal imaging with confocal scanning laser ophthalmoscopy (cSLO) coupled with optical coherence tomography (OCT) at 20\u00a0weeks of age. Another group of SOD1G93A mice (n=20, 6M/14F) and age-matched controls (n=20, 6M/14F) underwent longitudinal in vivo retinal imaging with the same device. Each retinal imaging session included infrared reflectance (IR) and blue reflectance (BR) cSLO coupled with OCT. Hyperreflective puncta located in the retinal nerve fiber layer (RNFL) were counted in a blinded fashion in ALS and control mice. The number of puncta at 20\u00a0weeks of age in ALS mice was compared with controls using Wilcoxon test. The rates of increase of puncta number were analyzed using a Generalized Linear Mixed-Effect Model (GLMM) for genotype, time, and sex. IR-cSLO coupled with OCT revealed hyperreflective puncta located in the RNFL of ALS mice. IR-cSLO fundus imaging at the age of 20\u00a0weeks showed ALS mice had significantly higher number of puncta compared to controls (2.1\u00b12.3 vs 0.5\u00b10.8; (mean\u00b1SD), respectively, p=0.036). GLMM analysis showed both ALS mutation and age were significantly associated with the rate of increase of puncta number (p=0.000232 and p=0.000366, respectively). In addition, female ALS mice had a steeper increase of puncta compared to male ALS mice (0.21\u00b10.04 log number puncta/week vs 0.16\u00b10.04, respectively; p=0.037). Our findings demonstrate distinct inner retinal nerve fiber layer pathology, detected using cSLO coupled with OCT, which worsens over time. These findings support the potential of retinal imaging as a translationally relevant, non-invasive biomarker for ALS diagnosis or disease monitoring in humans.",
"40628227": "ID: 40628227\nTitle: Reply to Scholz et al.\nAbstract: In our recent study1, we investigated the neural basis of attempts at forming voluntary visual imagery in individuals with aphantasia and found that although these individuals lack visual imagery experience, their early visual cortex exhibits stable, content-specific activation patterns during imagery attempts. Unlike in the neurotypicals, these neural representations, however, differ from those evoked during perception, as indicated by the failure of cross-decoding between imagery and perceptual tasks. In this response, we address Scholz et al.'s commentary2 on our findings and the broader implications for theories of unconscious imagery, emphasizing that while we do not claim the presence of unconscious imagery, our results suggest that early visual activity in aphantasia may reflect perceptual-like, but transformed or non-conscious, representations.",
"40667132": "ID: 40667132\nTitle: Herpes simplex virus 1 strain 17+ with R2 mutation in UL37 has residual retrograde transport.\nAbstract: Herpes simplex virus 1 (HSV-1) causes lifelong recurrent infections. Following primary infection of the oral or genital mucosa, HSV-1 travels retrogradely through axons and establishes latency in the cell body of ganglionic neurons of the peripheral nervous system. Periodic reactivation in neurons and anterograde transport of virions back to peripheral regions causes oral or genital ulcerations. Many host and viral factors implicated in retrograde and anterograde transport of HSV-1 have been identified. In particular, studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate retrograde transport of HSV-1 strain F. Here, we introduced the same R2 mutations in the highly neurovirulent HSV-1 strain 17+. We report that this R217 virus has residual retrograde travel. We show that R217 can establish latency in mouse models of ocular and vaginal infection and reactivate. These results contradict published evidence and show that the R2 mutation is not sufficient to fully prevent retrograde transport of HSV-1.",
"40675818": "ID: 40675818\nTitle: Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations.\nAbstract: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) that innervate skeletal muscles. However, certain MN groups including ocular MNs, are relatively resilient. To reveal key drivers of resilience versus vulnerability in ALS, we investigate the transcriptional dynamics of four distinct MN populations in SOD1G93A ALS mice using LCM-seq and single-molecule fluorescent in situ hybridization. We find that resilient ocular MNs regulate few genes in response to disease. Instead, they exhibit high baseline gene expression of neuroprotective factors, including En1, Pvalb, Cd63, and Gal, some of which vulnerable MNs upregulate during disease. Vulnerable MN groups upregulate both detrimental and regenerative responses to ALS and share pathway activation, indicating that breakdown occurs through similar mechanisms across vulnerable neurons, albeit with distinct timing. Meta-analysis across four rodent mutant Sod1 MN transcriptome data sets identify a shared vulnerability code of 39 genes, including Atf4, Nupr1, Ddit3, and Penk, involved in apoptosis, as well as a proregenerative and antiapoptotic signature consisting of Atf3, Vgf, Ina, Sprr1a, Fgf21, Gap43, Adcyap1, and Mt1 Machine learning using genes upregulated in SOD1G93A spinal MN predicts disease in human stem cell-derived SOD1E100G MNs and shows that dysregulation of VGF, INA, and PENK is a strong disease predictor across species and SOD1 mutations. Our study reveals MN population-specific gene expression and temporal disease-induced regulation that together provide a basis to explain ALS selective vulnerability and resilience and that can be used to predict disease.",
"40691358": "ID: 40691358\nTitle: [Assessment of myopia progression].\nAbstract: The global increase in myopia prevalence and associated secondary complications necessitates adequate monitoring of myopia progression. This review highlights the advantages and disadvantages of the most commonly used target parameters for assessing myopia progression: refractive error and axial length. Although refractive error is essential for the diagnosis and optical correction of myopia, axial length proves to be a\u00a0more reliable and clinically relevant parameter for monitoring progression and guiding preventive interventions. Axial length correlates more strongly with the risk of ocular complications and is less susceptible to diurnal variations and interventions that alter the eye's refractive power. Assessing myopia progression under preventive measures requires consideration of age-dependent physiological changes in axial length. Standardized comparison parameters, such as the cumulative absolute reduction in axial elongation (CARE) can facilitate the objective evaluation of the efficacy of the intervention. Regular monitoring of refraction and axial length should also be performed in young adults with risk factors, as myopia onset and progression can occur even at this age. Die globale Zunahme der Myopiepr\u00e4valenz und damit einhergehender Sekund\u00e4rkomplikationen erfordert eine ad\u00e4quate \u00dcberwachung der Myopieprogression. Diese \u00dcbersichtsarbeit beleuchtet die Vor- und Nachteile der gebr\u00e4uchlichsten Zielparameter zur Beurteilung der Myopieprogression: Refraktionsfehler und Achsenl\u00e4nge. Obwohl der Refraktionsfehler f\u00fcr die Diagnose und optische Korrektur der Myopie unerl\u00e4sslich ist, erweist sich die Achsenl\u00e4nge als zuverl\u00e4ssigerer und klinisch relevanterer Parameter zur \u00dcberwachung der Progression und zur Steuerung von Pr\u00e4ventionsma\u00dfnahmen. Die Achsenl\u00e4nge korreliert st\u00e4rker mit dem Risiko okul\u00e4rer Komplikationen und ist weniger anf\u00e4llig f\u00fcr tageszeitliche Schwankungen und Interventionen, die die Brechkraft des Auges ver\u00e4ndern. Die Beurteilung der Myopieprogression unter Pr\u00e4ventionsma\u00dfnahmen erfordert die Ber\u00fccksichtigung altersabh\u00e4ngiger physiologischer Ver\u00e4nderungen der Achsenl\u00e4nge. Standardisierte Vergleichsparameter wie CARE (\u201ecumulative absolute reduction in axial elongation\u201c) k\u00f6nnen die objektive Beurteilung der Wirksamkeit von Interventionen erleichtern. Auch bei jungen Erwachsenen mit Risikofaktoren sollte eine regelm\u00e4\u00dfige \u00dcberwachung von Refraktion und Achsenl\u00e4nge erfolgen, da eine Myopisierung auch in diesem Alter auftreten kann.",
"40692425": "ID: 40692425\nTitle: Comparison of the Peripapillary Structure-Vessel Density Relationship Before and After Axial Length Magnification Correction Using Different Methods.\nAbstract: To evaluate changes in OCTA-derived structural and vascular parameters before and after axial length (AL) magnification correction using two different formulas, and to explore their correlations with vessel density (VD). This study included 45 high myopic eyes and 45 age- and gender-matched controls. Both 6\u2009\u00d7\u20096\u2009mm2 optic nerve head imaging and biological measurement were performed using OCTA. Magnification correction was performed using both the Bennett formula and the device's built-in algorithm. Parameters analysed included retinal nerve fibre layer (RNFL) thickness, superficial vascular complex (SVC) VD, deep vascular complex (DVC) VD, and choroidal VD. In long AL eyes, uncorrected values underestimated RNFL thickness and SVC VD but overestimated DVC VD and choroidal VD; discrepancies increased with AL. The opposite pattern was observed in shorter eyes. After correction, all vascular parameters except DVC VD showed significant changes in the high myopia group, while non-high myopic eyes showed no significant differences. The two correction methods showed strong agreement across all layers. RNFL thickness correlated strongly with SVC VD, and choroidal thickness (CT) with choroidal VD, both before and after correction. Post-correction, AL was no longer associated with RNFL thickness or SVC VD, while its correlation with CT and choroidal VD persisted. Mediation analysis showed AL fully mediated the CT-choroidal VD relationship, with a stronger effect post-correction. Magnification correction is crucial in high myopic eyes. Both formulas showed high consistency. Correction eliminated AL's confounding effects on RNFL and SVC VD, while emphasising its mediating role between CT and choroidal VD.",
"40698100": "ID: 40698100\nTitle: Ganglion Cell Layer Thickness as a Biomarker for Amyotrophic Lateral Sclerosis Functional Outcome: An OCT study.\nAbstract: This study aims to evaluate various optical coherence tomography (OCT) parameters in patients diagnosed with amyotrophic lateral sclerosis (ALS). Assessment of BCVA was done using Snellen charts, and subjective refraction was done to achieve a BCVA for distance and near. Measurement of intraocular pressure (IOP) was done with Goldman applanation tonometry. Stereoscopic fundus examination was performed using a 90D lens to assess the status of the optic nerve and retina, ruling out any ocular pathology. The patients were then subjected to OCT scanning to measure optic nerve head and macular parameters. Optical coherence tomography was performed using CIRRUS\u2122 HD OCT (500-21822) (version 8.0.0.518) (Carl Zeiss Meditec, Dublin, CA, USA). The analyzed area was centered manually, and the absence of segmentation errors was confirmed for each scan. RE Avg RNFL and LE Avg RNFL showed weak correlations with ALSFRS, indicated by Pearson Correlation coefficients of 0.073 and -0.026, respectively. The p-values (0.637 and 0.86) suggested that these correlations were not statistically significant. RE Avg GCL and LE Avg GCL, on the other hand, exhibited moderate positive correlations with ALSFRS scores, with correlation coefficients of 0.337 (RE) and 0.389 (LE). These correlations were statistically significant, as indicated by p-values of 0.021 and 0.006, respectively, suggesting a substantial association between GCL thickness and ALS functional outcomes. All patients in our study were clinically diagnosed cases of ALS, as per the El Escorial criteria. Age group-wise analysis showed statistically significant thinning overall as well as quadrant-wise RNFL parameters in patients less than 50 years compared to age-matched controls, indicating that the pathological process occurring in larger motor neurons in ALS might also be happening in smaller sensory neurons of the retina, causing thinning, which was not due to age-related process. Although GCIPL thinning was occurring in our cases, though statistically not significant compared to control, the significant positive correlation observed between GCIPL and ALS functional outcome and between RNFL and GCIPL measurements highlighted the fact that though the axonal degeneration in retinal neurons might not be translating to the same extent in ganglion cells in ALS, the subtle thinning of GCIPL correlated strongly with functional disability in patients with ALS, implying better functional scores with higher values of GCIPL parameters. In summary, GCL measurements in both eyes showed a notable relationship with ALSFRS, whereas RNFL did not appear to correlate significantly.",
"40704719": "ID: 40704719\nTitle: Ophthalmic Quality of Life and Its Association With Visual Function, Accommodative and Binocular Vision Performance in Keratoconus Patients: A Study Using Rasch Analysis\u200f.\nAbstract: To investigate the relationship between ophthalmic quality of life with visual function and accommodative/binocular vision performance in patients with keratoconus (KCN), using the Keratoconus Outcomes Research Questionnaire (KORQ). Seventy patients with KCN were recruited in this study (average age: 27.04 \u00b1 5.60). A Persian adaptation of the KORQ was developed, and its psychometric properties were evaluated through Rasch analysis. The associations between study variables and the KORQ subscales, activity limitations (AL-S) and symptoms (S-S), were evaluated through linear regression models. The Persian KORQ demonstrated good psychometric properties after removing items 5 and 8 from the AL-S and items 4 and 5 from the S-S. The analysis showed a statistically significant direct association between the AL-S score and age (\u03b2: 0.280, P < 0.05). In addition, there was a statistically significant direct relationship between the AL-S score with best-corrected visual acuity in the better eye (\u03b2: 0.279, P = 0.048), binocular contrast sensitivity (\u03b2: 0.319, P = 0.033), and steep keratometry in the better eye (\u03b2: 0.409, p-0.007). The near negative fusional vergence parameters-blur (\u03b2: -0.460, P = 0.012), break (\u03b2: -0.403, P = 0.027), and recovery (\u03b2: -0.391, P = 0.033)-showed a statistically significant inverse association with the S-S score. The Persian KORQ is a reliable tool for assessing ophthalmic quality of life in Persian-speaking patients with KCN. The KCN-related AL-S are primarily influenced by age, basic visual functions, and the severity of KCN in the better eye. Deficits in certain binocular vision metrics, particularly a diminished near negative fusional vergence amplitude, may contribute to the symptoms reported by patients with KCN.",
"40721761": "ID: 40721761\nTitle: Accuracy of 7 intraocular lens power calculation formulas in primary angle-closure glaucoma eyes, according to axial length and anterior chamber depth.\nAbstract: To assess the impact of Axial Length (AL) and anterior chamber depth (ACD) on the performance of the Kane, EVO 2.0, Barrett Universal II (BU II), SRK/T, Haigis, Holladay 2 and Hoffer Q formulas when calculating intraocular lens power in primary angle-closure glaucoma (PACG) patients. Eye hospital, Wen Zhou Medical University, Zhejiang, China. Retrospective, consecutive case series. Patients who underwent cataract surgery diagnosed with PACG or not were included. The main outcome measures comprised mean prediction error (ME), mean absolute refractive error (MAE), median absolute refractive error (MedAE). Additionally, the proportions of eyes with postoperative refractive errors within \u00b1\u20090.25 diopter (D), \u00b1\u20090.50 D, \u00b1\u20090.75 D, and \u00b1\u20091.00 D were calculated. Subgroup analyses were conducted based on AL and ACD. A total of 116 eyes were included, with 66 in the PACG group and 50 in the control group. The PACG group showed significantly larger MAEs compared to the control group. In PACG eyes, the BUII formula tends to cause negative residual refractive errors, while the Kane, EVO, and Holladay 2 formulas often lead to positive ones (P\u2009<\u20090.01). Notably, the SRK/T and Haigis formulas demonstrated better predictability for ME (P\u2009<\u20090.01). PACG patients with an AL under 22\u00a0mm or an ACD under 2.5\u00a0mm have lower IOL power calculation predictability (P\u2009<\u20090.05). Subgroup analysis shows that PACG eyes with both AL under 22\u00a0mm and ACD under 2.5\u00a0mm have the lowest predictability and are most prone to significant prediction errors (P\u2009<\u20090.05). A negative correlation was found between postoperative prediction error and AL. PACG eyes showed lower prediction accuracy, especially in short ALs and shallow ACD cases. SRK/T and Haigis formulas had better ME predictability. The study stresses optimizing IOL power calculation formulas for PACG eyes, considering AL and ACD effects.",
"40736059": "ID: 40736059\nTitle: Effect of Defocus Incorporated Multiple Segments (Fog Vision +0.50 D) Combined With 0.01% Atropine on the Preclinical and Early Stages of Myopia in Children.\nAbstract: To retrospectively analyze the efficacy of multi-zone positive optical defocus lenses (DIMS) + fog vision + 0.01% atropine for the treatment of children with preclinical and early stages of myopia. The axial length (AL) and refraction were analyzed at baseline and after 12 months of follow-up in 192 eyes treated with combined therapy. The success of treatment was defined as an annual AL growth rate within the physiological growth range and myopia progression of -0.50 diopters (D)/year or greater. Subgroup analysis was performed to investigate the percentage of treatment success in the overall population compared to the subgroups based on baseline AL and age. Overall, the success rates were 87% and 93% for AL control and myopia control, respectively. Compared to before combined therapy, there was an increase in AL after treatment (boys: P < .001; girls: P < .001). The change in spherical equivalent (SE) was consistent with the change in AL, with both boys and girls showing an increase in SE after treatment, with a statistically significant difference in girls (boys: P = .059; girls: P = .001). There was no statistically significant difference in the percentage of treatment success in either boys or girls based on baseline AL and age subgroups compared to the overall population. The treatment regimen of DIMS + fog vision + 0.01% atropine demonstrated significant control effects on myopia in preclinical and early stages of myopia in children across different genders, baseline ALs, and ages. Timely intervention is recommended once a tendency toward myopia is observed in children.",
"40750900": "ID: 40750900\nTitle: Synergic action of MicroRNAs and Wnts delivered by motor neuron EVs in promoting AChR clustering.\nAbstract: The neuromuscular junction (NMJ) establishment occurs through complex communication events between motor neurons and muscle fibers; however, the molecular mechanisms leading to NMJ formation have yet to be fully elucidated. Little is known about the significance of extracellular vesicles (EVs) in mediating the interaction between motor neurons and muscle fiber in the NMJ establishment; this study investigates the role of motor neuron-derived EVs during the earliest stages of NMJ formation. NSC-34 cells have been used as a model of motor neurons; EVs have been isolated during neurite development using a serial ultracentrifugation protocol specifically adjusted to isolate large and small EVs. Isolated EVs were quantified through Nanoparticles Tracking Assay and characterized by Western Blot and TEM analyses. The microRNA (miRNA) cargo of EV subpopulations was identified by small-RNA sequencing and the predicted miRNA downstream targets were investigated. NGS analysis of small RNAs carried by NSC-34-derived EVs identified a total of 245 EV specific miRNAs, most of which are up-regulated in NSC-34 cells and EVs during neurite stretching. Target prediction analysis evidenced how these miRNAs synergically target the Wnt signaling pathway. Moreover, we found that NSC-34-derived EVs carry Wnt proteins, including Wnt11, Wnt4 and Wnt3a. Since several studies suggested a role for the Wnt-associated signaling network in NMJ formation, we investigated the potential role of NSC-34 EVs in NMJ development and demonstrated that EV administration to myotubes increases acetylcholine receptor (AChR) cluster formation, as revealed by immunofluorescence staining with \u03b1-bungarotoxin. Moreover, myotube treatment with NSC-34-derived EVs led to GSK3\u03b2 and JNK phosphorylation, followed by \u03b2-catenin nuclear translocation, suggesting that neuron-derived EVs can induce AChR clustering through Wnt pathway activation. These data demonstrate that EVs released from differentiated motor neurons carry multimodal signals, miRNAs, and Wnts, which can stimulate AChR clustering in myotubes, a fundamental preparatory stage for NMJ formation. These new data highlight that EVs may play a role in the NMJ establishment and function under physiological and pathological conditions, particularly neurodegenerative diseases.",
"40755069": "ID: 40755069\nTitle: Improvement in Patient-Reported Symptoms of Generalised Myasthenia Gravis With Rozanolixizumab in the Randomised Phase 3 MycarinG Study Using the MG Symptoms PRO.\nAbstract: In the Phase 3 MycarinG study (NCT03971422), rozanolixizumab improved myasthenia gravis (MG)-specific outcomes versus placebo in patients with generalised MG, including those measured by the five independent MG Symptoms patient-reported outcome (PRO) scales: Muscle Weakness Fatigability (MWF), Physical Fatigue (PF) and Bulbar Muscle Weakness (BMW) as secondary endpoints and Ocular Muscle Weakness and Respiratory Muscle Weakness (exploratory endpoints). This research aimed to provide further insights into these improvements. Post hoc analyses evaluated correlation (Pearson coefficient) between MG Symptoms PRO and subdomain scores of MG Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) at baseline. Proportions of responders reaching clinically meaningful thresholds and analyses at the item level (observed mean change and Rasch modelling of predicted change from baseline) are reported for MWF, PF, and BMW with rozanolixizumab versus placebo at Day 43. Correlation coefficients between MG Symptoms PRO and MG-ADL were strong (\u2265\u20090.7) for ocular and bulbar scores and moderate (0.5 to <\u20090.7) for other scores. Correlations with clinician-assessed QMG scores were generally weak (<\u20090.5). For MWF, PF, and BMW, greater proportions of responders were observed with rozanolixizumab 7\u2009mg/kg (46.9%, 31.3% and 26.6%, respectively) or 10\u2009mg/kg (56.5%, 48.4% and 32.3%) versus placebo (28.1%, 26.6% and 10.9%). Item-level analyses demonstrated rozanolixizumab benefit at a symptom-specific level. MG Symptoms PRO scales correlate well with concepts in MG-ADL while assessing additional concepts, such as PF and MWF. Results from the MG Symptoms PRO in MycarinG reflected improvements from baseline in patient-relevant symptoms, including fatigue, with rozanolixizumab.",
"40777082": "ID: 40777082\nTitle: Investigation of early axonal phenotypes in an iPSC-derived ALS cellular model using a microfluidic device.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of upper and lower motor neurons. Mutations in the FUS/TLS gene have been reported as the second most common mutation in Japanese patients with familial ALS. In recent years, lower motor neurons (LMNs) differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients have been widely used to analyze the mechanisms of neuronal cell death and degeneration. In this study, we developed a microfluidic device designed to observe axonal growth, morphology, and trafficking at high resolution in neurons derived from induced pluripotent stem cells (iPSCs) and tested whether our microfluidic device effectively evaluates neurodegenerative phenotypes. We used iPSCs carrying homozygous FUS/TLS mutations (FUS_H517D) to induce LMNs by expressing NEUROG2, ISL1, and LHX3 under the control of the tetracycline regulation system. After seven days of in vitro differentiation (DIV7), we confirmed that over 95% of iPSCs differentiated into HB9-positive LMNs. Notably, the cell viability of FUS_H517D LMNs was comparable to that of LMNs differentiated from iPSCs without the FUS/TLS mutation at DIV7. However, by DIV14 and DIV21, the viability of FUS_H517D LMNs was notably lower than that of control LMNs, indicating degeneration of FUS_H517D LMNs after differentiation. Using our microfluidic device, we assessed axonal phenotypes in FUS_H517D LMNs. Under oxidative stress conditions, we observed that the axonal length of FUS_H517D LMNs was significantly shorter than that of control cells as early as DIV7, with this axonal growth restriction becoming more pronounced by DIV11. This suggests that axonal growth restriction is an early detectable phenotype in degenerating neurons. Additionally, we examined mitochondrial trafficking within axons in our device, which is often disrupted in degenerative neurons. Our results showed a significant increase in the number of motile mitochondria in FUS_H517D LMNs, with retrograde transport accounting for a large portion of trafficking. Our microfluidic device-based culture and evaluation system using FUS_H517D LMNs offers a valuable ALS cellular model focused on early axonal phenotypes. This approach contributes to the study of molecular mechanisms underlying axonal degeneration in ALS.",
"40795306": "ID: 40795306\nTitle: In vivo self-assembled SOD1-siRNAs mitigate muscle atrophy and denervation in amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the death of both upper and lower motor neurons. Approximately 20% of familial ALS cases are associated with mutations in the superoxide dismutase type 1 (SOD1) gene. Developing a specific strategy to characteristically silence the pathogenic SOD1 gene remains a crucial goal amidst significant challenges. In this study, we developed a synthetic biology strategy to reprogramme the liver as a tissue chassis for the in vivo self-assembly of small extracellular vesicles (sEVs)-encapsulated SOD1-siRNA, aiming to target spinal neurons and silence mutant SOD1 specifically in Tg(SOD1G93A) transgenic mice. We designed a cytomegalovirus (CMV) promoter-directed synthetic construct to encode a SOD1-siRNA along with a neuron-targeting rabies virus glycoprotein (RVG) tagged on the sEV surface. Theoretically, upon liver uptake, this construct reprogrammes liver cells to generate and self-assemble SOD1-siRNAs into RVG-tagged sEVs. Subsequently, the sEV-encapsulated SOD1-siRNAs are transported via the endogenous sEV circulation and guided by the RVG tag to the spinal neurons. Experimental results illustrated that intravenous administration of this synthetic construct effectively facilitated in vivo self-assembly of SOD1-siRNAs into circulating sEVs. The functional delivery of SOD1-siRNAs to the spinal cord and cerebral cortex was confirmed through in vivo tracking of sEVs and sEV-encapsulated siRNAs. Treatment of Tg(SOD1G93A) transgenic mice with this construct significantly reduced mutant SOD1 protein levels in the spinal cord and cerebral cortex. Consequently, the characteristic symptoms of ALS, including decreased body weight, shortened lifespan, compromised motor function, muscle atrophy, neuroinflammation, motor neuron loss and neuromuscular junction degeneration, were substantially ameliorated by the synthetic construct. Furthermore, an AAV-based strategy was devised for the enduring self-assembly of sEV-encapsulated SOD1-siRNA, whereby a single injection led to substantial and sustained inhibition of mutant SOD1 and significant symptom amelioration in transgenic mice. Overall, this study established an effective and convenient therapeutic approach for mitigating muscle atrophy and denervation in animal model, presenting a promising solution for future ALS treatment.",
"40806377": "ID: 40806377\nTitle: Small Extracellular Vesicles in Neurodegenerative Disease: Emerging Roles in Pathogenesis, Biomarker Discovery, and Therapy.\nAbstract: Neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, ALS, and Huntington's pose a growing global challenge due to their complex pathobiology and aging demographics. Once considered as cellular debris, small extracellular vesicles (sEVs) are now recognized as active mediators of intercellular signaling in NDD progression. These nanovesicles (~30-150 nm), capable of crossing the blood-brain barrier, carry pathological proteins, RNAs, and lipids, facilitating the spread of toxic species like A\u03b2, tau, TDP-43, and \u03b1-synuclein. sEVs are increasingly recognized as valuable diagnostic tools, outperforming traditional CSF biomarkers in early detection and disease monitoring. On the therapeutic front, engineered sEVs offer a promising platform for CNS-targeted delivery of siRNAs, CRISPR tools, and neuroprotective agents, demonstrating efficacy in preclinical models. However, translational hurdles persist, including standardization, scalability, and regulatory alignment. Promising solutions are emerging, such as CRISPR-based barcoding, which enables high-resolution tracking of vesicle biodistribution; AI-guided analytics to enhance quality control; and coordinated regulatory efforts by the FDA, EMA, and ISEV aimed at unifying identity and purity criteria under forthcoming Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines. This review critically examines the mechanistic roles, diagnostic potential, and therapeutic applications of sEVs in NDDs, and outlines key strategies for clinical translation.",
"40819701": "ID: 40819701\nTitle: Ocular manifestations in Dengue Fever: A Systematic Review and Meta-Analysis.\nAbstract: Ocular manifestations in dengue fever remain underrecognized despite reports of vision-threatening complications. This systematic review and meta-analysis aimed to determine the pooled prevalence of ocular manifestations in dengue patients, characterizing their spectrum, frequency, and clinical significance. Dengue fever affects millions globally, predominantly in tropical regions. While systemic complications are well documented, ophthalmic involvement remains poorly defined, with variable prevalence estimates and unclear risk factors. Early recognition is crucial for timely intervention, particularly in endemic areas where clinical suspicion is low. A comprehensive search was conducted in PubMed, CINAHL, and LILACS. Eligible studies included observational studies reporting the prevalence of ocular manifestations in dengue patients. Risk of bias was assessed using Hoy et al.'s tool for prevalence studies. Pooled prevalence estimates were calculated using a random-effects model, and heterogeneity was assessed using I2 statistics. A total of 32 studies, including 11,426 patients, were included. The pooled prevalence of ocular manifestations, calculated from 16 studies, was 0.32 (95% CI: 0.22-0.45, I2 = 91.8%). Retro-ocular pain had a pooled prevalence of 0.20 (95% CI: 0.10-0.37, I2 = 99.6%), while blurred vision was reported in 0.11 (95% CI: 0.05-0.23, I2 = 92.8%). Among structural manifestations, subconjunctival hemorrhage had a prevalence of 0.18 (95% CI: 0.10-0.30, I2 = 94.1%), retinal hemorrhage 0.08 (95% CI: 0.05-0.12, I2 = 77.8%), maculopathy 0.04 (95% CI: 0.02-0.08, I2 = 91.6%), and uveitis 0.05 (95% CI: 0.01-0.24, I2 = 97.4%). Significant heterogeneity was observed across studies, likely due to differences in diagnostic criteria, study populations, and disease severity. This study highlights a substantial prevalence of ocular manifestations in dengue patients, emphasizing the need for increased clinical awareness, particularly in endemic regions. Given the heterogeneity in reported prevalence, future research should focus on prospective, standardized ophthalmologic assessments to improve early diagnosis and management.",
"40832743": "ID: 40832743\nTitle: Neurochemical biomarkers of amyotrophic lateral sclerosis: recent developments.\nAbstract: To provide an overview of the recent developments in the field of neurochemical biomarkers of amyotrophic lateral sclerosis (ALS). Neurofilaments, especially NFL, have been confirmed to be good biomarkers for ALS. NFL may be diagnostically useful but its main role is as prognostic and pharmacodynamic biomarker. Inflammatory biomarkers, especially the chitinases, might also serve as pharmacodynamic biomarkers in treatment trials targeting neuroinflammation. GFAP could reflect cognitive-behavioural impairment. CSF dipeptides are diagnostic biomarkers for ALS caused by the C9ORF72 exanucleotide repeat expansion and may be used to confirm target engagement by experimental drugs. Levels of TDP-43 (virtually the ideal biomarker for ALS) in CSF and plasma have not been demonstrated to be consistently altered in ALS. However, promising advancements have been achieved in seed amplification assays for the protein, in its quantification in plasma extracellular vesicles, and in the measurement of CSF levels of a protein reflecting splicing dysfunction of TDP-43. Finally, blood phosphorylated tau has emerged as an ALS biomarker linked to lower motor neuron (or muscle) pathology. NFL is still the best neurochemical biomarker for ALS. However, substantial advances have been recently made, especially regarding detection of TDP-43 and blood phosphorylated tau.",
"40838943": "ID: 40838943\nTitle: Choroidal Thickness Distribution and Its Association With Axial Length and Spherical Equivalent in Schoolchildren Assessed by Wide-Field Swept-Source Optical Coherence Tomography.\nAbstract: The purpose of this study was to evaluate the distribution of choroidal thickness (ChT) in schoolchildren using wide-field swept-source optical coherence tomography (SS-OCT) and to investigate its association with axial length (AL) and spherical equivalent (SE). This prospective study included 176 eyes from 88 healthy Japanese schoolchildren aged 6 to 15 years (mean age = 9.9 \u00b1 2.4 years). Wide-field SS-OCT was used to measure ChT across a 57 degrees \u00d7 57 degrees fundus area. After excluding poor-quality images, 169 eyes were included in the final analysis. The ChT distribution was evaluated by dividing the obtained images into a 3 \u00d7 3 grid comprising 9 sections. ChT measurements were performed automatically with custom-designed software. ChT values were compared among the nine regions, and correlations with AL and SE were assessed for each grid section. Additionally, the findings in schoolchildren were compared with historical data from adults. Mean ChT values across the 9 regions ranged from 172 \u00b1 29 \u00b5m in the nasal-inferior region to 307 \u00b1 39 \u00b5m in the temporal region. The choroid was thicker in the temporal and macular regions and thinner around the optic disc and inferior regions. Significant negative correlations were found between ChT and AL across all regions (R = -0.50 to -0.23, P < 0.05), indicating that longer ALs were associated with thinner choroids. Similarly, significant positive correlations were observed between ChT and SE (R = 0.19 to 0.55, P < 0.05), demonstrating that higher degrees of myopia were associated with thinner choroids. Moreover, ChT in schoolchildren was generally thicker compared to that in adults. This study provides a detailed analysis of ChT distribution in schoolchildren, revealing regional variability and a generally thicker choroid compared with adults. The significant correlations between ChT, AL, and SE across all regions suggest a potential role for ChT in ocular growth and myopia progression. These findings underscore the need for longitudinal studies to investigate causal relationships between ChT distribution and myopia development. Wide-field choroidal mapping identifies early structural biomarkers for pediatric myopia progression and control.",
"40868276": "ID: 40868276\nTitle: Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS.\nAbstract: Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization-spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways-including PI3K-AKT-mTOR, MAPK, Wnt/\u03b2-catenin, and integrated stress response cascades-undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome-lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3-CR3 axis), and excitatory-inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network \"meaning-making\"-a collapse of coordinated signal interpretation, triage prioritization, and adaptive response-the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning-a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration.",
"40889423": "ID: 40889423\nTitle: Oriented porous microtubules combined with CNTF-delivery directional guide axonal regeneration after traumatic optic neuropathy.\nAbstract: Neuroinflammation microenvironment and retinal ganglion cell (RGC) apoptosis are two critical barriers to axonal regeneration following traumatic optic neuropathy (TON). To overcome these challenges, we developed an innovative dual drug delivery strategy utilizing oriented porous nanofiber (OF) and ciliary neurotrophic factor (CNTF)-loaded delivery systems, aiming to promote axonal regeneration and restore RGC survival. Cerium oxide nanoparticles (Ce NPs) were physically mixed with poly(L-lactic acid)/polycaprolactone (PLA/PCL) solution to prepare oriented porous nanofibers (OF-Ce) via electrospinning and solvent evaporation techniques. The aligned porous nanofiber architecture supports drug loading, guides cell directional growth, and integrates Ce NPs properties to modulate the neuroinflammatory environment. Subsequently, neural stem cell-derived exosomes (NSC Exo) were applied onto the porous OF-Ce nanofiber microtubule (OF-Ce/Exo), stabilizing exosomes, improving hydrophilicity, and significantly reducing neuroinflammation while inhibiting glial scar formation. Importantly, these OF-Ce/Exo microtubules effectively guide the directional growth and migration in various cell types. Furthermore, CNTF was encapsulated into PEGylated mesoporous silica nanoparticles (PMSN-CNTF NPs) for sustained release, reducing PC12\u00a0cell apoptosis in inflammatory conditions. Notably, in situ implantation of OF-Ce/Exo microtubules, coupled with intravitreal injection of PMSN-CNTF NPs, significantly promoted axonal regeneration and alleviated RGC death in a rat optic crush model, highlighting their potential for treating TON.",
"40891506": "ID: 40891506\nTitle: TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.\nAbstract: TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development.",
"40894549": "ID: 40894549\nTitle: Lead (Pb) exposure results in cell type specific changes in the mouse retina and optic nerve.\nAbstract: Chronic exposure to lead (Pb) is known to cause deficits in neuronal function across the nervous system, including the visual nervous system. Visual deficits have been observed in both humans and rodent models following Pb exposure. However, how Pb exposure causes visual deficits is poorly understood. In this study, we evaluated the effects of Pb toxicity on the retina and optic nerve of the mouse visual nervous system. We used C57BL/6 adult mice of both sexes and divided them into one of three different exposure groups. Adult mice received daily oral gavage of 108mg/kg Na-acetate (control), 54mg/kg Pb-acetate (low dose), or 108mg/kg Pb-acetate (high dose) for 4 weeks. At the end of Pb exposure, whole blood, retina, and optic nerve samples were collected for Pb quantification by atomic absorption spectroscopy and tissue immunohistochemical analyses. Cell type specific markers were used to quantify changes in cell density of retinal ganglion cells (RGCs), oligodendrocytes (OLs), oligodendrocyte precursor cells (OPCs), and myelin structure. Following Pb exposure, we observed a small, but significant reduction in the cell density of RGCs in the retina. However, we found no significant changes in branch thickness or coverage of retinal vasculature following Pb exposure. In the optic nerve after Pb exposure, we found a significant reduction in the cell density of OLs and OPCs. Finally, using immunolabeling for Caspr and Nav1.6, we observed significant structural changes in nodes of Ranvier, suggesting a disruption in myelin structure. Our findings suggested that Pb toxicity may impair survival and maturation process of oligodendrocytes, changes in myelin structures, and potential demyelination of the optic nerve. These results provide the foundation for future investigations into the molecular mechanisms of Pb-dependent changes in myelination and visual nervous system function.",
"40895800": "ID: 40895800\nTitle: Boosting the Therapeutic Potential of Extracellular Vesicles Derived From Mesenchymal Stem Cells via Advanced Preconditioning for Neurodegenerative Disorders.\nAbstract: Acute and chronic neurodegenerative conditions (NDs) are major causes of disability and mortality worldwide. Acute NDs encompass conditions such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). On the other hand, chronic NDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Currently, no definitive cure exists for these diseases, and available therapies focus primarily on slowing the progression of symptoms. Mesenchymal stem cells (MSCs), due to their multilineage differentiation capacity, immunomodulatory abilities, and regenerative properties, have gained attention in regenerative medicine. In recent years, extracellular vesicles (EVs) derived from MSCs have shown great promise as a cell-free therapeutic approach, eliminating the risks associated with direct MSCs use, such as tumorigenicity and poor cell survival after transplantation. EVs have emerged as powerful mediators of intercellular communication and tissue repair, exhibiting immunomodulatory, anti-inflammatory, and proregenerative properties. However, limitations such as low EVs yield and reduced efficacy due to MSCs replicative senescence restrict their therapeutic potential. Preconditioning strategies, including hypoxia, 3D cultures, and biochemical priming, have been explored in other fields to enhance EVs properties, yet their specific application to NDs remains under-reported. This review aims to address this gap by analyzing the preconditioning methods used to boost the therapeutic potential of MSCs-derived EVs for neurodegenerative diseases. These preconditioning strategies may enhance EVs yield, functional cargo, and targeted therapeutic efficacy for treating acute and chronic NDs.",
"40905633": "ID: 40905633\nTitle: Targeting Amyotrophic Lateral Sclerosis with Gene Therapy: From Silencing Genes to Enhancing Neuroprotection.\nAbstract: Gene therapy is emerging as a transformative approach for treating amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease. While gene replacement has shown a groundbreaking success in spinal muscular atrophy, the complexity of ALS-due to frequent gain-of-function mutations and a heterogeneous etiology-presents significant challenges. Importantly, approximately 90% of ALS cases are sporadic, with unknown genetic mutation, further complicating patient stratification and therapeutic targeting. As a result, gene therapy strategies must often address multiple pathological mechanisms simultaneously. So far, current gene therapy strategies aim to either suppress toxic gene expression or promote neuroprotection, predominantly via viral-mediated delivery systems. This review will provide an overview of emerging preclinical and clinical gene therapy approaches for ALS, focusing on two main strategies: gene silencing and neuroprotection. Gene silencing techniques, including antisense oligonucleotides (ASOs), viral-mediated RNA interference, and gene editing, have demonstrated efficacy in reducing mutant gene expression, particularly in SOD1 and C9orf72 models, although clinical translation has so far yielded limited success. The recent Food and Drug Administration's approval of the ASO therapy Qalsody for SOD1-ALS underscores the clinical potential of these approaches. Neuroprotective strategies aim to enhance motor neuron survival through delivery of trophic factors, often targeting both central and peripheral tissues to harness retrograde transport mechanisms. We will discuss the advantages and limitations of various delivery vectors, targeting specificity, timing of intervention, and translational challenges, alongside current clinical trial data. This review aims to synthesize how these approaches may converge to address the multifaceted nature of ALS and guide the development of next-generation therapeutics.",
"40955291": "ID: 40955291\nTitle: Prevalence of ocular and visual abnormalities following symptomatic and asymptomatic congenital CMV infection: a systematic review and meta-analysis.\nAbstract: Cytomegalovirus (CMV), the most common congenitally acquired infection, can result in visual disability in affected children. We aimed to estimate the burden of eye and vision disorders amongst children with symptomatic and asymptomatic congenital cytomegalovirus infection (cCMV), to inform the development of guidance for the provision of care. In this systematic review and meta-analysis, we searched PubMed, Embase, and CINAHL databases up to 6th Feb 2025 for studies reporting ocular disorders or visual impairment (VI) outcomes following cCMV diagnosis. We included longitudinal or cross-sectional studies which reported the frequency of visual or ophthalmic outcomes following an initial diagnosis of symptomatic or asymptomatic cCMV. Summary data, and individual patient level data where available, on the proportions of children noted to have visual impairment or ophthalmic disorders and the manifestation of these disorders, were extracted from published reports. Pooled prevalence of eye and vision outcomes were estimated through random effects models computed using Restricted Maximum Likelihood (REML) estimation. We included studies at lower risk of bias (assessed using the Joanna Briggs Institute tool) in meta-analyses of prevalence (random-effect models) and undertook subgroup analyses. The review protocol was registered with PROSPERO, CRD42021284678. We identified 4488 articles of which 28 were eligible for inclusion. Of these, 15 studies (total 858 children with symptomatic, 1176 with asymptomatic cCMV) were eligible for meta-analyses. Median follow up time from diagnosis of cCMV ranged from 6 to 156 months. Estimated pooled prevalence in symptomatic cCMV of visual impairment (VI) and ocular disorders 9% (95% CI, 5-14%, I 2 = 51.09%) and 14% (95% confidence interval, CI, 5-31%, I 2 = 93.2%) respectively. Cerebral visual impairment (i.e. VI due to neurological insult rather than ocular disease) was the most commonly reported visual disability, with an estimated pooled prevalence of 10% (95% CI, 6-15%, I 2 = 24.9). Prevalence of ocular disorders (most commonly chorioretinitis, and optic nerve and anterior segment anomalies) was higher in studies with greater proportions of pre-term birth, hearing impairment, and those undertaken prior to 2017. Estimated pooled prevalence of VI and ocular disorders was 1% and <1% (95% CI, 0-2%, I 2 = 0%) respectively in asymptomatic cCMV. Visual disability in cCMV is a strong marker of the broader neurological insult. Ocular disorders are prevalent in symptomatic disease, with consequent need for ongoing ophthalmic care. The low prevalence of sight-impactful disorders in asymptomatic disease suggests little benefit for ongoing ophthalmic surveillance, particularly in health settings with established programmes for whole population childhood eye and vision screening. This review is limited by the absence of information on the timing of diagnosis of the eye and vision disorders, data which would support the development of timeline pathways for ophthalmic surveillance. Wellcome Trust, National Institute for Health and Care Research (NIHR).",
"40971256": "ID: 40971256\nTitle: Comment on: Changes in Aqueous Humor Cytokines and Metabolomics in Contralateral Eye After Unilateral Cataract Surgery.\nAbstract: We extend Li et al.'s investigation of aqueous humor (AH) metabolomics in sequential cataract surgery by referencing our prior study on interocular symmetry/asymmetry in AH metabolomic profiles from simultaneous bilateral cataract surgery in emmetropic patients, which demonstrated similar AH compositions in fellow eyes. We also illustrate variability with 2 sequential-surgery cases and highlight the most and least variable metabolites across 6 biochemical classes. Taken together with Li et al., these observations support careful attribution of second-eye changes to surgery versus biology. To extend the findings of Li et al. on AH metabolomics in sequential cataract surgery by incorporating reference data on interocular symmetry/asymmetry in AH metabolomic profiles and illustrating variability in sequential cases. We drew on our prior study of simultaneous bilateral cataract surgery in emmetropic patients, which demonstrated high interocular similarity, and examined AH metabolomic variability in 2 patients undergoing sequential cataract surgery. Baseline interocular comparisons highlight metabolic symmetry in the AH among patients undergoing simultaneous cataract surgery. In 2 additional cases, we identified the most and least variable metabolites across 6 biochemical classes among patients undergoing sequential cataract surgery, complementing the observations of Li et al.Conclusion:Our reference data help contextualize Li et al.'s results. Although based on limited cases, our findings emphasize the need for caution when interpreting AH metabolomics in sequential surgery to distinguish true intra- and inter-individual biological variability from potential surgical effects on the second eye. Multimodal approaches integrating metabolomic and vascular metrics may improve biomarker selection and inform surgical timing.",
"40971912": "ID: 40971912\nTitle: Intraocular lens power calculation formula accuracy in 1178 eyes with short axial length: systematic review and network meta-analysis.\nAbstract: To systematically review the literature and conduct a comprehensive quantitative analysis to compare the accuracy of different intraocular lens (IOL) calculation formulas in eyes with short axial lengths (ALs). The precision of the IOL formulas decreases when applied in eyes with short AL (AL <22 mm), and many new formulas for calculating IOL power have been proposed in the past few decades. However, the accuracy of these formulas has not been systematically compared when applied in eyes with short AL. This study systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases to collect relevant research literature published between January 2003 and September 2023. Included were prospective or retrospective clinical studies involving cataract patients with short AL (AL <22 mm) and reporting the following outcomes: mean absolute error, median absolute error (MedAE), and percentage of eyes with a prediction error (PE) within \u00b10.25 diopters (D), \u00b10.50 D, and \u00b11.00 D. A network meta-analysis was performed using R software (v. 4.2.1). 15 prospective or retrospective studies involving 1178 eyes and 12 calculation formulas were included in this study. The network meta-analysis showed that compared with the widely used Haigis formula, the Kane formula had a higher percentage of eyes with PE within the range of \u00b10.25 D, \u00b10.50 D, and \u00b11.00 D (all odds ratio >1, but P > .05). In addition, based on the surface under the cumulative ranking area (SUCRA), the Kane formula had the highest probability of predicting the PE of the eyes within the range of \u00b10.25 D, with its SUCRA value of 95.74%, followed by Haigis formula (94.79%) and Olsen Standalone formula (84.04%). The Kane and Olsen Standalone formulas had the lowest MedAE. The Kane, Haigis, and Olsen Standalone formulas may perform better than other formulas in calculating the IOLs power in eyes with short AL. Nonetheless, significant uncertainty remains in this area. The accuracy of these formulas in patients with short AL needs to be verified by large multicenter registry studies.",
"40986613": "ID: 40986613\nTitle: Theoretical influence of segmented axial length on intraocular lens power calculation in short eyes.\nAbstract: To compare the segmented axial length (AL) provided by the Argos with the traditional AL provided by the IOLMaster 700 in short eyes and assess their impact on intraocular lens (IOL) power calculation. IRCCS Bietti Foundation, Rome, Italy. Retrospective case series. Patients undergoing cataract or refractive surgery preoperative examinations were enrolled if their AL was <22.0 mm with the IOLMaster 700. The ALs given by the 2 biometers were compared. Using the formulas included in the ESCRS IOL calculator, the IOL power for a schematic eye was calculated with both AL measurements. In 78 eyes, the traditional mean AL (21.22 \u00b1 0.54 mm) was shorter than the segmented AL (21.29 \u00b1 0.51 mm, P < .0001) with a proportional bias (r2 = 0.3312, P < .0001). The difference decreased with thicker lenses (r2 = 0.4941, P < .0001). Based on the IOL power calculated when the traditional AL was entered and the first negative refractive value was aimed at, the predicted refraction was more myopic with the Argos AL (P < .0001). The difference ranged from -0.18 \u00b1 0.13 D (Cooke K6) to -0.24 \u00b1 0.18 D (Barrett Universal II). The same IOL power would have been recommended by the ESCRS IOL calculator in only 40% to 50% of eyes, irrespective of formula used. The difference was minimized when the sum-of-segments option was used. AL measurements provided by the Argos and IOLMaster 700 are not interchangeable for IOL power calculation in short eyes <22.0 mm.",
"40994605": "ID: 40994605\nTitle: Retinal vessel density alteration after FS-LASIK for myopia with different axial lengths.\nAbstract: To compare the effects of different types of negative pressure suction on the macular and optic disc retinal vessel density (VD) in myopic patients with different axial lengths (ALs) undergoing femtosecond laser-assisted excimer laser in situ keratomileusis (FS-LASIK) by optical coherence tomography angiography (OCTA). A prospective, nonrandomized, controlled study. Participants underwent FS-LASIK surgery were divided into the short AL group (SAL, 22\u2264AL<26 mm) and the long AL group (LAL, 26\u2264AL<28 mm) according to the different ALs. Further, the two groups were divided into subgroups according to the corneal flap using VisuMax or WaveLight FS200 femtosecond laser (FS) platform. All patients underwent OCTA before the surgery and 1-day/1-week/1-month after the surgery. ANOVA statistically analyzed data with two-factor repeated measurement in SPSS. Totally 108 participants (108 eyes, 18-35y) were divided into SAL group [22 patients (4 males and 18 females) were treated with VisuMax, and 24 (3 males and 21 females) were treated with WaveLight FS200] and LAL group [34 patients (4 males and 30 females) were treated with VisuMax, and 28 patients (6 males and 22 females) were treated with WaveLight FS200]. In the LAL group, there was no significant difference in macular superficial capillary plexuses vessel density (SCP-VD) in the fovea and perifovea region, but compared with the VisuMax subgroup, SCP-VD in the parafoveal region (t=2.647, P=0.010) and the whole area (t=2.030, P=0.047) in WaveLight FS200 subgroup decreased at one day after the operation and increased to a preoperative level at 1-week and 1-month after operation. There was no significant difference between SCP-VD in the two SAL subgroups, neither of deep capillary plexuses vessel density (DCP-VD) and optic nerve head vessel density (ONH-VD) in the SAL and LAL groups. With the increase of AL and suction intensity, a transient decrease of SCP-VD in the macular region is observed at 1d postoperatively during FS-LASIK, and it increases to preoperative level at 1-week and 1-month postoperatively. However, the AL and suction intensity do not affect the macular DCP-VD and ONH-VD.",
"41004400": "ID: 41004400\nTitle: Atypical features including acquired oculomotor apraxia in C9orf72-associated familial primary lateral sclerosis.\nAbstract: The phenotypic variability of C9orf72-associated disease is broadening, including atypical and non-motor presentations. C9orf72-associated neurodegeneration has only rarely been associated with primary lateral sclerosis (PLS), and even more rarely with ocular motor apraxia. Describe a family with C9orf72 mutation presenting with frontotemporal dementia (FTD) and atypical PLS phenotypes and discuss the implications regarding 1) where PLS lies on the ALS-FTD spectrum, and 2) how C9orf72 mutations influence PLS clinically. Chart review. A 52-year-old male experiencing 4 months of progressive right lower leg spasticity with a family history of FTD was referred to us. Within 15 months, he was anarthric and required a powered wheelchair. He developed acquired ocular motor apraxia, consistent with supranuclear ophthalmoplegia. He later developed laryngeal dystonia which led to his death. Ten years later, his 67-year-old brother presented with 8 months of progressive spastic dysarthria, hyperreflexia, right foot drop, and right facial weakness. Genetic testing revealed heterozygous C9orf72 hexanucleotide repeat expansion. This family's presentation expands on sparse reports of C9orf72-associated PLS. The proband showcases a severity of ocular motor deficits not yet reported in PLS, extending ocular motor findings in MND. These deficits also provide clinical evidence of degeneration outside the motor cortex/spinal cord in PLS. The symptomatology (laryngeal dystonia, rapid progression) clinically overlaps with ALS/FTD, suggesting PLS may lie on the ALS-FTD spectrum. The severity and atypicality of this case also support suggestions that C9orf72 mutations amplify the spectrum/severity of disease observed in TDP-43 proteinopathies.",
"41004427": "ID: 41004427\nTitle: MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis.\nAbstract: Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis and frontotemporal dementia with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice and patient-derived cells modelling TDP-43, SOD1 and C9ORF72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioural abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived extracellular vesicles that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.",
"41014556": "ID: 41014556\nTitle: ER stress tolerance is regulated by copper-dependent PERK kinase activity.\nAbstract: Pancreatic/PKR-like endoplasmic reticulum (ER) kinase (PERK) is a kinase that, in response to ER stress, mediates dual homeostatic and pro-apoptotic signaling. Thus, intricate regulation is required for physiological function. Attempts to modulate PERK activity have shown that the determinants of adaptive vs. maladaptive signaling remain ambiguous. Here, with purified protein, we provide evidence that PERK binds copper, identifies residues required for interaction, and demonstrates that copper is necessary for kinase activity. Furthermore, cellular PERK activity can be modulated via copper availability, and this regulatory relationship can be manipulated to dictate ER stress tolerance. Critically, these phenomena translate to phenotypes in vivo, as C. elegans harboring a \"PERK-copper mutant\" exhibit exacerbated ER-stress sensitivity. The copper-PERK paradigm suggests that copper homeostasis, as a regulator of PERK, may constitute a critical factor in resolving the long-standing ambiguity in endeavors to therapeutically target PERK.",
"41017972": "ID: 41017972\nTitle: Akkermansia muciniphila in neurological disorders: mechanisms and therapeutic potential via the gut-brain axis.\nAbstract: In recent years, the role of Akkermansia muciniphila (A. muciniphila) in neurological diseases has attracted increasing attention. As a probiotic, A. muciniphila is closely associated with host health, metabolism, and immunity, demonstrating therapeutic potential in various conditions such as obesity, atherosclerosis, inflammatory bowel disease, diabetes, and liver disorders. In the context of neurological diseases, A. muciniphila significantly influences the host brain through the microbiota-gut-brain axis (MGBA). This review summarizes the roles and mechanisms of A. muciniphila and its active components (e.g., the outer membrane protein Amuc_1100, extracellular vesicles AmEVs, and short-chain fatty acids SCFAs) in various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), depression, cerebral palsy (CP), epilepsy (EP), autism spectrum disorder (ASD), and amyotrophic lateral sclerosis (ALS). It exerts protective effects by enhancing the intestinal barrier, regulating lipid metabolism, producing SCFAs, secreting neuroactive substances, and inhibiting neuroinflammation, thereby suggesting novel therapeutic avenues for neurological disorders. However, due to limited data from large-scale human clinical trials and the complexity of disease mechanisms and host-microbiota interactions, its clinical translation faces considerable challenges. Future efforts should focus on multicenter randomized controlled trials and in-depth mechanistic studies utilizing technologies such as metabolomics to facilitate evidence-based clinical application.",
"41021147": "ID: 41021147\nTitle: Iron and Ferritin Dyshomeostasis Intersect with Sex, Age, and Disease Severity in Amyotrophic Lateral Sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor neurons. Due to heterogeneity in both cause and clinical phenotype, accuracy of diagnosis and efficacy of treatment remain challenging. An evolving body of evidence point to the importance of the \"gene-time-environment\" hypothesis in ALS onset and progression. Despite extensive research, understanding of the complex environmental risk factors remains fragmented. In this study, we comprehensively analyzed the associations between trace elements, biochemical signatures, and modifiable risk factors among ALS patients stratified by age, sex, type of onset, disease severity, and progression. Specifically, we investigated blood concentrations of cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), and iron (Fe) levels in 121 participants. Moreover, we examined the associations between trace metals, biochemical indicators including serum ferritin (SF), blood glucose, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), cerebrospinal fluid (CSF) cell count, CSF total protein, as well as history of hypertension, hazardous chemical exposure, drinking, and smoking in ALS patients. Specifically, we report that high Fe levels were found in male and spinal-onset patients. Moreover, high serum ferritin was positively associated with age of onset, blood iron and glucose, as well as high disease severity. Results from this study highlight the complex characteristics of ALS and provide new insight for understanding the intricate relationship between disease phenotype, metal homeostasis, and modifiable risk factors.",
"41024384": "ID: 41024384\nTitle: Exosome Proteomics of SOD1D90A Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss. Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations. Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1D90A mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay. Father, Son, and Daughter are at different disease stages and carry the SOD1D90A mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1D90A mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA. Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.",
"41028808": "ID: 41028808\nTitle: Insights from meta-analysis and experimental validation identify exosomal miR-146a-5p as a potential biomarker for sporadic amyotrophic lateral sclerosis.\nAbstract: MicroRNAs (miRNAs) have emerged as key regulators in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite growing evidence that miRNAs exhibit altered expression profiles in ALS, their utility as a biomarker remains limited. To address this, we conducted a meta-analysis using the Robust Rank Aggregation package, incorporating 20 differential miRNA profiling studies. Among these, miR-146a-5p emerged as the most dysregulated and significant miRNA in ALS (P\u2009=\u20090.0000142, P-adj\u2009=\u20090.0096), particularly in extracellular vesicle-derived studies. To evaluate its diagnostic accuracy, we validated miR-146a-5p expression in serum-derived exosomes and observed a significant increase in sporadic ALS (sALS) patients (n\u2009=\u200922) as compared to healthy controls (n\u2009=\u200918). Moreover, higher levels of miR-146a-5p were strongly associated with longer survival (\u2265\u20095\u00a0years) (P\u2009=\u20090.0135), with a positive correlation between miR-146a-5p expression and survival duration (P\u2009=\u20090.0313) in sALS patients. Further, gene set enrichment analysis of miR-146a-5p target genes highlighted critical involvement of the Immune system and NF-kappa B signaling pathways in ALS pathophysiology. These findings highlight miR-146a-5p as a potential biomarker for ALS.",
"41029500": "ID: 41029500\nTitle: Correlation between refractive errors and ocular biometric parameters at Al-Mustaqbal University, Iraq.\nAbstract: To establish the relationship between ocular biometry and refractive errors in young adult Iraqis by analyzing three critical biometric ocular parameters, including axial length (AL), corneal radius (CR), and central corneal thickness (CCT). A cross-sectional study was conducted on individuals aged 18-33 years at Al-Mustaqbal University, Iraq, including 1841 participants (3682 eyes). Quantitative measurements of AL, CR, and CCT were obtained using an Auto Kerato-Refractometer, IOL Master, and pachymetry techniques. Statistical analyses included Pearson correlation, multiple linear regression, one-way ANOVA, and independent samples t-tests to compare biometric parameters between refractive error groups. Generalized Estimating Equations (GEE) were applied to account for the correlation between fellow eyes. The overall mean AL was 24.45\u2009\u00b1\u20091.10\u00a0mm, mean CR was 7.37\u2009\u00b1\u20090.77\u00a0mm, and mean CCT was 555.83\u2009\u00b1\u200950.83\u00a0\u03bcm. Myopic participants had a significantly longer AL (25.11\u2009\u00b1\u20090.42\u00a0mm) compared to hyperopic participants (22.71\u2009\u00b1\u20090.65\u00a0mm; p\u2009<\u20090.001). Likewise, myopic eyes had significantly thicker corneas (CCT: 565.62\u2009\u00b1\u200912.68\u00a0\u03bcm) than hyperopic eyes (495.42\u2009\u00b1\u200918.74\u00a0\u03bcm; p\u2009<\u20090.001), as determined by independent samples t-tests. Females exhibited slightly longer ALs than males across both myopic and hyperopic groups (p\u2009<\u20090.0001). Regression analysis showed that AL was the strongest predictor of spherical equivalent (SE), followed by CR and CCT. The regression model including AL and CR explained 94.5% of the variance in SE (R\u00b2 = 0.945). The findings confirm that AL and CCT are strongly associated with refractive errors, with AL being a primary determinant. This study highlights the role of gender differences in biometric ocular parameters and provides valuable insights into the prevalence of refractive errors in young adults in Iraq. These results can inform future public health initiatives aimed at addressing refractive errors in this population.",
"41044342": "ID: 41044342\nTitle: Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.\nAbstract: Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1G93A mice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression.",
"41057909": "ID: 41057909\nTitle: Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch\u00ae 3-dimensional genomic regulatory immuno-genetic profiling.\nAbstract: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch\u00ae, that employs an algorithm-based CCs analysis. Using EpiSwitch\u00ae technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n\u2009=\u200947 patients with severe ME/CFS and n\u2009=\u200961 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch\u00aeCFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNF\u03b1, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.",
"41092899": "ID: 41092899\nTitle: Neurovascular dynamics in the spinal cord from development to pathophysiology.\nAbstract: The vasculature is increasingly recognized as an active regulator of homeostasis and repair, beyond conventional roles in nutrient delivery. In the central nervous system, vascular cells adopt region-specific traits tailored to the distinct demands of the brain, retina, and spinal cord. Despite long-standing interest in the spinal cord as a model for neural development and injury, its vascular organization and properties remain understudied. The assumption that spinal cord and brain neurovascular systems are built and function in the same way has limited progress. Here, we challenge this view by examining specific properties underlying spinal cord vascular development, physiology, and pathology. We highlight unique angioarchitecture and homeostatic mechanisms, and discuss how neurovascular disruption contributes to spinal disorders and regenerative failure after injury. Identifying critical knowledge gaps, we aim to stimulate new research in spinal cord neurovascular biology, redefining its importance for health and disease.",
"41099622": "ID: 41099622\nTitle: Oxidative denaturation of Cu/Zn-superoxide dismutase associated with neurodegenerative diseases.\nAbstract: Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) is a well-established pathological feature of familial amyotrophic lateral sclerosis (ALS). While amino acid substitutions in mutant SOD1 destabilize its structure and promote misfolding, oxidation has also been implicated in the pathological alterations of wild-type SOD1, particularly in neurodegenerative diseases including sporadic ALS. However, the impact of oxidation on SOD1 folding remains to be fully elucidated. Here, we demonstrate that Cys111 is primarily oxidized to sulfonic acid upon exposure of apo-SOD1 to hydrogen peroxide, as confirmed by the quantitation of thiol groups and mass spectrometry. Molecular dynamics simulations showed that sulfonylation of Cys111 disrupts the dimer interface and promotes monomerization. This monomeric form then facilitates the subsequent oxidation of buried Cys6, leading to structural disruption, as evidenced by circular dichroism spectroscopy and loss of thiol groups. SOD1 denaturation triggered by Cys111 oxidation became evident when zinc binding was impaired due to pathological mutations and/or under zinc-deficient conditions. Given that increased oxidative stress is frequently associated with many neurodegenerative diseases, modulating Cys111 oxidation may offer a potential strategy for maintaining SOD1 structural stability and preventing its pathological misfolding.",
"41102382": "ID: 41102382\nTitle: OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies.\nAbstract: Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-\u03baB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.",
"41109388": "ID: 41109388\nTitle: Allosteric pathway connects Zn(II) loss from SOD1 to known pathogenic mechanisms.\nAbstract: Cu,Zn superoxide dismutase (SOD1) is one of the proteins with mutations linked to hereditary forms of the amyotrophic lateral sclerosis neurodegenerative disorder. The protein is known for its enzymatic activity, but it has been shown to also have regulatory functions, which could be related to its pathogenic potential. Seemingly unrelated to its regulatory roles, the most important hypothesis on SOD1 pathogenicity is related to misfolding of the protein, specifically centered on the region corresponding to its residues 28-38. The present work explores the structural and dynamical effect of Zn(II) removal from SOD1, which is known to influence its regulatory roles, with coarse-grained simulations of 450\u03bcs per system. In agreement with experiment, we see an increased solvent exposure of the regulatory region (residues 5-18). We also see an increased solvent exposure of the misfolding-critical 28-38 region. We unveil the mechanism and interactions connecting Zn(II) loss, and solvent exposure of both regions. The present work allows for an unified understanding of two different pathogenic mechanisms of SOD1.",
"41145518": "ID: 41145518\nTitle: Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model.\nAbstract: Selective neuronal vulnerability is a defining feature of neurodegenerative disorders, exemplified by motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The nature of motor neurons underlying this selectivity remains unresolved. Here, by monitoring autophagy at single-cell resolution across the translucent zebrafish spinal cord, we identify motor neurons as the cell population with the highest autophagic flux. Large spinal motor neurons (SMNs), most susceptible to ALS, exhibit higher flux compared to smaller SMNs and ALS-resistant ocular motor neurons. Notably, large SMNs accelerates both autophagy and proteasome-mediated degradation, which are further augmented by TDP-43 loss. Additionally, acceleration of multiple unfolded protein response pathways indicates their innate tendency to accumulate misfolded proteins. Enhanced cellular degradation in large SMNs is neuroprotective as its inhibition halts axon outgrowth. These findings propose that cell size-associated degradation load underlies selective neuronal vulnerability in ALS, highlighting the alleviation of catabolic stress as a target of therapy and prevention.",
"41166771": "ID: 41166771\nTitle: Cerebrospinal fluid-driven extracellular vesicle as a potential diagnostic biomarker for multiple system atrophy.\nAbstract: Given that Parkinsonian disorders, including Parkinson's disease (PD) and multiple system atrophy-parkinsonism (MSA-P), often have similar clinical presentations, making a clinical diagnosis can be challenging. In the present study, we extracted and analyzed extracellular vesicles (EVs) from the cerebrospinal fluid of individuals diagnosed with PD (N\u00a0=\u00a016), MSA-P (N\u00a0=\u00a016), and amyotrophic lateral sclerosis (ALS) (N\u00a0=\u00a016), with the latter serving as the control group. Transcriptomic analysis identified 7426 and 8003 differentially expressed RNAs between MSA and ALS, and MSA and PD, respectively. Four transcripts (RN7SL3, RN7SL1, MIR19B2, and SYF2P2) were among the top six transcripts upregulated in MSA-P compared with both ALS and PD. Proteomic analysis revealed notable changes in the levels of corneodesmosin, psoriasin (S100A7), and dystroglycan1 in MSA-P compared with ALS and PD. Notably, S100A7 mRNA levels were also significantly lower in MSA than in the other diseases examined. Furthermore, we found a positive correlation between S100A7 mRNA levels and the heart mean/mediastinum mean ratio on 123I-metaiodobenzylguanidine myocardial scintigraphy, whereas SYF2P2 mRNA levels were negatively correlated with both the asymmetry index on dopamine transporter scans and Mini Mental State Examination scores. A positive correlation was found between S100A7 levels and motor symptoms. In distinguishing MSA-P from PD, MIR19B2 exhibited the highest Area Under Curve (AUC) of 0.867, demonstrating 100\u00a0% sensitivity and 68.7\u00a0% specificity. Conversely, the results for CDSN showed an AUC value of 0.847, with 58.3\u00a0% sensitivity and 100\u00a0% specificity. These combined transcriptomic and proteomic biomarkers could serve as valuable diagnostic tools for MSA.",
"41169217": "ID: 41169217\nTitle: Retinal proteomics in neurodegeneration: Insights into ocular and brain disorders.\nAbstract: Dysregulated proteome in the retina represents a promising avenue for discovering novel therapeutic targets and noninvasive diagnostic biomarkers for neurodegenerative diseases with ocular manifestations. Advanced mass spectrometry-based proteomics techniques have shown considerable potential in investigating the retinal proteome in diseases such as glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, as well as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Recent proteomics innovations are overcoming challenges such as limited sample size and protein coverage that previously hindered comprehensive retinal proteome analysis. Notably, the incorporation of artificial intelligence-driven computational pipelines, including Graphics Processing Unit-accelerated deep learning architectures, has markedly enhanced the precision and effectiveness of retinal proteomics. These advances facilitate high-resolution identification of novel protein signatures within large-scale multi-omics datasets. Furthermore, the integration of advanced artificial intelligence with state-of-the-art big data infrastructures supports the early detection of biomarkers and therapeutic targets in neurodegenerative diseases with ocular involvement, offering unprecedented disease specificity and sensitivity. In addition to these computational strides, emerging complementary and alternative technologies continue to provide valuable tools for retinal analysis, expanding the potential for identifying biomarker and therapeutic targets in both ophthalmic and neurodegenerative disorders. This review summarizes recent advancements in retinal proteomics, with a particular focus on neurodegenerative and ocular diseases.",
"41174080": "ID: 41174080\nTitle: Novel and classic imaging signs of increased intracranial pressure.\nAbstract: The arachnoid bulk ratio was recently described by Berhanu et al. on ultrasonography (US) as a potentially useful surrogate for intracranial pressure (ICP). We aimed to evaluate this novel neuroimaging index using magnetic resonance imaging (MRI) and determine the accuracy of the novel and classic imaging signs to diagnose increased ICP. Patients with suspected increased ICP were recruited to undergo optic nerve US and MRI before invasive ICP measurement. We included a total of 23 participants and determined the correlation of the novel ratio with ICP, compared to the optic nerve sheath diameter (ONSD), and we assessed the diagnostic accuracy of the novel and classic imaging signs through receiver operating characteristic (ROC) curve analysis. The arachnoid bulk ratio and ONSD were significantly larger in individuals with increased ICP on MRI (36% and 16%,p\u2009<\u20090.001) and on US (39% and 13%,p\u2009<\u20090.001). The ratio correlated very strongly with ICP on MRI and US (rs\u2009=\u20090.89 and rs\u2009=\u20090.92), outperforming the ONSD (MRI:rs\u2009=\u20090.67 and US:rs\u2009=\u20090.63). The Berhanu et al.'s ratio predicted increased ICP with a sensitivity of 100% and a specificity of 91% on MRI. The classic imaging signs with highest accuracy were the transverse sinus stenosis and ONSD, with a sensitivity of 89% and 91% and specificity of 100% and 92%,respectively. This novel ratio, which selectively assesses the perineural fluid space, provides an accurate prediction of ICP on MRI. When combined with classic imaging signs, it serves as a useful non-invasive surrogate in the clinical approach to these patients.",
"41213652": "ID: 41213652\nTitle: Letter to the Editor: Comment on Ku\u010d et al.'s \"Smoking and Risk of Uveitis: A Systematic Review and Meta-Analysis\".\nAbstract: ",
"41214888": "ID: 41214888\nTitle: Comparison of ocular biometry and refractive outcome between a new and classic optical biometer.\nAbstract: To compare the ocular biometry and refractive outcome between 2 optical biometers. Zhongshan Ophthalmic Center, Guangzhou, China. Prospective observational study. 953 patients with cataract underwent preoperative biometry including ZW-30 sum-of-segments (SOS) method (ZW SM ), ZW-30 composite method (ZW CM ), and IOLMaster 700. Agreement of axial length (AL), with or without Cooke-modified AL (CMAL) adjustment, was analyzed using Bland-Altman 95% limits of agreement (LoA). Subgroup analysis was used based on ALs (short eyes: AL <22 mm; normal eyes: 22 mm \u2264 AL <26 mm; long eyes: AL \u226526 mm). Refractive prediction accuracy was evaluated using the Emmetropia verifying optical (EVO) 2.0 formula and its SOS-optimized version (EVO 2.0 SOS ). In short and normal eyes, narrow 95% LoAs (<0.2 mm) were identified among 3 ALs. However, AL obtained by ZW SM was lower compared with this obtained by ZW CM and IOLMaster 700 (95% LoA -0.39 to 0.01 mm; -0.38 to 0.04 mm) in long eyes. CMAL adjustment enhanced the agreement of AL between ZW SM and ZW CM (95% LoA -0.01 mm to 0.02 mm), ZW SM and IOLMaster 700 (95% LoA -0.10 mm to 0.07 mm) in long eyes. Myopic prediction errors (PE) have been identified in the use of ocular biometric parameters obtained from ZW SM (mean PE [ME]: EVO 2.0, -0.19 diopters [D]; EVO 2.0 SOS , -0.18 D). After adjusting ME to zero, no difference was observed in PE calculated using any combination of formulas based on biometric measurements from 3 devices. This new segmented biometer demonstrated excellent agreement with IOLMaster 700 in short and normal eyes. However, ALs obtained by IOLMaster 700 are not interchangeable with the SOS method and require CMAL adjustment in long eyes. The application of the SOS method's ocular biometric parameters in refractive prediction led to myopic errors, which suggests constant optimization.",
"41237982": "ID: 41237982\nTitle: The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-implications for the toxic gain of function observed in ALS.\nAbstract: A subset of familial cases of amyotrophic lateral sclerosis (fALS) are caused by mutations to copper, zinc superoxide dismutase (Cu, Zn SOD1). Over 200 mutations to SOD1 that have been associated with fALS and the majority of these mutations are dominantly inherited. Thus, individuals are heterozygous and express both wild-type SOD1 and the mutant form of the protein. Paradoxically, the motor neuron disease accelerates in rodent models that mimic the co-expression of wild-type SOD1 with mutant fALS SOD1. Previously, we have shown that the loss of zinc from SOD1 triggers motor neuron death in culture due to a gained, redox activity catalyzed by the active-site copper. Furthermore, motor neuron toxicity of zinc-deficient SOD1 is enhanced by wild-type Cu, Zn SOD1. Because SOD1 exists as a non-covalent dimer, the enhanced toxicity might result from stabilization of the heterodimeric interface between zinc-deficient SOD1 and Cu, Zn-SOD1. However, experimentation with the heterodimer is difficult because SOD1 subunits exchange in minutes. To better characterize the role of dimer stabilization on the enhanced toxicity of fALS mutant SOD1 by wild type SOD1, we genetically tethered a zinc-deficient SOD1 subunit with a Cu, Zn SOD1 subunit with a 16-residue linker. The x-ray structure of the tethered heterodimer showed that the zinc-deficient subunit adopts a wild-type-like conformation and is not misfolded. The heterodimer intermediate also produced peroxynitrite from nitric oxide, and the tethered SOD1 was strikingly toxic to primary cultures of motor neurons. This work supports the concept that zinc-deficient SOD1 is a likely toxic intermediate in ALS. Furthermore, the wild-type allele in human familial-SOD1 ALS patients may physically contribute to the dominant inheritance of SOD1 mutations through heterodimer formation.",
"41250892": "ID: 41250892\nTitle: Co-localization of tau and TDP-43 after extracellular vesicle delivery to cells.\nAbstract: Perturbations in the metabolism of microtubule-associated protein tau (tau) underlie the pathology of a broad array of dementias, including chronic traumatic encephalopathy, amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) and approximately half of the dementias associated with frontotemporal lobar degeneration. We recently observed significantly increased hippocampal tau pathology in rats injected with pseudophosphorylated human tau (2N4R tauT175D) co-expressing an ALS-associated TAR DNA-binding protein 43 (TDP-43) mutant (TDP-43M337V) when compared to wild-type rats. To understand this mechanism, we examined whether the extracellular vesicles (EVs) derived from wild-type TDP-43 (wtTDP-43) or tau-expressing cells could transfer expression of these proteins to recipient cells, and whether co-localization of these proteins occurs. mCherry-wtTDP-43 or EGFP-tau constructs were expressed in HEK293 or SH-SY5Y cells. The secretome and EV fractions contained wtTDP-43 or 2N4R tau protein and RNA, and could transfer proteins into nontransfected cells. Co-localization was also detected in the cytosol of recipient cells. In silico modeling of tau and TDP-43 interactions suggests hydrogen bonding underlies this interaction. These studies further our understanding of the interaction between tau and TDP-43 by demonstrating their ability to co-aggregate and in providing a mechanism by which cell-cell transfer of either protein via extracellular vesicles can lead to these synergistic interactions.",
"41256634": "ID: 41256634\nTitle: LINE1 RNA dysregulation impairs chromatin accessibility in C9ORF72- and TDP-43-linked ALS/FTD.\nAbstract: The long interspersed element-1 (LINE1) retrotransposon RNAs are abnormally elevated in various neurodegenerative disorders, but their pathogenic roles remain unclear. Here we investigated the mechanism of LINE1 RNA accumulation and its function in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with C9ORF72 repeat expansion and TDP-43 loss-of-function, the leading causes of familial and sporadic forms of these neurodegenerative diseases. We show that LINE1 RNA is dysregulated due to an impaired nuclear exosome targeting (NEXT) degradation pathway. Its elevation epigenetically increases chromatin accessibility, enhancing global transcription via a retrotransposon-independent mechanism. Reducing LINE1 RNA mitigates chromosomal abnormalities and improves the survival of disease-relevant neurons. These findings uncover an essential noncoding RNA function and regulatory mechanism of LINE1 in neurons, providing insights into disease pathogenesis and highlighting potential therapeutic targets for neurodegenerative diseases.",
"41278139": "ID: 41278139\nTitle: Exosome-rich mesenchymal stem cell secretome improves strength in patients with amyotrophic lateral sclerosis, Kennedy disease, congenital myasthenic syndrome and Lewy body dementia.\nAbstract: Amyotrophic lateral sclerosis (ALS), Lewy Body dementia (LBD), Kennedy disease (KD), and Congenital Myasthenic Syndrome (CMS) are progressive motor disorders for which no disease modifying treatment exists. ALS and LBD are uniformly, and often rapidly, fatal. No treatment of any kind has ever resulted in actual improvement for ALS patients; the best that has been achieved is minor slowing of their progression. Forty-one preclinical studies of intra-nasal instillation of mesenchymal stem cell exosomes have, however, demonstrated complete safety and efficacy for models of a variety of neurocognitive and motor disorders. We hypothesized that intranasal exosomes treatment in humans would be completely safe and also effective for the treatment of motor disorders such as ALS, LBD, KD and CMS. 18 patients with ALS, Kennedy Disease, Congenital Myasthenic Syndrome, or Lewy Body Dementia had 32 AlloEx Exosome\u00ae treatments to assess safety, attenuation of disease, and increase in strength and motor function. The study was conducted under the clinical trial NCT07105371 found at clinicaltrials.gov/study/NCT07105371. There were no adverse events of any kind reported among these treatments. All patients, except for one, achieved some degree of clinical and strength improvement; the longest improvement was recorded at the 6-month follow-up. Intranasally-instilled AlloEx Exosomes\u00ae are completely safe, attenuate progression, and improve strength in ALS, Kennedy Disease, CMS, and LBD.",
"41279722": "ID: 41279722\nTitle: Superoxide dismutase impacts extracellular vesicle biogenesis and uptake.\nAbstract: Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play an important role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and the potential for EVs as diagnostic biomarkers, while the effect of pathogenic factors on EV release is less understood. Here, we defined how the key antioxidant enzyme superoxide dismutase 1 (SOD-1) affects EV shedding from sensory neuron primary cilia, enrichment of ciliary proteins packaged into EVs, and uptake of EVs by surrounding glia in vivo by imaging C. elegans expressing fluorescent protein-tagged EV cargos. We discovered that loss of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different cargo present in EVs shed from the ciliary base. Together, this suggests that redox balance has a subtype-specific effect on EV biogenesis, influencing neuron communication in vivo.",
"41328354": "ID: 41328354\nTitle: Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation.\nAbstract: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS), are characterized by progressive neuronal dysfunction and limited therapeutic options, largely due to the restrictive nature of the blood-brain barrier (BBB). Exosomes, naturally occurring extracellular vesicles (EVs), have gained attention as innovative drug delivery vehicles owing to their intrinsic ability to cross the BBB, minimal immunogenicity, high biocompatibility, and capability to carry diverse therapeutic cargos such as proteins, nucleic acids, and small molecules. Furthermore, exosomes can be bioengineered to enhance drug-loading efficiency and targeting specificity, positioning them as a versatile and effective platform for treating NDDs. In this review, we summarize recent advances in exosome biogenesis, secretion, and engineering, with an emphasis on innovative strategies for exosome isolation, drug loading, and surface modification. We further explore their roles in modulating neuroinflammation, promoting neural regeneration, and enabling precise therapeutic delivery. Critical challenges associated with large-scale production, quality control, and regulatory compliance under Good Manufacturing Practices (GMP) are also discussed. Collectively, these developments underscore the transformative potential of engineered exosomes in advancing precision therapies for neurodegenerative disorders and offer strategic insights into their clinical translation.",
"41334909": "ID: 41334909\nTitle: Herpes simplex virus 1 strain 17+ with R2 mutation in UL37 has residual retrograde transport.\nAbstract: Herpes simplex virus 1 (HSV-1) causes lifelong recurrent infections. Following primary infection of the oral or genital mucosa, HSV-1 travels retrogradely through axons and establishes latency in the cell body of ganglionic neurons of the peripheral nervous system. Periodic reactivation in neurons and anterograde transport of virions back to peripheral regions cause oral or genital ulcerations. Many host and viral factors implicated in retrograde and anterograde transport of HSV-1 have been identified. In particular, studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate retrograde transport of HSV-1 strain F. Here, we introduced the same R2 mutations in the highly neurovirulent HSV-1 strain 17+. We show that this R217 virus is highly attenuated in mice and acts as a potent vaccine that protects mice against acute HSV-1 infection. However, we report that the R217 virus has residual retrograde transport. We show that R217 can establish latency in mouse models of ocular and vaginal infection and reactivate. These results contradict published evidence and show that the R2 mutation is not sufficient to fully prevent retrograde transport of HSV-1. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen without a cure or vaccine. HSV-1 travels through nerves between the oral and genital mucosa and the peripheral nervous system, where it establishes lifelong latency. Studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate the retrograde transport of HSV-1 strain F from the mucosa to the nervous system. Here, we present contradictory findings. We report that an HSV-1 virus from strain 17+ with the same R2 mutation has residual retrograde transport. This shows that the R2 mutation is not sufficient to fully prevent the retrograde transport of HSV-1 in all settings. This finding may be particularly relevant for assessing the safety of prospective live-attenuated vaccines that include the R2 mutation.",
"41360752": "ID: 41360752\nTitle: Anionic Liposomes as Optimal Membrane Fusion Carriers Enabling in Situ Multiplexed Detection of Extracellular Vesicle MicroRNAs.\nAbstract: Extracellular vesicle (EV) microRNAs (miRNAs) are promising liquid biopsy biomarkers for non-invasive diagnosis, monitoring, and therapeutic evaluation of cancer. However, sensitive EV miRNA detection is hindered by complex pre-analytical processing. Here, the authors present an anionic liposome (AL) assisted membrane fusion strategy enabling one-step multiplexed quantification of EV miRNAs directly from plasma without EV isolation or RNA extraction, termed EValarm (Anionic Liposome Assisted miRNAs Monitoring for Extracellular Vesicles). Liposomes encapsulating probes are prepared using a microfluidic chip, achieving catalytic signal amplification after target recognition of miRNA. Systematic lipid screening identified ALs as optimal carriers, exhibiting minimal background and superior sensitivity compared to cationic and neutral liposomes. The AL-based assay delivered accuracy comparable to quantitative PCR with a streamlined workflow. Applied to 106 clinical samples from lymphoma patients and healthy controls, integration with artificial intelligence achieved high accuracy (AUC > 0.99). In summary, this study demonstrates a platform enabling direct and sensitive plasma EV miRNA detection, offering strong potential for clinical translation in cancer liquid biopsy.",
"41397032": "ID: 41397032\nTitle: Microglial Extracellular Vesicles Mediate C1q Deposition at the Pre-Synapse and Promote Synaptic Pruning.\nAbstract: C1q is released by microglia, localizes on weak synapses and acts as a tag for microglial synaptic pruning. However, how C1q tags synapses during the pruning period remains to be fully elucidated. Here, we report that C1q is delivered via extracellular vesicles by microglia to pre-synaptic sites that externalize phosphatidylserine. Using approaches to increase or reduce vesicles production in microglia, by C9orf72 knock out or pharmacological inhibition, respectively, we provided mechanistic evidence linking extracellular vesicle release to pre-synaptic remodelling in neuron-microglia cultures. In C9orf72 knockout mice, we confirmed larger production of microglial extracellular vesicles and showed augmented C1q presynaptic deposition associated with enhanced engulfment by microglia in the early postnatal hippocampus. Finally, we provide evidence that microglia physiologically release more vesicles during the period of postnatal circuit refinement. These findings implicate abnormal release of microglial extracellular vesicles in both neurodevelopmental and age-related disorders characterized by dysregulated microglia-mediated synaptic pruning.",
"41397557": "ID: 41397557\nTitle: Differential binding of copper and zinc to a TDP-43 RNA recognition motif decapeptide and disulfide formation at residues C173/5 revealed by ESI-MS/MS.\nAbstract: Copper (Cu) and zinc (Zn) metal ions play important roles in the proper functioning and localization of neurological proteins, such as transactive response DNA-binding protein 43 (TDP-43), which is linked to amyotrophic lateral sclerosis (ALS). Previous experimental and computational studies have identified putative Zn-binding regions within the RNA recognition motif 1 (RRM1) of TDP-43. However, Cu-binding interactions have been less explored despite their redox activity in regulating thiol (C173/175) conversion to disulfide within the RRM1 domain, influencing protein structure and function. Herein, the structural characterization and fragmentation pattern analysis of a TDP-43 decapeptide (166-HMIDGRWCDC-175), within RRM1, coordinated to Cu(II) and Zn(II) ions using electrospray ionization tandem mass spectrometry (ESI-MS/MS) was conducted under non-denaturing conditions. Higher-energy collision dissociation (HCD) fragmentation analysis identified that Cu(II) prefers His/Met residues, while Zn(II) was weakly coordinated to various binding sites in the peptide, specifically His, Met, Glu, Cys, Trp and Asp residues. Computational modeling using a metal ion binding server (MIB2) confirmed the binding sites and coordination sphere of metal-peptide complexes. No significant coordination to C173 and C175 was observed with Cu or Zn, as identified by using a double Cys mutant peptide. A complete thiol-to-disulfide conversion was observed in the presence of Cu(II)/(I) only, which was confirmed by the comparison of a preformed intramolecular disulfide peptide. Overall, unique differential coordination environments were observed for each metal ion with the peptide. The study provides new insights into metal ion interactions with TDP-43 RRM1 peptide, leading to a greater understanding of metal homeostasis in TDP-43 protein biochemistry and neurodegeneration.",
"41457335": "ID: 41457335\nTitle: Letter to the Editor: Comment on Palmieri et al.'s \"Uveitis Following Intravitreal Injections of Faricimab: A Case Report\".\nAbstract: The article provides valuable insight on presentation and management of isolated anterior uveitis and with vitritis following intravitreal (IVT) faricimab. We highlight additional points. First sterile intraocular inflammation (IOI) onset ranges from 1-35 days; however, two patterns have been described: acute onset within 5 days and delayed onset at approximately 14 days following a mean of four IVT injections, although it may occur after the first. Sterile IOI may be recognised by delayed onset, suggestive of a type IV hypersensitivity reaction rather than infectious causes and by absence of hypopyon, although may present in severe cases. Second, faricimab's dual inhibition may alter ocular immune surveillance, potentially facilitating herpes simplex virus reactivation. Increased vigilance for dendritic ulcers is therefore warranted, and antiviral therapy should be initiated prior to corticosteroids. Finally, management should be guided by severity, with anterior or vitreous tap considered to exclude exogenous endophthalmitis. Resolution typically occurs within 15 days.",
"41463293": "ID: 41463293\nTitle: Human Mutant Dynactin Subunit 1 Causes Profound Motor Neuron Disease Consistent with Possible Mechanisms Involving Axonopathy, Mitochondriopathy, Protein Nitration, and T-Cell-Mediated Cytolysis.\nAbstract: Mutations in the gene encoding the p150 subunit of the dynactin complex (DCTN1) are linked to amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Perry syndrome. These neurodegenerative diseases can cause muscle weakness and atrophy, parkinsonian-like symptoms, and paralysis. To examine the evolution of neuropathology caused by a mutation in DCTN1 and cellular mechanisms of disease for therapeutic discovery, we characterized mice expressing either human wildtype or mutant (G59S) DCTN1. Neuron-specific expression of mutant, but not wildtype, DCTN1 caused fatal age-related paralytic disease and motor neuron (MN) degeneration in the spinal cord with axonopathy and chromatolysis without apoptotic morphology. MNs became positive for cleaved caspase-3, cleaved caspase-8, and nitrated Hsp90. Mitochondria accumulated and appeared fragmented and dysmorphic and then were lost. This pathology was accompanied by invasion of CD95- and CD8-positive mononuclear T cells into the ventral horn and accumulation of TNF\u03b1 and IL9. Administration of the mitochondrial division inhibitor-1 (Mdivi-1) protected MNs and extended the lifespan of G59S-DCTN1 mice. A mitochondrial permeability transition pore inhibitor also extended lifespan. Thus, mutant DCTN1 causes degeneration of MNs associated with axonopathy, mitochondriopathy, nitrative stress, and caspase activation. It appears as retrograde neurodegeneration and inflammatory T-cell-like cytolysis. Mitochondria are possible therapeutic targets in DCTN1-linked neurodegenerative disorders.",
"41517507": "ID: 41517507\nTitle: Evolution of Retinal Morphology Changes in Amyotrophic Lateral Sclerosis.\nAbstract: Background/Objectives: To compare changes in the thickness of retinal layers between patients with amyotrophic lateral sclerosis (ALS) and healthy controls using optical coherence tomography. Amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motoneurons with a rapidly progressive course, but non-motor symptoms such as decreased ocular motility and reduced visual acuity have also been reported. Specific biomarkers or surrogate parameters assessing neurodegeneration in ALS are of interest. Methods: In a retrospective, longitudinal study using optic coherence tomography of the retinal layers, we compared changes in the thickness of the layers between patients with ALS and healthy controls. Correlations to clinical scores, such as the modified ranking scale, were analyzed. Results: In our cohort of patients with early ALS (disease duration 5.15 \u00b1 21.4 months at baseline), we neither observed differences in retinal layer thickness at baseline nor did the thickness changes in any retinal layer differ in comparison to healthy controls at baseline. Moreover, we observed no significant thickness changes over the course of the observational period in our patients with ALS. However, a correlation analysis revealed a negative association of the thickness change rates in the complex of ganglion cell and inner plexiform layer and the inner nuclear layer with a higher modified Rankin scale at follow-up. Conclusions: This study adds to the notion that OCT may not be a suitable tool to monitor atrophy and disease progression in ALS. However, further longitudinal studies with longer follow-up times and larger cohorts are warranted.",
"41532955": "ID: 41532955\nTitle: Unveiling the Proteomic Landscape of Extracellular Vesicles: Implications for Neurodegeneration and Neuroprotection.\nAbstract: Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to elucidate their roles in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and ischemic stroke. Across these conditions, EVs carry disease-relevant proteins that reflect and influence key pathological processes such as synaptic dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death. Proteomic profiling of brain- and biofluid-derived EVs has uncovered specific biomarkers and signaling pathways, ranging from tau and \u03b1-synuclein in AD and PD to mutant SOD1 in ALS and complement activation in stroke and TBI. Moreover, cell-type-specific EVs (e.g., from neurons, astrocytes, microglia, and stem cells) have been shown to exert either protective or deleterious effects, modulating apoptosis, axonal regeneration, and immune responses. Recent evidence highlights the translational potential of EVs as non-invasive biomarkers and therapeutic vectors across multiple disorders. By mapping shared and divergent proteomic signatures in EVs, we review the mechanistic relevance and clinical utility of EVs in neurodegeneration and CNS injury.",
"41546910": "ID: 41546910\nTitle: Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.\nAbstract: Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.",
"41567979": "ID: 41567979\nTitle: Brain-derived extracellular vesicles potentially mediate crosstalk with peripheral organs in neurodegenerative diseases.\nAbstract: Brain-Derived Extracellular vesicles (BDEVs) are emerging mediators of intra- and interorgan communication in neurodegenerative diseases (NDs) such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). A growing body of evidence suggests that BDEVs play an important role in modulating intercellular communication within the central nervous system in the pathogenesis of many NDs. By transporting non-coding RNAs (e.g., miRNAs) and important pathological proteins, BDEVs also influence peripheral organs and contribute to the progression of disease in the central nervous system (CNS). This review extends the understanding of NDs beyond solely brain dysfunction and gives a novel framework for the progression of these diseases, uniquely emphasizing the currently underexplored mechanisms by which BDEV-mediated communication exacerbates or potentially initiates peripheral dysfunction or complications. It maps and clarifies the specific and potential mechanisms by which CNS-originating EV activity proliferates systemic dysfunction, presenting new opportunities and areas for therapeutic and diagnostic treatments for NDs. These findings are contextualized across multiple NDs, including Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), by incorporating data on dysregulated BDEV miRNAs and toxic proteins to map the pathway of BDEV-mediated disease spread.",
"41598508": "ID: 41598508\nTitle: Surgical Outcomes and Differences in Values of Ocular Parameters Following Vitrectomy for Macular Hole over a 10-Year Period.\nAbstract: Background/Objectives: We aimed to compare the surgical outcomes of macular hole (MH) cases and evaluate how the axial length (AL) affected the outcomes. Methods: Six hundred and sixty-three eyes with MHs that underwent vitrectomy over the past 10 years were reviewed. The changes in AL were compared to those of 1948 eyes with idiopathic epiretinal membranes (ERMs) operated on during the same period. The MH cases for the 5 years from 2014 to 2018 were designated as the MH2014 group, and those from 2019 to 2023 as the MH2019 group. The ERM cases were divided similarly into the ERM2014 and ERM2019 groups. The clinical characteristics of the cases and surgical outcomes were compared. Results: The MH diameter, closure rate, and baseline and postoperative visual acuity were not significantly different. The use of the inverted internal limiting membrane flap technique was significantly higher in the MH2019 group (58%) than in the MH2014 group (24%, p < 0.001). The mean AL was significantly longer in the MH2019 group (25.2 \u00b1 2.4 mm) than in the MH2014 group (24.6 \u00b1 2.1 mm, p = 0.004). The incidence of myopic MHs with AL \u2265 26 mm and AL \u2265 30 mm was higher in the MH2019 group (30.9%, p = 0.008, 6.4%, p = 0.017, respectively). There was a significant trend for longer ALs over 10 years in the MH group (p = 0.002), but not in the ERM group. Conclusions: The increased AL and the rising proportion of eyes with myopic MHs indicate that the patient profile of eyes with MHs has changed over the past decade.",
"41612503": "ID: 41612503\nTitle: Diagnostic potential of cryptic exon-derived peptides in serum extracellular vesicles for sporadic amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration and loss of upper and lower motor neurons, with approximately 90% of cases being sporadic (sporadic ALS, SALS). A reliable diagnostic biomarker remains an unmet clinical need in SALS, with misdiagnosis and diagnostic delay hindering early management. The mislocalization of the RNA-binding protein TDP-43 (encoded by TARDBP), a pathological hallmark of SALS, could lead to aberrant splicing that produces transcripts with cryptic exons and, consequently, cryptic peptides. This study proposes cryptic peptides in serum extracellular vesicles as a novel candidate diagnostic biomarker of SALS. We included 10 healthy controls and 20 patients with SALS and quantified cryptic peptides predicted from cryptic exon sequences using mass spectrometry-based proteomics. Cryptic peptides from four proteins (RANBP1, IGLON5, ACTN1, ALPK2) were detected in participants, with the IGLON5 cryptic peptide detected significantly more frequently in SALS than in HC (adjusted P\u2009=\u20090.044). The number of detected cryptic peptides classified SALS and healthy controls with acceptable performance (area under the curve\u2009=\u20090.82). In conclusion, cryptic peptides could have diagnostic performance for SALS, warranting further validation.",
"41613186": "ID: 41613186\nTitle: Dual role of exosomes in neurodegenerative diseases: a molecular bridge between neuroinflammation and transmission of pathological proteins.\nAbstract: Neurodegenerative diseases (NDDs) are complex disorders characterized by the progressive loss of neuronal function. Their pathological mechanisms involve multiple levels, including neuroinflammation, abnormal protein aggregation, and disrupted cell signaling. Diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis (MS), and prion diseases not only severely impact patients' quality of life but also pose significant challenges for medical research due to their complex pathogenesis and the lack of effective treatments. In recent years, extracellular vesicles (EVs), particularly exosomes, have garnered increasing attention for their critical role in cell-to-cell communication. Exosomes are membrane-enclosed nanovesicles approximately 30-150\u202fnm in diameter that can carry proteins, lipids, nucleic acids, and other bioactive molecules, influencing recipient cells through paracrine or distant signaling. This review aims to summarize the roles of exosomes as mediators of neuroinflammation and as vehicles for intercellular transmission of pathogenic proteins in neurodegenerative diseases.",
"41621861": "ID: 41621861\nTitle: Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice.\nAbstract: Methylmercury (MeHg) is a global pollutant that readily crosses the blood-brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the effect of fetal exposure remains poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90-120 (P90-120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes (n = 4/group) in multiple pathways associated with neurodegeneration, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation.",
"41638908": "ID: 41638908\nTitle: TBK1 activity regulates the directionality of axonal transport of signalling endosomes.\nAbstract: The polarised and complex morphology of neurons poses massive challenges for efficient cargo delivery between the axon and soma, a process termed axonal transport. We have previously shown that the retrograde axonal transport of pro-survival, neurotrophic signalling endosomes relies on Rab7 in motor neurons, and that their trafficking is impaired in the early stages of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we report the effect of Rab7 phosphorylation on the transport of these signalling endosomes. We show that the ALS-linked kinase TBK1 phosphorylates Rab7 at S72 in neurons, altering its binding to cytoplasmic dynein adaptors. Accordingly, both TBK1 knockdown and the expression of a loss-of-function Rab7 mutant (S72E) induce aberrant bidirectional movement of signalling endosomes without modifying neuronal polarity or endosomal sorting. This alteration is specific for signalling endosomes, as axonal transport of lysosomes and mitochondria remains unaffected. We have therefore discovered a new TBK1 function that ensures the unidirectional transport of signalling endosomes, suggesting that reduced TBK1 activity determines retrograde transport dysfunctions and long-range signalling impairments.",
"41651252": "ID: 41651252\nTitle: Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, raising debate over whether ALS is a single disease or multiple disorders with similar symptoms. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are found in only 2-3% of ALS cases, yet misfolded SOD1 appears in both sporadic (sALS) and familial (fALS) patients. Furthermore, mutations in TDP-43 or FUS increase levels of misfolded SOD1 on extracellular vesicles (EVs). Small EVs isolated from ALS patient samples have been shown to cause death of wild-type motor neurons and myotubes, supporting the theory that EVs play a role in spreading disease. We hypothesize that the previously identified toxic trimeric SOD1 spreads via EVs in ALS and influences the distribution of other ALS-related proteins, suggesting a common mechanism. To test this, we isolate EVs from motor neuron-like cells expressing mutations that stabilize trimers. We then perform a sandwich enzyme-linked immunosorbent assay (ELISA) using a CD9 capture antibody to measure whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is affected by trimeric SOD1 using endocytosis and exocytosis inhibitors and analyze altered protein interaction pathways through co-immunoprecipitation and mass spectrometry proteomics. Our results show that VAPB, VCP, and Stathmin-2 increase on EVs when trimers are stabilized. The common pathway linking these ALS-associated proteins and SOD1 appears to involve multiple mechanisms, including the Caveolae endocytosis pathway, pointing to a novel hybrid EV release pathway in ALS. Overall, our findings show that trimeric SOD1 influences EV cargo and spread in ALS.",
"41652471": "ID: 41652471\nTitle: Large-scale mapping of the MCH network in ALS mice reveals the vulnerability of dopaminergic and GABAergic neurons in zona incerta.\nAbstract: Weight loss and hypermetabolism are early and prognostically significant features of amyotrophic lateral sclerosis (ALS) and are associated with hypothalamic atrophy and degeneration of melanin-concentrating hormone (MCH) neurons that regulate energy balance. To investigate whether MCH vulnerability arises from upstream network dysfunction, we performed whole-brain retrograde rabies tracing in SOD1G93A mice. We identified an early, selective loss of monosynaptic inputs from the zona incerta (ZI), a dopaminergic (DA)/gamma-aminobutyric acid (GABA)ergic nucleus that preceded MCH neuron degeneration. Neurochemical profiling confirmed the DA/GABAergic identity of these ZI input neurons, and ZI/DAergic neurons later degenerated. ALS-related pathology emerged early in the ZI, paralleling pathology in the motor cortex, while anterograde mapping revealed that motor cortical projections preferentially targeted the ZI, linking vulnerable motor and metabolic networks. Loss of ZI/DAergic neurons was observed in conjunction with weight loss in non-SOD1 ALS models. These findings identify the ZI as an early-affected node within hypothalamic networks and suggest that disruption of DA/GABAergic inputs to MCH neurons is associated with subsequent MCH and DA neuronal vulnerability, degeneration and metabolic imbalance in ALS.",
"41665722": "ID: 41665722\nTitle: Recombinant AMPs (Epinecidin-1 and its Variants): A New Hope against Invasive Fungal Infections against Candida spp. and Aspergillus flavus.\nAbstract: To enhance stability and antimicrobial efficacy of antimicrobial peptide (AMP) epinecidin-1, we previously engineered three variants - GK-epi-1, Variant-1 and Variant-2-by substituting alanine and histidine residues with lysine. Our current study focuses on the antifungal capabilities of Epinecidin-1 and its variants against the clinical isolates of Candida spp. (Candida albicans, C. tropicalis, C. krusei & C. glabrata) and Aspergillus flavus. Computational docking studies are evidenced, the peptides had strong affinity against all fungal receptor examined which indicates their efficacy to interact with the Candida cell membrane receptors (Exo-B-(1,3)-Glucanase, Secreted aspartic proteinase (SAP) 1 & N-terminal domain adhesin: Als 9\u2009-\u20092). Minimum Inhibitory Concentration (MIC), Minimum Fungicidal Concentration (MFC) and antibiofilm assays revealed its potent antifungal activity, particularly in disrupting biofilm formation. Effects of peptides on hyphal growth inhibition activity and Scanning Electron Microscopy (SEM) confirmed that the mechanism of action involves pore formation, hyphal disruption and induction of reactive oxygen species in Candida cell membrane. The antifungal spectrum was extended to A. flavus, a known ocular pathogen, where combination therapy using sub-inhibitory concentrations of Epinecidin-1 and its variant peptides with Amphotericin B and Miconazole showed enhanced synergistic effects, reducing required dosages for effective pathogen control.",
"41672113": "ID: 41672113\nTitle: Superoxide dismutase impacts extracellular vesicle shedding and uptake.\nAbstract: Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play a critical role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and on the potential for EVs as diagnostic biomarkers, while the effects of pathogenic factors on EV release are poorly understood. Using a functional endogenous reporter, we showed that the key antioxidant enzyme superoxide dismutase 1 (SOD-1) is expressed in C. elegans EV-releasing neurons, localizes to the cytoplasm, and reduces levels of reactive oxygen species (ROS). We then defined how sod-1 mutations affect EV shedding from sensory neuron primary cilia into the environment, ciliary enrichment of proteins packaged into EVs, and glial uptake of EVs in vivo, by imaging C. elegans expressing fluorescent protein-tagged EV cargoes. Deletion of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different EV subpopulation that is shed from the ciliary base, without affecting release into the environment. These results demonstrate that SOD-1 has a subtype-specific effect on the release of EVs with distinct signaling potentials. Intriguingly, we discovered that exposure to paraquat, which increases mitochondrial ROS, reduced the shedding of both distal tip and ciliary base-derived EVs. These opposing effects of the sod-1 mutations and paraquat treatment on EV release suggest that ROS in distinct subcellular compartments may differentially impact ciliary EV shedding.",
"41686369": "ID: 41686369\nTitle: Extracellular vesicles at the neuromuscular junction: messengers of synaptic health and disease.\nAbstract: Extracellular vesicles (EVs) have emerged as pivotal modulators of neuromuscular junction (NMJ) biology, reshaping our understanding of synaptic communication, maintenance, and degeneration. This review consolidates current insights into the roles of EVs derived from motor neurons, muscle fibers, and Schwann cells in regulating NMJ integrity. In healthy states, EVs deliver trophic factors, structural proteins, and regulatory RNAs that promote the clustering of acetylcholine receptors, presynaptic stability, and axonal growth. Motor neuron EVs carry Wnt7a, synaptophysin, and PGC-1\u03b1, while muscle-derived EVs deliver miR-206, agrin, and caveolin-3. Schwann cell EVs contribute neurotrophic support via NRG1 and GDNF. In contrast, diseased or aged NMJs exhibit EV cargo dysregulation, marked by the presence of misfolded proteins (e.g., SOD1, TDP-43), pro-inflammatory cytokines, and reduced regenerative miRNAs. These changes contribute to synaptic dismantling, neuroinflammation, and impaired repair in conditions such as ALS, SMA, MG, and sarcopenia. The review highlights the bidirectional nature of EV signalling and its dynamic regulation by neuronal activity and stress. Emerging therapeutic strategies include engineering EVs to deliver protective cargo, targeting them to NMJ components, and designing biomaterial-based depots for sustained release. Furthermore, EV signatures in blood and muscle hold promise as non-invasive biomarkers for early detection of NMJ decline in ALS, SMA, MG, and sarcopenia. Despite promising preclinical data, challenges remain in EV characterization, targeting specificity, and clinical translation. This review underscores a paradigm shift: EVs are not passive byproducts but active messengers of neuromuscular health and disease, with realistic applications in diagnostics, regenerative therapy, and personalized medicine.",
"41702277": "ID: 41702277\nTitle: Trace metal signatures in cerebrospinal fluid (CSF): Insights from an amyotrophic lateral sclerosis (ALS) hotspot on Mount Etna (Sicily, Italy).\nAbstract: Chronic exposure to trace metals has been increasingly recognized as a possible factor influencing the risk of amyotrophic lateral sclerosis (ALS). In the province of Catania, on the eastern slopes of Mount Etna, epidemiological investigations have highlighted the presence of a high-incidence cluster of the disease. Against this backdrop, the present study was designed to explore whether the concentrations of trace elements in cerebrospinal fluid (CSF) differ between ALS patients residing in this high-incidence area (In-Cluster) and those living in regions with lower incidence (Out-Cluster). For trace element analysis, CSF was analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Fourteen metals (Al, V, Mn, Co, Ni, Cu, Zn, As, Cd, Hg, Pb, Fe, Se, Mg) were quantified in standard and KED modes. No single metal concentration differed significantly between In-Cluster and Out-Cluster groups. However, In-Cluster patients frequently showed higher upper quartiles for Al, Mn, As, Hg, and Se, suggesting broader variability. Ratio analysis highlighted significant differences between groups, with higher Al/Cu ratios observed in In-Cluster patients. Sex-stratified analysis further revealed increased Mn-based ratios in females, with a significantly elevated Mn/Pb ratio. These patterns indicate possible dysregulation of trace metal homeostasis linked to environmental exposure. In conclusion, although statistical significance was limited, our findings suggest that chronic volcanic ash exposure may contribute to subtle imbalances between neurotoxic and neuroprotective elements in CSF, potentially influencing ALS susceptibility. Further studies integrating environmental monitoring, speciation analysis, and larger cohorts are needed to clarify the role of trace metals in ALS pathogenesis.",
"41739160": "ID: 41739160\nTitle: [On the urgency of treating ophthalmic emergencies].\nAbstract: In emergencies in ophthalmology a\u00a0distinction must be made between systemic emergency situations that manifest in the eye and purely ocular emergencies. The latter threaten vision to varying degrees and therefore require differentiated treatment and care by the ophthalmologist. This requires considerable responsibility and high expertise as all subdisciplines of ophthalmology can be affected. Due to demographic developments and other factors, the number of emergency patients is increasing, which requires adaptation in resources and clinical management of patients. Bei Notf\u00e4llen in der Augenheilkunde ist zwischen systemischen Notfallsituationen, die sich am Auge manifestieren, und rein okul\u00e4ren Notf\u00e4llen zu unterscheiden. Letztere bedrohen das Sehverm\u00f6gen in ganz unterschiedlichem Ausma\u00df und bed\u00fcrfen daher ophthalmologischerseits einer differenzierten Betrachtung und Versorgung. Diese erfordert besondere Verantwortung und gro\u00dfe Kompetenz, da alle Subdisziplinen der Augenheilkunde betroffen sein k\u00f6nnen. Nicht zuletzt wegen der demografischen Entwicklung nimmt die Anzahl der Notfallpatienten zu, was eine bessere Steuerung der Patienten erfordert.",
"41750213": "ID: 41750213\nTitle: Color Vision Deficits and Binocular Vision Dysfunction in Parkinson's Disease.\nAbstract: Background/Objectives: Visual dysfunction is a common non-motor symptom in Parkinson's Disease (PD), as evidenced by deficits in color vision (CV) and binocular vision (BV). Computerized CV tests, such as the Cambridge Color Test (CCT), are underutilized in this patient population despite the known limitations of common CV tests. Methods: In total, 19 PD and 12 control participants underwent a comprehensive eye exam, including ocular motility testing and the CCT, utilizing thresholds obtained along 12 contrast vectors to fit a discrimination ellipse. Findings were compared across groups, and the association with disease severity was analyzed. Results: PD participants showed increases in ellipse area (p = 0.012) and short-axis length (p = 0.009). PD participants demonstrated convergence insufficiency type exotropia (p < 0.001) and impaired stereopsis (p = 0.006). No significant correlation with UPDRS scores was seen for either BV or CV. Conclusions: PD participants exhibited binocular vision dysfunction with selective changes in color vision. CV changes are more variable in PD, likely due to mixed parvocellular and cortical dysfunction. Convergence insufficiency type exotropia is more common in PD, likely due to combined cortical and subcortical neurodegeneration. Both BV and CV changes occur independently of motor severity, emphasizing the need for routine visual testing regardless of symptom progression.",
"41751374": "ID: 41751374\nTitle: Mesenchymal Stem Cell-Based Therapies Applied in Neurological Diseases: A Systematic Review.\nAbstract: Background/Objectives: Neurodegenerative diseases (NDs) have a severe impact on patients' quality of life, and effective treatments remain limited. As the focus is on treating the symptoms, the root cause of the problem is commonly not addressed. Mesenchymal stem cells show an emerging potential due to the ability for self-renewal combined with their capability for differentiation into various cell lines, which makes them a strong candidate for regenerative therapies in general, and for application in neurological issues in particular. This article provides an overview of the safety, efficacy, and challenges associated with the use of mesenchymal stem cells (MSCs) and their derived secretome in clinical and preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Methods: A systematic search was conducted on PubMed to identify published studies providing clinical and preclinical evidence on the use of MSCs in neurodegenerative disorders. Results: Overall, the literature consistently indicates that MSCs and their derivatives exert disease-modifying effects across multiple NDs. Across AD, PD, HD and ALS, preclinical studies uniformly report improvements in behavioural outcomes, attenuation of neuroinflammation, and neuroprotective effects, largely mediated by MSCs' paracrine signalling rather than direct cell replacement. Clinical studies to date consistently support the safety and feasibility of MSC-based therapies, while efficacy signals remain modest, heterogeneous and predominantly short-term, highlighting the need for larger, well-controlled trials. Conclusions: Integration of genetic engineering, preconditioning, and EV technology may represent an emerging therapeutic approach that may complement existing neuroregeneration treatments, offering a scalable and minimally invasive frontier to improve long-term clinical outcomes in patients with AD, PD, HD, and ALS.",
"41776544": "ID: 41776544\nTitle: Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with no established disease-modifying therapy. Mesenchymal stem/stromal cells (MSCs) have been reported to exert neuroprotective effects in models of injury and disease, acting primarily through release of small extracellular vesicles (sEVs). MSC-derived sEVs (MSC-sEVs) have therefore attracted attention as a potential cell-free therapeutic approach for treating neurological conditions such as ALS. Because MSC-sEVs can cross both the nasal epithelial barrier and blood-brain barrier to reach the central nervous system (CNS), intranasal administration represents an attractive approach for repeated delivery of MSC-sEVs for long-term administration. In this study, we administered bone marrow-derived MSC-sEVs or vehicle intranasally to a SOD1(G93A) transgenic mouse model of ALS; the large majority of the sEVs had surface markers for exosomes. Dosing was for three consecutive days per week beginning one day after onset of neurological symptoms and continuing until a moribund state. Neurological score and body weight were recorded daily. Although total survival time and post-onset survival duration were not significantly prolonged by MSC-sEV treatment, MSC-sEV treatment significantly delayed progression from a mild symptom phase (NeuroScore 1) to more severe symptoms (NeuroScore 2) compared with vehicle-treated controls and showed a trend toward slower weight loss. These findings indicate that intranasal administration of MSC-sEVs can delay functional deterioration and prolong the mild impairment stage in an ALS mouse model. If translatable to human patients, such preservation of neurological function could represent a clinically meaningful outcome.",
"41781384": "ID: 41781384\nTitle: Decreased metallothionein-3 expression in the human spinal cord is a common feature of amyotrophic lateral sclerosis and multiple sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are devastating adult-onset neurological diseases with distinct pathological manifestations. Although growing evidence implicates copper dysregulation in both diseases, our understanding of this connection remains incomplete. In this study, we investigated metallothionein-3 (MT3), which is a key regulator of copper metabolism in the central nervous system (CNS), and its relationship to copper in the ALS and MS spinal cord. Using combined quantitative mass spectrometry approaches and immunohistochemical observations, we found a significant decrease in ALS and MS spinal cord MT3 levels compared to controls. This was correlated with levels of copper and MT3-copper binding, highlighting a strong relationship between copper and MT3 levels. These findings demonstrate decreased MT3 expression alongside copper as a common feature of ALS and MS supporting previously reported evidence for copper dysregulation in these diseases.",
"41783572": "ID: 41783572\nTitle: Copper Homeostasis and Cuproptosis in Neurological Disorders.\nAbstract: Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development. Copper homeostasis imbalance plays a critical regulatory role in neurological disorders.Cuproptosis is a unique form of copper-mediated cell death that plays a key role in neuronal injury.Many key questions regarding the differences in copper homeostasis and cuproptosis mechanisms among various neurological disorders remain unresolved.The interplay between copper and other metal ions (such as iron and zinc) in maintaining homeostasis may have important implications in neurological disorders.",
"41784766": "ID: 41784766\nTitle: The Impact of Myopia Control Spectacle Lens Designs on Visual Function.\nAbstract: To profile the immediate effect of defocus-modulating and contrast-modulating myopia control spectacle lens interventions on visual function. Healthy myopic (mean spherical equivalent (MSE) -4.25 to -0.50\u2009D) young adults, corrected with contact lenses, wore diffusion optics technology (DOT), defocus incorporated multiple segments (DIMS), highly aspherical lenslets (HAL) and standard single vision (SV) plano trial spectacle lenses, in a prospective, single-visit, double-blind, four-way randomised crossover study. Distance and near high- and low-contrast visual acuity (VA), contrast sensitivity, reading performance, accommodative facility, visual search task and accommodative accuracy were assessed foveally through the central zone (CZ) and/or peripheral zone (PZ) of the lenses. Twenty participants (16\u2009female) were recruited, with a mean (\u00b1SD) age of 22.4 (\u00b12.72) years and MSE -2.21 (\u00b11.10)\u2009D. VAs through the PZ differed significantly between myopia control lenses and SV, with the HAL and DIMS exhibiting lower VA across all testing conditions (all p\u2009<0.05) and DOT demonstrating equivalence to SV with high contrast letters. Contrast sensitivity was similarly reduced for all lenses through the CZ, while HAL and DIMS performed worse than both SV and DOT through the PZ (p\u2009<0.01). Near acuity threshold, reading speed and critical print size through the PZ were comparable for SV, DOT and HAL (all p\u2009>0.05), whereas DIMS exhibited worse near acuity threshold and critical print size (p\u2009<0.001). No significant differences emerged for error score (p\u2009=\u20090.53), accommodative facility refocusing cycles (all p\u2009>0.05) or visual search duration (CZ: p\u2009=\u20090.68; PZ: p\u2009=\u20090.35). Accommodative response was similar across lenses (all p\u2009>0.05); however, SV had lower variability at distance through the PZ than DOT, HAL and DIMS (p\u2009<0.001). All three myopia control lenses exhibited visual performance comparable to standard SV lenses through the CZ. Clinicians should note differences in visual performance, especially VA and reading speed through the lens periphery and their relative testing.",
"41785987": "ID: 41785987\nTitle: Spectrum of Colopathy and Severe Polyposis Associated With Pentosan Polysulfate Sodium Maculopathy: A Retrospective Case Series.\nAbstract: To expand the spectrum of gastrointestinal (GI) manifestations associated with pentosan polysulfate sodium (PPS) maculopathy. Retrospective case series. Eight patients (16 eyes) diagnosed with PPS maculopathy who also underwent GI evaluation between 2019 and 2025. Electronic medical records were reviewed for demographics, PPS dosage and duration, ocular findings, GI history, diagnostic presentation, and histopathology. Multimodal imaging included fundus photography, fundus autofluorescence, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography. Colonoscopy was performed in all patients with histopathologic analysis in selected cases. PPS maculopathy was staged according to Wang et al.'s classification system. Genetic testing was obtained in selected cases to exclude any form of inherited maculopathy or familial adenomatous polyposis. Clinical and imaging features of PPS maculopathy and GI pathological diagnosis, including polyposis, dysplasia, and inflammatory bowel disease. The cohort included 6 women and 2 men (median age: 68.5 years). Median PPS exposure was 25.4 years with a median cumulative dose of 2899 grams. At presentation, 62.5% of eyes were stage 1, 31.3% stage 2, and 6.3% stage 3. At final follow-up, 25% of eyes were stage 1, 50% stage 2, and 25% stage 3. Overall, 37.5% of eyes showed progression of maculopathy stage, and cRORA was present in 75% of eyes at last follow-up. Additional findings included acquired vitelliform lesions, outer retinal tubulations, epiretinal membranes, and type 2 macular neovascularization. Colonoscopy revealed severe adenomatous polyposis in 6 of the 8 patients (75%), with 3 requiring partial or total colectomy and 2 undergoing endoscopic resection. One patient developed ulcerative colitis, and 2 additional patients were diagnosed with Crohn's disease or microscopic colitis. The median latency to GI diagnosis was 10 years after PPS initiation. This study expands the recognized systemic toxicity of PPS, demonstrating that PPS maculopathy patients are at risk of concomitant colonic disease, including severe polyposis and dysplasia. The frequent detection of asymptomatic polyposis underscores the importance of colonoscopy screening in exposed patients, even in the absence of GI symptoms. Heightened interdisciplinary awareness and long-term surveillance are warranted to mitigate the vision- and life-threatening consequences of PPS toxicity.",
"41788972": "ID: 41788972\nTitle: Tolcapone Interferes With Key Pathological Features in Alzheimer's Disease.\nAbstract: Tolcapone, a clinically approved drug for the treatment of Parkinson's disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid-\u03b2 aggregation and toxicity, which are hallmark features of Alzheimer's disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age-related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid-\u03b2 and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal-amyloid-\u03b2 species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper-free amyloid-\u03b2 and copper-associated amyloid-\u03b2 complexes, using a combination of techniques including UV-vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid-\u03b2 monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid-\u03b2 for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal-free and metal aggregation pathways by preventing metal coordination to amyloid-\u03b2 or disrupting preformed amyloid-\u03b2-metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.",
"41796748": "ID: 41796748\nTitle: Accuracy of sixteen axial length adjusted intraocular lens power calculation formulas in long Caucasian eyes.\nAbstract: To compare the accuracy of sixteen intraocular lens (IOL) power calculation formulas incorporating targeted adjustments or regression-based modifications of axial length (AL) in eyes longer than 26.00\u202fmm. Retrospective observational study. The data of myopic patients with cataract who underwent uneventful phacoemulsification with in-the-bag implantation of a PARTIAL-RoF narrow IOL between January 2020 and June 2025 were reviewed. Preoperative IOL power was calculated using the IOLMaster 700 with six formulas: Barrett Universal II (BU II), Haigis, Hoffer Q, Holladay 1, Holladay 2, and SRK/T. The implanted IOL power was selected from BU II or SRK/T recommendations. Refraction was measured three months postoperatively. Postoperative IOL power predictions were generated using the following formulas or formula variants: K6, PEARL-DGS, Castrop, Eom, VRF CMAL; Holladay 1 with Wang-Koch 2 center optimization (WK2), modified Wang-Koch (MWK), non-linear regression (NLR), and Fam-adjusted method (F2); SRK/T WK2, SRK/T MWK, SRK/T F2; Holladay 2 NLR; Hoffer Q WK2; Haigis WK2; and Barrett True AL. The primary outcome measures were root mean square absolute error (RMSAE) and the percentage of eyes with prediction error (PE) within \u00b1 0.25 D, \u00b1 0.50 D, \u00b1 0.75 D, and \u00b1 1.00 D. One hundred sixty-four eyes with ALs ranging from 26.04\u202fmm to 29.72\u202fmm were included. RMSAE values across the sixteen formulas ranged from 0.393 (Holladay 1 NLR and SRK/T WK2) to 0.803 (Haigis WK2). The percentage of eyes with PE within \u00b10.50 D ranged from 35.98% (Haigis WK2) to 81.1% (Holladay 1 NLR). Holladay 1 NLR-followed by SRK/T WK2, Holladay 1 MWK, VRF CMAL, PEARL-DGS, and Eom-demonstrated significantly higher accuracy than most other formulas. Haigis WK2 and Hoffer Q WK2 were the least accurate. Certain modified third-generation formulas (Holladay 1 NLR, SRK/T WK2) achieve accuracy comparable to that of new-generation formulas (PEARL-DGS, K6, VRF CMAL) in IOL power calculations for long eyes. However, some third- and fourth-generation formulas-even after AL-based modification (Hoffer Q WK2, Haigis WK2)-continue to yield suboptimal results in this anatomical range.",
"41813079": "ID: 41813079\nTitle: OCT-based myopic index: a biological predictor for the progression of high myopia.\nAbstract: The growth of axial length (AL) can lead to high myopia and ocular deformation, especially causing microstructural changes in the fundus, which cannot be fully quantified by AL alone. We propose an optical coherence tomography (OCT)-based modified AL (Myopic Index) to represent the extent of fundus deformation caused by AL elongation and to explore its clinical significance in myopic progression prediction. A deep learning model was trained using 27\u2009539 cases of OCT images and referred ocular biometric data to evaluate the Myopic Index. By comparing the Myopia Index with the Measured AL, the difference of two AL indices (DAL) was calculated. We further prospectively employed 2866 cases of OCT images, which were categorised into short AL (Measured AL<22\u2009mm), normal AL (22 mm\u2264Measured AL<26\u2009mm) and long AL (\u226526\u2009mm), to evaluate the model ability of myopic progression prediction. The attention regions of images were also analysed. The Myopia Index was closely correlated with Measured AL (all p<0.001, R\u00b2=0.804 in all eyes). Specifically, the Myopia Index was closer to the Measured AL in eyes with long ALs, whereas in eyes with short and normal axial lengths, the Myopia Index clustered around 23-24\u2009mm. The visualisation model demonstrated that for eyes with short and normal ALs, attention regions were primarily concentrated on the retina; conversely, for eyes with long ALs, the choroidal layer and the retinal pigment epithelium layer received more attention. Moreover, DAL was significantly correlated with AL increment (p=0.038). The Myopia Index reflects the real status of fundus microstructures through fundus microstructures, with a particular focus on the choroid. The Myopia Index demonstrates good predictive capabilities for high myopia progression.",
"41818823": "ID: 41818823\nTitle: Effect of G4C2repeat expansions on the motion of lysosomes inside neurites.\nAbstract: The G4C2hexanucleotide repeat expansion (HRE) in the c9orf72 locus is a mutation associated with amyotrophic lateral sclerosis. Recent evidence suggests a link with disrupted axonal trafficking in neurons. Here, using a neuronal-like cell line without or transfected with G4C2repeats, we characterize the motion of lysosomes inside neurites. The neurites grew either aligned to patterned lines, or oriented freely on a 2D-substrate. Implementing time-resolved (local) mean squared displacement analysis lysosome trajectories were split into sub-diffusive, diffusive, and super-diffusive parts. Our results suggest that in the presence of the G4C2repeats, lysosome trafficking is hampered, exhibiting overall decreased mean squared displacement and speed, more prominently inside aligned neurites. Moreover, a prominent effect in the super-diffusive drift velocity and diffusive motion diffusion coefficient was evident when the motion occurred inside aligned neurites. Trajectories which included super-diffusive motion, exhibited a varied ratio of anterograde/retrograde/neutral for both neurite geometries in the presence of G4C2repeats but a similar velocity decrease for both directions in each neurite geometry. Our findings support the hypothesis that impaired axonal trafficking emerges in the presence of the G4C2HRE, and demonstrate that this effect is more prominent when the neurites are aligned.",
"41837970": "ID: 41837970\nTitle: Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related mechanisms, including neuroinflammation, iron homeostasis, and dysregulated microRNAs. To evaluate the safety, tolerability, and potential efficacy of PrimeC in people living with ALS. This was a randomized, double-blind, placebo-controlled, phase 2b trial conducted at 4 ALS referral centers from May 2022 to November 2023 and followed by 12-month open-label extension. Adults with definite or probable ALS and disease duration of 30 months or less were eligible. Of 73 screened, 69 were randomized and 68 were included in the intent-to-treat population. Participants were randomized 2:1 to receive PrimeC or placebo for 6 months, followed by open-label extension PrimeC for all. The primary outcome was safety and tolerability. The prespecified primary biomarker outcome was plasma neuron-derived-exosomal TAR DNA-binding protein 43 (TDP-43) or prostaglandinJ2. Secondary outcomes included change in ALS Functional Rating Scale-Revised (ALSFRS-R) score at 6 and 18 months, survival, and time-to-composite events. Exploratory biomarkers included neurofilament light chains, iron-regulatory proteins, and circulating microRNAs. The 68 participants were well balanced in age at entry and sex. In the PrimeC group, the mean (SD) age was 59.1 (9.1) years, and 27 of 45 participants were male. In the placebo group, the mean (SD) age was 55.0 (13.0) years, and 14 of 23 participants were male. PrimeC was well tolerated, with a safety profile comparable to placebo (adverse event rate, 66.7% PrimeC vs 65.2% placebo). Drug-related adverse events were more frequent with PrimeC (20.0% vs 4.3%), mostly mild to moderate, and transient. At month 6, the mean ALSFRS-R difference was 2.23 points between PrimeC and placebo (95% CI, -0.61 to 5.07; P\u2009=\u2009.12). At month 18, ALSFRS-R scores in participants continuously treated with PrimeC maintained a difference (7.92 points; 95% CI, 2.25 to 13.60; P\u2009=\u2009.007), with significant bulbar difference (3.18 points; 95% CI, 1.32 to 5.04; P\u2009=\u2009.001). Continuous treatment was associated with lower risk of ALS complications, including hospitalization, respiratory failure, or death (HR, 0.36; 95% CI, 0.15-0.85; P\u2009=\u2009.02). In the double-blind period, transferrin levels were preserved with PrimeC (1.90 \u03bcmol/L difference; P\u2009=\u2009.03), the negative ferritin-ALSFRS-R correlation observed in placebo (\u03c1\u2009=\u2009-0.50; P\u2009=\u2009.02) was abolished, and ALS-associated microRNAs were downregulated (log2 fold change: miR-199a-3p, -1.87; false discovery rate [FDR] P\u2009=\u2009.004; miR-199a-5p, -2.23; FDR P\u2009<\u2009.001; miR-181a-5p: -1.89; FDR P\u2009=\u2009.001; miR-181b-5p, -1.62; FDR P\u2009=\u2009.005). Prespecified neuron-derived exosome TDP-43/PgJ2 analyses will be reported separately following completion of development and analyses. PrimeC was safe and well tolerated over 18 months. Although not powered for efficacy, functional and biomarker findings support a confirmatory trial. ClinicalTrials.gov Identifier: NCT05357950.",
"41843090": "ID: 41843090\nTitle: [Imaging: new techniques for imaging of the vitreous body].\nAbstract: This review article addresses the central problem that although the vitreous body constitutes approximately 80% of the ocular volume, it can often only be insufficiently clinically assessed due to its transparency. This article therefore emphasizes the necessity for improved diagnostic methods to be able to make a better assessment of the actual role of the vitreous body in health and disease. Diese \u00dcbersichtsarbeit adressiert das zentrale Problem, dass der Glask\u00f6rper \u2013\u00a0obwohl er rund 80\u202f% des okul\u00e4ren Volumens ausmacht\u00a0\u2013 aufgrund seiner Transparenz klinisch oft nur unzureichend beurteilt werden kann. Diese Arbeit hebt damit die Notwendigkeit verbesserter diagnostischer Methoden hervor, um die tats\u00e4chliche Rolle des Glask\u00f6rpers in Gesundheit und Krankheit besser erfassen zu k\u00f6nnen.",
"41854827": "ID: 41854827\nTitle: Nonlinear and Asymmetric Refractive Sensitivity to Effective Lens Position Errors in Pseudophakic Eye Models.\nAbstract: To perform a theoretical analysis of refractive sensitivity to effective lens position (ELP) errors in pseudophakic eyes using an explicit vergence-based optical model, and to quantify how this sensitivity depends on axial length (AL) and corneal power across a wide biometric range. A paraxial two-lens thin-lens model of the pseudophakic eye was developed, explicitly parameterised by AL, total corneal power (TCP), intraocular lens (IOL) power and effective lens position (ELP). Refraction was calculated at the corneal plane using vergence propagation. For a fixed reference ELP, the emmetropic IOL power was derived analytically for each combination of AL and TCP, and subsequently held constant while ELP was perturbed by \u00b11.0\u2009mm. Simulations were performed for ALs from 19 to 31\u2009mm and corneal powers from 38 to 50 dioptres. Refractive changes were approximated using families of quadratic regression models as functions of AL. Refractive sensitivity to ELP errors was dominated by AL. Short eyes exhibited large refractive changes per millimetre of ELP error, whereas long eyes showed markedly reduced sensitivity. The relationship between refractive error and ELP displacement was nonlinear, resulting in asymmetric refractive effects for equal-magnitude anterior and posterior ELP deviations. TCP continuously modulated refractive sensitivity indirectly through its influence on the emmetropic IOL power required for a given optical configuration. Refractive sensitivity to ELP errors in pseudophakic eye models is inherently nonlinear and asymmetric. This sensitivity is primarily governed by AL, with TCP acting as a secondary but systematic modulator through its effect on emmetropic IOL power. By explicitly separating optical sensitivity from ELP prediction, this vergence-based framework provides a physical basis for understanding ELP-related refractive variability across the biometric spectrum.",
"41860208": "ID: 41860208\nTitle: Intravitreal Anti-vascular Endothelial Growth Factor in Retinopathy of Prematurity: A Bibliometric Analysis.\nAbstract: Retinopathy of prematurity (ROP) is one of the leading cause of blindness in premature infants. A bibliometric analysis on intravitreal anti-vascular endothelial growth factor (VEGF) in ROP was conducted. A comprehensive search of the article on the Scopus database was conducted with the terms related to \"anti-vascular endothelial growth factor and retinopathy of prematurity.\" Only original research and review articles published in the English language were considered. VOSviewer version 1.6.20 was used for the visualization and analysis of the data. Publication trend, productive countries, researchers' details, commonly cited documents, source and influential journals, and keyword occurrence were analyzed. A total of 329 studies were considered, of which 270 were original articles and 59 were review articles. The highest numbers of publications were seen in the year 2022. The United States, China, Turkey, India, and Taiwan were the top 5 countries that published research on the use of anti-VEGF in ROP. The most documents were published by Wei-Chi Wu (22) and Chi-Chun Lai (14), and Falavarjani et al's article had the most citations (737). A total of 2,504 keywords were identified. All keyword analysis revealed the occurrence of \"retinopathy of prematurity\" and \"human\" as a keyword was 290 and 286 times, respectively. Most articles and citations were found in Retina. The use of anti-VEGF in ROP is constantly evolving and bibliometric analysis highlights a research trend and influential authors and journals that have published significant work on it. This article can serve as a guide to conduct a literature review for future researchers.",
"41894255": "ID: 41894255\nTitle: Destabilized Soluble SOD1 Species as Potential Determinants of Disease Severity in Familial Amyotrophic Lateral Sclerosis.\nAbstract: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are linked to familial amyotrophic lateral sclerosis (ALS), yet the identity of the toxic molecular species remains unclear. We investigated the relationship between protein misfolding and pathogenicity by expressing GFP-tagged wild-type and mutant SOD1 (A4V, H46R, G93A) in mouse hippocampal HT22 cells. Western blotting under nonreducing conditions suggested that A4V, associated with rapid disease progression, was largely depleted of properly folded soluble SOD1 and instead produced highly destabilized soluble species. In contrast, H46R, associated with a milder phenotype, showed a moderate reduction in properly folded soluble SOD1 and generated partially folded/native-like conformers. G93A exhibited biochemical characteristics intermediate between those of A4V and H46R. A4V also showed a pronounced loss of GFP fluorescence, indicating severe structural destabilization; the extent of fluorescence loss in A4V, G93A, and H46R broadly correlated with clinical severity. Neither CuATSM nor ebselen\u2500targeting metal binding and disulfide formation, respectively\u2500rescued fluorescence, suggesting broader defects in SOD1 maturation. Nevertheless, both compounds inhibited ferroptosis, a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation, in HT22 cells, indicating alternative neuroprotective mechanisms. These findings identify destabilized soluble SOD1 species as a key toxic entity in ALS and highlight the utility of GFP-tagged constructs for evaluating folding status and screening therapeutic candidates.",
"41904071": "ID: 41904071\nTitle: Platelet-derived and platelet secretome biotherapies for precision neuromedicine.\nAbstract: Platelet-derived biotherapies are emerging as innovative approaches for complex neurological disorders requiring multimodal interventions. Platelet-derived products, including lysates, platelet concentrate supernatants, secretome, extracellular vesicles, and fractionated components, represent a scalable and clinically accessible biotechnology platform for precision neuromedicine. Platelets provide a reservoir of trophic factors, cytokines, chemokines, lipids, antioxidants, and noncoding RNAs with demonstrated neuroprotective, anti-inflammatory, and antiferroptotic effects in models of neurodegeneration, trauma, and aging. Preclinical and patient-derived omics and neuroimaging data can help characterize mechanisms of action, identify biomarkers, and refine platelet secretome preparations toward indication-specific formulations. Combined with virus inactivation and purification technologies adapted from plasma protein manufacturing, these advances position platelet-derived biotherapies as a rational and versatile path toward future acellular therapeutics for brain disorders.",
"41907197": "ID: 41907197\nTitle: Hereditary transthyretin amyloidosis mimicking ALS: First genetically proven case report from Saudi Arabia.\nAbstract: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder that may mimic motor neuron disease (MND), leading to misdiagnosis and delayed access to disease-modifying therapies. We report the first genetically confirmed case of ATTRv mimicking amyotrophic lateral sclerosis (ALS) in Saudi Arabia. A 47-year-old male presented with progressive right-sided limb weakness (proximal > distal) and dysarthria over 18\u00a0months. Neurological examination revealed fasciculations, distal atrophy, and brisk reflexes with normal muscle tone and no spasticity. Electrophysiological studies demonstrated a length-dependent sensorimotor axonal neuropathy with widespread denervation changes involving bulbar, cervical, and lumbosacral regions. Brain and spine MRI, along with whole-body CT, excluded structural or paraneoplastic causes. Genetic testing identified a pathogenic heterozygous variant in the TTR gene: NM_000371.4:c.424G\u00a0>\u00a0A (p.Val142Ile). Transthoracic echocardiography revealed mild concentric left ventricular hypertrophy. There was no clinical evidence of autonomic, renal, or ocular involvement. This case underscores the importance of considering ATTRv in patients presenting with atypical MND, particularly when clinically significant sensory symptoms, absent upper motor neuron signs, or unexplained cardiac abnormalities are present. Early diagnosis enables access to targeted therapies such as TTR stabilizers and gene-silencing agents, which can alter disease trajectory.",
"41919473": "ID: 41919473\nTitle: Long non-coding RNAs in neurodegenerative diseases - Molecular mechanisms, liquid biopsy biomarkers, and therapeutic targets: A review.\nAbstract: Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are age-related disorders characterized by progressive neuronal loss, cognitive decline, and limited options for disease-modifying treatments. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in neurodevelopment, neuronal homeostasis, and disease progression; however, their involvement in shared pathogenic pathways and clinical applications remains inadequately defined. This review consolidates recent experimental, transcriptomic, bioinformatic, and emerging clinical findings regarding the role of lncRNAs in NDDs. We examine how lncRNAs modulate common disease mechanisms, including protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, ferroptosis, synaptic failure, and aging-related neurodegenerative processes. These regulatory functions occur through various mechanisms, including epigenetic modifications, transcriptional regulation, post-transcriptional processes, and RNA-protein interactions, as well as novel mechanisms such as liquid-liquid phase separation (LLPS), peptide coding, and exosome-mediated intercellular communication.\u00a0Current evidence supports the potential of lncRNAs as minimally invasive liquid biopsy biomarkers, detectable in blood, cerebrospinal fluid (CSF), and extracellular vesicles. Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms. Overall, lncRNAs have emerged as central molecular regulators and promising candidates for translation in NDDs. Nonetheless, challenges related to specificity, validation, delivery across the blood-brain barrier, and clinical standardization must be addressed before their routine application in precision neurology.",
"41943905": "ID: 41943905\nTitle: Letter to the Editor: Comment on Upadhyaya et al.'s \"Intravitreal Clindamycin as an Adjuvant Therapy in Congenital Toxoplasma Retinochoroiditis in a Neonate - A Case Report\".\nAbstract: The novel work by Upadhyaya et al. suggests a potential use of intravitreal clindamycin for treating congenital toxoplasma retinochoroiditis. We share our clinical experience of encountering a sudden spike in intraocular pressure (IOP) after administering intravitreal clindamycin (5\u2009mg/0.5\u2009mL) in a neonate. Intravitreal injections are known to cause an increase in IOP immediately, which reduces in a few minutes. However, a smaller vitreous volume in neonates can cause an exponential increase in IOP immediately post-injection, posing a risk of optic nerve damage and compromise in retinal perfusion. We suggest modifying the intravitreal preparation of clindamycin to 0.5\u2009mg/0.025\u2009mL when used in neonates to reduce this risk while maintaining therapeutic efficacy.",
"41976821": "ID: 41976821\nTitle: Speculum-Induced Intraocular Pressure Elevation During Cataract Surgery and Its Association with Axial Length: A Retrospective Clinical Study.\nAbstract: Background/Objectives: This study aimed to characterize eyelid speculum-induced intraocular pressure (IOP) elevation during cataract surgery and identify ocular biometric factors that stratify susceptibility to this pressure response. This study was conducted at Zengyo Suzuki Eye Clinic, Kanagawa, Japan. Methods: In this retrospective observational study, we analyzed 100 eyes that underwent routine cataract surgery. IOP was measured immediately before and within 10 s of speculum opening in the seated position using a rebound tonometer. The eyelid speculum was opened to a maximal opening position, and the opening width was recorded. Biometric parameters included axial length (AL), central corneal thickness, white-to-white distance, anterior chamber depth, and temporal angle-opening distance. Associations between IOP elevation and biometric factors were analyzed. IOP elevation rate was quantified as the percentage increase from baseline. The discriminatory performance of axial length was evaluated using receiver operating characteristic (ROC) analysis. Results: Overall, 100 patients (100 eyes) were included in the analysis. Mean IOP increased significantly from 15.75 \u00b1 2.77 mmHg before speculum placement to 21.42 \u00b1 5.54 mmHg after placement. The mean IOP elevation rate was 36.0 \u00b1 27.4%. Shorter AL was consistently associated with a greater proportional IOP elevation. ROC analysis demonstrated consistent stratification of IOP elevation susceptibility by AL (area under the curve [AUC] = 0.645), with eyes shorter than 23.84 mm showing greater pressure elevation (sensitivity, 73.1%; specificity, 56.0%). Eyes in the upper quartile of the IOP elevation rate exhibited relatively greater pressure elevation. Conclusions: Eyelid speculum placement imposes a clinically meaningful IOP load during cataract surgery, with shorter ALs making eyes more biomechanically susceptible to IOP elevation.",
"42034125": "ID: 42034125\nTitle: Lead (Pb) exposure results in cell type specific changes in the mouse retina and optic nerve.\nAbstract: Chronic exposure to lead (Pb) is known to cause deficits in neuronal function across the nervous system, including the visual nervous system. Visual deficits have been observed in both humans and rodent models following Pb exposure. However, how Pb exposure causes visual deficits is poorly understood. In this study, we evaluated the effects of Pb toxicity on the retina and optic nerve of the mouse visual nervous system. We used C57BL/6 adult mice of both sexes and divided them into one of three different exposure groups. Adult mice received daily oral gavage of 108\u202fmg/kg Na-acetate (control), 54\u202fmg/kg Pb-acetate (low dose), or 108\u202fmg/kg Pb-acetate (high dose) for 4 weeks. At the end of Pb exposure, whole blood, retina, and optic nerve samples were collected for Pb quantification by atomic absorption spectroscopy and tissue immunohistochemical analyses. Cell type specific markers were used to quantify changes in cell density of retinal ganglion cells (RGCs), oligodendrocytes (OLs), oligodendrocyte precursor cells (OPCs), and myelin structure. Following Pb exposure, we observed a significant reduction in the cell density of RGCs in the retina. However, we found no significant changes in branch thickness or coverage of retinal vasculature following Pb exposure. In the optic nerve after Pb exposure, we found a significant reduction in the cell density of OLs and OPCs. Finally, using immunolabeling for Caspr and Nav1.6, we observed significant structural changes in nodes of Ranvier, suggesting a disruption in myelin structure. Our findings suggested that Pb toxicity may impair survival and maturation process of OLs, changes in myelin structures, and potential demyelination of the optic nerve. These results provide the foundation for future investigations into the molecular mechanisms of Pb-dependent changes in myelination and visual nervous system function.",
"42070160": "ID: 42070160\nTitle: miRNAs in Amyotrophic Lateral Sclerosis: Tiny Molecules, Tremendous Impact.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by progressive motor neuron degeneration, with diverse clinical manifestations and complex genetic and environmental triggers. The variability in disease progression underscores the necessity for tailored diagnostic and therapeutic approaches. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers and therapeutic targets in ALS. Dysregulation of specific miRNAs has been linked to mechanisms of ALS, including neuromuscular dysfunction, neuroinflammation, and neuronal survival/apoptosis. The potential of miRNA-based therapies, such as mimics and inhibitors, offers a more integrated approach by modulating entire disease networks, rather than targeting isolated pathways. However, challenges persist, particularly in delivering these therapies efficiently across the blood-brain barrier and minimizing off-target effects. Current delivery strategies involving nanoparticles, viral vectors, and exosome-based approaches require optimization for clinical use. This review synthesizes the latest research on miRNA-mediated mechanisms in ALS, evaluating their diagnostic, prognostic, and therapeutic potential, while highlighting the current limitations in clinical validation. It underscores the importance of standardized methodologies, multi-omics integration, and rigorous validation to facilitate the clinical translation of miRNA-based strategies. Standardized protocols and multicenter validation in large cohorts are essential to confirm the diagnostic accuracy of miRNAs, paving the way for their clinical application in ALS precision medicine.",
"42097486": "ID: 42097486\nTitle: Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.\nAbstract: Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.",
"42121359": "ID: 42121359\nTitle: Development of an Optical Defocus-Induced Myopia Model for Guinea Pigs Using Rigid Gas Permeable Contact Lenses.\nAbstract: Guinea pigs are a widely used mammalian model for studies of myopia and early ocular growth regulation more generally. The study reported here covers the development of rigid gas permeable (RGP) contact lenses (CLs) for guinea pigs, as an alternative to spectacle lenses for imposing optical defocus, recognized as an important modulator of eye elongation in young animals. New Zealand pigmented guinea pigs ( Cavia porcellus ) were used in this study, with the RGP lens design based on developmental corneal shape profiles derived from anterior segment optical coherence tomography data collected across a range of ages, as typically encountered in such studies. The validity of this CL-based approach was examined in a follow-up study, in which the ocular effects of -10, 0, and +5 diopters [D] RGP lenses, applied as continuous monocular optical defocus treatments, were tracked over 2 weeks, with the fellow untreated eyes of experimental animals serving as contralateral controls. Pretreatment baseline spherical equivalent refractive errors (RE) and axial length (AL) of both eyes were measured, along with follow-up weekly measurements over the wearing period. There were no differences in any of the ocular parameters between the three groups at baseline, while after two weeks of lens wear, there were significant differences between the -10 D group compared with 0 D and +5 D groups in both RE ( P <0.001) and AL ( P <0.05). Importantly, myopia was observed in all of the guinea pigs fitted with -10 D lenses, and overall, eyes fitted with -10 D lenses showed increased ALs and relative myopia compared with their fellows, while those fitted with +5 D lenses showed reduced ALs and relative hyperopia; the plano lens group fell in between (treated-fellow eyes: -10, 0, and +5 D lenses: -8.25, -1.0, and +0.5 D, and +0.16, +0.08, and -0.02 mm, respectively). Also importantly, no significant CL-related adverse ocular effects were observed. This study provides proof of principle that defocusing RGP CLs are a feasible alternative to spectacle lenses for studies of eye growth regulation in young guinea pigs and experimental myopia specifically, with potential application in investigations into novel approaches for controlling myopia progression and underlying mechanisms.",
"42156174": "ID: 42156174\nTitle: COMMD1 Induces Copper Deficiency of SOD1 by Inhibiting the Palmitoylation of CCS in ALS.\nAbstract: Mutations in superoxide dismutase 1 (SOD1) compromise its metal-binding capacity, resulting in protein misfolding and aggregation, which ultimately induces cellular apoptosis in amyotrophic lateral sclerosis (ALS). Copper metabolism domain containing 1 (COMMD1), a gene implicated in copper homeostasis, has not been thoroughly characterized in the context of ALS pathogenesis. In this study, we identified elevated COMMD1 expression in ALS, potentially contributing to diminished copper incorporation into SOD1. Knockdown of COMMD1 enhanced palmitoylation of the copper chaperone for SOD1 (CCS), facilitating its membrane translocation and promoting copper loading into SOD1, thereby conferring neuroprotection in ALS. Mechanistically, we established that COMMD1 knockdown augments CCS palmitoylation via activation of the hypoxia-inducible factor 1 subunit alpha (HIF-1\u03b1)/fatty acid synthase (FASN) signaling axis. In vivo investigations utilizing male hSOD1G93A transgenic mice demonstrated that COMMD1 deficiency markedly ameliorated the deterioration of motor function and prolonged survival duration. These findings collectively suggest that COMMD1 represents a potential therapeutic target for ALS intervention.",
"42178909": "ID: 42178909\nTitle: Membrane ATG8ylation in secretory autophagy.\nAbstract: Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: A\u03b2, amyloid-\u03b2; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.",
"42196458": "ID: 42196458\nTitle: The Molecular Basis of Partial Reversal or Significant Slowing of ALS, Parkinson's Disease, and Lewy Body Dementia by Mesenchymal Exosomes/Secretome.\nAbstract: Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson's disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up.",
"42231162": "ID: 42231162\nTitle: The roles of cytoplasmic dynein complex in various ocular disorders.\nAbstract: The cytoplasmic dynein complex mediates retrograde transport of various intracellular components and plays a critical role in mitosis, nuclear migration, organelle positioning, vesicle trafficking, misfolded protein clearance, and intercellular signaling. Mutations in human cytoplasmic dynein subunits and regulators have been directly linked to various neurological diseases and are increasingly recognized as contributors to ocular degenerative diseases. However, the precise mechanisms underlying ocular morphogenesis and degeneration remain poorly understood. Various animal models, including Drosophila, mouse, and zebrafish, have been established to investigate the pathogenesis of cytoplasmic dynein complex-related ocular disorders. Findings from these models indicate that dynein complex-related ocular pathologies often involve endoplasmic reticulum stress, impaired Notch signaling, and disrupted Sonic Hedgehog pathways. Systematically integrating gene functional data and molecular mechanism clues derived from different models can help refine the \"gene-phenotype-mechanism\" correlation network and may ultimately advance precision diagnosis and targeted therapy. Emerging evidence has highlighted the cytoplasmic dynein complex as a key factor in ocular development and disease. Integrating findings across model systems may enable more precise diagnosis and the development of targeted interventions for dynein-related ocular disorders.",
"42304076": "ID: 42304076\nTitle: Multi-omic analysis of deep learning-derived phenotypes links ophthalmic imaging to cardiovascular and neurological traits.\nAbstract: The eye is a recognized source of biomarkers for cardiovascular and neurodegenerative disease risk. Here we characterize the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integrating physiological, radiomic, metabolomic and genomic information. We trained retinal adversarial autoencoders to represent optical coherence tomography images and color fundus photographs as 256-dimensional embeddings. Retinal adversarial autoencoder-derived embeddings were associated with a range of cardiovascular and neurodegenerative diseases, including ischemic heart disease, cerebrovascular disease, Parkinson's disease and dementia. Examining associations across diverse omics datasets, we provide evidence linking ophthalmic imaging features to neurological and cardiovascular anatomy and function, lipid metabolism and gene sets associated with neurodegenerative pathology. Collectively, our findings show that ophthalmic features reflect complex, multisystem biological processes and reinforce the role of the eye as a composite indicator of systemic health.",
"42304926": "ID: 42304926\nTitle: Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.\nAbstract: Age-related macular degeneration (AMD) is caused by the degeneration of photoreceptors and retinal pigment epithelium (RPE) along with drusen deposition and is the leading cause of vision loss in older adults. Both these structures within the central nervous system (CNS) utilize common neuro-inflammatory mechanisms because the retina is an outgrowth of the brain. Like the brain, the eye has its own physical characteristics and surface molecules as well as a tendency towards specific immune reactions. Numerous distinct neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Frontotemporal dementia (FTD) that impact the brain present as eye symptoms, and the conventional diagnosis of these neurodegenerative disorders (NDs) is often preceded by ocular symptoms. Furthermore, several eye-specific disorders have characteristics in common with other CNS disorders. NDs and AMD share common key features, such as tau and amyloid-\u03b2 deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and m\u00fcller glia. Common pathological mechanisms include complement activation, amyloid aggregation, neuroinflammation, vascular impairment, and cell death, providing a basis for a convergent neuroimmune axis between retinal and cerebral degeneration. Comparing these age-related diseases will facilitate the identification of shared risk factors, convergent molecular pathways, and potential cross-applicable therapeutic strategies, such as anti-inflammatory, anti-complementary, anti-apoptotic, and anti-VEGF-based approaches. This knowledge may enhance understanding of neurodegenerative diseases, help identify early biomarker development for diagnosis, and enable the design of targeted therapeutic strategies.",
"42321919": "ID: 42321919\nTitle: SMN deficiency contributes to osteoporosis in spinal muscular atrophy by impairing Snap23 meditated muscle-derived extracellular vesicle secretion.\nAbstract: Spinal muscular atrophy (SMA), caused by mutations in survival motor neuron 1 (SMN1), presents with severe muscle atrophy and prevalent osteoporosis. Transcriptomic profiling of patient muscle biopsies revealed enrichment of extracellular vesicle genes, yet the contribution of SMA-EVs to SMA-associated bone loss and their link to SMN deficiency remain undefined. Clinical CT/MRI images of SMA and control subjects were acquired to quantify osteoporosis and muscle atrophy. SMA model mice (Smn1hSMN2/hSMN2ROSA26hSMN2/+) were phenotyped at 6 weeks by micro-CT and histology. EVs were isolated from muscles, validated (western blot, transmission electron microscope, nano-flow cytometry, BCA protein assay), and compared between genotypes. DiL-labelled EV biodistribution was tracked in vivo; uptake by BMSCs/BMMs was confirmed by confocal microscopy. Cytotoxicity was assessed by live/dead staining. Dose-response experiments evaluated the osteogenic and anti-osteoclastic activity of SMA-EVs. Comparison of the effects of SMA-EVs and CON-EVs were performed with adequate doses in vitro and in vivo, followed by EV replenishment in SMA mice. Osteogenic and osteoclastogenic gene expression was quantified by qPCR; ALP activity by ELISA. Bone and cell parameters were assessed by HE staining, TRAP staining, COL-1 immunofluorescence staining, and micro-CT. RNA-seq data were validated by Western blot. Lentiviral shRNA and over-expression plasmids were used to generate muscle cells with stable SNAP23 knock-down or up-regulation, and AAV-mediated muscle-specific Snap23 over-expression was employed in mice to define the role of muscular SNAP23 in EV secretion and its impact on bone mass. Mice carrying extra SMN2 transgenic copies were analyzed to delineate the SMN-SNAP23 relationship. SMA patients and mice exhibited a significantly diminished capacity of skeletal muscle to secrete EVs, which were readily internalized by BMSCs and BMMs, dose-dependently promote osteogenic differentiation and suppress osteoclast formation. Adequate-dose SMA-EVs matched CON-EVs efficacy, and SMA-EVs supplementation effectively rescued the osteoporotic phenotype in SMA. Transcriptomics indicated impaired SNARE complex-mediated vesicle secretion pathway. We further demonstrated that deficiency of SMN protein drives downregulation of its downstream key SNARE component, SNAP23, thereby impairing the efficiency of SMA-EV secretion. Our work elucidates a novel disease-specific mechanism for SMA osteoporosis-dysfunction of the SMN-SNAP23-EVs axis-and highlights the therapeutic potential of replenishing SMA-EVs or targeting this axis, offering a promising strategy to improve skeletal health in SMA.",
"42331015": "ID: 42331015\nTitle: Malnutrition as a Risk Factor for Cerebral and Glaucomatous Neurodegeneration - Mechanisms and Therapeutic Strategies.\nAbstract: BACKGROUND: Neurodegenerative diseases are an increasing challenge for healthcare systems in the context of demographic change. They affect the central nervous system, including the brain-manifesting, for example, as dementia-as well as the retina, as seen in glaucoma or age-related macular degeneration. Malnutrition-defined as quantitative or qualitative under- or overnutrition-affects key mechanisms that contribute to neuronal and retinal neurodegeneration. OBJECTIVE: The aim of this study is to systematically present the pathophysiological mechanisms of malnutrition-related neurodegeneration, to evaluate the current evidence on dietary patterns and cognitive health, and to derive practical clinical strategies for nutritional optimization. METHODS: Narrative literature review based on peer-reviewed publications from the fields of nutritional medicine, geriatrics, neurology, ophthalmology, and public health. RESULTS: Malnutrition promotes oxidative stress, mitochondrial dysfunction, chronic neuroinflammation, and vascular dysregulation, and it influences neurotransmitter synthesis. These mechanisms are relevant to both cerebral and ocular neurodegenerative processes. The Mediterranean diet and the MIND diet are associated with a significantly reduced risk of cognitive impairment; for ocular diseases, interventional studies in age-related macular degeneration in particular demonstrate protective effects of antioxidant supplementation, whereas evidence for glaucoma is currently based predominantly on observational data. Screening approaches and micronutrient diagnostics enable early identification of at-risk individuals. Building on this, individualised dietary interventions and targeted supplementation of selected nutrients could be potentially preventive and stabilising therapeutic strategies. CONCLUSION: Malnutrition is a key modifiable risk factor for neurodegenerative diseases of the brain and retina. More intense integration of nutritional diagnostics and therapy into neurological, geriatric, and ophthalmological care structures appears warranted. Neurodegenerative Erkrankungen stellen angesichts des demografischen Wandels eine zunehmende Herausforderung f\u00fcr das Gesundheitswesen dar. Sie betreffen das zentrale Nervensystem, einschlie\u00dflich des Gehirns, etwa in Form von Demenz, sowie die Retina, wie beim Glaukom oder bei der altersabh\u00e4ngigen Makuladegeneration. Fehlern\u00e4hrung \u2013 verstanden als quantitative oder qualitative Unter- bzw. \u00dcberversorgung \u2013 beeinflusst zentrale Mechanismen, die zur neuronalen und retinalen Neurodegeneration beitragen. Ziel dieser Arbeit ist es, die pathophysiologischen Mechanismen fehlern\u00e4hrungsbedingter Neurodegeneration systematisch darzustellen, die aktuelle Evidenzlage zu Ern\u00e4hrungsmustern und kognitiver Gesundheit zu bewerten sowie praxisnahe klinische Strategien zur Ern\u00e4hrungsoptimierung abzuleiten. Narrative Literatur\u00fcbersicht basierend auf Publikationen mit Peer-Review-Verfahren aus den Bereichen Ern\u00e4hrungsmedizin, Geriatrie, Neurologie, Ophthalmologie und Public Health. Fehlern\u00e4hrung f\u00f6rdert oxidativen Stress, mitochondriale Dysfunktion, chronische Neuroinflammation sowie vaskul\u00e4re Dysregulation und beeinflusst die Neurotransmittersynthese. Diese Mechanismen sind sowohl f\u00fcr zerebrale als auch f\u00fcr okul\u00e4re Neurodegenerationsprozesse relevant. Mediterrane Ern\u00e4hrung und MIND-Di\u00e4t sind mit einem signifikant reduzierten Risiko kognitiver Beeintr\u00e4chtigung assoziiert; f\u00fcr okul\u00e4re Erkrankungen zeigen insbesondere Interventionsstudien bei AMD protektive Effekte antioxidativer Supplementierung, w\u00e4hrend f\u00fcr das Glaukom bislang vorwiegend beobachtende Daten vorliegen. Screening-Ans\u00e4tze und Mikron\u00e4hrstoffdiagnostik erm\u00f6glichen die fr\u00fchzeitige Identifikation von Risikopersonen. Darauf aufbauend stellen individualisierte di\u00e4tetische Ma\u00dfnahmen sowie die gezielte Supplementierung ausgew\u00e4hlter N\u00e4hrstoffe potenziell pr\u00e4ventive und stabilisierende therapeutische Strategien dar. Fehlern\u00e4hrung ist ein zentraler, modifizierbarer Risikofaktor neurodegenerativer Erkrankungen des Gehirns und der Retina. Eine st\u00e4rkere Integration ern\u00e4hrungsmedizinischer Diagnostik und Therapie in neurologischen, geriatrischen und ophthalmologischen Versorgungsstrukturen erscheint sinnvoll.",
"42331016": "ID: 42331016\nTitle: Imbalanced Trace Elements as Risk Factors in the Pathogenesis of Glaucoma.\nAbstract: Glaucoma, a neurodegenerative disease, is characterised by ocular pathogenic patterns, yet also by cerebral pathologies, particularly within the visual pathway. Oxidative stress is involved in glaucoma pathogenesis, similar to other neurodegenerative diseases, such as Alzheimer's disease. Trace elements can intervene within these molecular processes (e.\u200ag., via enzymes) and in the event of imbalances, also cause pathological changes. This review aims to provide an overview of the common features of glaucoma and other neurodegenerative diseases, focusing on the influence of imbalanced trace elements such as zinc, copper, iron and selenium, and oxidative stress. Das Glaukom weist als neurodegenerative Erkrankung neben den okul\u00e4ren Ver\u00e4nderungen, auch zerebrale Pathologien, vor allem innerhalb der Sehbahn auf. Gemeinsam mit anderen neurodegenerativen Krankheiten, wie z.\u200aB. dem Morbus Alzheimer, findet sich bei Glaukom eine Mitbeteiligung des oxidativen Stresses an der Pathogenese der Erkrankung. Spurenelemente verm\u00f6gen, via spezifische Enzyme, in diese molekularen Abl\u00e4ufe einzugreifen und im Falle einer Dysbalance, diese auch pathologisch zu ver\u00e4ndern. Der vorliegende \u00dcbersichtsartikel m\u00f6chte einen \u00dcberblick \u00fcber die gemeinsamen Features von Glaukom mit weiteren neurodegenerativen Erkrankungen geben \u2013 mit Fokus auf den Einfluss von dysbalancierten Spurenelementen, wie Zink, Kupfer, Eisen und Selen und oxidativem Stress.",
"42332177": "ID: 42332177\nTitle: Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.\nAbstract: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.",
"42334608": "ID: 42334608\nTitle: [Calculating IOL\u00a0power - principles, development and current challenges].\nAbstract: The formulae for calculating intraocular lens (IOL) power have undergone considerable development. In recent years in particular, novel approaches based on artificial intelligence (AI) have been incorporated into the calculation models. The aim is to discuss both classical and new principles of IOL calculation, to present the current classification, to explain new approaches and to compare the performance of the formulae based on current reviews and meta-analyses. This article is a\u00a0narrative review without any claim to completeness. The literature selection was based on relevant publications identified through medical databases and specialist journals. Initial publications on the formulae and articles on classification systems were identified and analyzed, followed by an evaluation of current reviews and meta-analyses to compare the performance capabilities. The spectrum of IOL formulae ranges from historical refraction-based and regression-based approaches, classical vergence and ray tracing to modern AI-based methods. Many of the contemporary formulae used integrate multiple methodologies. In recent years there has been a\u00a0clear trend towards reducing prediction errors with the advent of newer formulae, particularly in short eyes. Modern IOL formulae are preferable to traditional ones and outdated guidelines regarding formula selection should be updated. Many modern formulae are universally applicable and yield similarly good results. Further developments will reduce the number of outliers but will likely never eliminate them entirely. HINTERGRUND: Die Berechnung der Intraokularlinsenst\u00e4rke hat sich zunehmend weiterentwickelt. Insbesondere in den letzten Jahren haben KI-basierte Ans\u00e4tze Einzug in die Berechnungsmodelle gefunden. Ziel ist es, klassische und neue Prinzipien der IOL-Berechnung zu diskutieren, die aktuelle Klassifikation darzustellen, neue Ans\u00e4tze zu erl\u00e4utern und die Leistungsf\u00e4higkeit der Formeln anhand aktueller Reviews und Metaanalysen zu vergleichen. Es handelt sich um einen narrativen Review ohne Anspruch auf Vollst\u00e4ndigkeit. Die Literaturauswahl erfolgte auf Basis relevanter Publikationen aus medizinischen Datenbanken und Fachzeitschriften. Erstpublikationen zu den Formeln sowie Arbeiten zur Klassifikation wurden identifiziert und analysiert. Anschlie\u00dfend erfolgte eine Auswertung aktueller Reviews und Metaanalysen zum Vergleich der Leistungsf\u00e4higkeit. Das Spektrum der Intraokularlinsenformeln reicht von historischen refraktions- und regressionsbasierten Ans\u00e4tzen \u00fcber klassische Vergenz- und Raytracing- bis hin zu modernen KI-basierten Formeln. Viele der aktuell verwendeten Formeln integrieren mehrere Ans\u00e4tze. In den letzten Jahren zeigt sich ein deutlicher Trend zur Verringerung des Vorhersagefehlers mit dem Aufkommen neuerer Formeln, insbesondere bei kurzen Augen. Moderne Formeln sind den klassischen vorzuziehen, und veraltete Leitlinien zur Formelwahl sollten aktualisiert werden. Viele der modernen Formeln sind universell einsetzbar und zeigen \u00e4hnlich gute Ergebnisse. Weiterentwicklungen werden die Anzahl von Ausrei\u00dfern reduzieren, aber vermutlich nie g\u00e4nzlich eliminieren.",
"42351263": "ID: 42351263\nTitle: Dynamic integration of skeletal muscle signals via extracellular vesicles in motor neuron diseases.\nAbstract: Extracellular vesicles (EVs) are heterogenous lipid bilayer-enclosed particles secreted by virtually all cell types. They encapsulate a diverse array of bioactive molecules, including proteins, lipids, nucleic acids, and metabolites, which can be transferred to recipient cells, thereby modulating their function and phenotype. In recent years, skeletal muscle-derived EVs (SkM-EVs) have emerged as key players in the bidirectional communication between skeletal muscle and motor neurons, contributing to the establishment and maintenance of neuromuscular homeostasis. Disruptions in this intercellular signalling have been implicated in the pathophysiology of motor neuron diseases (MNDs) such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). In these contexts, SkM-EVs may contribute to disease progression by delivering pathogenic cargo, including misfolded proteins and aberrant RNAs, to motor neurons. A comprehensive understanding of SkM-EV biology, particularly their roles in neuromuscular communication, could offer critical insights into disease mechanisms and identify novel opportunities for biomarker discovery and therapeutic intervention. This review synthesizes current knowledge on the functional roles of SkM-EVs in motor neuron health and disease and evaluates their potential as diagnostic tools and therapeutic vectors in the context of MNDs.",
"42352907": "ID: 42352907\nTitle: The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.\nAbstract: Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in the brain, with glial cell-derived EVs increasingly recognized for their roles in maintaining brain homeostasis and contributing to the progression of neurodegenerative diseases. By transferring a diverse cargo of bioactive molecules, including proteins, RNAs, and organelles, EVs influence recipient cell behavior and overall brain function. In neurodegenerative conditions, glial EVs can either propagate pathogenic signals or deliver neuroprotective and regenerative cues, depending on their cellular origin and molecular composition. This context-dependent heterogeneity highlights the need for physiologically relevant human models to investigate EVs biology. Human induced pluripotent stem cell (iPSC)-derived glial models provide a disease-relevant platform, as they recapitulate key pathological features of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). When further integrated with brain organoid platforms, these iPSC-based systems enable the generation of three-dimensional environments that closely resemble in vivo EVs dynamics. Importantly, glial EVs can modulate cellular pathways involved in neuronal survival and function. Indeed, their potential to interact with and, under specific experimental conditions, traverse the blood-brain barrier (BBB) has contributed to growing interest in their application for biomarker discovery and therapeutic development. Engineered and patient-specific EVs derived from iPSCs are emerging as promising tools for targeted, cell type-specific, therapeutic approaches, although their clinical applicability still requires further validation. This review discusses the emerging evidence supporting the dual role of iPSC-derived glial EVs in health and disease, underscores the translational potential of iPSC-based platforms for mechanistic studies, and outlines their promise as precision medicine tools for diagnostics and therapy.",
"42362968": "ID: 42362968\nTitle: Longitudinal cognitive outcomes in two progressive supranuclear palsy clinical trials.\nAbstract: Progressive supranuclear palsy (PSP) causes executive dysfunction, fluency deficits, and behavioral changes. We examined longitudinal changes in PSP cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Using the RBANS and executive function and fluency tests from 486 and 377 participants in the PASSPORT (NCT03068468) and tilavonemab (NCT02985879) clinical trials, we assessed linear mixed models of cognitive subtest score change, controlling for disease duration, age, sex, and treatment group. The greatest declines occurred in subtests assessing visuospatial (figure copy, figure recall), executive function (Color Trails, coding), and fluency (primarily semantic fluency), although controlling for motor and ocular motor disability reduced the magnitude of score decline. Subtests assessing immediate and delayed memory (story recall, story memory, list recall, list recognition) declined slowly or not at all. Cognition in PSP is characterized by declines in executive, visuospatial function, and fluency, with relative preservation of memory.",
"42372734": "ID: 42372734\nTitle: An open-label Phase 2a study of fasudil in amyotrophic lateral sclerosis: safety and exploratory endpoints.\nAbstract: The primary objective was to assess the safety of oral fasudil in amyotrophic lateral sclerosis (ALS) patients. Changes in serum neurofilament light (NfL) levels and the ratio of phosphorylated to total AKT (pAKT/tAKT) were exploratory endpoints. This was a multicenter, open-label study. Two 31-patient cohorts were sequentially enrolled and treated with either 180\u2009mg or 300\u2009mg per day of oral fasudil for 24\u2009weeks. The primary endpoint was safety. Secondary endpoints evaluated changes in the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity, and muscle strength. We also assessed changes in serum NfL and pAKT/tAKT ratios in plasma (neuron-derived) and CSF (total) extracellular vesicles (EVs). Eighty-one percent (25/31) and 71% (22/31) of patients completed 24\u2009weeks of treatment in the 180 and 300\u2009mg cohort, respectively. Fasudil was safe and well tolerated, with predominantly mild drug-related adverse events. Secondary endpoints, though not statistically significant, were directionally consistent with a treatment effect. Exploratory analyses showed a 15.4% reduction in serum NfL at 24\u2009weeks (p\u2009=\u20090.001) in the 180\u2009mg cohort, with no change in the 300\u2009mg cohort (-0.4%, p\u2009=\u20090.990). The NfL reduction was inversely correlated with ALSFRS-R decline (Spearman\u2009=\u2009-0.45, p\u2009=\u20090.028). Ratios of pAKT/tAKT, a pharmacodynamic marker of rho kinase (ROCK) inhibition, were significantly increased at 24\u2009weeks in plasma (neuron-derived) and CSF EVs. Oral fasudil is safe and well-tolerated in ALS patients. The reduction in NfL and demonstration of CNS target engagement, supports studying the 180\u2009mg dose in a double-blind placebo-controlled study.",
"42391458": "ID: 42391458\nTitle: Elevated urea levels in human frontotemporal dementia and amyotrophic lateral sclerosis post-mortem brain tissue: evidence of a multi-dementia pathogenic mechanism.\nAbstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent two neurodegenerative diseases on opposite sides of a movement disorder continuum. However, like many other neurodegenerative diseases, the molecular pathogenesis of FTD and ALS is not fully understood. Our group has previously reported evidence for a pervasive elevation of brain urea levels in five other dementia-causing diseases. However, brain urea levels have yet to be measured in ALS and FTD. Here, we employed ultra-high-performance liquid chromatography-tandem mass spectrometry to characterize brain urea differences between control (n\u2009=\u200914/12) and ALS/FTD (FTD: n\u2009=\u20098/9; ALS: n\u2009=\u200913/14) cases in post-mortem tissue from two brain regions with different levels of neuropathological burden (high versus low). Elevated urea levels were observed in both the frontal cortex (high neuropathological burden) and primary visual cortex (low neuropathological burden) in cases with FTD. Contrastingly, in cases with ALS, elevated urea was observed in the primary motor cortex (high neuropathological burden), but not the dentate nucleus (low neuropathological burden). These results not only suggest that elevated urea levels are also present in ALS and FTD but imply that elevated brain urea is linked to a multi-dementia pathogenic mechanism. In contrast to ALS, the observation of elevated urea in regions of both high and low neuropathological burden in FTD implies that this phenotype is likely widespread and, therefore, may play a larger role in the pathogenesis of disease. Such a mechanism could offer new directions for developing treatments targeting this underlying pathology.",
"42420060": "ID: 42420060\nTitle: Development of a target product profile for artificial intelligence in diabetic eye screening in England: a modified Delphi consensus study.\nAbstract: Artificial intelligence (AI) health-care technologies offer a means of addressing the growing gap between health-care capacity and demand. However, few technologies have met the complex requirements of health-care systems for adoption. Diabetic eye screening (DES) in England exemplifies the difficulty of understanding these requirements and translating them into real-world implementation decisions. This Review responds to a recognised policy need to develop a target product profile (TPP) for a DES AI system for use in England. The TPP outlines the requirements of the English health-care system for such a device and was developed using a modified Delphi consensus process involving interviews, surveys, and a consensus meeting. Participants included people living with diabetes, health-care professionals, health-care managers and leaders, regulators and policy makers, and developers. Thirty-five product specifications were agreed upon, covering areas such as clinical validity, utility, and environmental sustainability. Our TPP establishes clear criteria for DES AI development and deployment in England, and this TPP development process can serve as a template for initiatives to create TPPs for other AI health technologies and settings.",
"42430469": "ID: 42430469\nTitle: Congenital blindness reduces myelination in human visual cortex.\nAbstract: Sensory experience is critical for cortical maturation, but the cellular consequences of its absence remain poorly understood in humans. Using in vivo sub-millimeter 3 T and 7 T MRI and ultra-high-gradient diffusion MRI, we investigated the effects of congenital blindness on the human early visual cortex. Blind individuals showed reduced R2* and MTsat-markers of iron and myelin-along with increased diffusivity, orientation dispersion, and reduced neurite density in the gray and superficial white matter. Cortical thickness was increased in blind individuals and associated with lower myelin and iron, questioning the long-standing assumption that increased thickness primarily reflects disrupted pruning. Our results provide no direct evidence for disrupted pruning. However, they suggest reduced myelination and oligodendrogenesis as key effects of congenital blindness and highlight the critical role of sensory input in shaping and stabilizing cortical circuits.",
"42436372": "ID: 42436372\nTitle: Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.\nAbstract: Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n\u2009=\u200921) and healthy controls (n\u2009=\u200916), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P\u2009=\u20090.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.",
"42436563": "ID: 42436563\nTitle: Context of use matters: interpreting extracellular vesicle TDP-43 as a biomarker in ALS.\nAbstract: ",
"42458453": "ID: 42458453\nTitle: Extracellular vesicles as a liquid biopsy for amyotrophic lateral sclerosis: a systematic review and meta-analysis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome diagnosed clinically using standardized criteria, with neuropathological confirmation of motor neuron loss and TDP-43 aggregates in postmortem brain tissue. Extracellular vesicles (EVs) have emerged as potential minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. Following PRISMA guidelines, we searched PubMed and EMBASE from inception to May 21st, 2026. Forty-one studies met inclusion criteria. Where published summary statistics were available, these were used directly; where they were not, data were reconstructed from figures or obtained from authors and re-analyzed to derive standardized effect sizes and exploratory diagnostic accuracy estimates. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. EV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in EVs from ALS vs. controls (SMD\u2009=\u20091.30) with high heterogeneity (I\u2009=\u200997.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC\u2009=\u20090.839). No publication bias was found across both meta-analyses. EV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. This work highlights the need for standardized protocols, transparent data sharing, and independent validation.",
"42487414": "ID: 42487414\nTitle: Invited Commentary on: Gaebe et al's \"Effectiveness and Safety of Extracellular Vesicle-Based Therapies for Non-Surgical Facial Rejuvenation: A Systematic Review\": Extracellular Vesicles in Aesthetic Medicine: Promise Requires Proof.\nAbstract: ",
"42505348": "ID: 42505348\nTitle: Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.\nAbstract: Copper is an essential trace element required for numerous enzymatic processes in the brain, including mitochondrial metabolism, antioxidant defense, and gene expression regulation. Recent studies have further implicated copper in a newly defined form of regulated cell death termed cuproptosis, providing a mechanistic framework for copper-dependent cytotoxicity. Increasing evidence indicates that copper dyshomeostasis is a common feature of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), where it is associated with protein misfolding, redox imbalance, and neuronal vulnerability. Nevertheless, the mechanistic link between copper dysregulation and neuronal cell death remains incompletely defined. In this review, we systematically summarize the molecular mechanisms governing copper homeostasis and intracellular copper trafficking, while providing a timely, updated, and in-depth overview of the mechanistic basis and emerging biology of cuproptosis. We further comprehensively evaluate the current evidence linking copper dysregulation and cuproptosis-related pathways to neurodegenerative diseases, with particular emphasis on distinguishing mechanistic causation from pathological correlation. Importantly, we discuss current therapeutic strategies and emerging clinical efforts targeting copper metabolism, while highlighting the major challenges in defining the pathological significance and mechanistic contribution of cuproptosis in neurodegenerative diseases. Collectively, this review provides an updated framework for understanding the pathological significance and translational potential of cuproptosis in neurodegenerative diseases.",
"42508418": "ID: 42508418\nTitle: [Delayed Diagnosis of Primary Sj\u00f6gren's Syndrome presenting as Atypical Migraine - A Case Report].\nAbstract: Primary Sj\u00f6gren's Syndrome usually presents with Sicca symptoms but may initially manifest with non-specific neurological complaints such as migraine, paresthesia or dizziness. A 34-year-old woman reported recurrent headaches, dizziness, and a single episode of mild aphasia; she was initially diagnosed with migraine without aura. Despite stage-appropriate therapy, additional symptoms such as dry mouth and eyes as well as arthralgia developed. Cranial imaging was unremarkable. Orbital Doppler sonography revealed widened optic nerve sheaths. Autoimmune serology was positive for ANA, ENA, and Anti-SSA antibodies. Schirmer test, tear film break-up time, and salivary flow confirmed sicca syndrome. After diagnosis, treatment with prednisolone and hydroxychloroquine was initiated, leading to a significant improvement in neurological and extraglandular symptoms. Pilocarpine along with supportive eye and oral care improved the sicca symptoms. Non-specific neurological symptoms may represent early in Primary Sj\u00f6gren's Syndrome, highlighting the importance of early serological testing and interdisciplinary evaluation. Das prim\u00e4re Sj\u00f6gren-Syndrom zeigt meist Sicca-Symptome, kann aber fr\u00fch unspezifische neurologische Beschwerden wie Migr\u00e4ne, Par\u00e4sthesien oder Schwindel verursachen.Eine 34-j\u00e4hrige Patientin klagte \u00fcber rezidivierende Kopfschmerzen, Schwindel und einmalige leichte Aphasie; zun\u00e4chst wurde Migr\u00e4ne ohne Aura diagnostiziert. Trotz stadiengerechter Therapie traten zus\u00e4tzliche Symptome wie Mund- und Augentrockenheit sowie Arthralgien auf.Die kranielle Bildgebung war unauff\u00e4llig. In einer Orbita-Dopplersonografie zeigten sich verbreiterte Optikus-Nervenscheiden. Bei der Autoimmunserologie waren ANA, ENA und Anti-SSA positiv. Schirmer-Test, Tr\u00e4nenfilm-Break-Up-Time und Speichelfluss best\u00e4tigten ein Sicca-Syndrom.Nach der Diagnosestellung wurde eine Therapie mit Prednisolon und Hydroxychloroquin eingeleitet, wodurch sich die neurologischen und extraglandul\u00e4ren Beschwerden deutlich besserten. Pilocarpin und eine begleitende Tr\u00e4nen- und Mundpflege verbesserten die Sicca-Symptome.Unspezifische neurologische Symptome k\u00f6nnen Fr\u00fchmanifestationen eines prim\u00e4ren Sj\u00f6gren-Syndroms sein, weshalb eine fr\u00fche serologische Abkl\u00e4rung und interdisziplin\u00e4re Diagnostik entscheidend sind.",
"42509340": "ID: 42509340\nTitle: [Prepapillary vitreous exudate as the first ocular manifestation of Beh\u00e7et's disease: A case report].\nAbstract: Beh\u00e7et's disease is a systemic inflammatory disorder that frequently presents with ocular involvement in the form of non-granulomatous panuveitis and retinal vasculitis. A prepapillary inflammatory vitreous infiltrate represents a rare but potentially characteristic manifestation. We report the case of a 29-year-old female patient presenting with acute, painless visual loss in the right eye. Clinical examination revealed non-granulomatous anterior uveitis with bilateral vitritis and a prepapillary inflammatory vitreous infiltrate in the right eye. Optical coherence tomography (OCT) demonstrated a typical mushroom-shaped prepapillary infiltrate associated with serous macular detachment. Fluorescein angiography revealed optic disc and peripheral leakage. Infectious causes were excluded. In the context of recurrent oral and genital aphthous ulcers, the patient fulfilled the diagnostic criteria for Beh\u00e7et's disease. Following intravenous high-dose corticosteroid pulse therapy, treatment with adalimumab was initiated. This resulted in significant functional and anatomical improvement, with regression of the prepapillary inflammatory vitreous infiltrate and the serous retinal detachment. A prepapillary inflammatory vitreous infiltrate is a rare but important diagnostic sign of ocular Beh\u00e7et's disease and may be a key finding, particularly in patients presenting with initial ocular involvement. Early diagnosis and prompt initiation of immunosuppressive therapy are essential for visual prognosis. HINTERGRUND: Der Morbus Beh\u00e7et ist eine systemische entz\u00fcndliche Erkrankung, die sich h\u00e4ufig mit okul\u00e4rer Beteiligung in Form einer nichtgranulomat\u00f6sen Panuveitis und retinalen Vaskulitis manifestiert. Ein pr\u00e4papill\u00e4res entz\u00fcndliches Glask\u00f6rperinfiltrat stellt eine seltene, jedoch potenziell charakteristische Manifestation dar. Wir berichten \u00fcber eine 29-j\u00e4hrige Patientin mit akut aufgetretener, schmerzloser Visusminderung am rechten Auge. Klinisch zeigte sich eine nichtgranulomat\u00f6se anteriore Uveitis mit beidseitiger Vitritis sowie eine pr\u00e4papill\u00e4re Glask\u00f6rperverdichtung am rechten Auge. Die optische Koh\u00e4renztomographie (OCT) zeigte ein typisches \u201echampignonf\u00f6rmiges\u201c pr\u00e4papill\u00e4res Infiltrat mit begleitender ser\u00f6ser Makulaabhebung. Die Fluoreszenzangiographie ergab eine papill\u00e4re und periphere Leckage. Infekti\u00f6se Ursachen wurden ausgeschlossen. In Zusammenschau mit rezidivierenden oralen und genitalen Aphthen erf\u00fcllte die Patientin die Kriterien f\u00fcr Morbus Beh\u00e7et. Nach einer intraven\u00f6sen hochdosierten Kortikosteroidsto\u00dftherapie wurde eine Behandlung mit Adalimumab eingeleitet. Darunter kam es zu einer deutlichen funktionellen und morphologischen Besserung mit R\u00fcckbildung des pr\u00e4papill\u00e4ren Infiltrats und der ser\u00f6sen Netzhautabhebung. Das pr\u00e4papill\u00e4re entz\u00fcndliche Glask\u00f6rperinfiltrat ist ein seltenes, aber wichtiges diagnostisches Zeichen einer okul\u00e4ren Manifestation des Morbus Beh\u00e7et und kann insbesondere bei initialer okul\u00e4rer Pr\u00e4sentation wegweisend sein. Eine fr\u00fchzeitige Diagnose und rasche Einleitung einer immunsuppressiven Therapie sind entscheidend f\u00fcr die Visusprognose.",
"42512084": "ID: 42512084\nTitle: Retinal Thickness and Vascular Density Changes in Amyotrophic Lateral Sclerosis Assessed by Optical Coherence Tomography Angiography.\nAbstract: Background: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder involving neurovascular dysfunction. The retina allows in vivo assessment of neurovascular changes. This study evaluated retinal structural and microvascular alterations in ALS using optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A). Methods: This cross-sectional study included 46 participants with ALS and 19 healthy controls. Retinal thickness and vascular density in the superficial and deep retinal capillary plexuses and the choriocapillaris were quantified using OCT and OCT-A. Group comparisons and logistic regression analyses were performed to assess associations with ALS. Subgroup analyses were conducted according to clinical phenotype. Results: In total, 124 eyes were analyzed. ALS was associated with increased average retinal thickness (p = 0.023) and reduced vascular density in the superficial retinal capillary plexus (p = 0.005), deep retinal capillary plexus (p < 0.001), and choriocapillaris (p = 0.004). In logistic regression analyses, retinal thickness was positively associated with ALS status (OR = 1.42, p = 0.023), whereas higher vascular density in the superficial plexus, deep plexus, and choriocapillaris was associated with lower odds of ALS. No significant differences were observed between bulbar- and spinal-onset ALS phenotypes. Conclusions: ALS is associated with structural and microvascular retinal alterations detectable by OCT and OCT-A. These findings support the presence of systemic neurovascular dysfunction and highlight retinal imaging as a promising, non-invasive approach for investigating disease mechanisms and developing potential biomarkers.",
"42512450": "ID: 42512450\nTitle: Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.\nAbstract: Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-\u03b2 and tau aggregates in AD, \u03b1-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.",
"42526365": "ID: 42526365\nTitle: A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS. A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I2 statistic. A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD\u00a0=\u00a0-0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD\u00a0=\u00a0-0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant. This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder. PROSPERO identifier CRD420251076035.",
"42530644": "ID: 42530644\nTitle: [Cogan syndrome as a\u00a0rare cause of deafness].\nAbstract: Cogan syndrome is a\u00a0rare systemic disease characterized by the occurrence of audiovestibular and ocular symptoms. We present the case of a\u00a062-year-old female patient who received a\u00a0cochlear implant after unilateral deafness. Despite successful implantation, the disease progressed with chronic headache, recurrent otitis, fluctuating intracochlear impedances, and slowly progressing hearing loss in the contralateral ear. Through interdisciplinary collaboration, the diagnosis of Cogan syndrome was established, and biological therapy was initiated. Das Cogan-I-Syndrom ist eine seltene Systemerkrankung, die sich durch das Auftreten audiovestibul\u00e4rer und okul\u00e4rer Symptome auszeichnet. Wir pr\u00e4sentieren den Fall einer 62-j\u00e4hrigen Patientin, die nach einseitiger Ertaubung ein Cochleaimplantat erhielt. Trotz regelrechter Implantation kam es zu einem protrahierten Verlauf mit chronischer Zephalgie, wiederkehrender Otitis, schwankenden intracochle\u00e4ren Impedanzen sowie langsam progredientem H\u00f6rverlust der Gegenseite. In interdisziplin\u00e4rer Zusammenarbeit wurde die Diagnose des Cogan-I-Syndroms gestellt und eine Biologikatherapie eingeleitet.",
"42533344": "ID: 42533344\nTitle: Ethical challenges in treatment-goal transitions in invasively ventilated ALS: a case-based topical review.\nAbstract: In advanced amyotrophic lateral sclerosis (ALS), eye movements often represent the last channel for intentional communication. While oculomotor function has traditionally been considered relatively preserved, emerging evidence indicates progressive impairment in long-term survivors on tracheostomy-invasive ventilation (TIV). As a result, eye-based communication may become increasingly unreliable before complete loss, challenging clinical decision-making and advance care planning (ACP). We conducted a case-based topical review integrating clinical observation and literature to examine the trajectory of oculomotor decline, its impact on communication, and implications for treatment decisions. Three patients with ALS receiving TIV in a home-care setting illustrate key clinical and ethical challenges. Across cases and literature, oculomotor decline followed a gradual trajectory from effective eye-tracking communication to a complete locked-in syndrome. We identify a transitional phase of communicative ambiguity, in which residual ocular signals persist but can no longer be reliably attributed to intentional, patient-controlled communication. This phase is characterized by increasing inconsistency of signals and a divergence between observable responses and their interpretive certainty, creating uncertainty in assessing patient preferences. Communicative ambiguity represents a clinically underrecognized but critical threshold in advanced ALS, marking the transition from direct patient autonomy to interpretative and surrogate-based decision-making. Failure to recognize this phase risks misinterpretation of patient intent and may undermine goal-concordant care. Timely and iterative ACP, initiated before communication becomes unreliable, is essential. We further propose four clinical pathways for treatment goal conversations, highlighting their differing implications for timing, symptom burden, and ethical decision-making."
},
"globalTags": {
"alzheimer\u2019s disease": 6,
"huntington disease": 2,
"parkinson disease": 7,
"amyotrophic lateral sclerosis": 122,
"biomarkers": 28,
"molecular mechanism": 1,
"neurodegenerative disease": 5,
"therapeutic targets": 2,
"humans": 159,
"extracellular vesicles": 44,
"liquid biopsy": 4,
"publication bias": 1,
"clinical trials": 2,
"neuron-derived extracellular vesicles": 1,
"neuropathology": 2,
"pharmacodynamic biomarkers": 1,
"surrogate endpoints": 1,
"tdp-43": 8,
"exosomes": 24,
"endogenous retroviruses": 1,
"female": 53,
"male": 63,
"middle aged": 38,
"aged": 31,
"gene products, env": 1,
"als": 26,
"endogenous retrovirus": 1,
"herv-k": 1,
"motor neuron disease": 8,
"nanoparticle tracking analysis": 1,
"neurodegeneration": 14,
"visual cortex": 6,
"myelin sheath": 3,
"blindness": 1,
"adult": 27,
"white matter": 4,
"iron": 9,
"magnetic resonance imaging": 9,
"frontotemporal dementia": 4,
"urea": 1,
"brain": 13,
"autopsy": 2,
"tandem mass spectrometry": 2,
"akt": 1,
"fasudil": 1,
"neurofilament light chain (nfl)": 1,
"rho kinase (rock)": 1,
"induced pluripotent stem cells": 3,
"neurodegenerative diseases": 51,
"neuroglia": 3,
"animals": 71,
"blood-brain barrier": 7,
"cell communication": 5,
"glial cells": 1,
"ipsc": 1,
"motor neuron": 6,
"sma": 1,
"glaucoma": 6,
"trace elements": 3,
"oxidative stress": 5,
"risk factors": 4,
"muscle-bone crosstalk": 1,
"muscle-derived extracellular vesicles": 1,
"osteoporosis": 1,
"snares": 1,
"spinal muscular atrophy": 3,
"lewy body disease": 2,
"mesenchymal stem cells": 6,
"secretome": 4,
"case-control studies": 3,
"administration, intranasal": 2,
"lbd": 1,
"pd": 1,
"exosome": 7,
"atg8ylation": 1,
"extracellular vesicles and particles": 1,
"noncanonical autophagy": 1,
"secretory autophagy": 1,
"unconventional protein secretion": 1,
"micrornas": 12,
"amyotrophic lateral sclerosis (als)": 8,
"mirnas": 1,
"precision medicine": 1,
"acellular biotherapies": 1,
"inflammation": 5,
"omics-guided biologics": 1,
"platelet extracellular vesicles (p-evs)": 1,
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