ID: 42035155
Title: Air pollution and mortality in a University of Michigan amyotrophic lateral sclerosis cohort: a survival analysis.
Abstract: BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, fatal, neurodegenerative disease. With limited treatment options, identifying modifiable risk factors that impact ALS survival is an important goal. Air pollution may be one such risk factor, yet the research on this topic is limited. METHODS: We assessed survival for ALS patients at the University of Michigan Pranger ALS Clinic who were recruited to participate in a prospective cohort study between 2009 and 2022. Participants’ personal characteristics were linked with residential air pollutant levels of fine particulate matter mass (PM2.5), nitrogen dioxide (NO2), and ozone (O3), as well as several particle components, including black carbon (BC), nitrate, sulfate, and sea-salt (as a negative control) over follow-up. To assess the role of air pollution on ALS mortality we used time-dependent Cox proportional hazards models with days from diagnosis as the time axis, adjusted for potential confounders and co-pollutants. RESULTS: Across the 1,276 total years of person-time during follow-up (2.7 ± 2.5 years per participant) there were 329 deaths. In fully adjusted multi-pollutant models, one interquartile range (IQR) (2.1 µg/m3) higher 1-year average PM2.5 was associated with a 66% (HR 1.66 per IQR; 95% CI 1.03–2.68) increase in the hazard of death. The other pollutants were not associated with death in participants with ALS . CONCLUSIONS: This finding suggests a seven month longer median survival for a 2.1 µg/m3 decrease in 1-year average PM2.5, which is significant given that ALS lacks a cure and that existing treatments only extend survival by a few months.

ID: 42113599
Title: Amyotrophic Lateral Sclerosis: A Review.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness due to degeneration of upper motor neurons in the brain and lower motor neurons in the brainstem and spinal cord. It affects approximately 25 000 individuals in the United States. Amyotrophic lateral sclerosis is characterized by progressive painless muscle weakness that typically begins in a focal region of the body, such as limb muscle weakness causing hand weakness or foot drop (65%), cranial muscle weakness causing speech or swallowing problems (20%-25%), or axial muscle weakness causing bent posture (5%-10%), and spreads to other body regions over time. The disease usually manifests with dysfunction indicative of both upper motor neurons (causing muscle stiffness and spasticity) and lower motor neurons (causing weakness, fasciculations, atrophy, and flaccidity). After onset, weakness spreads through the musculature and typically causes death due to respiratory muscle weakness. Among people with ALS, approximately 85% have sporadic ALS, which is not associated with known environmental or genetic factors, and 15% have familial ALS. Amyotrophic lateral sclerosis is diagnosed based on clinical features, which can be supported by results of electromyography. More than 60 genes have been associated with ALS, and most are autosomal dominant. Pathogenic variants in chromosome 9 open reading frame 72 (C9orf72) are found in 40% of all familial ALS cases, and pathogenic variants in superoxide dismutase 1 (SOD1) are found in 20% of patients with familial ALS. Patients with ALS survive a mean of 3 to 5 years after diagnosis, and there are currently no curative therapies. Clinical care primarily focuses on symptom management and quality of life. Three US Food and Drug Administration (FDA)-approved disease-modifying therapies are available in the United States. Riluzole and edaravone are oral medications that slow ALS progression by up to 2 to 4 months, and tofersen is an intrathecally administered gene therapy for patients with SOD1 gene variants. Specialized multidisciplinary teams, comprising neurologists, nurses, therapists, dietitians, and social workers, are associated with improved survival (4-7 months) and quality of life. Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disorder of upper and lower motor neurons. No curative therapies exist. Two oral medications, riluzole and edaravone, are approved by the FDA and modestly decrease disease progression in sporadic ALS. Tofersen, an intrathecally administered gene-based therapy, is also FDA approved and slows disease progression in patients with SOD1 pathogenic gene variants.

ID: 42191932
Title: Motor neuron disease in Africa: a critical appraisal of the literature.
Abstract: Motor neuron disease (MND) refers to a group of neurodegenerative diseases that cause motor neuron degeneration and death. The most common subtype, amyotrophic lateral sclerosis (ALS), is characterized by both upper and lower motor neuron impairment, which can manifest clinically in the bulbar region or asymmetrically in a limb. Typically, the disease progresses over several months, and death from respiratory failure occurs within 2-5 years of onset. As we highlight in this Review, data on MND in Africa are sparse, although common observations in this region - and in other populations with relatively low life expectancy - include apparent earlier disease onset and lower disease incidence compared with the rest of the world. In view of the HIV epidemic in Africa, we critically examine the evidence for an association between ALS and HIV infection. We briefly discuss conditions that might be regarded as ALS mimics and summarize the limited data on MND genetics in this region. Other issues pertinent to people living with MND in Africa include the absence of cognitive and behavioural data and the limited access to multidisciplinary clinics, therapies and palliative care. We share our perspective on how the ALS Africa Network is coordinating a shift in the African MND landscape to improve patient care.

ID: 42195033
Title: From Mutation to Manifestation: Penetrance in Amyotrophic Lateral Sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. While most cases are sporadic, around 10% are familial. Recent genetic studies show that many apparently isolated cases carry pathogenic mutations, highlighting the importance of penetrance, the probability that a causal mutation manifests clinically. This review focuses on mutation penetrance in ALS (C9orf72, SOD1, TARDBP, FUS genes), its variability across genes, age, and environmental or genetic modifiers, and its implications for genetic counseling. Identification of pathogenic mutations informs the monitoring of relatives and, in some cases, gives access to targeted therapies or clinical trials. Counseling of asymptomatic relatives must consider incomplete penetrance, which can lead to delayed or absent disease manifestation. ALS exists on a clinical and genetic continuum including related disorders, such as frontotemporal dementia, further influencing risk interpretation. Advances in panel, whole-exome and whole-genome sequencing refine our understanding of penetrance and enable precise diagnostics, and potential tailored therapies. Understanding penetrance is therefore essential to translate mutation discovery into informed clinical decisions and genetic counseling in ALS.

ID: 42224592
Title: miR-146a is a pleiotropic regulator of motor neuron degeneration.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Here, we have profiled motor neuron microRNAs (miRNAs) during motor neuron degeneration in vivo to gain a better understanding of ALS pathophysiology. We demonstrate that one miRNA, miR-146a, is downregulated in diseased motor neurons despite upregulation in bulk tissue. Genetic deletion of miR-146a significantly extended survival in SOD1G93A mice with heterozygous animals demonstrating the largest benefit. A corresponding reduction in spinal cord gliosis but not motor neuron loss was observed. Finally, we observed that a proportion of miR-146a knockout animals develop spontaneous paralysis, motor neuron loss and chronic neuroinflammation with advanced age. Together these findings demonstrate that a single miRNA influences multiple aspects of motor neuron disease and highlights the complex role for neuroinflammation in ALS pathogenesis.

ID: 42247653
Title: Drivers of Rising Prevalence in Major Motor Neurodegenerative Diseases: Temporal Trends in Sweden and France (2003-2022).
Abstract: The prevalence of Parkinson disease (PD), multiple sclerosis (MS), and motor neuron diseases (MNDs) is rising globally. However, it is unclear to what degree this is related to an increase in incidence or to improved survival after diagnosis. We performed 2 nationwide, population-based, retrospective cohort studies, including all individuals living in Sweden between 2001 and 2016 and living in France between 2009 and 2022, respectively. Pooled mixed-effects regression models, with country as a random effect, were used to determine temporal trends in prevalence, crude and age-standardized and sex-standardized incidence, and age and life expectancy at diagnosis. Annualized prevalence of PD, MS, and MNDs increased significantly between 2003 and 2022 in the pooled model (PD: prevalence ratio [PR] per year = 1.014, p < 0.001; MS: PR = 1.029, p < 0.001; MND: PR = 1.028, p < 0.001). While the crude incidence of both PD and MS remained nearly stable over time (PD: incidence rate ratio [IRR] per year = 0.998, p < 0.001; MS: IRR = 0.992, p < 0.001), the standardized incidence showed a more marked decrease for PD (IRR = 0.986, p < 0.001) while remaining almost unchanged for MS (IRR = 0.995, p < 0.001). For MNDs, both the crude and standardized incidence increased over time (crude IRR = 1.018, p < 0.001; standardized IRR = 1.008, p < 0.001). Life expectancy at diagnosis of PD increased between 2003 and 2013 (+0.95 months per calendar year, p < 0.001) and then decreased between 2013 and 2022 (-1.20 months, p = 0.002), while it increased significantly over the entire study period for MS (+2.35 months, p < 0.001) and MNDs (+0.34 months, p = 0.01). These findings indicate that the rising MS prevalence is largely survival-driven and the rising MND prevalence reflects a true increase in incidence, whereas PD prevalence grows modestly, largely independent of incidence. Depending on the mechanism that drives prevalence, whether increased incidence reflecting changing risk factor exposures, improved survival due to therapeutic advances, or demographic aging of the population, inferences about underlying causes differ substantially between PD, MS, and MNDs, with direct implications for health care planning and etiologic research.

ID: 42265995
Title: Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.
Abstract: Amyotrophic lateral sclerosis (ALS) patients are rarely encountered before age 25 years, often associated with genetic variants. SOD1 gene variants are well-known to account for a subset of adult-onset ALS but have only been described in a handful of early onset patients. Variants affecting residue 125 in SOD1 have been described in adult-onset ALS patients with a rapid progression. Here we report two such patients. The clinical, genetic, and electrodiagnostic findings of two unrelated adolescents with juvenile onset rapidly progressive SOD1 -ALS are described. Patient 1 presented at 16 and patient 2 at 15 years-of-age with lower limb onset of weakness, lower motor neuron examination findings, and rapid progression over months to involve all body regions. Both patients underwent extensive laboratory, electrophysiologic, and radiologic testing ruling out any alternate etiologies. For both patients, whole-exome sequencing revealed the pathogenic variant p.Asp125Gly in the SOD1 gene inherited from asymptomatic fathers. These two patients expand the phenotypic spectrum of SOD1 -ALS, demonstrating a rapidly progressive juvenile lower limb onset phenotype associated with the p.Asp125Gly variant inherited with incomplete penetrance. Recognition and further characterization of juvenile SOD1 -ALS are important in light of the advances in targeted therapies.

ID: 42268433
Title: FUS-associated ALS in Taiwan: genetic spectrum, clinical features, and a founder haplotype of p.H517D.
Abstract: To characterize the genetic spectrum and clinical features of FUS-associated amyotrophic lateral sclerosis (ALS) in a Taiwanese cohort and to investigate whether the recurrent p.H517D variant represents a founder mutation. All coding exons and flanking intronic regions of FUS were analyzed by Sanger sequencing in 650 unrelated Taiwanese patients with ALS. Clinical characteristics of patients carrying FUS variants were evaluated. Haplotype analysis using polymorphic microsatellite markers flanking FUS was performed to assess a potential founder effect of the p.H517D variant. Eight distinct heterozygous pathogenic FUS variants were identified in 11 probands and five affected relatives, including six missense and two frameshift variants. The most frequent variant was p.H517D, detected in four probands. A novel frameshift variant, p.G499Vfs*30, was identified as a de novo mutation in a juvenile-onset ALS patient. Compared with the non FUS-associated ALS cohort, patients with FUS-associated ALS had a significantly younger mean age at onset (40.1 vs 56.6 years) and more frequent bulbar onset (50% vs 19%). Haplotype analysis suggested a common founder for the p.H517D variant. FUS mutations accounted for 1.7% of ALS cases in this Taiwanese cohort. The recurrent p.H517D variant appears to represent a population-specific founder mutation. Patients with FUS variants presented with earlier disease onset and heterogeneous clinical phenotypes, and de novo variants contributed to juvenile-onset disease.

ID: 42298083
Title: The lung-brain axis in neurodegeneration: inflammatory, immune, and vascular mechanisms with therapeutic implications.
Abstract: Neurodegenerative and chronic pulmonary diseases represent major global health challenges and have widely been investigated separately. Emerging evidence indicates the existence of a lung-brain axis, through which pulmonary pathology and environmental exposures can influence neurological health. The current review highlights the mechanistic and clinical evidence linking chronic lung inflammation, air pollution, and immune dysregulation to the onset and progression of Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). A pathway-based framework is presented in which lung inflammation, systemic cytokine release, oxidative stress, blood-brain barrier disruption, immune priming, and protein misfolding mediate lung-to-brain communication. Associations between chronic obstructive pulmonary disease, asthma, particulate matter exposure, and adverse neurological outcomes including cognitive decline, brain atrophy, disease progression, and elevated neurodegenerative risk are emphasized. Specific mechanisms are addressed, including immune-mediated effects in multiple sclerosis, inhalation-driven protein aggregation in Parkinson's disease, and vascular and oxidative injury contributing to dementia and amyotrophic lateral sclerosis. COVID-19 is considered a clinical model of acute lung-brain axis disruption, demonstrating inflammation-driven neurocognitive consequences, and its role in this context was also highlighted. Additionally, potential preventive and therapeutic strategies are discussed, highlighting pulmonary health and environmental exposure reduction as modifiable factors that may help mitigate neurological disease. This integrative review underscores the clinical relevance of the lung-brain axis and calls for interdisciplinary strategies to improve neurological outcomes through pulmonary and environmental interventions.

ID: 42299014
Title: Pathogenic Proteins Driving ALS Pathogenesis: Molecular Mechanisms and Translational Therapeutic Perspectives.
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, with protein aggregation as a central pathological hallmark. Key pathogenic proteins, including TDP-43, SOD1, FUS, and dipeptide repeat proteins (DPRs) from C9orf72 expansions, drive disease progression through diverse but converging mechanisms. TDP-43 proteinopathy, present in nearly all ALS cases, involves cytoplasmic mislocalization, misfolding, and aggregation, disrupting RNA processing, protein transport, and DNA repair. Similarly, SOD1 and FUS mutations promote toxic protein aggregation, impairing cellular homeostasis and contributing to neuronal dysfunction. C9orf72-derived DPRs exert toxicity by interfering with nucleocytoplasmic transport. The propagation of these pathogenic proteins between neurons and glia, often via prion-like mechanisms, underlies the characteristic spread of ALS pathology throughout the nervous system. Cellular protective responses, such as molecular chaperones and the ubiquitin-proteasome system, attempt to mitigate aggregation but are often overwhelmed in disease states. Mitochondrial dysfunction, oxidative stress, and disturbances in calcium homeostasis are also implicated, with evidence showing that SOD1 mutations can alter redox balance and mitochondrial function in both neurons and non-neuronal cells. Impaired DNA repair mechanisms, involving proteins such as TDP-43, FUS, NEK1, and VCP, have emerged as important contributors to ALS pathogenesis, linking protein aggregation to genomic instability. Recent therapeutic strategies focus on directly targeting misfolded proteins using small molecules, peptides, or antisense oligonucleotides to inhibit aggregation or enhance clearance, offering hope for disease modification. Understanding the interplay between protein aggregation, impaired RNA metabolism, and cellular stress responses is crucial for developing effective translational therapies for ALS.

ID: 42302791
Title: ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.
Abstract: Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.

ID: 42304913
Title: Nicotine Versus Non-Nicotine Constituents in Neurodegenerative Risk: Evidence from Multivariable Mendelian Randomization.
Abstract: Nicotine has complex neuropharmacological actions through nicotinic acetylcholine receptors, but its independent role in neurodegenerative diseases remains unclear because tobacco smoke contains many non-nicotine toxicants. This uncertainty limits the interpretation of nicotine- and nAChR-targeted therapeutic strategies, especially as electronic nicotine delivery sys-tems become more common. We used Mendelian randomization to genetically separate nicotine-related effects from smoking-related non-nicotine effects on major neurodegenerative diseases and related prodromal conditions. We performed univariable two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Summary-level exposure data for cigarettes per day (CPD) and the nicotine metabolite ratio (NMR) were analyzed against individual-level, smoking-stratified outcome data derived from 337,334 UK Biobank participants, to evaluate their respective causal effects across six neurodegenerative outcomes: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tremor, early cognitive impairment (EC), and other neurodegenerative diseases (OND). MVMR analyses revealed that nicotine exposure was a causal risk factor for AD (ever smokers: OR=0.90, 95% CI 0.83-0.98; current smokers: OR=0.76, 95% CI 0.64-0.91). Nicotine exerted a causal protective effect against tremor (OR=1.24, 95% CI 1.03-1.49) and EC (OR=1.14, 95% CI 1.04-1.24) in current smokers. Non-nicotine tobacco constituents were identified as risk factors among former smokers for EC (OR=1.61, 95% CI 1.04-2.50). Exposure to nicotine can increase the risks of AD, while conferring protective effects against tremor and EC. Furthermore, exposure to non-nicotine tobacco constituents acts as a risk factor for the incidence of EC.

ID: 42304926
Title: Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.
Abstract: 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-β deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and müller 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.

ID: 42307135
Title: Brain activity in an end-stage ALS patient suggests the presence of an unresponsive wakefulness syndrome.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons. It is widely assumed that cortical structures beyond motor neurons are relatively preserved, and patients in the end-stage ALS are regarded as being in complete locked-in syndrome (cLIS). However, emerging evidence suggests substantial heterogeneity in cognitive functioning among ALS patients, indicating possible extra-motor cortical involvement and impaired levels of consciousness. We report a case study assessing electrophysiological markers and auditory system integrity to evaluate the presence of covert consciousness in end-stage ALS. The patient was a 42-year-old woman with bulbar-onset, end-stage ALS, a six-year disease duration, and no means of communication. She underwent several EEG-based protocols, including resting-state EEG (RS-EEG), a passive auditory oddball paradigm, and 40 Hz auditory steady-state responses (ASSR). Audiological evaluation comprised transient-evoked and distortion-product otoacoustic emissions, as well as auditory brainstem responses (ABR). RS-EEG was dominated by prefrontal 1-3 Hz activity resembling frontal intermittent rhythmic delta activity. Power spectra were poorly differentiated and consistent with a 1/f profile. No event-related potentials were observed in the oddball paradigm, and no ASSR responses were detected. Audiological testing revealed absent otoacoustic emissions and ABR indicating severe to profound hearing loss. Our findings indicate severe cortical dysfunction and provide no electrophysiological evidence of covert consciousness. The electrophysiological profile closely resembles that observed in unresponsive wakefulness syndrome. This case supports the hypothesis that advanced ALS following cLIS onset may be more appropriately conceptualized as a disorder of consciousness rather than persistent cLIS.

ID: 42317073
Title: PML as a neuroprotective guardian: Leveraging nuclear protein quality control to mitigate neurotoxicity of an ALS-associated NEK1 variant.
Abstract: Insoluble protein aggregates are a hallmark of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). The ubiquitin-proteasome system (UPS) serves as a neuroprotective quality control mechanism that clears aggregates. PML nuclear bodies (NBs) were proposed to serve as hubs for SUMO-primed ubiquitylation and degradation of misfolded proteins. Georgiadou et al. provide evidence that an ALS-linked NEK1 truncation mutant is recruited to PML NBs, where it likely undergoes SUMOylation and ubiquitylation. In mice, PML loss exacerbates ALS-like symptoms, while induced PML expression delays disease onset. These findings establish PML as a key regulator of proteostasis and highlight PML induction as a potential therapeutic strategy for ALS and related proteinopathies.

ID: 42322392
Title: ECAS-Based Neuropsychological Phenotyping in Amyotrophic Lateral Sclerosis: A Retrospective Study Comparing Different Algorithms.
Abstract: This study aimed to compare different algorithms based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) to classify patients with amyotrophic lateral sclerosis (ALS) according to their neuropsychological phenotype to identify possible discrepancies among these systems. ECAS-Cognitive and -Carer Interview (ECAS-C/-CI) scores of N = 901 patients with ALS without a formal diagnosis of dementia were retrospectively retrieved. Patients were classified, pursuant to Strong et al.'s criteria, as cognitively and behaviourally normal (ALScbn), cognitively and/or behaviourally impaired (ALSci/bi/cbi), or Possible ALS-FTD, according the following ECAS-based algorithms: (1) Abrahams', solely addressing ECAS-C total and ALS-Specific subtotals; (2) Poletti et al.'s, addressing single task-level ECAS-C scores; (3) "Subscale", addressing ECAS-C subscales (i.e., Language, Executive, Fluency, Memory and Visuospatial). All algorithms relied on single-item-level ECAS-CI scores for behavioural classifications. Whilst agreement rates among these classifications were moderate to high (84-86%; Cohen's k = 0.78-0.81), and some discrepancies emerged: (1) "ALScbn-to-ALSci" and "ALSci-to-ALScbn" re-classifications occurred across the three comparisons, ranging from ~ 11% to ~ 24%; (2) the most classificatory disagreements (~ 43%) occurred for the ALScbi category when comparing single task-level (Poletti) to total-level (Abrahams) algorithms, with patients being re-classified as either ALSbi or Possible ALS-FTD; (3) ~ 24% of Abraham's Possible ALS-FTD cases were re-classified as either ALScbi or ALSbi by the Subscale approach. Different ECAS-based algorithms for deriving Strong's phenotypes might yield slight discrepancies that could under- or overestimate a given classification.

ID: 42332177
Title: Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.
Abstract: 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.

ID: 42333954
Title: Thinning of the oral motor cortex is linked to impaired speech in amyotrophic lateral sclerosis.
Abstract: Most individuals with amyotrophic lateral sclerosis (ALS) develop bulbar impairment as their disease progresses. The ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subscore and neurological examination of upper (UMN) and lower motor neurons (LMN) are routinely used to assess this dysfunction but have inherent limitations. Speech‑derived measures have shown promise for capturing bulbar decline with greater sensitivity, but their neurobiological correlates remain unclear. This study examined the associations between quantitative speech measures and cortical thinning in ALS. Data from the Canadian ALS Neuroimaging Consortium were analyzed. Speech measures were extracted from audio recordings of the standardized "Bamboo Passage". Cortical thickness was calculated from T1‑weighted MRI scans. General linear models first compared cortical thickness between patients with ALS and healthy controls. Associations between the speech measures and cortical thickness were then assessed within the ALS group. Patients with ALS showed cortical thinning across bilateral frontotemporal regions, with the largest clusters in the bilateral motor cortices. Reduced speaking and articulation rates were associated with thinning in both oral motor cortices. In contrast, the ALSFRS-R bulbar subscore and UMN and LMN bulbar burden showed no significant associations. Measures of pausing behavior were negatively associated with frontal cortical regions. Thinning of the oral motor cortex in ALS was linked to reduced oral motor function, supporting speaking and articulation rate as sensitive markers of bulbar motor neuron degeneration. These measures demonstrated neuroanatomical associations that the ALSFRS-R bulbar subscore and neurological examination findings did not, highlighting their potential value for monitoring bulbar dysfunction in ALS.

ID: 42338888
Title: Interplay between B vitamins, fiber, and Bacteroides abundance: a predictive model for anxiety and depression in amyotrophic lateral sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease that not only affects motor function but is also associated with gastrointestinal and emotional disturbances. Recent research highlights the potential role of gut microbiota and diet in modulating these symptoms, suggesting a complex interaction between nutrition, intestinal health, and presence of anxiety and depression in ALS patients. This study aims to investigate the relationship between dietary intake, gut microbiota composition, and presence of anxiety and depression in patients with amyotrophic lateral sclerosis (ALS). A cross-sectional study conducted with a sample of 48 patients with bulbar-onset or spinal-onset ALS from different regions of Spain. Dietary intake was assessed through 24-h records and food frequency questionnaires, while anxiety and depression were evaluated using validated scales that formed a latent factor called emotional distress. Stool consistency was assessed following the Bristol Stool Scale and the abundance of bacterial microbiota was quantified. Confirmatory factor analysis identified a nutritional factor composed of vitamins B1, B2, B9, C, and fiber, revealing a significant inverse association with anxiety and depression levels. The predictive model revealed both direct and indirect effects of this factor on presence of anxiety and depression, mediated by Bacteroides abundance and stool consistency. This model explained 19% of the variance in psychological distress. Our findings suggest that a diet rich in B vitamins, C vitamin and fiber may help improve emotional well-being in patients with ALS, highlighting the importance of nutritional strategies, as well as the role of Bacteroides related to stool consistency in patients with ALS.

ID: 42345500
Title: Formaldehyde neurotoxicity: Effects on the mammalian brain, cognitive function, and neurodegenerative risk. A scoping review.
Abstract: Aqueous formaldehyde (FA) solution, known as formalin, is currently the primary agent used for preserving tissue samples and anatomical specimens. Formaldehyde is widely used in laboratories and the chemical industry; it also occurs as an air pollutant and endogenous cellular metabolite. The potential carcinogenic effects of formalin on the respiratory tract are well documented. A less recognized consequence of occupational exposure to FA is its detrimental effect on the central nervous system (CNS) and brain function. A literature review was conducted to investigate the effects of FA on the brain. Five databases were searched: PubMed, Web of Science (WoS), Embase, ScienceDirect, and Google Scholar. To describe the effects of FA exposure and endogenous FA generation, 35 relevant publications were collected and analyzed. The literature review demonstrated that inhalation is the most common route of FA exposure. Several studies have shown that FA may cause hippocampal damage, disrupt melatonin secretion, and induce a wide range of cognitive disorders with varying characteristics and severity. These disorders include memory impairment, disturbances in balance and spatial orientation, learning difficulties, sleep disturbances, impaired judgment, and prolonged reaction times to stimuli. Increased endogenous FA concentration has also been associated with a higher risk of neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis. The literature analysis demonstrated the high neurotoxicity of FA, which may lead to numerous neuropsychiatric disorders. We aim to draw attention to the risks associated with the routine use of formalin, particularly among anatomists and pathologists, and to encourage consideration of less harmful alternative preservation agents.

ID: 42350385
Title: Intravenous administration of an engineered AAV9-gene-silencing vector suppresses human SOD1 and extends survival in an ALS mouse model.
Abstract: Adeno-associated virus (AAV)-mediated gene silencing offers a promising strategy for achieving durable therapeutic effects with a single administration. Mutations in the human superoxide dismutase 1 (hSOD1) gene, inherited in an autosomal dominant manner, lead to motor neuron degeneration in amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease with no effective treatment. In this study, we employed AAV9 to deliver to the SOD1G93A ALS mouse model artificial microRNAs targeting SOD1, embedded in dual miR-33 scaffolds driven by the promoter of the human survival motor neuron 1 (hSMN1) gene. A single intravenous injection achieved widespread and sustained suppression of SOD1, preserved α-motor neurons, maintained neuromuscular junctions (NMJs), and improved muscle function. These benefits are translated into significantly improved respiratory function, motor performance, and survival. Therapeutic efficacy was observed both when the treatment was administered pre-symptomatically and during symptomatic stages. Compared with previous AAV-based interventions, the survival benefit achieved in this IV delivery approach is unprecedented, supporting its potential for clinical translation in SOD1-linked ALS and other central nervous system (CNS) diseases caused by gain-of-toxicity gene mutations.

ID: 42351201
Title: Learning a distance for the clustering of patients with amyotrophic lateral sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with median survival of 3-5 years. Patient responses to treatments vary widely, highlighting the need for personalized care. Clustering patients based on disease progression could improve prognosis, guide clinical decision-making, and optimize clinical trial design. This study aimed to identify robust ALS patient clusters using ALS Functional Rating Scale-Revised (ALSFRS-R) scores and to determine diagnostic parameters predictive of cluster membership, enabling earlier stratification and targeted management. Data from the Tours ALS center registry (April 1997-October 2023) were analyzed; after preprocessing, 353 patients monitored every three months between January 2004 and July 2023 with ALSFRS-R, clinical, biological, and demographic data were retained. After preprocessing to handle missing or aberrant data, a weakly supervised approach labeled patient pairs based on their ALSFRS-R sequences. These labels were used to train a classifier to learn a distance for off-the-shelf clustering algorithms. Multiple configurations were tested, varying clustering algorithms, dimensionality reduction method, and number of clusters. Random Forest (RF) model predicted cluster membership from diagnostic parameters. Optimal clustering was selected using silhouette score, validated with Kaplan-Meier survival analysis. Stability and robustness were assessed with the Adjusted Rand Index (ARI) and silhouette score respectively. Predictive performance was evaluated using specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV). Diagnostic parameters associated with clusters were identified using Kruskal-Wallis and chi-squared tests for continuous and categorical variables. Three clusters (n = 139, 121, 93) were identified, demonstrating strong separation (silhouette ≈ 0.6) and high stability of results (ARI ≈ 0.7). Survival differed significantly among clusters: over 50% of patients in the third cluster survived beyond 50 months, compared to less than 25% in the other clusters. Thirteen diagnostic parameters-including ALSFRS-R subscores, IgG levels, albumin quotient, and time to diagnosis-were key predictors of cluster membership. Cluster prediction achieved specificity and NPV ≈ 0.75, with close sensitivity and PPV compared to state-of-the-art methods. This framework successfully stratifies ALS patients into clinically meaningful clusters, revealing underlying disease heterogeneity and providing strong prognostic insight. Such classification can facilitate personalized care, guide therapeutic decisions, and inform the design of targeted interventions to improve outcomes. Not applicable.

ID: 42359357
Title: Innate immune crosstalk in ALS/FTD pathogenesis.
Abstract: Marked by protein aggregation, impaired proteostasis, organelle stress, and chronic neuroinflammation, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a clinically, genetically, and pathologically overlapping disease spectrum. Increasing evidence indicates that innate immune activation is not merely a secondary response to neuronal injury, but an active driver of disease progression. In this review, we elaborate on how ALS/FTD-associated genetic lesions and pathogenic protein aggregates, including TDP-43, SOD1, FUS, and C9orf72-derived dipeptide repeat proteins, engage three interconnected innate immune pathways: cGAS-STING, NLRP3 inflammasomes, and TREM2-DAP12 signaling. We further highlight emerging crosstalk among these pathways, in which cGAS-STING and NLRP3 reinforce inflammatory signaling, while NLRP3-driven TREM2 shedding may impair microglial clearance and perpetuate proteostatic failure. Understanding this immune network may help define disease subtypes, identify biomarkers, and guide combinatorial therapeutic strategies that suppress harmful inflammation while preserving protective microglial functions.

ID: 42360043
Title: Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%-15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's t-test, with a p < 0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold p < 0.05 and 74 proteins with FDR < 0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.

ID: 42365206
Title: Navigating the CBD: How Urban Risk Environment Shapes Daily Life for People Who Use Drugs in Edmonton's Central Business District.
Abstract: Public drug use in urban central business districts (CBDs) presents an urgent public health challenge in Canada. People who use drugs (PWUD) in CBDs navigate intersecting risks related to criminalization, stigma, hostile architecture, urban redevelopment, and limited access to essential services-factors that compound health disparities and increase morbidity and mortality. Yet CBDs also function as sites of informal social networks, mutual aid, and adaptive survival strategies that, while precarious, constitute critical resources for daily safety and belonging. This focused ethnographic study, conducted in Edmonton's CBD between July 2022 and September 2023, draws on 25 semi-structured interviews and over 170 h of embedded field immersion to investigate how intersecting environmental forces shape the daily lives of PWUD. Using Collins et al.'s (2019) intersectional risk environment framework and Duff's (2009) enabling environment concept, we analyzed how physical, social, economic, and policy environments-operating across micro and macro levels-produce differential harms and, simultaneously, generate precarious yet meaningful sites of connection, resourcefulness, and collective care. Findings reveal how displacement, over-policing, and gentrification-driven spatial change coexist with participants' place-based belonging, moral economies of reciprocity, and culturally grounded survival knowledge. We argue that effective interventions must account for this co-production of risk and enabling conditions and that urban governance must center the voices of those most structurally affected.

ID: 42367369
Title: Preparing Amyotrophic Lateral Sclerosis Clinics to Provide Longitudinal Care for Individuals Carrying ALS Risk Variants.
Abstract: Emerging genetic therapies and the expansion of genetic testing are identifying individuals carrying amyotrophic lateral sclerosis (ALS) risk variants who would benefit from surveillance and early intervention. Anticipating the geographic distribution and clinical needs of this population is essential for optimizing care delivery and ensuring readiness as new therapies become available. We estimate the number of individuals in the United States carrying ALS risk variants and project the clinical engagement required to support this population. This is especially timely because ALS clinics are already grappling with rising numbers of patients with symptomatic ALS and deep funding cuts. We developed a population model to estimate the number of symptomatic individuals with gene-positive ALS and asymptomatic gene carriers across US states over the next decade (year 1: 2026). State-level ALS prevalence and incidence were calculated using 2 approaches: (1) race-adjusted ALS rates from the Atlanta metropolitan study applied to 2023 Census demographics and (2) observed state-level ALS case counts from the National ALS Registry (2011-2018). Gene-positive cases were estimated using published frequencies of SOD1, C9orf72, FUS, and TARDBP pathogenic variants. At-risk relatives were modeled assuming autosomal-dominant inheritance with ∼5 first-degree and ∼7 second-degree living relatives per proband, and broad uptake of cascade genetic testing. Surveillance needs were modeled as 1 annual visit per asymptomatic carrier, which was normalized by the number of ALS centers per state. In year 1 (2026), the model estimated 2,704 symptomatic gene-positive ALS carriers. With an average of 4.25 carrier relatives per proband, 10,944 asymptomatic carriers were projected nationwide. Most states required <50 additional visits per clinic annually, with 12 states in the 50-99 range and none exceeding 100. By year 10 (2035), the model projected 7,474 symptomatic and 26,111 asymptomatic carriers. State-level demand shifted substantially: only 6 states remained below 50 visits per clinic annually; 22 reached 50-99; 18 reached 100-199; and 3 exceeded 200. Gene-targeted testing is projected to substantially increase ALS clinic visits among asymptomatic gene carriers. While current infrastructure may accommodate the initial rise, within a decade, most states will require significant expansion. Anticipating and planning for this growth now is essential to ensure seamless integration of gene-positive individuals into ALS care.

ID: 42371053
Title: Neurodegenerative diseases and environmental risk factors: an overview of the available scientific evidence.
Abstract: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are among the most well-known and prevalent neurodegenerative disorders. These diseases result from an interaction between the environment and genetically predisposed individuals. This review examines the evidence available in the literature underlying this multifaceted interaction, focusing on various chemical substances such as metals, fertilizers, and herbicides, as well as toxic agents of microbiological origin, including cyanobacteria and their neurotoxins. In addition, the pathways through which toxic substances can enter the human body are discussed, such as air and water, which may lead to absorption through the lungs, the gastrointestinal tract, the skin, and mucosae. The routes by which neurotoxic substances gain access to the human body may help explain the increased risk of developing neurodegenerative diseases observed in sports played on soil and grass surfaces, such as soccer, American football, and golf.

ID: 42384233
Title: Genome-wide spectrum of coding DNA variations in Indian patients with amyotrophic lateral sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapies, emphasizing the need for deeper understanding of disease pathogenesis. While more than 40 ALS-associated genes have been identified, their contribution varies significantly across populations and the data from the Indian population remains scarce. We aimed to comprehensively characterize the spectrum of coding DNA variations in ALS-associated genes and identify novel genetic contributors in an Indian cohort. Whole-exome sequencing on 761 ALS patients and 917 in-house healthy controls and repeat-primed PCR for expansions (C9orf72, ATXN2, NOTCH2NLC, NOP56) were performed. Variants were classified using ACMG guidelines, and rare variant association testing was conducted. Overall diagnostic yield was 15.90%, with pathogenic/likely pathogenic variants. Familial ALS showed higher diagnostic yield (36.95%) than sporadic ALS (12.96%). SOD1 dominated familial cases (53.85%), while OPTN, SOD1 and FIG4 were prevalent in sporadic cases. Homozygous SOD1 variants in six patients correlated with juvenile/young onset (< 30 years). C9orf72 expansions (4%) and ATXN2 repeats (1.7%) were identified at frequencies comparable with Asian cohorts. Rare variant analysis identified JAK2 as a novel genome-wide significant signal (FDR = 3.5 × 10-5). This first large-scale genomic survey of Indian ALS patients showed SOD1 being the predominant cause of fALS, while OPTN, FIG4, and other genes drive disease amidst low C9orf72 frequency. The novel JAK2 association suggests a potential neuroinflammatory mechanism, highlighting the importance of studying diverse populations to uncover distinct genetic etiologies.

ID: 42393482
Title: Diverging trends in motor neuron disease burden in China: an ageing-driven increase despite declining age-standardised rates - a GBD 2021 analysis.
Abstract: Age-standardised rates of motor neuron disease (MND) have declined in many settings, yet the absolute burden continues to rise in ageing populations. Whether this divergence is driven by demographic change or epidemiological shifts remains unclear, particularly in China. Using data from the Global Burden of Disease Study 2021, we analysed trends in MND burden in China from 1990 to 2021. Decomposition analysis was applied to quantify the contributions of population ageing, population growth, and changes in age-specific rates. Age-specific incidence patterns were compared with global estimates, and key findings were validated against recent Chinese epidemiological studies. Despite declining age-standardised prevalence and DALY rates, the absolute number of cases and DALYs increased substantially. Population ageing accounted for 46.0% of the increase in DALYs, followed by population growth (35.0%) and changes in age-specific rates (19.0%). Age-specific incidence rates in China were consistently lower than global estimates. External validation demonstrated high consistency with national epidemiological studies. The increasing burden of MND in China is primarily driven by demographic ageing rather than increasing disease risk. Declining age-standardised rates may mask growing healthcare demands in rapidly ageing populations.

ID: 42394962
Title: Decremental responses following repetitive nerve stimulation in spinal and bulbar muscular atrophy.
Abstract: The presence of decremental responses following repetitive nerve stimulation (RNS) in amyotrophic lateral sclerosis (ALS) is well established. However, in spinal and bulbar muscular atrophy (SBMA), a rare X-linked recessive lower motor neuron disease, the incidence and distribution of decremental responses across different muscles have not been thoroughly investigated. Patients with SBMA were retrospectively identified in our database. RNS at a frequency of 3 Hz was performed on five muscles: the abductor pollicis brevis (APB), abductor digiti minimi (ADM), upper trapezius, deltoid, and facial muscles (frontalis or nasalis). A total of forty patients were identified. A significant (> 5%) decremental response in at least one muscle was observed in all patients. It was observed more frequently in proximal muscles than in distal muscles: deltoid (86%), trapezius (70%), facial muscles (44%), APB (37%) and ADM (25%). The magnitude of the decremental response in the deltoid was significantly higher than that in the other muscles. Our results demonstrated that decremental responses were frequently observed in patients with SBMA, with a distribution pattern similar to that in ALS. The fact that the decremental responses are observed in SBMA having an extremely chronic course would be relevant for the pathophysiological mechanism of the decremental response. The RNS findings provide valuable insights into the pathological mechanisms of SBMA and may contribute to the development of future treatments.

ID: 42397462
Title: A case study of comprehensive association analysis and risk prediction of amyotrophic lateral sclerosis in a Chinese population.
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with significant genetic heterogeneity. While large-scale studies have characterized its genetic architecture in European populations, the genetic basis of ALS in the Chinese population remains under-explored. To address this gap, we conducted a comprehensive genetic analysis on a cohort of 40 Chinese individuals (32 ALS patients and 8 controls) using whole genome sequencing. We employed the Phenotype-Covariate Genetic Correlation method to estimate SNP-based heritability on the liability scale and utilized LDAK-KVIK for gene-based association analysis. Our analysis revealed a SNP-based heritability (h2SNP) of approximately 25.1% in this Chinese cohort, with a positive correlation between minor allele frequency and heritability, highlighting the substantial contribution of common variants. Gene-based analysis prioritized candidate risk genes, including MIB1, TMED2, and DOC2B, which implicate ubiquitin-mediated protein degradation and intracellular vesicle trafficking in ALS pathogenesis. In risk prediction models, the BOLT-LMM approach achieved a robust mean Area Under the Curve (AUC) of 0.883. This study provides the first comprehensive estimate of SNP-based heritability in a sequenced Chinese ALS cohort and supports the "polygenic background" hypothesis. The identification of candidate risk genes and the preliminary validation of polygenic risk scoring highlight the potential for future genetic stratification in Chinese patients.

ID: 42399099
Title: Global epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with the global epidemiological profile remaining incompletely understood. While previous systematic reviews existed, an updated comprehensive synthesis is needed to delineate the disease burden. We searched PubMed, Embase, Scopus, Web of Science and Cochrane databases from inception to 18 February 2025, for studies reporting the incidence, prevalence or mortality of ALS in the general population. Pooled estimates with 95% CIs were calculated, and subgroup analyses were performed. Of 29 110 articles initially screened, 142 were included. Global pooled incidence was 1.65 per 100 000 person-years (95% CI 1.43 to 1.91), prevalence was 5.05 per 100 000 population (95% CI 4.26 to 5.99) and mortality was 1.26 per 100 000 person-years (95% CI 0.94 to 1.69). Both incidence rate ratio (IRR=0.74) and prevalence rate ratio (PRR=0.69) indicated significantly lower disease burden in females than in males. The burden of disease exhibited a marked age-dependent pattern, peaking at ages 70-79. Temporal trend analyses revealed a consistent increase in prevalence from 1963 to 1999 onwards, while incidence peaked in 2014-2017. Geographically, incidence and prevalence were highest in Europe, North America and Oceania and lowest in Asia and South America. The disease burden was significantly higher in high-income countries compared with both upper-middle-income and lower-middle-income countries. This systematic review provides updated global ALS burden estimates, showing variations by sex, age, time and geography and underscoring the complex interplay of genetic, environmental and socioeconomic factors, with implications for health planning, resource allocation and etiological research.

ID: 42399152
Title: Macrophage inclusions in patients undergoing antisense oligonucleotide therapy for ALS or SMA: A retrospective and transversal study.
Abstract: Intrathecal antisense oligonucleotides (ASOs) have revolutionized the management of genetic motor neuron diseases. Nusinersen is approved for spinal muscular atrophy (SMA) caused by SMN1 mutations, and tofersen for amyotrophic lateral sclerosis (ALS) linked to SOD1 mutations. Since their approval, some studies reported the presence of macrophagic inclusions in cerebrospinal fluid (CSF) of patients treated with ASOs, first in nusinersen-treated patients and more recently in those receiving tofersen. These findings remain poorly characterized, and their clinical significance is unclear. We first conducted a retrospective study in 21 patients (132 CSF samples): six treated with tofersen (every 4 weeks) and 15 with nusinersen (every 4 months). CSF samples were analyzed for macrophagic inclusions, their time of onset, and persistence over time. To assess clinical and inflammatory correlates of macrophagic inclusions, we then performed an analysis of CSF inflammatory biomarkers and serum ferritin and neurofilament light chain tests in 18 of these patients still under treatment. In tofersen-treated patients, macrophagic inclusions were consistently observed and persisted over time, except in one case. In nusinersen-treated patients, inclusions were rare and transient. An inflammatory CSF profile was associated with the presence of inclusions, but their cellular nature remained undetermined. Notably, tofersen-treated patients with "tofersenophages" exhibited favorable clinical responses. Macrophagic inclusions appear more frequent in the CSF of tofersen-treated patients than previously reported. While their origin remains unclear, they seem linked to CSF inflammation without precluding a beneficial therapeutic response.

ID: 42403529
Title: Paid homecare worker support for people living with motor neurone disease: A secondary analysis of people living with motor neurone disease and family member perspectives.
Abstract: People living with motor neurone disease (MND) increasingly receive complex, life-sustaining interventions at home, including ventilation, tube feeding, and cough assist support. These demands place substantial strain on family carers and often require input from paid homecare workers. Despite their essential role, little is known about how homecare workers contribute to complex MND care, how they integrate within multidisciplinary teams, or how families experience their involvement. To examine people living with MND and family members' perspectives of homecare worker roles, responsibilities, relationships when complex interventions are required. A qualitative secondary analysis of data from two prior studies exploring home ventilation and tracheostomy ventilation in MND. Seven relevant NVivo nodes and 33 sub-nodes from interviews with 68 participants were re-coded using a deductive framework. Fourteen new nodes and 11 sub-nodes were generated and organised into three themes: care commissioning and provision; relationships; and the home environment. Participants described fragmented and inconsistent care commissioning, requiring families to advocate persistently for adequate support. Challenges included funding barriers, high staff turnover, and limited MND-specific knowledge, which undermined trust and compromised safe, effective care. Relationships with homecare workers ranged from highly valued, stable partnerships to strained interactions shaped by competence concerns, emotional labour, and mismatched expectations. The presence of homecare workers and medical equipment transformed the home into a quasi-clinical space, reducing privacy, disrupting routines, and requiring households to adapt around care provision. Yet strong relationships with homecare workers could enhance quality of life. Homecare workers play a critical role in delivering complex home-based MND care, yet quality is inconsistent. Improving training, stabilising staffing, supporting care coordination, and preparing families for the relational and environmental impact of homecare are essential for fostering sustainable, trusted care relationships, and improving outcomes for people living with MND and their families. Paid homecare support for people with motor neurone disease: Insights from people with MND and their families This study explores how people living with motor neurone disease (MND), and their family members, experience support from paid homecare workers when complex medical interventions, such as ventilation, feeding tubes, suction and hoists are needed at home. As care needs increase, families often need help from paid homecare workers, yet no research has asked families about what this support is like. To address this, we re-analysed interview data from two earlier studies about living with home ventilation in MND, and developed three main themes: Care commissioning and provision: Participants described the process of securing a care package as confusing and often exhausting, with multiple organisations involved. Families frequently had to push to get the support they needed. Problems included shortages of trained staff, high staff turnover, and delays caused by complex funding rules. Relationships with homecare workers: Good homecare workers made a huge positive difference. Relationships with homecare workers ranged from highly positive, built on trust, skill and becoming ‘part of the family’, to strained, particularly when workers lacked MND-specific training or confidence with equipment. Trust was crucial: when present it eased pressure on families but when absent it increased stress and vigilance. Impact on the home environment: Having carers in the house, changed home life, reducing privacy, disrupting household routines, and living spaces became filled with medical equipment and ever-present homecare workers. Families described feeling like hosts in their own homes and sometimes having to manage the emotional labour of being polite or accommodating even when exhausted. Overall, the study shows that homecare workers play an essential role in complex MND care, but quality is inconsistent. Better coordination and support for families to manage these close relationships within the home are vital to reduce pressure on families and improve quality of life.

ID: 42404161
Title: Perspective and quality of life in amyotrophic lateral sclerosis patients undergoing percutaneous endoscopic gastrostomy.
Abstract: Percutaneous endoscopic gastrostomy (PEG) is commonly used to manage dysphagia and nutritional failure, which are among the most frequent and severe complications of amyotrophic lateral sclerosis (ALS). While several studies assessed PEG indications, outcomes, and prognostic factors, there is no evidence regarding ALS patients' perspectives and health-related quality of life (HRQoL) associated with PEG. This study included 48 consecutive ALS patients. At the 1-month follow-up after PEG, patients and their caregivers completed a PEG satisfaction questionnaire regarding their decision to proceed with the PEG-tube placement. HRQoL was assessed using the Gastrointestinal Quality of Life Index (GIQLI) and the Short Form-36 (SF-36). In total, 77.1% of patients and 88.9% of caregivers confirmed that they would prefer to have a PEG tube placed again if required (p > 0.001); 93.8% of patients felt that PEG made feeding easier, exerting a positive effect on overall wellbeing (83.3%) and increasing survival rates (93.8%) (p > 0.001); 54.2% felt that PEG was cosmetically acceptable. Consistent positive rates were reported by caregivers. The GIQLI digestion subscale values significantly improved from baseline (28.3; SD = 6.6) to discharge (30.97, SD = 5.84) and were maintained at 1-month follow-up (30.21, SD = 6.7; p = 0.014). Conversely, in follow-up assessments, we observed a significant reduction in the SF-36 physical component summary (PCS) subscale (baseline = 33.3; 1-month follow-up = 28.61; p = 0.032), which was accompanied by a significant worsening in the GIQLI physical dimension subscale (baseline = 9.63; 1-month follow-up = 7.38; p = 0.044). This study provides preliminary evidence that ALS patients have a positive perspective on PEG positioning, which may also have a beneficial effect on HRQoL related to gastrointestinal function.