Durable medical equipment (DME)-wheelchairs, non-invasive ventilation, gastrostomy tubes, and communication devices-provides vital support for individuals with amyotrophic lateral sclerosis (ALS). Here, we describe DME use in COURAGE-ALS evaluating reldesemtiv's efficacy and safety in ALS, to evaluate if DME use can be considered an endpoint of interest in ALS trials. COURAGE-ALS, a multicentre, double-blind, randomized, placebo-controlled clinical trial was conducted at 83 sites in the United States, Canada, Europe, and Australia. Participants were randomized 2:1 to receive reldesemtiv or placebo for 24 weeks, followed by 24 weeks of active drug treatment. Exploratory outcomes included reasons for prescribing, extent of use, DME types, and regional differences. Among 482 participants, 166 (34.4%) were using at least one DME item at baseline. Among 276 participants completing study visits through Week 24, 130 (47.1%) initiated use of a total of 188 new DME items post-baseline through 24 weeks. Manual wheelchairs were most used at baseline (89 items) and initiated (47 items) during the trial. Both baseline DME use and initiating a new item were associated with lower ALS Functional Rating Scale-Revised scores and worse quality of life. The trial was terminated early due to futility. Treatment assignment did not impact DME use. Regional disparities were noted. This study shows that DME is commonly prescribed to ALS trial participants. Further understanding of geographic differences in DME access and their impact on clinical outcomes is warranted prior to including DME use as an endpoint in ALS trials. ClinicalTrials.gov identifier: (NCT04944784).

Neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and are frequently linked to metal dysregulation, oxidative stress, and immune dysfunction. Metallothioneins (MTs), a family of cysteine-rich, metal-binding proteins, are critical in maintaining metal homeostasis, mitigating oxidative damage, and modulating immune responses, functions highly relevant in these pathologies. MTs regulate essential metals like copper and iron by preventing their participation in harmful redox reactions and control zinc availability for enzymatic and signaling processes. They also detoxify neurotoxic metal(oid)s such as cadmium, mercury, lead, and arsenic, thereby reducing their adverse neurological and immunological effects. In autoimmune neurodegeneration, MTs modulate pro- and anti-inflammatory cytokines (e.g., IL-6, TNF-α, IL-10) and influence immune cell activity, particularly microglia and T cells, which are central to neuroinflammation and autoimmunity. Through these mechanisms, MTs play a dual role in sustaining immune homeostasis and counteracting oxidative stress. Their capacity to integrate metal regulation with immune modulation positions them as promising therapeutic targets, with preclinical and some clinical evidence supporting strategies to enhance MT expression or develop MT-mimetic agents to address both metal dysregulation and immune imbalance. Additionally, MTs show emerging utility as biomarkers, as alterations in MT isoform expression and metal-bound complexes in biofluids have been associated with disease onset, progression, and therapeutic response in specific neurodegenerative conditions. This article reviews the multifaceted roles of MTs in neurodegenerative diseases, emphasizing their function in metal and immune regulation and their emerging potential as therapeutic targets and clinical biomarkers.

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.

Accelerated brain aging in amyotrophic lateral sclerosis and its prognostic associations: a cohort study

DNAJC7, a member of the J-domain protein (JDP/Hsp40) family, plays a key role in protein homeostasis by regulating Hsp70 activity and preventing protein aggregation. Mutations in DNAJC7 have been linked to amyotrophic lateral sclerosis (ALS); yet, the molecular mechanisms by which these variants impair chaperone function remain poorly understood. DNAJC7 is a conserved chaperone featuring both a canonical J-domain, essential for Hsp70 activation, and three TPR domains, which serve as protein-protein binding interfaces. Here, we investigate the structural and functional consequences of the ALS-associated E425K mutation located within the conserved J-domain. Using NMR spectroscopy, we show that although the E425K mutation does not alter the structure of the protein, it significantly disrupts the conserved J-domain-Hsp70 interaction. We further identify a second Hsp70-binding interface within the TPR domains, which interacts with the C-terminal EEVD motif of Hsp70. This TPR-EEVD interaction is preserved in the E425K mutant but cannot compensate for the loss of J-domain binding or restore DNAJC7-dependent Hsp70 activation. Functionally, we show that the TPR domains of DNAJC7 directly bind TDP-43 and prevent its aggregation and that this holdase activity is retained in the E425K mutant. However, the mutant fails to support client transfer to Hsp70 and the subsequent Hsp70-mediated substrate refolding. Together, these findings demonstrate that DNAJC7 requires coordinated action of both J-domain and TPRs to regulate Hsp70 function and that disruption of J-domain-mediated activation uncouples DNAJC7 from the Hsp70 cycle, providing a mechanistic basis for its dysfunction in ALS.

Biomolecular condensates, a type of subcellular or membraneless organelle, form through liquid-liquid phase separation (LLPS) driven by multivalent interactions. As an RNA-binding protein, FUS participates in biological processes by forming dynamic liquid condensates via LLPS, with its abnormal fibrous aggregation associated with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Experiments show that phosphorylation inhibits LLPS of the FUS low-complexity domain (LCD) under low salt conditions, whereas for full-length FUS, phosphorylation does not block initial LLPS but inhibits the conversion of liquid droplets to toxic aggregates. The molecular mechanism underlying the difference between the two remains unknown. In this molecular dynamics simulation study, we examined condensate structural characteristics and compared wild-type (WT) versus phosphorylated condensates, revealing the molecular details of how full-length FUS avoids LLPS impairment through synergistic compensatory regulation among various domains. As for the FUS-LCD system, the extent to which their LLPS is reduced by phosphorylation is associated with the number of phosphorylation sites. Moreover, we have developed a model for analyzing the viscoelasticity of the condensates, which revealed that altered interaction patterns impact condensate viscoelasticity. This study characterizes the postphosphorylation architecture of FUS condensates and elucidates the molecular mechanisms by which phosphorylation regulates condensate formation and properties.

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 nm 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.

Exploring the Value of Brain T2* Weighted and FLAIR Imaging for Diagnosing Amyotrophic Lateral Sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) progressively impairs motor function, compromising speech and limiting communication. Augmentative and alternative communication (AAC) is essential to maintain autonomy, social participation, and quality of life for people with ALS (PALS). This review maps technological developments in AAC, from low-tech tools to advanced brain–computer interface (BCI) systems. Methods: We conducted a scoping review following the PRISMA extension for scoping reviews. PubMed, Web of Science, SciELO, MEDLINE, and CINAHL were screened for studies published up to 31 August 2025. Peer-reviewed RCT, cohort, cross-sectional, and conference papers were included. Single-case studies of invasive BCI technology for ALS were also considered. Methodological quality was evaluated using JBI Critical Appraisal Tools. Results: Thirty-seven studies met inclusion criteria. High-tech AAC—particularly eye-tracking systems and non-invasive BCIs—were most frequently studied. Eye tracking showed high usability but was limited by fatigue, calibration demands, and ocular impairments. EMG- and EOG-based systems demonstrated promising accuracy and resilience to environmental factors, though evidence remains limited. Invasive BCIs showed the highest performance in late-stage ALS and locked-in syndrome, but with small samples and uncertain long-term feasibility. No studies focused exclusively on low-tech AAC interventions. Conclusions: AAC technologies, especially BCIs, EMG and eye-tracking systems, show promise in supporting autonomy in PALS. Implementation gaps persist, including limited attention to caregiver burden, healthcare provider training, and the real-world use of low-tech and hybrid AAC. Further research is needed to ensure that communication solutions are timely, accessible, and effective, and that they are tailored to functional status, daily needs, social participation, and interaction with the environment.

Genetic modifiers are genes that, while not directly causing disease, can alter the onset, progression, severity, or specific phenotypes of a disease by interacting with the primary disease-causing genes. Despite their importance, knowledge of these modifiers remains fragmented across different experimental models of neurodegenerative disorders (NDs). To address this lacuna, we developed eVGeMdb (https://project.iith.ac.in/cgntlab/eVGeMdb/), a manually curated, comprehensive database of experimentally validated genetic modifiers of major NDs, including Amyotrophic Lateral Sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Spinocerebellar ataxias, Fragile X-associated Tremor/Ataxia Syndrome, and other general PolyQ disorders. eVGeMdb integrates modifiers from commonly used diverse experimental model systems, including Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, cellular models (human, mice, Drosophila cells), and mouse. The database currently incorporates over 17000 entries, each annotated with experimental context, gene-specific functional information, relevant human orthologs, and links to protein–protein interaction networks and enriched pathways. The resource enables cross-disease and model-specific comparisons, allowing the identification of both universal and disease-specific modifiers. By consolidating dispersed genetic modifier information into a single, accessible platform, eVGeMdb provides a comprehensive tool for researchers in the field to explore modifier effects, prioritize experimental validations, formulate novel hypotheses, and investigate pathophysiological mechanisms underlying neurodegenerative disorders.

A dive into the untapped potential of marine compounds in counteracting neurodegeneration.

Focus on the excitatory and inhibitory neurotransmission imbalance in amyotrophic lateral sclerosis: a harmful disease player or a potential therapeutic opportunity?

Zebrafish neural regeneration: mechanistic insights into human nervous system repair.

Compartment-specific transcriptome of motorneurons reveals impaired extracellular matrix signaling and activated cell cycle kinase in FUS-ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neurons disease with multifactorial etiology. The epidemiology of ALS in France is mainly documented through the Limousin regional registry (FRALim). We aimed to determine the incidence and clinical characteristics of ALS cases over a 20-year period in another French region, the Pays de la Loire, served by a single centralized diagnostic center. All patients diagnosed with ALS at the Angers University Hospital reference center between 2003 and 2023 were retrospectively included. Demographic and clinical data were extracted from medical records, and incidence rates were calculated using annual population estimates from the National Institute of Statistics and Economic Studies. Spatial analyses were performed to identify over-incidence areas and potential environmental or occupational determinants. A total of 1,316 patients were diagnosed with ALS during the study period, corresponding to a crude incidence rate of 1.88 cases per 100,000 person-years (95% CI 1.78-1.98), with no significant variation over time. The standardized incidence rate was 1.73 (95% CI 1.63-1.83). The mean age at symptom onset was 63.6 ± 11.2 years, 58.7 % of patients were male. The mean disease duration was 3.7 ± 3.5 years. ALS onset was spinal in 70.3 %, bulbar in 27.9 %, and respiratory in 1.7 % of cases. Familial or genetic forms accounted for 6 % of patients. Four geographical over-incidence areas were identified, with no correlation found with pesticide use, air pollution, or other environmental indicators. One occupational cluster was observed among farmers in a specific commune, prompting a dedicated investigation. This 20-year retrospective study provides the first epidemiological data on ALS in western France. The incidence and clinical features are consistent with national and European data. The identification of spatial and occupational clusters underlines the importance of continued regional surveillance and of prospective, registry-based studies to clarify environmental and occupational risk factors for ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of motor neurons. Early detection of bulbar symptoms is crucial for timely diagnosis and intervention; however, variability in symptom progression complicates clinical assessment. This retrospective observational study aimed to classify patients with ALS into three groups-spinal onset, spinal onset with bulbar involvement, and bulbar onset-and to identify speech evaluation metrics that effectively differentiate these groups. Data from 68 patients with ALS were retrospectively analyzed. Speech samples were collected and evaluated for alternating motion rate (AMR), maximum phonation time (MPT), nasality, maximum tongue pressure (MTP), speech rate, and speech intelligibility. Group comparisons and receiver operating characteristic (ROC) curve analyses were conducted to assess discriminatory ability. AMR significantly differed among the three groups, with the spinal-onset group demonstrating the highest rates and the bulbar-onset group showing the lowest rates. ROC analysis indicated that AMR exhibited excellent discriminatory power, particularly in distinguishing spinal- from bulbar-onset ALS. Significant differences were also observed in MTP, nasality, speech rate, and speech intelligibility, although some metrics were less effective in differentiating the intermediate group. No significant group differences were found in MPT. These findings suggest that the AMR is a sensitive and easily administered measure for detecting bulbar symptoms and distinguishing ALS subtypes. The intermediate characteristics observed in the spinal-onset with bulbar involvement group support this classification as a distinct clinical phenotype. Combining AMR with secondary measures such as MTP, nasality, speech rate, and speech intelligibility may enhance early detection of bulbar symptoms and improve clinical decision-making.

Mutations in the superoxide dismutase 1 (SOD1) gene are a predominant, genetic cause of amyotrophic lateral sclerosis (ALS). Given the marked variability in SOD1 variant prevalence and clinical manifestations across global populations, this study aimed to characterize the genetic and clinical profile of SOD1-associated ALS (SOD1-ALS) in a large cohort of Indian patients. Whole-exome sequencing (WES) was performed for the retrospective cohort, along with comprehensive bioinformatic analyses and interpretation of genetic variants. Data were analyzed using descriptive statistics and Kaplan-Meier survival analysis to assess clinical and survival outcomes. Among 765 individuals who underwent WES, 37 probands (4.8%) from 33 families were identified with SOD1-ALS, representing a substantial 24.2% of familial ALS (fALS) cases. Patients showed a male preponderance (1.64:1) with a mean age at onset of 41.9 ± 13.1 years. Analysis revealed 23 distinct pathogenic/likely pathogenic SOD1 variants, including four novel variants. Remarkably, a high frequency of homozygous variants (6 patients) were observed in the cohort, which were associated with earlier disease onset. Most patients presented with a lower limb onset (67.6%) and a lower motor neuron phenotype. Survival was noted to be prolonged in carriers of H47R, V88M, and I152N variants, while those with juvenile onset showed reduced survival. In conclusion, this study provides the first comprehensive characterization of SOD1-ALS in the Indian population, revealing a distinct genetic profile with a unique spectrum of SOD1 variants and a higher prevalence of homozygous cases. These detailed genotype-phenotype correlations contribute significantly to the genetic etiology of ALS.

Facial-onset SOD1 amyotrophic lateral sclerosis: A case report and systematic review.

Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of α-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of α-synuclein from Aβ. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.

PurposeAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive loss of motor neuron function and disruption of the blood-brain barrier are key features of ALS. Under the influence of chemokines, peripheral immune cells migrate into the central nervous system, thereby affecting the neuronal microenvironment. The aim of this study is to classify ALS based on the immune characteristics of peripheral blood in patients with the disease, and to construct prognostic models.Patients and MethodsA total of 397 ALS patients and 645 healthy controls (GSE112676 and GSE112680) were included. ALS chemotactic subtypes were constructed based on differentially expressed genes of chemokine and chemokine receptors (CCRs). The Cibersort algorithm was used to investigate the abundance of immune cells in peripheral blood. Univariate Cox regression analysis was performed to screen for CCRs genes, clinical characteristics, and immune cells associated with prognosis. Prognostic models were constructed based on these variables. Finally, external validation was conducted using samples from ALS patients diagnosed at the First Affiliated Hospital of Sun Yat-sen University.ResultsThere were significant differences in the abundance of peripheral immune cells between ALS patients and healthy controls. 17 CCRs genes were identified as differentially expressed. CCL23, CCR8, CXCR4, site of onset, age of onset, and “CD4 naive T cells” were demonstrated to be significantly correlated with survival time. Two chemotactic subtypes were established. Eight prognostic models could distinguish between high-risk and low-risk ALS patients. At year five, the areas under the receiver operating characteristic curves for the PlsRcox, Coxboost, and Xgboost algorithms were 0.747, 0.733, and 0.728, respectively. External test sets successfully validated these results.ConclusionALS patients exhibit peripheral immune abnormalities. Peripheral immune status could be used to distinguish ALS subtypes and construct prognostic models. Understanding peripheral immune changes in ALS patients may inform potential immunotherapies.