bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–05–24
fifty-four papers selected by
Luca Bolliger, lxBio
  1. Targeting lipid nanoparticle mediated co-delivery of edaravone and kaempferol for amyotrophic lateral sclerosis therapy.
  2. CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.
  3. Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.
  4. A Consensus Clustering Approach to Amyotrophic Lateral Sclerosis Phenotyping.
  5. CHI3L1 (YKL-40) and Chit-1 expressing glia in the white matter of ALS, FTLD and AD: correlations to pathology and disease duration.
  6. Clinical drug development in amyotrophic lateral sclerosis: industry-reported challenges and opportunities.
  7. TDP-43 Acetylation at the Neuroimmune Interface: A Hypothesis-Driven Framework for Peripheral Inflammatory Stratotypes in ALS.
  8. Identification of Reliable Biomarkers for ALS Through Machine Learning Approach.
  9. Tofersen in SOD1-Associated Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Regulatory Milestones.
  10. Unraveling the Pathological Mechanisms and Biomarkers of Amyotrophic Lateral Sclerosis: A Comprehensive Review.
  11. Quantitative Gait Analysis Reveals Distinct Patterns Associated With Pyramidal Involvement in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.
  12. The New York Genome Center ALS Consortium resource integrates postmortem tissue transcriptomics and whole genome sequencing to empower biological discovery.
  13. Dysregulation of arginase and arginine pathways in neurodegenerative diseases: Metabolic and cellular dysfunction and therapeutic implications.
  14. Types and frequencies of adverse events across clinical trials for patients with amyotrophic lateral sclerosis: an analysis of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.
  15. Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.
  16. Functional Activity of TDP-43: A Direct Biomarker for ALS.
  17. Primary Lateral Sclerosis French National Diagnostic and Care Protocol.
  18. Evaluation of Digital Technologies for Home-Based Assessment in People With Amyotrophic Lateral Sclerosis.
  19. Immunotherapeutic landscape of amyotrophic lateral sclerosis: A bibliometric analysis of research trends, translational priorities, and collaboration networks (2006-2025).
  20. Interplay of NMDAR and AMPAR in the Pathophysiology of Alzheimer's, Parkinson, ALS, Huntington's, and Epilepsy: An Update in Therapeutic Perspective.
  21. Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.
  22. Strengthening care and research in ALS in Southeast Asia: a call for action.
  23. COMMD1 Induces Copper Deficiency of SOD1 by Inhibiting the Palmitoylation of CCS in ALS.
  24. Translation and psychometric validation of the Persian version of amyotrophic lateral sclerosis cognitive behavioral screen (ALS-CBS) and revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R).
  25. Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.
  26. Lessons Learned From a Feasibility Study of Longitudinal Palliative Care for Patients With Amyotrophic Lateral Sclerosis.
  27. Living Outside the ALS Home - Everyday Experiences, Challenges and Needs of Adult Children with a Parent with ALS.
  28. Environmental Personal Exposure Clusters to Investigate Multiple Sclerosis and Amyotrophic Lateral Sclerosis Progression.
  29. The use of high-density surface electromyography in amyotrophic lateral sclerosis: a scoping review.
  30. Improving ALS Clinic Care Through Experience-Based Co-Design: A Participatory Action Research Study.
  31. The neuroprotective effects of Dexmedetomidine: key mechanisms focusing on neuronal programmed cell death.
  32. Comment on "Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis".
  33. Evaluating the Role of Order and Time Information for Classifying Sequences of Healthcare Events Derived from Claims Data.
  34. Transport pathways across the blood-brain barrier for waste clearance and drug delivery.
  35. Exosomal miRNA in cerebrospinal fluid as biomarkers for neurodegenerative disease.
  36. Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.
  37. The effects of a mobile healthcare application on speech and swallowing in amyotrophic lateral sclerosis.
  38. Molecular Mechanisms of Neurodegeneration: A Focus on Cholinergic Dysfunction and the Therapeutic Potential of Rivastigmine Derivatives.
  39. Kinetics and Spatial Distribution of β-Sheet Development in TDP-43CTD Condensate Maturation.
  40. Peptide-mediated delivery of an α-synuclein-targeting antisense oligonucleotide: Pharmacokinetics, safety, and central nervous system efficacy in a synucleinopathy model.
  41. High prevalence of CNS-directed autoantibodies in patients with schizophrenia.
  42. ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons.
  43. Immunomodulatory Nanocarriers in Multiple Sclerosis: Dual Targeting of Microglia and Mitochondria for Precision Neurotherapy.
  44. Clinical characterization and natural history of ALS8/VAPB p.Pro56Ser: upper motor neurone signs, survival, and functional milestones in 78 patients.
  45. Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.
  46. Neutrophil-Like Mitochondria Enable Blood-Brain Barrier Transmigration and Neuroprotection.
  47. Artificial intelligence in multi-omics analysis of neurological diseases.
  48. Dynamic Modulation of the Gut Microbiome in Neurodegenerative Diseases: Mechanisms, Therapeutic Potential, and Clinical Perspective.
  49. TDP-43: a critical amplifier of Alzheimer's disease beyond amyloid and tau.
  50. Embedding Palliative Care Clinicians in ALS Teams Improves ALS Clinicians' Confidence in Their Patient Management and Satisfaction With Palliative Care.
  51. Blood - brain barrier breakdown and neurovascular unit failure in the progression of Alzheimer's disease.
  52. Perceptions of Speech-Language Pathology Care in Amyotrophic Lateral Sclerosis: A Patient-Centered Exploratory Study.
  53. [Antibiotic Penetration into the Central Nervous System: Decoding the Blood: Brain Barrier and Antibiotics through "Structure" to Inform Therapeutic Strategy].
  54. Pay No Attention to the Man Behind the Curtain.
  1. Nanoscale. 2026 May 20.
    Targeting lipid nanoparticle mediated co-delivery of edaravone and kaempferol for amyotrophic lateral sclerosis therapy.
    Junrong Tian, Zhuanzhuan Jin, Yike Chi, Pu Wang, Huili Sun.
      Amyotrophic lateral sclerosis (ALS) is characterized by a progressive and selective loss of motor neurons in the central nervous system, particularly in the brain and spinal cord. However, the main cellular mechanisms and cell death pathways leading to motor neuron degeneration have not yet been clarified. Research indicates evidence of ferroptosis in ALS, and the natural compound kaempferol has been demonstrated to inhibit neuronal ferroptosis. However, damage to the blood-brain barrier (BBB) prevents the drug from penetrating the central nervous system, which significantly reduces its therapeutic efficacy. Here, we developed a targeted delivery system named Eda/Kae@Lip-RGD (EKLR), which consisted of liposome-grafted RGD peptides for the co-delivery of the drugs kaempferol and edaravone, capable of crossing the BBB to provide co-delivery of kaempferol and edaravone for combined treatment of ALS. As expected, treatment with EKLR for one month significantly slowed down weight loss and improved athletic performance in SOD1G93A transgenic mice. Mechanistically, this nanomedicine suppressed ferroptosis by upregulating the antioxidant proteins GPX4 and SLC7A11, alongside the downregulation of Nrf2 and ACSL4 levels, thus collectively preserving neuronal integrity. Meanwhile, EKLR restored the normal morphology and the survival rate of neurons and maintained the mitochondrial structure and morphological integrity. Accordingly, this nanoplatform may represent a distinctive and potentially effective strategy for achieving neuroprotection in ALS as well as in other disorders of the central nervous system.
    DOI:  https://doi.org/10.1039/d6nr00300a
  2. Brain. 2026 May 20. pii: awag178. [Epub ahead of print]
    CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.
    Project MinE ALS Sequencing Consortium
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.
    Keywords:  ALS; CYP2D6; amyotrophic lateral sclerosis; pharmacogenetics
    DOI:  https://doi.org/10.1093/brain/awag178
  3. Jpn J Radiol. 2026 May 18.
    Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.
    Satoru Morimoto, Shinichi Takahashi, Hideyuki Okano.
      Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Imaging biomarkers; Induced pluripotent stem cells (iPSCs); Precision medicine; Translational and reverse translational research; iPSC-based drug discovery
    DOI:  https://doi.org/10.1007/s11604-026-02000-x
  4. Stud Health Technol Inform. 2026 May 21. 336 338-342
    A Consensus Clustering Approach to Amyotrophic Lateral Sclerosis Phenotyping.
    Pilar M Ferraro, Sara Narteni, Marta Lenatti, Francesca Oliveri, Chiara Gemelli, Corrado Cabona, Antonio Uccelli, Alessia Paglialonga, Maurizio Mongelli, Angelo Schenone.
      Amyotrophic Lateral Sclerosis (ALS) phenotyping is a challenging task due to its heterogeneous nature and low prevalence. In this paper, we introduce a data-driven approach to support the characterization of ALS phenotypes based on clinical data from a battery of examinations. A consensus clustering method is proposed to identify stable clusters across multiple random data sub-samples, with the objective of discovering whether the retrieved patients' groups and related features align with clinical phenotypes and medical knowledge. Results suggest consistent profiles for bulbar onset ALS patients, driven by onset characteristics, whereas spinal onset ALS patients exhibit greater within-phenotype heterogeneity.
    Keywords:  consensus clustering; disease phenotyping; motoneuron diseases
    DOI:  https://doi.org/10.3233/SHTI260173
  5. BMJ Neurol Open. 2026 ;8(1): e001225
    CHI3L1 (YKL-40) and Chit-1 expressing glia in the white matter of ALS, FTLD and AD: correlations to pathology and disease duration.
    Chelsea Mauri Tran, Nisha Reddy, J K Thomas, Vinisha Venugopal, Robert Bowser.
       Background: Chitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1) protein levels are increased in the cerebrospinal fluid (CSF) of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Few studies have examined the spatial expression of chitinase-expressing cells with respect to neuropathologic hallmarks of disease.
    Methods: RNA sequencing was used to examine Chit-1 and CHI3L1 gene expression in the spinal cord and motor cortex. Immunohistochemistry was used to characterise the distribution of Chit-1 and CHI3L1 expressing cells in ALS, C9-ALS, FTLD, AD and non-neurologic disease controls. Immunofluorescence confocal microscopy was used to correlate distribution of Chit-1 and CHI3L1 expressing cells to TDP-43 pathology.
    Results: Chit-1 gene expression was increased in the spinal cord, and CHI3L1 expression was increased in both the spinal cord and motor cortex of patients with sALS and C9-ALS when compared with controls. Highest levels of Chit-1+ glia were in cortical regions that contain hallmark neuropathology for each neurodegenerative disease. CHI3L1+ glia were only significantly increased in sALS. Neither Chit-1+ nor CHI3L1+ glia was in close proximity to phosphorylated TDP-43 (pTDP) containing neurons in the motor cortex grey matter; however, there was a significant co-localisation of glial pTDP with Chit-1 and CHI3L1 in the motor cortex white matter.
    Conclusions: Chit-1 and CHI3L1 expressing cells were most abundant in the white matter of cortical regions affected by each neurodegenerative disease and the spinal cord. Chit-1 or CHI3L1 expressing cells in the white matter often contained pTDP. We also observed correlations between levels of Chit-1 or CHI3L1 expressing cells in the white matter to disease duration.
    Keywords:  ALS; MOTOR NEURON DISEASE; NEUROPATHOLOGY
    DOI:  https://doi.org/10.1136/bmjno-2025-001225
  6. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 20. 1-10
    Clinical drug development in amyotrophic lateral sclerosis: industry-reported challenges and opportunities.
    Famke S Cosijn, Jordi W J van Unnik, Lieza G Exalto, Larah N de Groot, Daphne N Weemering, Rene C van Rijssen, Roel G Vink, Leonard H van den Berg, Ruben P A van Eijk.
       OBJECTIVE: The pharmaceutical industry plays a pivotal role in amyotrophic lateral sclerosis (ALS) drug development, yet the challenges and priorities remain largely unexplored. This study aims to identify industry-perceived opportunities for ALS and examine industry perspectives on trial design.
    METHODS: A survey study was conducted among pharmaceutical companies involved in ALS drug development. The survey was based on literature review and interviews with industry experts. Final survey topics included scientific and operational challenges as well as preferred design settings for phase 2 and 3 clinical trials. Respondents were asked to rank trial-related topics using Likert scales.
    RESULTS: In total, 53 industry professionals responded, representing 42 international companies. Respondents identified three major scientific challenges: heterogeneity in disease progression, lack of reliable biomarkers, and insensitive efficacy measures. Insufficient funding, high dropout rates, and staffing shortages emerged as main operational barriers. For phase 2 trials, neurofilament light chain was most often prioritized as primary outcome, whereas the ALS Functional Rating Scale-Revised was prioritized for phase 3, although priority rankings varied considerably among respondents. Expected median sample sizes were 100 patients (range 20-300) for phase 2 and 300 patients (range 60-800) for phase 3. Overall, 58% of the respondents indicated that standardizing aspects of trial design could enhance trial quality and success rates.
    CONCLUSIONS: This study provides an overview of the industry-perceived challenges, exposing strategic knowledge gaps related to disease and clinical heterogeneity. Standardization of key trial design elements may help mitigate these challenges and better align ALS drug development efforts.
    Keywords:  Amyotrophic Lateral Sclerosis; clinical trials; drug development; industry perspectives; trial standardization
    DOI:  https://doi.org/10.1080/21678421.2026.2671167
  7. Neurochem Res. 2026 May 22. pii: 169. [Epub ahead of print]51(3):
    TDP-43 Acetylation at the Neuroimmune Interface: A Hypothesis-Driven Framework for Peripheral Inflammatory Stratotypes in ALS.
    Guido Attilio Condorelli, Alessio Iozzia, Deborah Bonifacio, Anamaria Pelin.
      Transactive Response Deoxyribonucleic Acid-Binding Protein-43 (TDP-43) acetylation may couple motor-neuron degeneration to systemic immune orchestration in Amyotrophic Lateral Sclerosis (ALS). Upon nuclear clearance and mislocalisation, TDP-43 enters the periphery; acetylation shapes its conformation, trafficking and immunogenicity. This narrative review synthesises single-cell transcriptomics, proteomic immunoprofiling and clinical inflammatory phenotyping to examine whether site-specific acetylated TDP-43 species may be associated with peripheral inflammatory signatures relevant to ALS immunopathology. By integrating separate datasets on acetylated TDP-43, monocyte phenotypes and cytokine modules, we propose two provisional endotypes characterised by monocyte reprogramming, cytokine modules and Blood-Brain Barrier (BBB) dysfunction-each representing clinically actionable pathways. Framed as a provisional neuroimmune interface, the acetylation state is considered here as a plausible molecular correlate and potential therapeutic entry point: a measurable clue to inform pharmacological targeting and, potentially, a modifiable target via p300CREB-Binding Protein (CBP)-Histone Deacetylase (HDAC) axes or sirtuin activity. Recasting TDP-43 from neuropathological hallmark to immunoactive sentinel supports a shift from descriptive nosology to stratified immunotherapy, in which treatment allocation is informed by acetylation-defined peripheral signatures.
    Keywords:  Amyotrophic Lateral Sclerosis; Immune stratotype; Peripheral neuroinflammation; Post-translational modification; TDP-43 acetylation
    DOI:  https://doi.org/10.1007/s11064-026-04770-2
  8. Stud Health Technol Inform. 2026 May 21. 336 1705-1709
    Identification of Reliable Biomarkers for ALS Through Machine Learning Approach.
    Renu Yadav, Pragya Pragya, Jac Fredo Agastinose Ronickom.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and limited diagnostic biomarkers. Identifying robust molecular biomarkers for ALS remains a major challenge due to disease heterogeneity and high-dimensional gene expression data. In this study, we developed a machine learning (ML) based pipeline integrating transcriptome data and feature selection to identify potential ALS biomarkers. RNA-Seq data of motor neuron disease patients and healthy controls were obtained from publicly available GEO datasets, followed by preprocessing was performed. We implemented two ensembled ML models such as eXtreme gradient boosting (XGBoost) and random forest (RF) algorithms under a five-fold stratified cross-validation framework to identify the differentially expressed genes. These models were evaluated using the performance metrics. We identified top 10 genes ranked by feature importance from the XGBoost and RF models. Notably, the DCN (Decorin) gene appears consistently in the top 10 features of both models, underscoring its stability and biological relevance. Both ML models exhibited excellent classification performance, with RF achieving 98.8% accuracy and XGBoost achieving 97.6% accuracy, alongside consistently high sensitivity, specificity, precision, and F1-score values. This work highlights the utility of transcriptomic data and ML in identifying key genes as biomarkers for diagnostic and therapeutic potential in ALS.
    Keywords:  Amyotrophic Lateral Sclerosis; Biomarkers; Feature Importance; Machine learning; Transcriptomic data
    DOI:  https://doi.org/10.3233/SHTI260516
  9. Eur J Pharm Sci. 2026 May 21. pii: S0928-0987(26)00137-5. [Epub ahead of print] 107563
    Tofersen in SOD1-Associated Amyotrophic Lateral Sclerosis: From Molecular Mechanisms to Regulatory Milestones.
    Antonio J Braza, Montserrat Viñas-Bastart, Maria Sureda-Rosich, Beliu García-Parra, Josep M Guiu-Segura, Pilar Modamio.
       BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder characterized by degeneration of upper and lower motor neurons. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 2% of ALS cases and are associated with toxic protein misfolding and aggregation. Tofersen is an antisense oligonucleotide therapy designed to reduce the synthesis of mutant SOD1 protein through targeted mRNA degradation. While this strategy represents a gene-specific therapeutic approach for a subset of ALS patients, evidence regarding its efficacy, effectiveness and long-term outcomes continues to be evaluated in clinical trials and post-marketing studies.
    OBJECTIVE: First, to describe the molecular mechanisms underlying SOD1-associated ALS and second, to analyze the therapeutic development, clinical outcomes, and regulatory evolution of tofersen.
    METHODS: A narrative review was conducted in PubMed on preclinical and clinical studies published from 2016 through late 2025, complemented by an analysis of public registries and regulatory documentation. Clinical trials were identified through ClinicalTrials.gov and the Clinical Trials Information System (CTIS), and official reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were reviewed to contextualize their development and regulatory evaluation.
    RESULTS: Fifty-three publications were identified, of which 20 met predefined inclusion criteria after screening and full-text review. Preclinical studies showed reduced mutant SOD1 expression and prolonged survival in transgenic models. Phase I-II trials demonstrated safety, favorable pharmacokinetics, and dose-dependent reductions in SOD1 in the cerebrospinal fluid and plasma neurofilament light chain (NfL) levels. Although the phase III VALOR trial did not meet the primary ALSFRS-R endpoint (a validated questionnaire-based functional rating scale-revised for determining ALS disease progression) at 28 weeks, significant reductions in the surrogate biomarker NfL indicated target engagement and supported accelerated regulatory approval. Extension data suggested potential clinical benefit with early treatment. Ongoing studies, including ATLAS in presymptomatic carriers, and real-world European data support continued evaluation, alongside accelerated regulatory approvals by FDA and EMA.
    CONCLUSION: Tofersen marks a paradigm shift in ALS management, establishing the foundation for precision medicine in neurodegenerative diseases. Its ongoing evaluation in the ATLAS trial will determine whether early intervention can prevent or delay disease onset in presymptomatic SOD1 mutation carriers.
    Keywords:  Amyotrophic lateral sclerosis; SOD1 mutation; antisense oligonucleotide therapy; biomarkers; neurofilament light chain; regulatory approval; tofersen
    DOI:  https://doi.org/10.1016/j.ejps.2026.107563
  10. Curr Neuropharmacol. 2026 May 15.
    Unraveling the Pathological Mechanisms and Biomarkers of Amyotrophic Lateral Sclerosis: A Comprehensive Review.
    Mei Qi, LiLi Fei, Wei Cui, Philip Wing-Lok Ho, Simon Ming-Yuen Lee, Jin Li, Zaijun Zhang.
      Amyotrophic lateral sclerosis (ALS) is an devastating neurodegenerative disorder with a very fast course and a very high fatality rate. The review discusses the intricate pathophysiology of ALS, such as the alterations caused by the genetic mutations of the C9orf72 and SOD1 genes, the misfolding and aggregation of proteins, oxidative stress, the excitotoxicity of glutamate, neuroinflammation, malfunctions in mitochondria, and axonal transport. Heterogeneity of the disease makes the development of biomarkers in ALS challenging; however, some promising candidates have been identified. Protein aggregation markers, including TDP-43 and SOD1, oxidative stress markers, such as 8-oxodG, neuroinflammatory markers, such as CRP and MCP-1, and neurological injury markers, such as NfL and pNfH, have potential in diagnosis, monitoring, and prediction. The miRNAs and particular metabolites can also provide clues to the molecular basis of ALS. The creation of biomarkers is challenged by the presence of a significant amount of disease heterogeneity and the lack of animal model reliability. The review highlights the importance of further research on biomarkers aimed at improving the diagnosis, treatment, and development of drugs for ALS. It supports the concept of a systematic biomarker development process, including genetic testing and molecular subgroup analysis, to enhance diagnostic accuracy and prognostic prediction capabilities. Exploring the interrelationship between the pathological process of ALS and the treatment based on multi-biomarker strategies is crucial for achieving effective management of this disease. As our understanding of ALS deepens, we expect to discover more new biomarkers in the future. This will significantly improve the diagnosis, treatment, and overall management of this devastating diseas.
    Keywords:  Amyotrophic lateral sclerosis; biomarkers; drug development; neuroinflammation; oxidative stress; pathological mechanisms
    DOI:  https://doi.org/10.2174/011570159X431460260227095109
  11. Brain Behav. 2026 May;16(5): e71498
    Quantitative Gait Analysis Reveals Distinct Patterns Associated With Pyramidal Involvement in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.
    Nan Hu, Ming Qi, Ning Su, Dingding Zhang, Jiangxia Zhang, Yun Xu, Kai Wang, Yuming Xu, Zhenzhong Li, Bo Hu, Lihua Wang, Bo Wu, Lan Chu, Yinzhou Wang, Hong Jiang, Zhengqi Lu, Jian Wu, Xiangmin Fan, Fei Han, Feng Tian, Jing Yuan, Mingsheng Liu, Yicheng Zhu.
       OBJECTIVE: To dissect specific gait abnormalities associated with upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS) by controlling for overall disease severity and to develop a multivariate classification model.
    METHODS: We performed 3D gait analysis on 118 ALS patients and 1796 healthy controls (HC). ALS patients were categorized into those with ALS with UMN dysfunction((ALS-UMN), n = 70) and those without ALS without UMN signs ((ALS-Numn), n = 48) lower limb UMN signs based on neurological examination. Gait parameters were compared, and their association with UMN involvement was analyzed using partial correlation (controlling for ALSFRS-R score) and machine learning models (Random Forest and Least Absolute Shrinkage and Selection Operator (Lasso) regression).
    RESULTS: Compared with HC, ALS patients exhibited widespread gait deterioration (e.g., reduced speed, increased step width, p < 0.001). After controlling for ALSFRS-R, specific parameters, including reduced stride, increased step width, prolonged double support, and elevated gait cycle time asymmetry, remained independently associated with UMN severity (PENN score, p < 0.01). A multivariate model incorporating key features demonstrated fair discriminative ability for identifying ALS-UMN patients, with an area under the curve (AUC) of 0.690, a sensitivity of 0.816, and a specificity of 0.418.
    CONCLUSION: Quantitative gait analysis reveals a distinct spatiotemporal pattern linked to UMN dysfunction in ALS. A model based on gait features shows potential, particularly high sensitivity, for identifying patients with pyramidal signs, supporting the exploratory utility of objective gait metrics for motor phenotyping in ALS, pending external validation.
    Keywords:  UMN dysfunction; amyotrophic lateral sclerosis; gait
    DOI:  https://doi.org/10.1002/brb3.71498
  12. medRxiv. 2026 May 04. pii: 2026.04.29.26350889. [Epub ahead of print]
    The New York Genome Center ALS Consortium resource integrates postmortem tissue transcriptomics and whole genome sequencing to empower biological discovery.
    NYGC ALS Consortium
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with substantial genetic and clinical heterogeneity that impedes therapeutic development. Large-scale multi-tissue genomic resources have transformed the study of neuropsychiatric and neurodegenerative diseases, but no equivalent resource exists for ALS. Here we present the full NYGC ALS Consortium dataset, combining whole-genome sequencing from 4,746 donors and bulk RNA-seq from 2,574 samples across 8 brain and spinal cord regions from 695 donors across the ALS disease spectrum. Our catalogue of small variants, structural variants, and short tandem repeats identified likely pathogenic mutations in 15.6% of ALS cases. Gene expression and mRNA splicing analysis across 5 major tissues reveals shared and region-specific features, highlighting microglial and T-cell dysregulation in the spinal cord. Mapping the genetic regulation of expression and splicing across tissues identified associations with 6 ALS risk loci, whereas allele-specific rare variant analysis detected expression effects for C9orf72 and OPTN . All data are immediately publicly available.
    DOI:  https://doi.org/10.64898/2026.04.29.26350889
  13. Free Radic Biol Med. 2026 May 19. pii: S0891-5849(26)00763-X. [Epub ahead of print]252 559-579
    Dysregulation of arginase and arginine pathways in neurodegenerative diseases: Metabolic and cellular dysfunction and therapeutic implications.
    Martyna Nalepa, Aleksandra Skweres, Michał Węgrzynowicz.
      Neurodegenerative diseases are increasingly recognized as disorders associated with metabolic dysfunction with arginine metabolism emerging as a significant contributor. Arginase, by regulating the balance between arginine and ornithine, is positioned at the crossroads of multiple arginine metabolic pathways, thereby controlling a variety of cellular processes essential for proper brain homeostasis. Chronic disruption of these pathways may lead to dysfunction of neurons and glia ultimately resulting in the induction of neurodegenerative processes. In this review, based on data from patients and experimental models, we synthesize and critically evaluate evidence demonstrating alterations in arginase isoenzymes and associated metabolic pathways in Alzheimer's Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. We discuss mechanisms through which dysregulation of arginase and arginine metabolism may contribute to neurodegeneration, including disturbances in nitrogen metabolism, oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Based on this body of evidence, we propose therapeutic strategies targeting arginase-related pathways, with the aim of preserving cellular metabolic homeostasis to ameliorate disease progression. Finally, we outline directions for future research, emphasizing that a proper understanding of the physiological roles of arginase isoenzymes and their disease-, stage-, and cell-specific dysregulation will be essential for the development of effective metabolically targeted therapies against neurodegenerative diseases.
    Keywords:  Alzheimer's disease; Ammonia; Amyotrophic lateral sclerosis; Arginase; Arginine; Huntington's disease; Neurodegeneration; Nitric oxide; Parkinson's disease; Polyamines; Urea
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.285
  14. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 20. 1-11
    Types and frequencies of adverse events across clinical trials for patients with amyotrophic lateral sclerosis: an analysis of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.
    Pooled Resource Open-Access ALS Clinical Trials Consortium
       OBJECTIVE: Symptoms of amyotrophic lateral sclerosis (ALS) may present as adverse events (AEs) in ALS clinical trials. Identifying anticipated AEs independent of investigational drug is crucial for trial design and required by the FDA for safety reporting and assessment in drug development. This study describes anticipated AEs and their predicted incidence in ALS trials, leveraging data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.
    METHODS: Placebo-treated people living with ALS (age ≥18 years, disease duration ≤36 months, ≥50% of predicted vital capacity at screening) were included. A confirmed diagnosis per the El Escorial criteria was required for a sensitivity analysis. Reported AEs were grouped based on pathophysiology and implications in clinical management and safety monitoring. AEs were further consolidated, with seven anticipated groups pre-specified for analysis. AE incidence proportions (IPs) and rates in person-years were estimated.
    RESULTS: The analysis included 1,388 participants (mean [SD] age: 56.8 [11.3] years; mean [SD] disease duration: 1.4 [0.6] years). IP was ≥5% for 24 AE groups, highest for falls and injuries (18.8%), headaches (13.5%), muscle weakness (13.1%), and gastrointestinal signs and symptoms (13.1%). Of seven pre-specified AE groups, falls, injuries, and fractures were the most frequent (23.0%), followed by severe respiratory failure and disorders including dyspnea (19.1%) and dysphagia (10.5%). Sensitivity analysis results were comparable (n = 931), although IPs were generally lower.
    CONCLUSIONS: These new findings will facilitate a systematic approach for safety monitoring and reporting in ALS trials, enable detection of true safety signals that may be obscured by these events, and support clinical development.
    Keywords:  Motor neurons degeneration; anticipated adverse events; drug safety; future trials; new treatments
    DOI:  https://doi.org/10.1080/21678421.2026.2667290
  15. Cureus. 2026 May;18(5): e109147
    Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.
    Ngo Cheung.
      Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurological disease with limited disease-modifying treatment options and, for many patients, a short survival window. The clinical course varies widely. Limb weakness, bulbar impairment, respiratory decline, fine-motor dysfunction, cognitive change, mood symptoms, and fatigue may each appear at different times and progress at different rates. This variability suggests that motor neuron loss alone may not fully explain the patient-level pattern of symptoms. This article is a narrative hypothesis framework, not a clinical guideline or a validated stratification tool. Established ALS biology, associative genomic findings, preclinical observations, computational predictions, and author-derived hypotheses are therefore separated throughout the article. This review brings together four interlinked studies by the current author as a primary hypothesis-generating corpus, which proposes that synaptic plasticity fragility may initiate a microglial pruning continuum shared by major depressive disorder and ALS, while ALS-specific progression may depend on mitochondrial stress, oxidized nicotinamide adenine dinucleotide (NAD+) compensation failure, and collapse of autophagy under aging-related limits. The model presented here maps symptom domains to vulnerable circuit compartments and separates three broad biological states: compensated plasticity, fragile plasticity, and network collapse. A compact mechanistic formulation is used to describe the balance between pruning pressure, glutamatergic burden, and aging stress on one side, and oxidative phosphorylation capacity, NAD+ reserve, and autophagic clearance on the other. The framework also incorporates opposing phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway patterns that may distinguish ALS from frontotemporal dementia (FTD) within an aging context. The result is a falsifiable, biomarker-oriented hypothesis model for future studies, not an evidence-based diagnostic or therapeutic algorithm.
    Keywords:  als–ftd spectrum; amyotrophic lateral sclerosis; autophagy; microglial pruning; mitochondrial dysfunction; nad+; precision neurology; synaptic plasticity
    DOI:  https://doi.org/10.7759/cureus.109147
  16. medRxiv. 2026 May 04. pii: 2026.05.04.26352054. [Epub ahead of print]
    Functional Activity of TDP-43: A Direct Biomarker for ALS.
    Kirti Shila Sonkar, Vito Levi D'Ancona, Jade Cramp, Hannah Shilling, Ellie Giles, Tyler Howell-Bray, Becky Fillingham, Merit E Cudkowicz, Avindra Nath, Jeffrey D Rothstein, Robert Bowser, Barbara Borroni, Alessandro Padovani, James D Berry, Ghazaleh Sadri Vakili, Emanuele Buratti, Ian P Thrippleton.
      TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA-binding activity using synthetic UU rich RNA probes. We analyzed 1,080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 ligation activity was elevated in ALS (mean 390 a.u.) versus controls (304 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); with a 366 a.u threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal likely reflects increased extracellular, probe-competent TDP-43 species. This assay provides direct functional measurement of disease-relevant TDP-43 biology, supporting applications in diagnostic discrimination, genotype stratification, and progression monitoring in prospective studies.
    DOI:  https://doi.org/10.64898/2026.05.04.26352054
  17. Rev Neurol (Paris). 2026 May 21. pii: S0035-3787(26)00525-4. [Epub ahead of print]
    Primary Lateral Sclerosis French National Diagnostic and Care Protocol.
    P Corcia, E Bernard, E de la Cruz, V Danel, M-H Soriani, N Guy, F Esselin, G Bruneteau, P-F Pradat, V Goutines, J Catherine, N Eyraud, P Cheve, A Fernandez, D Erazo, P Couratier.
      Primary lateral sclerosis (PLS) is a rare neurodegenerative motor neuron disease characterized by progressive and selective involvement of the central motor neuron within the bulbar and spinal regions. It is estimated to account for 1-5% of motor neuron diseases and typically presents in the fifth or sixth decade of life, with a slight male predominance. According to current consensus criteria, the diagnosis relies on the demonstration of progressive upper motor neuron dysfunction in the absence of lower motor neuron involvement, with persistence of isolated upper motor neuron signs for at least four years in order to exclude a slowly progressive upper motor neuron-predominant form of amyotrophic lateral sclerosis (ALS). The French Motor Neuron Disease Network (FILSLAN) developed a National Diagnostic and Care Protocol (PNDS) with the aim of standardizing diagnostic criteria, optimizing differential diagnosis, and providing evidence-based recommendations for therapeutic management and follow-up across the national territory. These recommendations were elaborated in accordance with the methodological framework of the French National Authority for Health for rare diseases. The protocol provides practical guidance for establishing PLS as a diagnosis of exclusion, distinguishing it from ALS and hereditary spastic paraplegias, and organizing appropriate clinical and paraclinical investigations. It also outlines indications for genetic testing in selected cases and defines a multidisciplinary management strategy centered on symptomatic treatment, early rehabilitation, respiratory and nutritional surveillance, and psychosocial support. Given the slower progression of PLS compared with ALS, biannual multidisciplinary follow-up is generally appropriate. This protocol aims to harmonize clinical practice and improve patient care while acknowledging the current absence of disease-modifying therapies.
    Keywords:  Diagnostic criteria; Multidisciplinary management; Primary lateral sclerosis; Upper motor neuron disease
    DOI:  https://doi.org/10.1016/j.neurol.2026.04.006
  18. Ann Clin Transl Neurol. 2026 May 20.
    Evaluation of Digital Technologies for Home-Based Assessment in People With Amyotrophic Lateral Sclerosis.
    Arne Mueller, Vanessa Vallejo, Mónica Povedano Panadés, Orla Hardiman, Véronique Danel-Brunaud, Senda Ajroud-Driss, Philippe Couratier, Jeremy Shefner, Anna Gokey, Mike DiCesare, Erin Lennox, Jens Praestgaard, Lucie Brujin, Peggy Allred, Ram Miller.
       OBJECTIVE: Digital technologies hold promise for transforming healthcare by enhancing personalized treatments and offer valuable opportunities to improve patient care. Here, we evaluated several novel, self-administered, home-based, digital endpoints for their association with corresponding conventional standard clinical measures (primary) in people living with Amyotrophic Lateral Sclerosis (ALS).
    METHODS: This was a longitudinal study in people with ALS who were followed up to 9 months. A total of 33 participants were enrolled in the study. At each of six visits, participants were evaluated with a battery of conventional standard measurements to determine ALS disease progression and quality of life. Between visits, participants performed weekly home-based self-assessments with digital health technologies (DHT) and self-administered ALSFRS-R. Cross-sectional analysis of DHTs anchored to ALSFRS-R and longitudinal analyses were performed and compared to standard clinical measures.
    RESULTS: Of the 33 participants, 20 completed the study, and 13 discontinued before completing the planned 9-month follow-up mainly due to disease progression. The distribution of various digital metrics in home-based assessments corresponded well with the sub-scores of ALSFRS-R in the cross-sectional analyses, with the strongest construct validity for digital speaking rate. In the longitudinal analysis, a weak but significant trend in most metrics was observed, with the strongest trend in the duration of the Timed Up and Go (high variability between participants).
    INTERPRETATION: The findings from this study provide insights into the potential of digital endpoints to evaluate people living with ALS with the goal of reducing the burden of study participation and improving the efficiency of ALS clinical trials.
    Keywords:  ALS functional rating scale‐revised; ALSFRS‐R; amyotrophic lateral sclerosis; digital endpoints; home‐based; self‐administered
    DOI:  https://doi.org/10.1002/acn3.70429
  19. Hum Vaccin Immunother. 2026 Dec;22(1): 2664985
    Immunotherapeutic landscape of amyotrophic lateral sclerosis: A bibliometric analysis of research trends, translational priorities, and collaboration networks (2006-2025).
    Ming Zhang, Wenshuo Yang, Junxin Wang, Biqi Zou, Jialin C Zheng, Qihui Wu, Ge Gao.
      Amyotrophic lateral sclerosis (ALS) remains a major therapeutic challenge, with immune dysregulation increasingly recognized as a critical driver of disease progression. Despite extensive mechanistic research, no immunotherapeutic approach has achieved consistent disease-modifying effects, raising questions about whether this translational gap reflects biological complexity or structural misalignment within the research ecosystem. To characterize the intellectual evolution of ALS immunotherapeutics research, identify immune targets with translational potential, and evaluate collaboration patterns that may influence translational efficiency, we performed a bibliometric analysis of 2,256 publications indexed in Web of Science and Scopus using network-based approaches including co-citation clustering, keyword co-occurrence, and citation burst detection implemented in CiteSpace, VOSviewer, and R-Bibliometrix. Publication output increased 8.4-fold over the study period, delineating three developmental phases. Thematic analyses revealed a shift from early emphasis on microglial biology and SOD1-based models toward recent focus areas including the gut-brain axis, C9orf72-associated immune dysregulation, and advanced immunomodulatory strategies. Collaboration networks remain predominantly regional despite strong contributions from the United States, Europe, and Asia, with limited integration between mechanistic research groups and clinical trial consortia. Among immune-directed therapeutic strategies, regulatory T cell modulation and microglial-targeted approaches exhibit the highest translational readiness. These findings suggest that the lack of effective ALS immunotherapeutics reflects not only biological complexity but also structural and strategic misalignment within the research ecosystem. This bibliometric analysis provides a systems-level framework to guide more integrated translational strategies in ALS immunotherapeutics development.
    Keywords:  Amyotrophic lateral sclerosis; C9orf72 repeat expansion; clinical translation; immunotherapeutics; neuroinflammation; regulatory T cells
    DOI:  https://doi.org/10.1080/21645515.2026.2664985
  20. Curr Neuropharmacol. 2026 May 16.
    Interplay of NMDAR and AMPAR in the Pathophysiology of Alzheimer's, Parkinson, ALS, Huntington's, and Epilepsy: An Update in Therapeutic Perspective.
    Diksha Tiwari, Arghya Mukherjee, Santosh Singh.
      Glutamate-mediated excitotoxicity is a central driver of neurodegeneration and represents a shared pathogenic mechanism across neurodegenerative diseases and epilepsy, with N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-tors (AMPARs) occupying central roles in synaptic plasticity, Ca²⁺ signalling, and neuronal survival. Dysregulation of these receptors disrupts the balance between pro-survival and pro-death pathways, accelerating neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lat-eral sclerosis (ALS), Huntington's disease (HD), and epilepsy. Disease-specific triggers converge on common patterns of receptor dysregulation, including a shift toward extrasynaptic NMDAR signal-ling and the pathological emergence of Ca²⁺-permeable AMPARs (CP-AMPAR), ultimately driving synaptic failure and neuronal loss. Although numerous NMDAR and AMPAR-directed modulators have demonstrated neuroprotective efficacy in preclinical models, clinical translation has been lim-ited by inadequate spatial, kinetic, and subunit selectivity, as well as adverse effects arising from the disruption of physiological glutamatergic transmission. In this review, we synthesize the literature published between June 1990 and March 2025 to develop an integrative framework that links recep-tor localization, downstream Ca²⁺-dependent signalling, astrocytic regulation, mitochondrial dys-function, and disease progression across these disorders. By critically evaluating both successful and failed therapeutic strategies, we provide insight into evident research gaps in the field and the neces-sity of addressing them to develop precise multi-target approaches at both the genetic and cellular levels as next-generation therapeutics. Such an approach would be essential to move beyond indis-criminate receptor blockade strategies, which have repeatedly proven ineffective over the decades, and towards a future of durable neuroprotection.
    Keywords:  Alzheimer’s disease; Neurodegeneration; Parkinson’s disease; amyotrophic lateral sclerosis; epilepsy; huntington’s disease
    DOI:  https://doi.org/10.2174/011570159X466249260418090832
  21. Curr Opin Pharmacol. 2026 Apr 27. pii: S1471-4892(26)00028-7. [Epub ahead of print]88 102632
    Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.
    Ahmed M Abd-Eldayem, Renad A Mohammed.
      Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, Riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer's disease (AD), Huntington's disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of Riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in Riluzole pharmacology and outlines key considerations for future mechanistic and translational research.
    DOI:  https://doi.org/10.1016/j.coph.2026.102632
  22. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 21. 1-6
    Strengthening care and research in ALS in Southeast Asia: a call for action.
    Wai Yee Fung, Sheila Agustini, Jakkrit Amornvit, Josiah Chai, Ludwig F Damian, Nurul Fadli, Dk Hjh Norazieda Pg Hj Mohd Yassin, Southanalinh Keovilayhong, Dhayalen Krishnan, Kongkiat Kulkantrakorn, Minh Duc Nguyen Tran, Kay Ng, Hoang T T Nghia, Ohnmar Ohnmar, Dayangku Siti Nur Ashikin Pengiran Tengah, Mario Prado, Rabani Remli, Arada Rojana-Udomsart, Tu Quoc Le Tuan, Ahmad Yanuar, Nortina Shahrizaila.
      In Southeast Asia (SEA), healthcare resources, infrastructure, and access to therapies in amyotrophic lateral sclerosis (ALS) remain limited compared to other parts of the Asia-Pacific region. Many SEA countries continue to face delays in diagnosis, fragmented care pathways, and limited representation in international research. Beyond health system challenges, ALS in SEA may also differ biologically. Emerging studies suggest that genetic variants and clinical phenotypes in Asian populations are not fully mirrored in Western cohorts. In this report, the authors summarize their country-specific background and status of care in ALS as well as their consensus on future strategies and actions. Key short- and long-term strategies are proposed, highlighting the critical need for regional collaboration and patient engagement to advance ALS care and research in the region.
    Keywords:  Amyotrophic Lateral Sclerosis; Southeast Asia; epidemiology; genetics; research
    DOI:  https://doi.org/10.1080/21678421.2026.2671159
  23. J Neurosci. 2026 May 19. pii: e1803252026. [Epub ahead of print]
    COMMD1 Induces Copper Deficiency of SOD1 by Inhibiting the Palmitoylation of CCS in ALS.
    Xiaoli Su, Xingli Tan, Ying Wang, Weiwei Liang, Di Wang, Di Huo, Hongyong Wang, Yan Qi, Wenmo Zhang, Ling Han, Dongmei Zhang, Ming Wang, Jing Xu, Shuyu Wang, Jing Wang, Honglin Feng.
      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-1α)/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.Significance Statement Superoxide dismutase 1 (SOD1) was the first identified mutant gene associated with amyotrophic lateral sclerosis (ALS). Mutations in SOD1 compromise its metal-binding function, resulting in neuronal apoptosis, a hallmark of ALS pathogenesis. Utilizing the SOD1G93A models of ALS, our findings revealed that COMMD1 deficiency significantly elevates copper incorporation into SOD1, consequently attenuating cellular apoptosis. These results suggest that targeted inhibition of COMMD1 could represent a potential therapeutic strategy for ALS treatment.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1803-25.2026
  24. Curr J Neurol. 2025 Jan 04. 24(1): 16-22
    Translation and psychometric validation of the Persian version of amyotrophic lateral sclerosis cognitive behavioral screen (ALS-CBS) and revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R).
    Elnaz Naserzadeh, Nahid Olfati, Saeed Akhlaghi, Maryam Emadzadeh, Azra Rashidnezhad, Shahriar Nafissi, Farzad Fatehi, Payam Sarraf, Bahram Haghi-Ashtiani, Bentolhoda Ziaadini, Behnaz Ansari, Ali Asghar Okhovat, Keivan Basiri, Reza Boostani.
      Background: The Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen (ALS-CBS) and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) are widely recognized tools for evaluating cognitive, behavioral, and functional changes in patients with amyotrophic lateral sclerosis (ALS). Given the increasing number of ALS cases in Persian-speaking communities, there is a critical need for culturally and linguistically adapted versions of these instruments. The objective of this study was to translate the ALS-CBS and ALSFRS-R into Persian and evaluate their validity and reliability to ensure their applicability in clinical practice and research. Methods: The Persian versions of the ALS-CBS and ALSFRS-R questionnaires were developed using the translation-back translation method. The translated questionnaires were administered to 36 individuals diagnosed with ALS. To assess content validity, neuromuscular specialists evaluated each item based on relevance, clarity, simplicity, necessity, and comprehensiveness, using content validity ratio (CVR) and content validity index (CVI) measures. Internal consistency reliability was assessed using Cronbach's alpha coefficient. Test-retest reliability was evaluated using the intra-class correlation coefficient (ICC). Statistical analysis was conducted using SPSS software. Results: All questionnaire items demonstrated satisfactory face validity after expert-guided revisions. The minimum acceptable values for CVI (≥ 0.78) and CVR (≥ 0.62) were achieved by correcting items that initially scored below the threshold. Reliability analysis revealed ICC values of 0.969 and 0.816 for the cognitive and behavioral sections of the ALS-CBS, respectively, and 0.909 for the ALSFRS-R. Cronbach's alpha coefficients were 0.791 for the ALS-CBS behavioral section and 0.825 for the ALSFRS-R, indicating acceptable internal consistency. Conclusion: The Persian versions of the ALS-CBS and ALSFRS-R have been shown to be both valid and reliable. These adapted tools provide valuable resources for assessing the cognitive, behavioral, and functional status of patients with ALS in Persian-speaking populations, ultimately supporting more accurate diagnosis, monitoring, and disease management.
    Keywords:  Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen; Amyotrophic Lateral Sclerosis Functional Rating Scale; Behavioral; Cognition; Functional; Reliability and Validity
    DOI:  https://doi.org/10.18502/cjn.v24i1.20299
  25. Eur J Med Chem. 2026 May 14. pii: S0223-5234(26)00396-X. [Epub ahead of print]315 118951
    Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.
    Maciej Czuba, Katarzyna Szafrańska, Marcin Kolaczkowski, Monika Marcinkowska.
      TRPML1, a lysosomal Ca2+ channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics.
    Keywords:  Lysosomal dysfunction; Lysosomal storage disorders; Neurodegenerative diseases; Protein aggregates; TRPML1 agonist
    DOI:  https://doi.org/10.1016/j.ejmech.2026.118951
  26. Muscle Nerve. 2026 May 18.
    Lessons Learned From a Feasibility Study of Longitudinal Palliative Care for Patients With Amyotrophic Lateral Sclerosis.
    Jocelyn Zwicker, Ian C Smith, Shirley H Bush, Jill Rice, Rebekah Murphy, Ari Breiner, Usha Buenger, Belinda Zehrt, Jodi Warman-Chardon, Christine L Watt.
       INTRODUCTION/AIMS: The benefits of initial palliative care (PC) consultation for patients with amyotrophic lateral sclerosis (ALS) have been previously described. The aim of this study was to explore the evolution of PC needs of patients with ALS over time through analysis of PC follow-up visits.
    METHODS: Patients followed at a multidisciplinary ALS clinic received PC consultations and follow-ups between October 2020 and April 2022. All patients who received at least one PC follow-up visit were included in this study. Physician documentation of the visits was analyzed for sub-themes and topics. Topics discussed during visits and visit frequency were examined in the context of patient variables.
    RESULTS: The 26 patients had at least one PC follow-up visit (range 1-12 visits). Topics of discussion varied by individual rather than disease status and were often discussed repeatedly. Compared to initial consultations, follow-up visits featured more frequent discussion of sialorrhea and less frequent discussion of constipation, pain, and prognosis (all p < 0.05). Care coordination was discussed in 82% of follow-ups. Time between follow-up visits shortened as the disease progressed. Medical assistance in dying (MAID) was discussed by 31% of patients either at initial consultation or follow-up.
    DISCUSSION: Each individual with ALS has unique PC needs. PC specialist resource planning should anticipate higher frequency visits for patients later in the disease course. Given the importance of care coordination and the scarcity of PC specialists, we recommend further study of effective models of care coordination. We recommend that PC specialists be comfortable counseling patients on MAID.
    Keywords:  amyotrophic lateral sclerosis; longitudinal study; motor neuron disease; palliative care
    DOI:  https://doi.org/10.1002/mus.70283
  27. J Soc Work End Life Palliat Care. 2026 May 16. 1-27
    Living Outside the ALS Home - Everyday Experiences, Challenges and Needs of Adult Children with a Parent with ALS.
    Lene Olesen, Stine Kaysen Moèll, Lone Knudsen.
      Adult children of a parent with ALS may be highly burdened and in need of support, but studies of their experiences and needs are scarce. The aim of this study was to explore everyday experiences, challenges and needs of adult children living outside the home of a parent with amyotrophic lateral sclerosis (ALS). The design was qualitative using Interpretive Description methodology and Sense of Coherence as framework. Focus group interviews were conducted with 16 adult children. Participants experienced changes in relationship and roles with siblings and parents when ALS moved into the family. Their parents' disease evoked a need for understanding ALS and its trajectory as the disease raised questions, concerns, and sorrow. Furthermore, having a parent with ALS led to strong and mixed emotions and dilemmas like bad conscience, self-blame, gratitude and closeness and wanting to be there but also not being able to bear witnessing the deterioration of their parent. Adult children experience profound challenges and needs related to their parent's disease. They need information and support from professionals and peers as they struggle to balance the demands related to ALS and everyday life with family, work and leisure. Professionals should provide support for this vulnerable group who appear highly burdened practically and emotionally by the situation.
    Keywords:  Adult children; amyotrophic lateral sclerosis; everyday challenges; family caregivers; motor neuron disease
    DOI:  https://doi.org/10.1080/15524256.2026.2672970
  28. Stud Health Technol Inform. 2026 May 21. 336 173-177
    Environmental Personal Exposure Clusters to Investigate Multiple Sclerosis and Amyotrophic Lateral Sclerosis Progression.
    Pietro Bosoni, Mahin Vazifehdan, Helena Aidos, Inês Alves, Giovanni Birolo, Guglielmo Faggioli, Sergio González-Martínez, Marta Gromicho, Aleksandar Jovanović, Borko Kostić, Enrico Longato, Umberto Manera, Eleonora Tavazzi, Erica Tavazzi, Riccardo Bellazzi, Roberto Bergamaschi, Maria Fernanda Cabrera, Adriano Chiò, Mamede de Carvalho, Barbara di Camillo, Piero Fariselli, Nicola Ferro, Sara C Madeira, Arianna Dagliati.
      Reliable prognosis in Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) is hampered by data scarcity and variability. Beyond clinical variables, evidence suggests that environmental data can help capture disease trajectories. We investigated whether personal environmental measures can be organized into stable patterns that inform prognosis. In a multicenter cohort, 293 patients with MS or ALS were equipped with Atmotube air-quality sensors. We normalized volatile organic compound (VOC) time series and computed Dynamic Time Warping distances to capture temporal similarity. Hierarchical clustering yielded five daily exposure clusters, which were profiled using Atmotube variables (season, day type, humidity, temperature) and patient self-reports (work status, time outdoors), and evaluated by day-level differences between personal and fixed-station variables. These clusters can support interpolation of missing wearable intervals and generation of context-aware exposure estimates, thereby strengthening environmental inputs for prognostic modeling in MS and ALS.
    Keywords:  Environmental Data; Exposure Trajectories; Sclerosis; Wearable Device
    DOI:  https://doi.org/10.3233/SHTI260131
  29. J Neuroeng Rehabil. 2026 May 19.
    The use of high-density surface electromyography in amyotrophic lateral sclerosis: a scoping review.
    Patricia A Bayer, Steven J O'Bryan, Hannah J Thomas, Alessandro Del Vecchio, Gayatri Jain, Dario Farina, Alessandra Ferri.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in muscle weakness and atrophy. This neuronal loss is partially compensated for by the collateral sprouting of surviving motor neurons, leading to the formation of enlarged motor units (MUs). These MU adaptations, together with hyperexcitability and altered descending messages from the brain, lead to altered characteristics of the MU action potential shape and discharge pattern, that can be captured using high-density surface electromyography (HDsEMG). The aim of this review is to survey all available literature, investigating how HDsEMG has been used in ALS, and highlight differences in methods and outcomes to allow comparison between studies.
    METHODS: A systematic literature search was conducted using four databases (PubMed, Scopus, IEEE Xplore, and Academic Search Ultimate) to identify studies employing HDsEMG in individuals diagnosed with ALS. Eligible studies were reviewed to examine experimental protocols, hardware and software configurations and reported outcome measures.
    RESULTS: Out of 168 identified articles, 26 were included in this review. High heterogeneity was observed in recording methods, analysis, and reporting strategies. Based on measurable features of MU behaviour and morphology, the outcomes reported in the studies were grouped into five main categories: fasciculations, MU properties, MU discharge characteristics, multiple discharges and number of MUs.
    CONCLUSIONS: HDsEMG represents a promising non-invasive technique that allows for repeated, longitudinal measurements as well as the detection of multiple MUs and their individual analysis, the potential of which has not been fully explored. HDsEMG has a strong potential for clinical use in ALS, but its application should first be based on a clear understanding of disease pathophysiology. The findings of this review highlight the urgent need for a consensus on standardised protocols and reporting practices for the application of HDsEMG in ALS research, along with the development of methods that can sensitively indicate disease-specific physiological changes to improve comparability, reproducibility. This understanding will improve how HDsEMG findings are interpreted and support the translation of HDsEMG into a diagnostic tool.
    Keywords:  Amyotrophic lateral sclerosis; High-density surface electromyography; Motor neuron disorder; Motor unit
    DOI:  https://doi.org/10.1186/s12984-026-02022-6
  30. Muscle Nerve. 2026 May 20.
    Improving ALS Clinic Care Through Experience-Based Co-Design: A Participatory Action Research Study.
    Ambereen K Mehta, Sonya U Steele, Isha Shah, Kevin Wang, Ashley Booth, Christy Swain, Aparna Desai, Karishma A Popli, Nicholas J Maragakis, Rebecca Wright.
       INTRODUCTION/AIMS: Multidisciplinary clinics (MDCs) are the standard of care for amyotrophic lateral sclerosis (ALS), yet little is known about how well they meet patient and care partner needs, or how stakeholder engagement can be used to strengthen these services. The aim of this study was to explore the experiences of people living with ALS (pALS), care partners (cALS), and staff in an ALS MDC to identify care gaps and collaboratively develop improvement strategies.
    METHODS: We conducted a six-stage experience-based co-design (EBCD) study comprising narrative interviews with pALS, cALS, and ALS clinic staff, followed by validation events and co-design workshops. Data were analyzed using reflexive thematic analysis. Priority areas for improvement were identified through collaborative ranking and translated into actionable interventions through iterative working groups.
    RESULTS: A total of 11 pALS, eight cALS, and 10 clinic staff participated. Two shared priority domains were identified: (1) communication and relationships across the care continuum, and (2) navigational and supportive resources. Stakeholders unanimously identified communication and relationships between cALS and staff as the highest priority for improving MDC care delivery. Key strategies included pre-visit orientation materials, pacing information delivery aligned with patient readiness, and incorporating digital tools to enhance flexible access to resources.
    DISCUSSION: Curated, iterative education is essential for pALS and cALS across the disease trajectory. Improvement strategies developed through equitable stakeholder partnership may yield different, and potentially more patient-centered priorities for ALS MDC care delivery than strategies developed by any single stakeholder group alone.
    Keywords:  amyotrophic lateral sclerosis; experience‐based co‐design; multidisciplinary care; participatory research; patient experience; quality improvement
    DOI:  https://doi.org/10.1002/mus.70279
  31. Front Neurol. 2026 ;17 1762900
    The neuroprotective effects of Dexmedetomidine: key mechanisms focusing on neuronal programmed cell death.
    Jinxin Pan, Hui Yang.
      In the central nervous system (CNS), programmed cell death (PCD) of neurons, is precisely regulated by various biomolecules to maintain neuronal development, establish neural structures, and maintain CNS homeostasis. Under the stimulation of pathologic factors, the abnormal cascade of PCD signals leads to irreversible damage to neuronal cells, resulting in the occurrence and progression of neurological deficits and neurodegenerative diseases (NDDs). Dexmedetomidine (DEX), a selective α2-adrenoceptor agonist, is widely used for relieving anxiety, sedation, and pain management in clinical anesthesia and critical care. A growing body of research confirms that DEX has neuroprotective effects, including reducing postoperative agitation and pain, protecting the blood-brain barrier, maintaining hemodynamic stability, minimizing neuronal damage, and alleviating neuroinflammation and oxidative stress. In this study, we will summarize the neuroprotective effects of DEX in various CNS diseases, with a focus on its regulatory role and molecular mechanisms in neuronal PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, and parthanatos. We also explored the therapeutic potential of PCD as a target and strategy to underpin the neuroprotective effects of DEX.
    Keywords:  Dexmedetomidine; neurodegenerative diseases; neuron; neuroprotection; programmed cell death
    DOI:  https://doi.org/10.3389/fneur.2026.1762900
  32. Clin Neurol Neurosurg. 2026 May 12. pii: S0303-8467(26)00172-1. [Epub ahead of print]268 109480
    Comment on "Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis".
    Madhuri Tribhuvan, Shashikant N Phatke.
      
    Keywords:  Amyotrophic lateral sclerosis; Environmental risk factors; Gene-environment interaction; Neurodegeneration; Traumatic head injury
    DOI:  https://doi.org/10.1016/j.clineuro.2026.109480
  33. Stud Health Technol Inform. 2026 May 21. 336 879-883
    Evaluating the Role of Order and Time Information for Classifying Sequences of Healthcare Events Derived from Claims Data.
    Corentin Faujour, Stéphane Bouee, Corinne Emery, Anne-Sophie Jannot.
      Sequences of healthcare events from claims data are increasingly used for predictive modeling. Despite the rise in popularity of neural networks, the benefit of modeling event order and timing remains underexplored. We simulated patient trajectories using parameters estimated from claims data including 22,000 amyotrophic lateral sclerosis (ALS) cases and 22,000 age and gender-matched controls. The simulation reproduced irregular event timing and condition-related activity that increased near an incident diagnosis. We compared three model families for population classification: frequency-based models, sequential models (long short-term memory and Transformer architectures) capturing event order, and sequential models incorporating temporal information. Performance was evaluated using the area under the ROC curve (AUC) at multiple time points before diagnosis. Sequential models outperformed frequency-based baselines by about +0.06 AUC on average, confirming the benefit of modeling event order. Adding time information provided no noticeable improvement, and results were stable across different time encoding and scaling methods. These findings suggest that, in claims-based classification tasks, event order captures most of the useful temporal signal, while explicit time encoding offers limited additional benefit under similar conditions.
    Keywords:  Claims Data; Healthcare Event Sequences; Neural Networks; Sequence Classification; Temporal Features
    DOI:  https://doi.org/10.3233/SHTI260305
  34. Fluids Barriers CNS. 2026 May 16. pii: 74. [Epub ahead of print]23(1):
    Transport pathways across the blood-brain barrier for waste clearance and drug delivery.
    Lea S Gröbner, Claus U Pietrzik.
      The blood-brain barrier (BBB) displays a highly organized and complex structure, which is important for maintaining brain homeostasis and protecting the brain from foreign molecules or pathogens. Receptor-mediated transcytosis (RMT) is one of the main delivery pathways across the BBB for molecules that cannot pass the barrier via, e.g. paracellular diffusion. For understanding the treatment options in neurodegenerative diseases such as Alzheimer´s disease (AD), it is important to investigate transport pathways and mechanisms at the BBB for a potential delivery of drugs, antibodies or other compounds across the BBB. This review provides an overview of the different transport variants across the BBB and how they can be targeted in order to promote internalization or secretion into or out of the brain. Therefore, we want to focus on two characterized proteins: the low-density lipoprotein receptor-related protein 1 (LRP1), which is a key mediator of amyloid β (Aβ) clearance from the brain during AD, and transferrin receptor 1 (TfR1), which is already used as a target for antibody-delivery into the brain. Additionally, this review discusses two other important proteins, which have been less frequently addressed in research regarding transport mechanisms: P-glycoprotein (P-gp) as another transporter at the BBB and proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol homeostasis which promotes the degradation of the low-density lipoprotein receptor (LDLR) and LRP1. For these four main proteins, we aim to highlight existing approaches for targeting or inhibiting the aforementioned receptors or proteins. The approaches enable a higher penetration of the BBB, a better distribution in the brain, and ultimately fewer side effects of antibodies or nanoparticles. Here, we include lecanemab, trontinemab, dual TfR/CD98hc shuttles, evolocumab and alirocumab, immunoliposomes and other nanoparticles targeting TfR1 or LRP1. We will further highlight approaches which differ from these common ideas and demonstrate the current state of the art regarding drug delivery and waste clearance across the BBB.
    Keywords:  Antibody modification; Blood-brain barrier; Drug delivery; LRP1; Nanocarrier; Neurovascular unit; PCSK9 inhibitors; TfR1; Transcytosis; Waste clearance
    DOI:  https://doi.org/10.1186/s12987-026-00812-7
  35. Clin Chim Acta. 2026 May 19. pii: S0009-8981(26)00276-7. [Epub ahead of print]590 121094
    Exosomal miRNA in cerebrospinal fluid as biomarkers for neurodegenerative disease.
    Mubarak A Alamri, Muhammad Afzal, Surya Nath Pandey, Obaid Afzal, Mohamed Ahmed Akela, A Rekha.
      Cerebrospinal fluid protein biomarkers, such as the Aβ42/Aβ40 ratio, phosphorylated tau, and neurofilament light chain, have significantly advanced the diagnostic process for Alzheimer's disease. Nonetheless, these biomarkers face challenges in effectively distinguishing Alzheimer's disease from frontotemporal dementia or Parkinson's disease from dementia with Lewy bodies. This limitation arises from overlapping protein profiles and the variability inherent in immunoassay techniques. A complementary class of analytes is exosomal microRNAs in cerebrospinal fluid, where these non-coding RNAs are secreted by neurons, astrocytes, and microglia, are resistant to RNase degradation, and have a disease-specific expression pattern. This review critically evaluates the existing evidence of cerebrospinal fluid exosomal miRNAs as diagnostic biomarkers in Alzheimer's disease, frontotemporal dementia, Parkinson's disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Exosome isolation techniques and detection platform characteristics were compared using RT-qPCR, droplet digital PCR, and small RNA sequencing. Pre-analytical factors, such as collection protocols, hemolysis contamination, freeze-thaw cycling, and circadian sampling variation, were assessed. miRNA profiling data based on disease stratification, receiver operating characteristic performance of the combinatorial panel, and strategies combining exosomal miRNAs with core cerebrospinal fluid proteins were synthesized. This article brings together disease-specific miRNA signatures, pre-analytical standardization needs, and diagnostic accuracy analyses in a translational model to fill the literature gap and form the basis for developing exosomal miRNA panels for rigorously validated clinical laboratory practice.
    Keywords:  Biomarker; Cerebrospinal fluid; Differential diagnosis; Exosomal microRNA; Neurodegenerative disease; Pre-analytical variables
    DOI:  https://doi.org/10.1016/j.cca.2026.121094
  36. bioRxiv. 2026 May 05. pii: 2026.04.30.722019. [Epub ahead of print]
    Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.
    Neelam Shahani, Rupkatha Banerjee, Courtney MacMullen, Neelam Sharma, Mohammad Habibi, Henry D Wasserman, Nathaniel C Noyes, Puhan Zhao, Bahaa Elgendy, Michael D Cameron, Thomas D Bannister, Lamees Hegazy, Brian N Finck, Ronald L Davis.
      Mitochondrial (MT) dysfunction is a key driver of ALS pathology. Without a healthy MT system, motor neurons (MN) function at sub-optimal levels and die. In addition, other effects of ALS, like axon/dendrite degeneration, may occur from a pathophysiological cascade spurred by MT dysfunction. A phenotypic screen identified Dipyridamole (DPM), an FDA-approved and safe drug, as having extraordinary effects on ALS patient induced pluripotent stem cell (iPSC)-derived MNs. The drug prevented MT fragmentation, loss of MT content, impaired MT bioenergetics, axon/dendrite degeneration, and premature MN death, extending neuronal survival by more than fivefold. Importantly, its efficacy extended across iPSC-derived neurons representing two different familial forms of ALS (C9orf72, TDP43) and Alzheimer's disease (PSEN1), implying broad neuroprotection across ALS forms and other neurodegenerative diseases. DPM increased MT respiration and pyruvate uptake in a mechanism requiring the Mitochondrial Pyruvate Carrier (MPC), mechanistically explaining its biological activities. Thus, DPM is a promising drug to repurpose or refine for treating neurodegenerative diseases or other diseases that would benefit by augmenting pyruvate uptake into MT.
    Teaser: Dipyridamole, an FDA-approved drug, restores mitochondrial function and protects neurons in ALS and Alzheimer's disease.
    DOI:  https://doi.org/10.64898/2026.04.30.722019
  37. Digit Health. 2026 Jan-Dec;12:12 20552076261452405
    The effects of a mobile healthcare application on speech and swallowing in amyotrophic lateral sclerosis.
    Yeongju Cho, Sun Young Won, Hyanghee Kim, Hye Kyoung Lee, Sung-Rae Cho.
       Background: Amyotrophic lateral sclerosis (ALS) impairs oral motor function, negatively affecting patients' speech and swallowing abilities, as well as quality of life.
    Objective: This study aims to evaluate the effectiveness of A Successful Swallowing with Effortful Training (ASSET) program, included in the 'The 365 Healthy Swallow Health Coach application' in preserving speech and swallowing abilities in ALS patients through self-training.
    Methods: In this 8-week quasi-experimental study, 13 participants were allocated to either the app-guided ASSET training group (n=7; three sessions per day, five days per week) or a usual-care control group (n=6) based on their clinical visit schedules. To evaluate changes over time and compare the two groups, linear mixed models were employed. Changes in ALS severity scale (ALSSS), Diadochokinetic (DDK) task, speech intensity, Speech Handicap Index-15, Dysphagia Handicap Index, Swallowing Quality of Life (SWAL-QOL), and Brief Inventory of Swallowing Assessment-15 were assessed.
    Results: ALSSS speech scores was relatively preserved from 5.43 (95% CI 3.01-7.84) to 5.29 (95% CI 2.87-7.70) in the ASSET treatment group, but declined from 6.33 (95% CI 3.73-8.94) to 4.83 (95% CI 2.23-7.44) in the control group, with a significant group-by-time interaction (p=.017). DDK/tuh/and/kuh/were relatively preserved from 11.86 to 11.71 and from 12.29 to 11.57 respectively in ASSET group, but declined from 11.67 to 7.50 and from 11.83 to 7.17 in the control group, with significant interactions in/tuh/(p=.032) and/kuh/(p=.044). SWAL-QOL total score was relatively preserved from 155.86 to 149.71 in ASSET group, but declined from 154.67 to 125.17 in the control group, with a significant interaction (p=.011).
    Conclusions: The findings suggest that ASSET program may help preserve speech and swallowing function in patients with ALS. Future research should validate the ASSET program with a larger, adequately powered sample size.
    Keywords:  amyotrophic lateral sclerosis; mobile healthcare; quality of life; speech; swallowing
    DOI:  https://doi.org/10.1177/20552076261452405
  38. Curr Top Med Chem. 2026 May 11.
    Molecular Mechanisms of Neurodegeneration: A Focus on Cholinergic Dysfunction and the Therapeutic Potential of Rivastigmine Derivatives.
    Kuldeep Singh, Pranshul Sethi, Divya Jain, Jeetendra Kumar Gupta, Zaid Waqar, Bhupendra Singh, Rukhsar Syed, Mohammad Tabish, Mukesh Chandra Sharma.
      Neurodegenerative diseases progressively impair neuronal structure and function, leading to cognitive decline, motor dysfunction, and paralysis. Among the underlying mechanisms, cholinergic dysfunction-characterized by degeneration of cholinergic neurons and reduced acetylcholine (ACh) levels-plays a central role in disease progression, particularly in Alzheimer's disease (AD) and Parkinson's disease (PD). According to the cholinergic hypothesis, memory loss and cognitive impairment are directly linked to disrupted ACh-mediated neurotransmission. Rivastigmine, a dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor, enhances synaptic ACh levels but is limited by a short half-life, modest efficacy, and gastrointestinal side effects. This review highlights the molecular mechanisms underlying cholinergic dysfunction, including oxidative stress, mitochondrial impairment, protein aggregation, neuroinflammation, and synaptic dysregulation, while emphasizing rivastigmine and its derivatives as emerging therapeutic candidates. Structural modifications of rivastigmine have yielded multifunctional derivatives with improved selectivity, blood-brain barrier penetration, and neuroprotective properties, including antioxidant, anti-amyloid, and anti-inflammatory activities. These advances suggest that rivastigmine derivatives could serve as promising multi-targeted agents for neurodegenerative disorders. Future directions include integrating these compounds with nanotechnology-based delivery systems and precision medicine approaches to overcome pharmacokinetic limitations and optimize patient outcomes.
    Keywords:  Acetylcholine; Alzheimer’s disease; Cholinergic dysfunction; Drug derivatives; Molecular mechanisms; Neurodegenerative diseases; Neuronal degeneration; Rivastigmine; Synaptic plasticity.
    DOI:  https://doi.org/10.2174/0115680266380856251204044937
  39. ACS Chem Neurosci. 2026 May 22.
    Kinetics and Spatial Distribution of β-Sheet Development in TDP-43CTD Condensate Maturation.
    Sashary Ramos, Matthew D Watson, Jennifer C Lee.
      Cytosolic inclusions of aggregated TAR DNA-binding protein 43 (TDP-43) are hallmarks of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. A prevailing hypothesis suggests that TDP-43 condensates undergo a liquid-to-solid transition during maturation, involving the formation of β-sheet-rich, amyloid-like aggregates. To test this hypothesis, we sought to study the temporal and spatial evolution of protein secondary structure within individual condensates by Raman spectroscopy. We measured in vitro β-sheet development of the C-terminal domain of TDP-43 (TDP-43CTD) at the single-condensate level under physiological solution conditions. All condensates showed apparent single-exponential kinetics (k = 1.6 × 10-5 s-1) for the disordered-to-β-sheet transformation, as indicated by increased amide-I intensity and a shift of the amide-III band to lower energy. Interestingly, the water bend-libration band exhibited a slower rate (k = 4.0 × 10-6 s-1), suggesting that changes in the water environment lag behind protein conformational rearrangement. Further, Raman maps revealed that protein density is highest near the condensate center, whereas β-sheet content is mostly uniform in the interior of the condensate. The unexpected difference between the spatial distributions of β-sheet content and protein density challenges the typical concentration-dependent model of protein aggregation. Importantly, rare events were captured where condensates exhibited spatially asymmetric β-sheet development, revealing localized structural heterogeneity not detectable by ensemble measurements. Collectively, these results provide insight into the temporal and spatial dynamics of protein structure within TDP-43CTD condensates and demonstrate the utility of Raman spectral imaging for tracking condensate maturation.
    Keywords:  Raman microspectroscopy; amide-I; amide-III; amyotrophic lateral sclerosis; bend-libration; phase separation; secondary structure
    DOI:  https://doi.org/10.1021/acschemneuro.6c00226
  40. Drug Metab Dispos. 2026 Apr 17. pii: S0090-9556(26)00073-5. [Epub ahead of print]54(6): 100304
    Peptide-mediated delivery of an α-synuclein-targeting antisense oligonucleotide: Pharmacokinetics, safety, and central nervous system efficacy in a synucleinopathy model.
    Rijwan U Ahammad, Bao Quach, Sahar Salehi, Robert A Rissman, Brian Spencer.
      Effective blood-brain barrier penetration is a major challenge for antisense oligonucleotide (ASO) therapies targeting neurodegenerative diseases. We utilized an 11-amino acid peptide derived from apolipoprotein B (ApoB11) that binds the low-density lipoprotein receptor to cross the blood-brain barrier, to deliver an ASO systemically to the central nervous system (CNS) and suppress targeted transcripts in neurodegenerative disease models. This study evaluates the pharmacokinetics, CNS penetration, and therapeutic efficacy of ApoB11:2'-O-methyl ASO-α-Syn, an ASO for α-synuclein (α-Syn) suppression in synucleinopathies. After a single intraperitoneal injection (2 mg/kg) in C57BL/6 mice, ApoB11:ASO-α-Syn showed robust brain penetration, reaching peak concentrations (maximum concentration [Cmax] = 0.14 nmol/mg) at 1.5 hours and persisting at high levels over the 96-hour observation period, indicating prolonged CNS retention. Immunofluorescence confirmed widespread uptake in neurons and endothelial cells. The ASO also accumulated in the liver (Cmax = 419.5 nmol/mg, t1/2 = 104.9 hours), consistent with receptor-mediated uptake. Acute and subacute toxicity studies revealed no systemic toxicity at the highest nonlethal dose (32 mg/kg). In a mouse model of dementia with Lewy bodies overexpressing human α-Syn, ApoB11:ASO-α-Syn reduced α-Syn mRNA and protein levels in the hippocampus and cortex by ∼50% at 16 mg/kg, a reduction that is biologically meaningful based on human genetic evidence (SNCA duplications/triplications) and preclinical studies. These results demonstrate that ApoB11 is an effective ASO carrier for CNS delivery, and that partial α-Syn reduction is expected to have disease-relevant effects, supporting its potential as a therapeutic strategy for synucleinopathies. SIGNIFICANCE STATEMENT: This study demonstrates that systemically delivered ApoB11-conjugated antisense oligonucleotides effectively cross the blood-brain barrier, achieve sustained central nervous system retention, and produce a biologically meaningful reduction (∼50%) in α-synuclein expression in a transgenic mouse model of synucleinopathy. These findings highlight a minimally invasive, peptide-mediated strategy for targeting neurodegenerative diseases and overcoming major delivery limitations of antisense oligonucleotide therapies.
    Keywords:  Antisense oligonucleotide; Blood-brain barrier; Central nervous system; Pharmacokinetics; Systemic delivery; α-Synuclein
    DOI:  https://doi.org/10.1016/j.dmd.2026.100304
  41. bioRxiv. 2026 May 07. pii: 2026.05.04.722731. [Epub ahead of print]
    High prevalence of CNS-directed autoantibodies in patients with schizophrenia.
    Katlyn Nemani, Jillian R Jaycox, Ugur Akcan, Benjamin M Schuman, Sung M Yeon, Nina Harano, Kai Qin, Alison A Notestine, Sean M Carroll, Brent S McKenzie, Leon Furchtgott, Adrienne C Lahti, Richard W Tsien, Dritan Agalliu, Donald C Goff, Aaron M Ring.
      Schizophrenia is a severe neuropsychiatric disorder whose etiology and biological heterogeneity remain poorly understood. Immune dysregulation has long been implicated, but the breadth and clinical significance of autoantibody responses remain unclear beyond rare individual examples. Here we use Rapid Extracellular Antigen Profiling-a proteome-scale assay for autoantibodies against extracellular and secreted proteins-to profile 352 individuals with schizophrenia and 971 community controls. We find that schizophrenia is marked by a striking elevation in extracellular autoantibody burden, present near disease onset, and approaching nearly twice control levels in the most severely ill patients. This burden increases with age in a pattern that diverges from controls and targets central nervous system antigens, including neuroactive receptors, neuronal ion channels, proteins involved in synaptic function, and blood-brain barrier integrity. Autoantibodies against blood-brain barrier antigens impair barrier function ex vivo and are associated with broader central nervous system autoreactivity, supporting a model in which barrier disruption promotes loss of tolerance to brain antigens. At the clinical level, higher baseline autoantibody burden predicts reduced responsiveness to the antipsychotic risperidone, suggesting that autoantibodies contribute to treatment resistance. Together, these findings identify humoral autoimmunity as a pervasive component of schizophrenia and imply that therapies that reset humoral immunity or reduce autoantibody burden may benefit patients beyond those with currently recognized antibody-mediated syndromes.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.05.04.722731
  42. Commun Biol. 2026 May 19.
    ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons.
    Caoimhe Kerins, Ivo Lieberam, Eileen Gentleman.
      Perineuronal nets (PNNs) are extracellular matrix structures that stabilise synaptic inputs and play a role in regulating neuronal plasticity. Although PNN dysregulation is observed in several neurological disorders, their relevance to amyotrophic lateral sclerosis (ALS) remains unclear. In particular, the extent to which PNN alterations reported in ALS animal models are motor neuron (MN)-intrinsic is unknown. We investigated whether human pluripotent stem cell-derived MNs form PNN-like structures in vitro, and whether ALS-associated mutations alter this process. We show that PNN-like structures containing hyaluronan, tenascin-R, and aggrecan form in in vitro co-cultures of iPSC-derived MNs and astrocytes, and that their formation and gene expression were not altered by ALS mutations. To explore whether PNN dysregulation reflects contributions from other cell types or selective MN vulnerability, we conducted meta-analyses of transcriptomic datasets from pluripotent stem cell-derived astrocytes carrying ALS-associated mutations, as well as datasets comparing MN populations with differential susceptibility to ALS. These analyses revealed no consistent differences in PNN-related gene expression within human stem cell-derived MNs. In contrast, transcriptomic analyses of human post-mortem ALS tissues revealed dysregulation of PNN-related genes, including core PNN components. Taken together, these findings indicate that PNN-related alterations described in ALS animal models are not reproduced by ALS-associated mutations in MNs alone, and instead point to a role for additional cellular components within the central nervous system.
    DOI:  https://doi.org/10.1038/s42003-026-10244-6
  43. Antiinflamm Antiallergy Agents Med Chem. 2026 May 15.
    Immunomodulatory Nanocarriers in Multiple Sclerosis: Dual Targeting of Microglia and Mitochondria for Precision Neurotherapy.
    Ayushi Bhandari, Shikha Baghel Chauhan, Indu Singh, Chirag Jain.
      The chronic neuroinflammatory and neurodegenerative disease known as Multiple Sclerosis (MS) is characterized by mitochondrial dysfunction and ongoing microglial activation. Developments in nanomedicine have enabled the design of immunomodulatory nanocarriers that target mitochondria and microglia simultaneously, thereby addressing two key pathogenic characteristics. By delivering antioxidants and anti-inflammatory drugs straight to microglia and their mitochondria, these systems increase the effectiveness and specificity of treatment. This review summarizes preclinical research on nanocarriers for delivery to the central nervous system, including liposomes, polymeric nanoparticles, dendrimers, amphiphilic polymer nanoparticles, and modified exosomes, for the years 2020-2025. Functionalized liposomes containing microglia-specific peptides or Toll-like receptor 4 ligands can boost microglial uptake by up to five times, which causes cells to adopt anti-inflammatory characteristics. By incorporating antioxidants such as coenzyme Q₁₀ and N-acetylcysteine, and by using polymeric nanoparticles with mitochondrial- targeting groups, such as triphenyl phosphonium, these nanoparticles improve blood-brain barrier penetration and restore mitochondrial function. Dendrimers and exosomes facilitate effective intracellular and mitochondrial transport, reducing oxidative stress and inflammatory signaling, whereas amphiphilic polymer nanoparticles target scavenger receptors to decrease protein aggregation and neuroinflammation. In MS models, dual-targeting nanocarriers that combine mitochondrial repair and microglial modulation exhibit synergistic neuroprotective effects. Even with promising preclinical findings, there are still obstacles to overcome to achieve clinical translation, scale up production, and ensure long-term safety. Early microglial modulator experiments using sophisticated delivery devices show promise. Finally, dual-targeting immunomodulatory nanocarriers present a new precision neurotherapy strategy for multiple sclerosis. Sustained improvement of clinical pathways, safety, and pharmacokinetics may revolutionize therapeutic approaches and enhance patient outcomes.
    Keywords:  Multiple sclerosis; dual-targeted delivery systems; immunomodulatory nanocarriers; liposomes.; microglia targeting; mitochondrial dysfunction
    DOI:  https://doi.org/10.2174/0118715230437703251219204750
  44. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 21. 1-9
    Clinical characterization and natural history of ALS8/VAPB p.Pro56Ser: upper motor neurone signs, survival, and functional milestones in 78 patients.
    Christian Marques Couto, Elisa De Melo Queiroz, Waneska Souza Lima, Savana Camilla De Lima Santos, Osvaldo José Moreira Nascimento.
       OBJECTIVE: Amyotrophic lateral sclerosis type 8 (ALS8), caused by the VAPB p.Pro56Ser mutation, is a rare familial motor neurone disease with an incompletely characterized profile. We aimed to characterize the clinical phenotype, upper motor neurone (UMN) sign prevalence, survival, and functional milestones.
    METHODS: We retrospectively analyzed 78 patients with ALS8 confirmed via molecular testing or familial linkage analysis from 57 apparently unrelated families. UMN signs were assessed using a five-item composite of pyramidal signs. Survival and milestones were estimated using Kaplan-Meier analysis.
    RESULTS: Median age at onset was 44.9 years; 51% were men. Onset was lumbar in 94%, proximally predominant. UMN signs were present in 53 patients; none exhibited clonus. At admission, 51% had spinal-onset ALS, 42% progressive muscular atrophy (PMA) and 6% flail leg; 30% of patients with PMA subsequently developed UMN signs. Survival was 21.9 years; times to wheelchair dependence and noninvasive ventilation were 7.0 and 10.0 years, respectively. Bulbar involvement occurred in 17 (21.8%) patients, predominantly as dysphonia. UMN status did not affect survival (p = 0.312). The standardized mortality ratio was 4.54 (95% CI 2.77-7.01), supporting disease-related excess mortality.
    CONCLUSIONS: ALS8 is a slowly progressive motor neurone disease with lumbar onset, ascending progression, and frequent but subtle UMN signs. Survival was markedly prolonged but functional decline followed a predictable sequence. These findings expand the phenotypic characterization of ALS8 and support genetic counseling and anticipatory management.
    Keywords:  ALS8; VAPB; motor neuron disease; progressive muscular atrophy; upper motor neuron signs
    DOI:  https://doi.org/10.1080/21678421.2026.2674020
  45. Curr Genomics. 2025 ;26(6): 469-494
    Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.
    Zaid Waqar, Pranshul Sethi, Divya Jain, Kuldeep Singh, Omar Awad Alsaidan, Sami I Alzarea, Jeetendra Kumar Gupta, Swati Saxena, Mukesh Chandra Sharma.
      Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by the pathological aggregation of proteins such as amyloid-β, tau, and alpha-synuclein. These hallmark proteins play central roles in disease progression and represent promising targets for therapeutic intervention. Advances in precision medicine, driven by genomic technologies such as CRISPR-Cas systems, RNA-based therapies, and high-throughput sequencing, have enabled the development of tailored strategies to modulate these pathological pathways. This review examines the integration of genomic approaches in targeting amyloid-β, tau, and alpha-synuclein, emphasizing their potential to mitigate disease progression and improve patient outcomes. We highlight current progress in preclinical and clinical studies, discuss challenges associated with translating these therapies into clinical practice, and explore future directions for achieving therapeutic precision in neurodegenerative disorders. By examining the interplay of genetic, molecular, and therapeutic innovations, this review underscores the transformative potential of genomic medicine in addressing the unmet needs of neurodegenerative disease treatment.
    Keywords:  CRISPR-Cas; Precision medicine; alpha-synuclein; amyloid-β; genomic therapies; neurodegenerative diseases; tau
    DOI:  https://doi.org/10.2174/0113892029372437251010114053
  46. ACS Nano. 2026 May 18.
    Neutrophil-Like Mitochondria Enable Blood-Brain Barrier Transmigration and Neuroprotection.
    Namjo Shin, Yina Wu, Jinwon Park, Junho Byun, Seongsoo Lee, Wooin Lee, Jaiwoo Lee, Yu-Kyoung Oh.
      Mitochondrial transplantation has emerged as a promising therapeutic strategy for neurological diseases associated with mitochondrial dysfunction. However, its application to central nervous system (CNS) disorders remains limited by the restrictive nature of the blood-brain barrier (BBB). Here, we report neutrophil-like mitochondria (nePM@Mito), engineered by coating isolated mitochondria with neutrophil plasma membranes to facilitate CNS delivery. By presenting neutrophil-derived surface adhesion molecules, nePM@Mito interact with endothelial receptors and recapitulate key features of neutrophil transendothelial migration, facilitating BBB crossing via endothelial exocytosis. In a mouse model of Parkinson's disease, intravenous administration of nePM@Mito leads to pronounced CNS accumulation and attenuation of oxidative stress. Delivered mitochondria restore mitochondrial function and increase tyrosine hydroxylase expression in dopaminergic neurons of the substantia nigra, resulting in elevated dopamine levels and improved motor performance. Notably, neutrophil membrane functionalization endows mitochondria with CNS-homing capability while preserving their intrinsic biological activity. The neutrophil-like mitochondrial delivery strategy provides a versatile platform for overcoming BBB limitations and offers a promising therapeutic approach for neurodegenerative diseases involving mitochondrial dysfunction.
    Keywords:  Parkinson’s disease; blood−brain barrier; mitochondrial transplantation; neuroprotection; neutrophil-like mitochondria
    DOI:  https://doi.org/10.1021/acsnano.5c22296
  47. Prog Mol Biol Transl Sci. 2026 ;pii: S1877-1173(26)00016-5. [Epub ahead of print]222 207-228
    Artificial intelligence in multi-omics analysis of neurological diseases.
    Karamveer, Basant K Tiwary.
      The integration of multi-omics data using Artificial Intelligence (AI) is rapidly transforming the landscape of neurological disease research. As our understanding of complex brain disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and schizophrenia deepens, there is an ever-increasing demand for sophisticated tools for handling and interpreting high-dimensional biological data. In this chapter, we explore the integration of AI and multi-omics in neurobiology, describing the evolution of AI techniques from classical rule-based systems to cutting-edge deep learning frameworks and foundation models. We provide a comprehensive guide to matching specific omics combinations with appropriate AI methods to answer targeted neuroscientific questions, discuss major neurological disease-specific databases and resources, and present detailed case studies that highlight the real-world potential and clinical translation of these approaches. Additionally, we address the existing technical, ethical, and interpretability challenges that must be overcome for successful clinical implementation. By the end of this chapter, readers will be equipped with both theoretical knowledge and practical guidance to choose and apply appropriate AI tools in multi-omics neurological disease research.
    Keywords:  Artificial intelligence; Deep learning; Machine learning; Multi-omics; Neurological diseases
    DOI:  https://doi.org/10.1016/bs.pmbts.2026.01.016
  48. Compr Physiol. 2026 Jun;16(3): e70165
    Dynamic Modulation of the Gut Microbiome in Neurodegenerative Diseases: Mechanisms, Therapeutic Potential, and Clinical Perspective.
    Shilpa Devi, Nabendu Debnath, Pooja Yadav, Shree Satyavolu, Ashok Kumar Yadav, Neetu Tyagi.
      The gut and brain communicate bidirectionally through the gut microbiota, forming a complex network often referred to as the "microbiota-gut-brain axis." The gastrointestinal microbiome produces various metabolites, including short-chain fatty acids (SCFAs), tryptophan-derived compounds, and secondary bile acids. Research indicates that disruptions in the intestinal microbiota (dysbiosis) and impaired gut-brain axis are associated with various neurological conditions. The central nervous system (CNS) influences digestive processes via the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). On the other hand, the gut reciprocally affects brain function through microbial metabolites, neuroactive substances, and intestinal hormones via multiple pathways, including neural (vagal), immune, and endocrine signaling; however, only a subset of metabolites can directly access the CNS due to blood-brain barrier (BBB) selectivity. These microbial metabolites can directly or indirectly influence the CNS and modulate neuro-immune signaling by activating receptors, such as the aryl hydrocarbon receptor (AhR) and G protein-coupled receptors (GPCRs). By acting as ligands for these receptors, metabolites modulate neural signaling and exert neuroprotective effects. This review discusses how probiotic-derived metabolites modulate the gut-brain axis and provide neuroprotective effects, focusing on the receptors they activate and their downstream signaling pathways involved in neuroprotection.
    Keywords:  G protein‐coupled receptors (GPCRs); circadian rhythm; dysbiosis; gut microbiome; neuroinflammation; probiotic; short‐chain fatty acids (SCFAs); tryptophan metabolites
    DOI:  https://doi.org/10.1002/cph4.70165
  49. Neuroscience. 2026 May 20. pii: S0306-4522(26)00341-6. [Epub ahead of print]
    TDP-43: a critical amplifier of Alzheimer's disease beyond amyloid and tau.
    Abhideep Roy, Sushila Chhetry, Hiramoni Deka, Rubina Roy, Pallab Bhattacharya, Basant Kumar Patel, Anupom Borah.
      TAR DNA-binding protein 43 (TDP-43) proteinopathy has recently emerged as a pivotal, yet underrecognized, contributor to the multifaceted neuropathology of Alzheimer's disease (AD). While amyloid-β and tau have long been established as cardinal pathological hallmarks, growing evidence delineates TDP-43 as a critical participant of neurodegeneration, intricately interwoven with amyloid and tau pathologies. TDP-43 mislocalization, post-translational modifications, and aggregation potentiate neuronal loss through disruption of RNA metabolism, nucleocytoplasmic transport, and protein homeostasis. This tripartite interplay manifests in synergistic and possibly multidirectional pathological cascades that amplify neuronal vulnerability and cognitive decline, thereby complicating the clinical and pathological complexity of AD. Here, we critically reviewed the mechanistic crosstalk among TDP-43, amyloid-β, and tau, focusing on preclinical and clinical evidence, highlighting possible convergent pathways of aggregation, propagation, and neurodegeneration. Moreover, this review also evaluates mitochondrial dysfunction, autophagy failure, and inflammation as underlying events associated with TDP-43 pathology. Therefore, we argue for a reconceptualization of AD as a dynamic proteinopathy network, with TDP-43 as a core integrative node influencing disease onset and its progression. Notably, we discuss emerging diagnostic modalities associated with molecular tracers of TDP-43, providing prospects for future biomarker identification. Finally, this review articulates the translational relevance of TDP-43 therapy in AD and related neurological disorders, emphasizing the necessity of holistic approaches that transcend the traditional amyloid-tau paradigm to effectively tackle the full spectrum of AD pathobiology.
    Keywords:  Amyloid beta; Autophagy; Inflammation; Mitochondrial dysfunction; Protein Aggregates; Tau
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.05.024
  50. Muscle Nerve. 2026 May 22.
    Embedding Palliative Care Clinicians in ALS Teams Improves ALS Clinicians' Confidence in Their Patient Management and Satisfaction With Palliative Care.
    Astrid Grouls, Yaowaree L Leavell, Ambereen K Mehta, Gayle Kojimoto, David L O'Riordan, Samuel Maiser, Benzi M Kluger, Steven Z Pantilat, Kara E Bischoff.
       INTRODUCTION/AIMS: Specialty palliative care (SPC) can improve symptoms and well-being for people living with ALS. Few studies capture how ALS clinicians utilize or are impacted by SPC. We sought to understand how the presence of SPC clinicians on ALS teams impacts ALS clinicians' referrals to and satisfaction with SPC.
    METHODS: We conducted a survey of interdisciplinary ALS clinicians to understand their confidence in their team's care, SPC referral patterns, and satisfaction with SPC. We compared responses from ALS clinicians with and without SPC in their team.
    RESULTS: 141 ALS clinicians completed the survey, having primarily neurology, nursing, and therapy backgrounds. ALS clinicians who had SPC embedded in their team reported more confidence in their team's ability to address pain (63.3% v 37.4%, p < 0.001), dyspnea (88.8% v 70.8%, p = 0.05), and end-of-life needs (71.4% v 52.1%, p = 0.005). They reported fewer SPC referral barriers and referred to SPC for different reasons. ALS clinicians with SPC on their team were more satisfied with SPC's ability to help with motor symptoms (92.7% v 71.4%, p = 0.02), dyspnea (98.3% v 86.7%, p = 0.04), and care coordination (90.0% v 73.5%, p = 0.04).
    DISCUSSION: The presence of SPC embedded within multidisciplinary ALS teams is associated with ALS clinicians feeling more confident in their team's ability to address certain care needs, more satisfied with the care provided by SPC, and experiencing fewer barriers to involving SPC. Additional research should explore how embedding SPC on ALS teams impacts patient outcomes.
    Keywords:  amyotrophic lateral sclerosis; neuromuscular disease; specialty palliative care
    DOI:  https://doi.org/10.1002/mus.70291
  51. Bioinformation. 2026 ;22(3): 1673-1678
    Blood - brain barrier breakdown and neurovascular unit failure in the progression of Alzheimer's disease.
    Suvarna Prasad, Sangeeta Gupta, Asha Premlata Omega Oraon, Ana Paula Molina Recalde, Jessica Julieta Cañarte Moreira, Génesis Nathalie Moyano Salazar, Paolo David Torres Cañarte, Camila Inés Racines Navas.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β deposition and tau pathology. Recent research highlights the role of blood-brain barrier (BBB) breakdown and neurovascular unit (NVU) dysfunction in disease initiation and progression. These factors contribute to neuroinflammation, cerebral hypoperfusion and impaired waste clearance. Despite this, the relationship between BBB integrity, NVU function and cognitive decline in AD remains inadequately understood. Data shows that blood-brain barrier disruption and neurovascular unit dysfunction are critical predictors of cognitive decline in Alzheimer's disease.
    Keywords:  Alzheimer's disease (AD); Blood-brain barrier (BBB); cerebral perfusion; cognitive impairment; neurovascular unit (NVU)
    DOI:  https://doi.org/10.6026/973206300221673
  52. Muscle Nerve. 2026 May 18.
    Perceptions of Speech-Language Pathology Care in Amyotrophic Lateral Sclerosis: A Patient-Centered Exploratory Study.
    Jennafer D Best, Mario A Landera, Ruixuan Ma, Bridget J Perry.
       INTRODUCTION/AIMS: Given limited research on patient perspectives of speech-language pathology (SLP) services in ALS care, this study aimed to assess the satisfaction with, and understanding of, SLP services by people with ALS (pwALS) and to examine the alignment between services received and patient-reported impairments.
    METHODS: A cross-sectional survey assessing pwALS' perceptions of SLPs was distributed from October 2024 to January 2025 through electronic mailing lists of relevant professional organizations. A questionnaire examined pwALS' understanding of the SLP role, satisfaction levels, alignment between patient-reported impairments and SLP interventions, and perceived gaps in care. Responses were analyzed using descriptive statistics, with open-ended items analyzed using qualitative analysis.
    RESULTS: The 81 survey respondents consisted of pwALS (81.5%), caregivers (11.1%), family members (4.9%), and others (2.5%). Overall satisfaction with SLP care was high, though open-ended responses revealed gaps in understanding. Many were unaware of the full scope of SLP services; only 17.3% recognized cognitive evaluation and 8.6% cognitive therapy, compared with speech (77.8%) and swallowing (81.5%) evaluations. Reported services often did not align with communication and swallowing needs, but patients educated about a service were significantly more likely to use it.
    DISCUSSION: Overall satisfaction with SLP care was high; however, open-ended responses revealed gaps in understanding, unmet needs, and limited awareness of the full scope of SLP services. This misalignment highlights the need for improved patient and caregiver education regarding the role and timing of SLP involvement to enhance engagement, appropriate service use, and outcomes in ALS care.
    Keywords:  ALS; dysarthria; dysphagia; multidisciplinary care; speech‐language pathologist
    DOI:  https://doi.org/10.1002/mus.70286
  53. Brain Nerve. 2026 May;78(5): 417-425
    [Antibiotic Penetration into the Central Nervous System: Decoding the Blood: Brain Barrier and Antibiotics through "Structure" to Inform Therapeutic Strategy].
    Yukio Takeshita.
      Clinical outcomes of central nervous system (CNS) infections are determined by not only pathogen coverage but also whether an antibiotic can cross the blood-brain barrier (BBB) to achieve sufficient exposure at the target site. The BBB is a prototypical example of "organ-specific vascular specialization" established by (1) the non-fenestrated nature and tight junctions of cerebral capillary endothelial cells and (2) endothelial cell regulation by pericytes and astrocytes. Therefore, CNS penetration of antibiotics should be understood as an interaction between physicochemical properties of drugs (lipophilicity, molecular weight, ionization state, and polarity) and the BBB state throughout the disease course (from the acute inflammatory phase to post-resolution). To assist readers in estimating passive BBB permeability simply by inspecting structural formulas, we provide a practical workflow-from identifying key functional groups (red-circle annotation) to a three-tier ("likely to pass," "may pass during inflammation," and "unlikely to pass under usual conditions") classification-and demonstrate workflow efficacy using four representative compounds. Reasons why meningeal gadolinium enhancement on magnetic resonance imaging cannot be taken as direct "proof" of antibiotic penetration are summarized, and treatment strategies from acute phase through recovery are discussed.
    DOI:  https://doi.org/10.11477/mf.188160960780050417
  54. J Am Psychoanal Assoc. 2026 May 18. 30651261442465
    Pay No Attention to the Man Behind the Curtain.
    Bruce Reis.
      This paper will raise critical concerns regarding the utilization of artificial intelligence (AI) in psychoanalysis-in and around clinical settings and in its literature. The author will explore fantasies about AI on the part of patients and analysts alike. While AI may be intended for particular purposes, the author will explore how we will regularly misuse machine learning and in addition how the very large companies behind these programs will seek to use them to their own ends. The author will explore the effects of AI on users, the simulation of emotion and relationship and how, especially for certain types of people, this can represent a dangerous situation.
    Keywords:  AI; danger situations; robot overlords
    DOI:  https://doi.org/10.1177/00030651261442465
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