bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–10–18
sixty papers selected by
Luca Bolliger, lxBio
  1. Assessing the metabolic rate in patients with Amyotrophic Lateral Sclerosis, Progressive Muscular Atrophy, and Primary Lateral Sclerosis.
  2. Neurovascular Modulation of the Blood-brain Barrier Using Focused Ultrasound for Antisense Therapy Delivery in Amyotrophic Lateral Sclerosis.
  3. Vascular profiling of the spinal cord and cortex reveals region-specific endothelial dysfunction and fibroblast remodeling in human ALS.
  4. DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.
  5. All Roads Lead to Rome: Resting-State Criticality as a Neurophysiological Marker of Brain-Computer Interface (BCI) Performance in People with Amyotrophic Lateral Sclerosis (ALS) and Healthy Participants.
  6. Bullous Pemphigoid in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Study of 1,067 Cases.
  7. Phenotypic Profiling of SOD1-G93A Mice: Integrating Sciatic Nerve Histopathology with Systemic Chemokine Dynamics During ALS Progression.
  8. Isolated Axoplasm from Squid and Pathogenic Mechanisms in Amyotrophic Lateral Sclerosis.
  9. Diagnostic evolution of carbonic anhydrase 3 (CA3) in Amyotrophic Lateral Sclerosis (ALS): an emerging prognostic biomarker.
  10. Crossing the Blood-brain Barrier: Emerging Nanotechnological Approaches for Neurodegenerative Disease Therapy.
  11. Statin Exposure and Survival Outcomes in Amyotrophic Lateral Sclerosis in an Asian Cohort.
  12. Combined rituximab and magnesium acetyl taurate therapy attenuates neurodegeneration via ERK/c-JNK/P38MAPK signaling modulation in methylmercury-induced amyotrophic lateral sclerosis-like neurotoxicity.
  13. Short-term Classification of Neurodegenerative Diseases using Time-series Features Based on Analysis of Gait Dynamics.
  14. Prognostication in Amyotrophic Lateral Sclerosis: A Narrative Review of Pre-Diagnosis and Functional Outcomes.
  15. The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.
  16. Mapping the evidence on dignity therapy in amyotrophic lateral sclerosis: a scoping review.
  17. CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.
  18. Transcutaneous Carbon Dioxide Monitoring in Amyotrophic Lateral Sclerosis: A Scoping Review.
  19. Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.
  20. History of Head Injury and Risk of Amyotrophic Lateral Sclerosis: An Updated Comprehensive Systematic Review with Meta-Analysis of 5,033,215 Participants.
  21. Needs and Expectations of ALS Patients and Caregivers: An Integrated Perspective.
  22. ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways.
  23. Motor Neuron Disease in a Dish: The Power of Human Induced Pluripotent Stem Cell-Derived Spinal Motor Neurons and Glial Cells.
  24. HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.
  25. Serum neurofilament and measures of lower motor neuron dysfunction in amyotrophic lateral sclerosis.
  26. Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.
  27. Multiple sclerosis occurrence with gut microbial metabolites and sex hormones.
  28. Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions.
  29. Partial convergence of alternative polyadenylation changes across ALS-Associated RNA-Binding proteins.
  30. Restoring Neural Homeostasis via Class II HDAC Modulation: Mechanistic Insights and Therapeutic Opportunities.
  31. Exploring potential genetic correlation and causality between cathepsins and neurodegenerative diseases: Insight from Mendelian randomization analyses.
  32. Brain-computer interfaces and neuroprostheses for severe speech impairment in amyotrophic lateral sclerosis.
  33. Ethical Dilemmas in Predictive Testing for Monozygotic Twins With Hereditary ALS: A Clinical Case Report.
  34. Salivary Dim-Light Melatonin Onset is Associated with Functional Decline, Respiratory Symptom Emergence, and Survival in Early Amyotrophic Lateral Sclerosis.
  35. "Morphological, Functional, and Molecular Progression of Blood-Brain Barrier Dysfunction in Alzheimer's Disease".
  36. Multimodal MRI insights into glymphatic clearance and blood-brain barrier integrity in healthy aging.
  37. Intracranial metastasis as a mimic of amyloid-related imaging abnormalities.
  38. Ataxin-2 downregulation rewires neuronal and astrocytic metabolism to protect against TDP-43 toxicity.
  39. The Gut-Brain Axis and Neurodegenerative Diseases: From Mechanistic Pathways to Therapeutic Interventions.
  40. An integrative transcriptomic atlas of ALS and aging skeletal muscle defines shared and distinct molecular programs of degeneration.
  41. Sigma-1 Receptor Mitigates Poly-GR-Associated Redox Dysregulation by Restoring NRF2/HO1 Signaling in C9orf72-Associated ALS.
  42. Targeting the Gut to Modify Parkinson's Disease: From Mechanisms to Potential Therapeutics.
  43. Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery.
  44. Immunosenescence as a modifiable driver of neurodegenerative diseases: Pathways and multidimensional emerging strategies for Alzheimer's and Parkinson's diseases.
  45. An acoustic-only multivariable diagnostic model for Parkinson's disease using bowel sound acoustic signatures.
  46. Post-traumatic dementia: Advances in understanding neurodegenerative mechanisms.
  47. Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.
  48. [Effect of electroacupuncture at Jiaji (EX-B2) on disease progression in mice with amyotrophic lateral sclerosis based on NLRP3/Caspase-1/ASC signaling pathway].
  49. Bee-Derived Products in Neurodegenerative Diseases: Bioactive Constituents, Redox-Modulating Mechanisms, Evidence, and Translational Perspectives.
  50. Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.
  51. An Interpretable Framework for Identifying EEG Spectral Biomarkers of Pathological Brain Aging.
  52. Targeting the microbiota-gut-brain axis in Alzheimer's and Parkinson´s disease: recent therapeutic approaches.
  53. New insight into Alzheimer's disease: small molecule-Aβ in the brain transport and peripheral organ clearance.
  54. Association Between Neuropsychological Test Performance and Neuroimaging Findings in Cognitive Impairment: A Retrospective Cohort Study.
  55. Multiple Sclerosis During Pregnancy and the Postpartum Period: Diagnostic and Multidisciplinary Challenges in Two Cases.
  56. Neuroimmune Dynamics of the Microglia-astrocyte Axis: Implications for Neurodegenerative Disorders as a Double-edged Sword.
  57. NAD+ signaling in Parkinson's disease: molecular mechanisms and therapeutic perspectives.
  58. Artificial intelligence algorithms for the prediction of cognitive decline and dementia: A theoretical-historical narrative review.
  59. Atomistic simulation of blood-brain barrier permeability of propolis-derived natural compounds.
  60. Histopathology-correlated evaluation of magnetic resonance spectroscopy for high-grade glioma prediction: A small-scale neuro-oncology study with exploratory machine learning.
  1. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Oct 12. 1-10
    Assessing the metabolic rate in patients with Amyotrophic Lateral Sclerosis, Progressive Muscular Atrophy, and Primary Lateral Sclerosis.
    Mark R Janse van Mantgem, Merle M Kuiper, Frederik J Steyn, Cory J Holdom, Myrte Meyjes, Annemieke Kok, Shyuan T Ngo, Leonard H van den Berg, Ruben P A van Eijk.
       OBJECTIVE: To determine whether resting energy expenditure (REE) differs between patients with amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).
    METHODS: Patients with ALS, PMA, and PLS were enrolled between 2017 and 2021 in a prospective cross-sectional study. REE was measured by indirect calorimetry. Body composition was assessed using air displacement plethysmography and used to calculate predicted resting energy expenditure (pREE). Metabolic index (MI) was defined as mREE relative to pREE and expressed as a percentage. Differences between disease categories were assessed using multivariable regression adjusted for sex, age, fat-free mass, fat mass, height, and smoking status.
    RESULTS: In total, 79 patients with ALS, 33 with PMA, and 30 with PLS were included. MI of ≥110% was observed in 55.7% of patients with ALS, 27.3% with PMA, and 26.7% with PLS. After adjustment, MI differed significantly between disease subtypes (p = 0.019), with the highest mean observed in ALS (108.5%, 95% CI 105.8-111.1), followed by PMA (105.9%, 95% CI 102.6-109.3) and PLS (103.2%, CI 99.8 -106.6). Metabolic measures were not statistically correlated with disease-specific clinical characteristics.
    CONCLUSIONS: Our findings suggest that metabolic phenotype varies across MND subtypes. In the absence of non-neurological controls, findings are best interpreted as indicating that MI-defined hypermetabolism is most prevalent in ALS; however, whether metabolic rate is increased in PMA or PLS relative to the general population remains unknown.
    Keywords:  Amyotrophic lateral sclerosis; metabolic index; primary lateral sclerosis; progressive muscle atrophy; resting energy expenditure
    DOI:  https://doi.org/10.1080/21678421.2026.2745871
  2. Curr Neurovasc Res. 2026 Oct 07.
    Neurovascular Modulation of the Blood-brain Barrier Using Focused Ultrasound for Antisense Therapy Delivery in Amyotrophic Lateral Sclerosis.
    Sujit Kumar Mohanty, M K Vijayalakshmi, Sambasivam Gopinath, J Jaisudha, Deepak Venkatraman, Tozer Meena Sandela, Vasanth Kumar Mohan.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and the blood-brain barrier (BBB) restricts CNS delivery of macromolecular therapeutics such as antisense oligonucleotides (ASOs). Focused ultrasound (FUS) with microbubbles enables transient, noninvasive opening of the BBB for deliver SOD1-targeted ASOs.
    METHODS: A narrative review of the literature in PubMed, Scopus, Web of Science, and Google Scholar (2020-2025) was conducted to evaluate FUS-assisted delivery of SOD1-targeted ASOs, with an emphasis on lipid- and calcium phosphate (CaP)- based nanoparticles.
    RESULTS: Preclinical studies showed that FUS-mediated BBB opening (250 kHz; mechanical index 0.33; 30-s exposure; 0.15 mL/kg microbubbles) increased brain accumulation of nanoparticle- encapsulated ASOs by >3.5-fold compared with FUS without microbubbles. CaP lipid nanoparticles (~73 nm; -21 mV; 23-30% encapsulation efficiency) encapsulating tofersen demonstrated pH-responsive intracellular release. In wild-type and G93A SOD1 transgenic mice, FUS combined with CaP-ASO nanoparticles reduced SOD1 expression in sonicated cortical regions and increased lumbar spinal motor-neuron counts without detectable neuroinflammation or tissue damage.
    DISCUSSION: Combining FUS-mediated BBB modulation with CaP nanoparticles provides a minimally invasive strategy for CNS ASO delivery. Observed spinal cord effects suggest wider CNS distribution, potentially involving CSF transport and retrograde axonal pathways. Clinical translation requires optimising FUS parameters, conducting long-term safety assessments, and managing skull acoustic variability.
    CONCLUSION: MRI-guided FUS combined with CaP lipid nanoparticles represents a promising non-invasive platform for SOD1-targeted ASO delivery and precision gene therapy in ALS.
    Keywords:  Blood-brain barrier (BBB); CNS drug delivery; amyotrophic lateral sclerosis (ALS); antisense oligonucleotides (ASOs); focused ultrasound (FUS); neurovascular unit
    DOI:  https://doi.org/10.2174/0115672026509618261001075016
  3. Acta Neuropathol Commun. 2026 Oct 10. pii: 213. [Epub ahead of print]14(1):
    Vascular profiling of the spinal cord and cortex reveals region-specific endothelial dysfunction and fibroblast remodeling in human ALS.
    Kuo Liao, Jianing Lin, Yangfan Zhou, Sebastian A Lewandowski.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Increasing evidence suggests that neurovascular dysfunction contributes to ALS pathogenesis, but a comprehensive understanding of vascular cell alterations in the human central nervous system remains lacking. Here, to systematically characterize neurovascular changes in ALS, we curated single-nucleus transcriptomic datasets from human spinal cord and cortical tissues with a specific focus on vascular cell populations. Comparative analyses revealed substantial vascular perturbations in the spinal cord compared to the cortex. Among vascular-associated cell populations, endothelial cells and fibroblasts exhibited the most pronounced transcriptional alterations. Endothelial cells from ALS spinal cords displayed reduced blood-brain barrier integrity signatures and increased expression of inflammatory and stress-response programs, with the greatest changes manifested in capillary endothelial cells. In parallel, we generated a refined cellular atlas of spinal cord fibroblasts and identified three major fibroblast populations, including a distinct LAMA1low perivascular fibroblast subtype. Fibroblast signatures were found to be consistently elevated in ALS across single-nucleus transcriptomic, bulk transcriptomic, and experimental validation datasets. Together, our findings establish a region-resolved view of neurovascular alternations in human ALS, which is characterized by endothelial barrier dysfunction and disease-associated remodeling of specialized perivascular fibroblasts. These findings broaden the cellular framework of ALS pathogenesis beyond neuronal and glial alterations and highlight the neurovascular niche as an integral component of human ALS disease biology.
    Keywords:  ALS; Blood–brain barrier; Endothelial cell; Fibroblast; Vasculature; snRNA-seq
    DOI:  https://doi.org/10.1186/s40478-026-02449-x
  4. Handb Clin Neurol. 2026 ;pii: B978-0-443-19043-8.00014-1. [Epub ahead of print]219 381-397
    DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.
    Lee J Martin.
      Amyotrophic lateral sclerosis (ALS), the 3rd most frequent neurodegenerative disease, is fatal. Skeletal muscles, neuromuscular junctions, and motor neurons in the cerebral cortex, brainstem, and spinal cord that control swallowing, breathing, and movement degenerate, causing paralysis, respiratory arrest, and death. Clinically meaningful disease mechanisms are unknown, and no effective therapies are available. ALS is a polygenic heterogeneous disease seen in 5%-10% of patients as inherited, but most patients have no inheritance pattern. ALS appears to manifest as a complex interplay between many genes in multiple tissues, individual lifestyle, the environment, and metabolism. Monozygotic twin and triplet studies of ALS suggest that epigenetic mechanisms could be involved in the pathogenesis because discordance is seen. Epigenetic anomalies involving DNA and RNA methylation occur in human ALS. Cell and animal models show that motor neuron development and degeneration can be regulated by DNA methylation. This chapter summarizes the DNA and RNA epigenetic anomalies that are prominent in human ALS and models of ALS, concluding with the suggestion that they are promising therapeutic targets with small molecules.
    Keywords:  6-Methyladenosine; Cytosine methylation; DNMT3A; Motor neuron; RNA demethylase
    DOI:  https://doi.org/10.1016/B978-0-443-19043-8.00014-1
  5. Res Sq. 2026 Sep 29. pii: rs.3.rs-10422321. [Epub ahead of print]
    All Roads Lead to Rome: Resting-State Criticality as a Neurophysiological Marker of Brain-Computer Interface (BCI) Performance in People with Amyotrophic Lateral Sclerosis (ALS) and Healthy Participants.
    Tomko Settgast, Oren Shriki, Georg Northoff, Federico Zilio, Seyyed Bahram Borgheai, Yalda Shahriari, Andrea Kübler.
      This exploratory study investigates the relationship between resting-state brain dynamics (EEG) and subsequent brain-computer interface (BCI) performance in people with amyotrophic lateral sclerosis (ALS) and healthy participants. Grounded in the critical brain hypothesis, we examined whether neurophysiological markers of criticality in resting-state EEG correlate with subsequent BCI performance. We analyzed neuronal avalanche dynamics, multiscale criticality measures, the spectral slope, and Lempel-Ziv complexity across two datasets: a longitudinal single-case study of a person in the locked-in state after a disease history with ALS (Dataset 1) and longitudinal data from 5 people with ALS and single sessions from 6 healthy participants (Dataset 2). Neuronal avalanche dynamics, the spectral slope, and Lempel-Ziv complexity consistently correlated with subsequent BCI performance in people with ALS. Conversely, healthy participants showed inverted correlation patterns for the neuronal avalanche dynamics. While group comparisons were not statistically significant, effect size analyses indicated supercritical brain dynamics in people with ALS. We integrate these findings into the B-ARC (BCI-Aptitude through Resting-State Criticality) framework proposing an inverted U-shaped relationship between the proximity of resting-state brain activity to criticality and BCI control. In this framework, healthy participants approach the critical optimum from a subcritical regime, while people with ALS appear to approach it from a putatively supercritical regime characterized by cortical hyperexcitability. These findings and the proposed framework provide potential resting-state predictors of BCI aptitude in people with ALS and may inform the detection of so-called Windows of Consciousness .
    DOI:  https://doi.org/10.21203/rs.3.rs-10422321/v1
  6. Intern Med. 2026 Oct 15.
    Bullous Pemphigoid in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Study of 1,067 Cases.
    Kentaro Kawama, Kota Bokuda, Hideki Kimura, Kentaro Hayashi, Tomoya Kawazoe, Keigo Totani, Yoshiyuki Matsuki, Keisuke Ishizawa, Juri Sawada, Yumi Itagaki, Michiko Haraguchi, Chiharu Matsuda, Yuki Nakayama, Miyuki Yabuki, Kazushi Takahashi, Toshio Shimizu.
      Background　Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurons. Bullous pemphigoid (BP) is an autoimmune blistering disease associated with autoantibodies against BP180 and BP230. Previous studies have suggested an increased incidence of BP in patients with ALS. However, the neurological status and disease severity of patients with ALS at the time of BP onset remain insufficiently characterized. This study aimed to investigate the frequency and clinical characteristics of BP in patients with ALS.Methods　In this retrospective study, we reviewed the medical records of 1,067 patients with ALS who were admitted to our institution between April 2010 and May 2025. Patients who developed BP after the onset of ALS were identified. BP was diagnosed by dermatologists based on clinical findings and, when available, by immunological or histopathological examinations. Disease severity at BP onset was assessed based on the ambulatory status and ventilatory support requirements.Results　Seven of the 1,067 patients (0.66%) developed BP after ALS onset. The median interval between ALS and BP onset was 8.0 years (IQR 5.0-16.5). At BP onset, four patients (57.1%) were bedridden, four (57.1%) required tracheostomy and invasive ventilation, and two (28.6%) required non-invasive ventilation. Five patients (71.4%) required enteral feeding. The median age at BP onset was 68.0 years (IQR, 64.0-72.5). BP180 antibody testing was positive in three of the six patients. The lesions most commonly involved both the extremities and the trunk.Conclusion　BP may occur more frequently in ALS patients than in the general population. Clinicians should consider BP when evaluating cutaneous lesions in patients with ALS.
    Keywords:  amyotrophic lateral sclerosis; autoantibodies; autoimmune.; bullous pemphigoid; frequency; motor neuron disease
    DOI:  https://doi.org/10.2169/internalmedicine.7919-26
  7. Int J Mol Sci. 2026 Sep 25. pii: 8604. [Epub ahead of print]27(19):
    Phenotypic Profiling of SOD1-G93A Mice: Integrating Sciatic Nerve Histopathology with Systemic Chemokine Dynamics During ALS Progression.
    Ekaterina Martynova, Marat Mukhamedyarov, Emmanuel Kabwe, Svatlana Khaiboullina, Owen Simwalangana, Maria Markelova, Albert Rizvanov, Svetlana Arkhipova, Ilnur Salafutdinov.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, leading to muscle atrophy and fatal respiratory failure. While neuroinflammation is a hallmark of ALS, the temporal and spatial relationship between systemic inflammation and peripheral nerve degeneration remains poorly understood. In the present study, the transgenic SOD1-G93A mouse model was employed to conduct a longitudinal analysis of amyotrophic lateral sclerosis (ALS) progression. We integrated morphometric and ultrastructural examinations of the sciatic nerve with immunofluorescent profiling of the spinal cord (GFAP, IBA1, NG2). In addition, cytokine and chemokine dynamics were analyzed using 33-plex multiplex assay in the serum at various stages of the disease. Histological analysis revealed a progressive decline in myelin fiber density within the sciatic nerve and axonal death. As the disease progressed, Schwann cells exhibited morphological features consistent with a pro-fibrotic shift, as suggested by collagen accumulation observed on TEM. However, direct confirmation of a fibrotic phenotype requires additional markers (e.g., Col I/III, α-SMA, TGF-β) and was not assessed in this study. Significant motor neuron loss and robust glial activation were demonstrated in the spinal cord. Blood plasma analysis identified a coordinated systemic up-regulation of MCP-3, Eotaxin, CTACK, and TECK. There was lack of inflammatory cell infiltration in the peripheral nerve tissues. Our results indicate that ALS-associated peripheral nerve degeneration in the SOD1-G93A mice model is primarily a degenerative process characterized by early demyelination and without leukocyte infiltration. However, increased levels of MCP-3, Eotaxin, CTACK, and TECK are associated with disease progression and may reflect ongoing central neuroinflammation. While these changes are temporally consistent with blood-spinal cord barrier dysfunction reported in SOD1 mice, direct assessment of barrier integrity was not performed in this study. These data highlight the potential of blood chemokines as step biomarkers and highlight the compartmental nature of inflammation in ALS, where systemic immune changes do not necessarily equate to local inflammation in the peripheral nerve.
    Keywords:  SOD1-G93A mice; amyotrophic lateral sclerosis; astrocytes; cytokine multiplex analysis; demyelination; microglial cells; myelin fibers; neurodegeneration; peripheral nerve; spinal cord; ultrastructural analysis
    DOI:  https://doi.org/10.3390/ijms27198604
  8. J Vis Exp. 2026 Oct 13.
    Isolated Axoplasm from Squid and Pathogenic Mechanisms in Amyotrophic Lateral Sclerosis.
    Amanda Onoichenco, Sarah L Morris, Sarah Aloe, Kaitlynn McCay, Yuyu Song, Scott T Brady.
      The squid giant axon is an experimental model that has been instrumental in providing answers to many fundamental questions in cell biology, including the discovery of the motor protein kinesin and probing molecular mechanisms of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). The giant axon offers scale and ease of access that is not possible in mammalian models. The power of this model stems from the fact that one can introduce reagents and proteins that would not cross a plasma membrane at defined concentrations in a buffer environment that is closely modeled on normal components of the axoplasm. By leveraging the unique biology of the squid axon, early studies were able to define the channels and ion specificities of the action potential. Subsequent studies using video-enhanced contrast- differential Interference contrast microscopy (VEC-DIC) and the isolated axoplasm led to the identification of kinesins, a class of motor proteins responsible for intracellular vesicle trafficking toward the plus end of microtubules. This combination of isolated axoplasm and advanced imaging continues to provide insights into pathogenic mechanisms for adult-onset neurodegeneration, including ALS, and regulation of fast axonal transport, a process disrupted in motor neuron disease. Here, procedures for dissecting the giant axon, isolating axoplasm, and perfusing defined amounts of proteins and/or reagents into the axoplasm are detailed, as well as methods for visualizing and interactively analyzing vesicle traffic in real time. This model represents a singular avenue to understand the critical function of neurons, shedding light on the mechanisms driving ALS pathology and other neurodegenerative diseases. This system also offers a tractable platform for drug testing, where candidate therapeutic compounds can be introduced directly into the axoplasm, and their effects on vesicle trafficking can be assessed in real time, providing a rapid and physiologically relevant means of identifying potential ALS therapeutic targets.
    DOI:  https://doi.org/10.3791/72560
  9. Expert Rev Neurother. 2026 Oct 15. 1-7
    Diagnostic evolution of carbonic anhydrase 3 (CA3) in Amyotrophic Lateral Sclerosis (ALS): an emerging prognostic biomarker.
    Nitesh Sanghai, Geoffrey K Tranmer.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease traditionally viewed as a motor neuron disorder in which muscle atrophy occurs secondary to neuronal loss. However, recent clinical proteomic advances have highlighted carbonic anhydrase 3 (CA3), a muscle-enriched enzyme, as a promising biomarker associated with ALS disease progression. Therefore, considering ALS a neurocentric disease is not untenable.
    AREAS COVERED: In this review, the authors examined the emergence of CA3 as an ALS biomarker and evaluated evidence from recent large-scale clinical consortium studies supporting its diagnostic and prognostic utility. They also compare CA3 with established biomarkers, neurofilament light chain (NEFL), a surrogate endpoint approved by the FDA.
    EXPERT OPINION: Discoveries of CA3 biomarker in ALS highlight that peripheral skeletal muscle is not merely a passive bystander, but an integral participant in ALS disease progression. Unlike NEFL, which primarily reflects neuroaxonal injury, CA3 may capture early neuromuscular dysfunction preceding motor neuron degeneration. CA3's emergence as an ALS biomarker supports a more integrated neuromuscular model of ALS and provides a compelling rationale for incorporating CA3 into multimodal diagnostic, prognostic, and pharmacodynamic biomarker panels to accelerate ALS drug discovery, therapeutic evaluation, and precision clinical trial development, highlighting their complementary roles in early diagnosis, patient stratification, and therapeutic clinical trial design.
    Keywords:  Amyotrophic lateral sclerosis (ALS); biomarkers; carbonic anhydrase 3 (CA3); neurofilament light chain (NEFL); pharmacodynamic biomarker
    DOI:  https://doi.org/10.1080/14737175.2026.2748281
  10. Curr Neurovasc Res. 2026 Oct 02.
    Crossing the Blood-brain Barrier: Emerging Nanotechnological Approaches for Neurodegenerative Disease Therapy.
    Alpana, Hitesh Kumar Dewangan.
      Neurodegenerative disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD) are characterized by progressive neuronal degeneration and severe therapeutic limitations due to the Blood-Brain Barrier (BBB). Recent advances in nanotechnology have enabled the development of nanoscale drug delivery systems capable of improving BBB penetration and enhancing therapeutic efficacy. This review discusses recent progress in Lipid Nanoparticles (LNPs), polymeric nanoparticles, exosomes, magnetic nanoparticles, gold nanoparticles, graphene quantum dots, and RNAloaded nanocarriers for brain-targeted delivery. Special emphasis is placed on receptor-mediated transcytosis, intranasal delivery, magnetic targeting, and ionizable lipid nanoparticle systems for nucleic acid delivery. Recent nanoformulations including curcumin-loaded nanoparticles, siRNA- loaded lipid nanoparticles, dopamine-loaded liposomes, and lactoferrin-functionalized polymeric nanoparticles are critically compared based on BBB penetration, therapeutic efficacy, toxicity, and translational potential. Furthermore, current clinical challenges including nanotoxicity, pharmacokinetics, large-scale manufacturing, and regulatory barriers are discussed. Nanotechnology- based therapeutics represent a promising strategy for improving diagnosis and treatment of neurodegenerative disorders and may facilitate the future development of precision nanomedicine.
    Keywords:  Nanotechnology; drug delivery; nanoformulation; nanomaterial; neurodegenerative disorders.
    DOI:  https://doi.org/10.2174/0115672026454704261001071449
  11. Muscle Nerve. 2026 Oct 12.
    Statin Exposure and Survival Outcomes in Amyotrophic Lateral Sclerosis in an Asian Cohort.
    Anushika Raheja, Kexin Ang, Bernett Lee, Seyed Ehsan Saffari, Eng King Tan, Crystal Jing Jing Yeo.
       INTRODUCTION: Data from Asian cohorts on whether statin therapy affects amyotrophic lateral sclerosis (ALS) progression are limited. We examined whether statin exposure was associated with ALS disease duration or tracheostomy-free survival in a multiethnic Asian ALS cohort.
    METHODS: Data from patients diagnosed with ALS between 2012 and 2025 were retrospectively reviewed. Patients were categorized as "ever" or "never" statin users for primary analyses, and as "never," "former," or "current" users at diagnosis for additional analyses. Disease duration was defined as time from symptom onset to death, and tracheostomy-free survival as time from symptom onset to tracheostomy or death without tracheostomy. Kaplan-Meier and Cox regression analyses evaluated associations between statin exposure and both outcomes. Additional analyses examined statin discontinuation after diagnosis using time-varying exposures. Sensitivity analyses excluded post-diagnosis imitators and applied 30-, 90-, and 180-day lags.
    RESULTS: Among 103 ALS patients, 27 (26.2%) had ever received statins. Statin exposure was not significantly associated with disease duration (hazard ratio [HR]: 1.42, 95% CI: 0.64-3.14, p = 0.387) or tracheostomy-free survival (HR: 1.04, 95% CI: 0.50-2.18, p = 0.913). Post-diagnosis statin discontinuation was associated with shorter survival in a time-varying analysis (HR: 6.52, 95% CI: 1.48-28.74, p = 0.013), although this finding was hypothesis-generating. Sensitivity analyses did not show statistically significant associations.
    DISCUSSION: In this multiethnic Asian ALS cohort, statin exposure was not significantly associated with disease duration or tracheostomy-free survival. These findings add to the evidence that statins do not need to be discontinued due to ALS diagnosis. Larger studies are needed to define this association.
    Keywords:  Asia; amyotrophic lateral sclerosis; disease progression; statins; survival analysis
    DOI:  https://doi.org/10.1002/mus.70427
  12. Naunyn Schmiedebergs Arch Pharmacol. 2026 Oct 13.
    Combined rituximab and magnesium acetyl taurate therapy attenuates neurodegeneration via ERK/c-JNK/P38MAPK signaling modulation in methylmercury-induced amyotrophic lateral sclerosis-like neurotoxicity.
    Trina Saha, Sidharth Mehan.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, oxidative stress, neuroinflammation, mitochondrial dysfunction, and dysregulation of intracellular signaling pathways. The present study investigated the neuroprotective potential of rituximab (RTXMB), alone and in combination with magnesium acetyl taurate (MACT600), against methylmercury (MLMC5)-induced ALS-like pathology in adult Wistar rats through modulation of the ERK/c-JNK/P38MAPK signaling pathway. ALS was induced by oral administration of MLMC5 (5 mg/kg) for 21 days. RTXMB (50 and 100 mg/kg) and MACT600 (600 mg/kg) treatments were administered from day 22 to day 42. Behavioral assessments, neurochemical estimations, ELISA, Western blotting, hematological analysis, gross morphology, and histopathological evaluations were performed. MLMC5 exposure produced significant impairments in locomotion, muscular strength, cognition, and emotional behavior, accompanied by increased oxidative stress, inflammatory cytokines, glutamate excitotoxicity, apoptotic markers, methylmercury accumulation, and dysregulation of ERK/c-JNK/P38MAPK signaling. Moreover, MLMC5 caused marked demyelination, neuronal degeneration, neurotransmitter imbalance, skeletal muscle damage, and hematological dysfunction. RTXMB treatment significantly attenuated these pathological alterations in a dose-dependent manner, with RTXMB100 showing greater neuroprotective efficacy. Combined administration of RTXMB100 and MACT600 demonstrated the most pronounced therapeutic effects by restoring antioxidant defenses, suppressing neuroinflammation and apoptosis, normalizing neurotransmitter levels, preserving myelin integrity, and improving neuronal morphology. The findings suggest that RTXMB, particularly in combination with MACT600, exerts potent neuroprotective effects against ALS-like pathology via modulation of MAPK signaling pathways and may represent a promising therapeutic strategy for ALS management.
    Keywords:  Amyotrophic lateral sclerosis; ERK/c-JNK/P38MAPK signaling; Magnesium acetyl taurate; Methylmercury-induced neurotoxicity; Neuroprotection; Rituximab
    DOI:  https://doi.org/10.1007/s00210-026-05948-9
  13. J Biomed Phys Eng. 2026 Oct;16(5): 395-406
    Short-term Classification of Neurodegenerative Diseases using Time-series Features Based on Analysis of Gait Dynamics.
    Negar Monfared Jahromi, Ali Maleki.
       Background: Neurodegenerative Diseases (NDDs) refer to disorders, leading to the gradual degeneration of neurons in the human nervous system and profoundly affecting individuals' motor and cognitive functions. Early diagnosis and monitoring of the progression of NDDs are of critical importance.
    Objective: The primary aim of this study is to present an automatic diagnostic method using time-domain analysis of short-term gait signals of two consecutive steps, for the classification of Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and a Healthy Control Group (HC).
    Material and Methods: This analytical study used datasets from PhysioNet, including 64 five-minute recordings from 13 individuals with ALS, 15 with Parkinson's, 20 with Huntington's, and 16 healthy individuals. To reduce noise and enhance signal quality, a median filter was applied. The preprocessed gait signals were then systematically segmented into consecutive two-step windows, which were used to construct the feature vectors. Finally, the constructed feature vectors were used as inputs for both linear and nonlinear classifiers. The proposed method was evaluated by calculating the accuracy index.
    Results: The quaternary classification of ALS vs. PD vs. HD vs. HC using the bag-tree classifier achieved an accuracy of 82.8%. Furthermore, for the binary classifications of HC vs. HD, HC vs. ALS, HC vs. PD and NDD vs. HC, the accuracies were 88.4%, 97.6%, 90% and 89.1%, respectively.
    Conclusion: Gait dynamics analysis has a high potential for the rapid diagnosis of neurodegenerative diseases. Short term analysis in two consecutive stages enables the use of the Kinect sensor for gait analysis.
    Keywords:   Classification; Consecutive Steps; Gait Analysis; Neurodegenerative Diseases; Short-Time
    DOI:  https://doi.org/10.31661/jbpe.v0i0.2510-1997
  14. NeuroRehabilitation. 2026 Oct 10. 10538135261490936
    Prognostication in Amyotrophic Lateral Sclerosis: A Narrative Review of Pre-Diagnosis and Functional Outcomes.
    Amber Vocelle, Erik Ensrud, Ileana M Howard.
      Amyotrophic Lateral Sclerosis (ALS) is a very heterogeneous disease, yet some of the most common questions received by physicians in the ALS clinic are "how much time do I have?" and "what can I expect to happen next?" This line of inquiry is not strictly limited to patients; clinicians also need an idea of prognosis to appropriately plan for treatment decisions and prepare the patient and caregiver for future care needs. This narrative review synthesizes current evidence on prognostic indicators in ALS, organized across three temporal phases: factors preceding diagnosis, factors present at diagnosis, and factors emerging after diagnosis. Pre-diagnosis predictors include age at onset, sex, socioeconomic status, genetic background, premorbid Body Mass Index (BMI) and nutritional status, and comorbid disease. At diagnosis, clinical phenotype and site of onset, diagnostic delay, baseline Amyotrophic Lateral Sclerosis Functional Rating Score-Revised (ALSFRS-R) and forced vital capacity, cognitive involvement, fluid biomarkers, and electrophysiologic measures carry prognostic weight. Post-diagnosis, the trajectory is refined by the rate of ALSFRS-R decline, serial respiratory measures, and weight loss, and is actively modified by clinical interventions including noninvasive ventilation, enteral nutrition, disease-modifying therapy, and multidisciplinary care. Notably, quality of life does not track with physical decline, consistent with the disability paradox described in other severe neurological conditions. For neurorehabilitation, these indicators support a shift from reactive to anticipatory practice: timing equipment provision, communication support, respiratory intervention, and goals-of-care discussions to the predicted trajectory rather than to established deficit. Refinement of prognostic models may also improve stratification in ALS clinical trials.
    Keywords:  amyotrophic lateral sclerosis; biomarkers; function; outcome; prognosis; survival
    DOI:  https://doi.org/10.1177/10538135261490936
  15. Metab Brain Dis. 2026 Oct 14. pii: 235. [Epub ahead of print]41(1):
    The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.
    Aslı Aksoy Gündoğdu, Neslihan Gücüyener Özkan, Demet Özbabalık Adapınar.
      Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.
    Keywords:  Axonal transport; Microtubule dynamics; Neurodegeneration; Tauopathy; Tubulin code; α-synuclein
    DOI:  https://doi.org/10.1007/s11011-026-02001-9
  16. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Oct 13. 1-10
    Mapping the evidence on dignity therapy in amyotrophic lateral sclerosis: a scoping review.
    Annalisa Pini, Claudia Cobel, Filippo Moretti, Giulia Governatori, Milena Bonamici, Tamara Gobbato, Loredana Buonaccorso, Francesca Sireci, Luca Ghirotto.
      Objective: To systematically map and synthesize the existing literature on the use of Dignity Therapy (DT) in amyotrophic lateral sclerosis (ALS), with particular attention to feasibility, acceptability, therapeutic outcomes, and clinical adaptations required for patients and caregivers. Methods: A systematic scoping review was conducted searching PubMed/MEDLINE, CINAHL, PsycINFO, and Scopus for studies published in the last ten years examining DT in individuals with ALS. Eligible studies were charted and compared qualitatively due to heterogeneity in design, outcomes, and measurement tools. Results: A total of 237 records were identified, of which five met the eligibility criteria. DT was generally feasible in ALS, including in advanced disease stages, when adapted with augmentative communication devices, email correspondence, or videoconferencing. Acceptability was high across studies, with participants frequently reporting meaningful engagement with the narrative process and positive perceptions of the generativity document. Qualitative evidence indicated potential benefits in existential well-being, emotional adjustment, maintenance of identity, and family communication. Quantitative outcomes were inconsistent, showing variable effects on dignity-related distress, mood symptoms, and spiritual well-being. Caregiver responses were mixed, with some reporting perceived support and others noting limited immediate impact. Conclusions: DT appears to be a promising intervention for addressing existential and relational needs in ALS, though current evidence is limited by small sample sizes and methodological variability. Larger, methodologically rigorous studies are needed to clarify therapeutic effects, optimize delivery adaptations, and evaluate outcomes for both patients and caregivers.
    Keywords:  Amyotrophic lateral sclerosis; caregivers; dignity therapy; existential distress; narrative intervention; palliative care
    DOI:  https://doi.org/10.1080/21678421.2026.2742818
  17. Inflamm Res. 2026 Oct 12. pii: 237. [Epub ahead of print]75(1):
    CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.
    Sanjana Sahu, Parag Jain, Karan Kumar Dharme, Krishna Yadav.
       BACKGROUND: Neuroinflammation is a characteristic feature of many neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Uncontrolled activation of microglia and astrocytes results in the production of proinflammatory mediators that contribute to neuronal dysfunction and degeneration.
    PURPOSE: CRISPR/Cas9 genome-editing technology provides highly precise targeting of genes involved in these pathways, enabling the deletion, correction, or modulation of disease-associated genetic alterations. Nonetheless, effective delivery of CRISPR components to the central nervous system (CNS) remains a major challenge because of protective barriers such as the blood-brain barrier (BBB), as well as concerns regarding genomic instability and immunogenicity.
    METHODS: Nanotechnology-guided delivery platforms, such as lipid nanoparticles, liposomes, dendrimers and polymeric carriers, have been developed as promising strategies to address these challenges. These nanosystems can improve biodistribution, pharmacokinetic behavior, and cellular uptake, while potentially reducing off-target effects and systemic toxicity.
    RESULTS: The preclinical studies demonstrate successful modulation of key neuroinflammatory targets, including the NLRP3 inflammasome, triggering receptor expressed on myeloid cells 2 (TREM2), Janus kinase (JAK) signaling, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, with potential therapeutic relevance to neurodegenerative diseases. In addition, novel techniques, such as mitochondrial base editing, prime editing, and epigenetic modulation, expand the scope of CRISPR-mediated therapeutic strategies. Although outcomes from animal models are promising, translation to the clinical setting requires careful consideration of safety, ethical concerns, and long-term efficacy.
    CONCLUSIONS: This review highlights the potential of integrating CRISPR/Cas9 with nanodelivery systems to advance precision medicine for neuroinflammatory disorders, while emphasizing their potential for therapeutic applications in complex CNS conditions. Ongoing studies aimed at optimizing delivery and reducing off-target effects will be essential for advancing these approaches toward clinical practice.
    Keywords:  BBB; CRISPR/Cas9; JAK signaling; NLRP3; Nanodelivery; Neuroinflammation
    DOI:  https://doi.org/10.1007/s00011-026-02383-7
  18. Eur J Neurol. 2026 Oct;33(10): e70782
    Transcutaneous Carbon Dioxide Monitoring in Amyotrophic Lateral Sclerosis: A Scoping Review.
    Cláudia Santos Silva, Mamede de Carvalho.
       BACKGROUND: Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Conventional pulmonary function tests are effort-dependent and may fail to detect early nocturnal hypoventilation. Transcutaneous carbon dioxide (PtcCO2) measurement is a non-invasive method for assessing ventilation, but its role in ALS remains unclear. We performed a scoping review to map the current evidence.
    METHODS: PubMed, Web of Science, Scopus, and Google Scholar were searched from inception to April 2026. Original studies evaluating PtcCO2 monitoring in ALS were included. Due to heterogeneity in study designs, populations, and outcomes, a narrative synthesis was performed, categorized by study characteristics, measurement protocols, and clinical endpoints.
    RESULTS: Twenty-one studies were included. Most were observational and conducted in tertiary centres. Twelve studies evaluated PtcCO2 as a surrogate marker for nocturnal hypoventilation, mainly to guide initiation or titration of non-invasive ventilation. Definitions of hypoventilation and reported PtcCO2 metrics varied widely. Only three studies evaluated PtcCO2 in relation to respiratory impairment or hypercapnia, but none reported formal measures of diagnostic accuracy. Evidence regarding the prognostic value was limited and inconsistent. Three studies showed that nocturnal hypercapnia preceded abnormalities in spirometry or daytime hypercapnia.
    CONCLUSIONS: PtcCO2 monitoring shows promise as a non-invasive method for assessing nocturnal ventilatory abnormalities in ALS, including nocturnal hypoventilation. However, due to methodological heterogeneity, its diagnostic and prognostic roles remain uncertain. Current evidence is insufficient to support PtcCO2 as a standalone criterion for NIV initiation. Large-scale prospective studies with standardized protocols are essential to delineate its clinical utility.
    Keywords:  amyotrophic lateral sclerosis; nocturnal hypoventilation; respiratory insufficiency; scoping review; transcutaneous carbon dioxide monitoring
    DOI:  https://doi.org/10.1111/ene.70782
  19. Pflugers Arch. 2026 Oct 14. pii: 93. [Epub ahead of print]478(11):
    Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.
    José Castro, Mamede de Carvalho, Michael Swash.
      Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha-gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.
    Keywords:  Amyotrophic lateral sclerosis; Fusimotor denervation; Gamma motor neuron; Muscle spindle; Proprioception; Spinal interneuron
    DOI:  https://doi.org/10.1007/s00424-026-03224-6
  20. Neuroepidemiology. 2026 Oct 12. 1
    History of Head Injury and Risk of Amyotrophic Lateral Sclerosis: An Updated Comprehensive Systematic Review with Meta-Analysis of 5,033,215 Participants.
    Yousef Hawas, Ahmed Abdelmageed, Mark Messak, Abdulrahman Ziada, Mohamed Gamal, Thoria I Eissa Ghanem, Maya Magdy Abdelwahab, Mostafa Meshref, Muataz Omar Kashbour.
       BACKGROUND: Head injury has been proposed as a potential modifiable risk factor for amyotrophic lateral sclerosis (ALS); however, prior studies have yielded inconsistent findings. We aimed to re-evaluate this association through an updated systematic review and meta-analysis, incorporating the latest evidence and exploring the influence of injury severity, frequency, timing, and definition.
    METHODS: A systematic search of PubMed, Scopus, Web of Science, Embase, EBSCO, and ProQuest from inception to January 2026 was conducted. Observational studies (cohort and case-control) reporting the association between head injury and ALS risk were included. Pooled effect estimates were generated using random-effects models. Subgroup, sensitivity, cumulative, and publication bias analyses were performed.
    RESULTS: Twenty-nine studies encompassing 5,033,215 participants were included. These comprised 22 case-control studies and seven cohort studies. Case-control meta-analysis showed that head injury was associated with 36% higher odds of ALS (AOR = 1.36; 95% CI: 1.24-1.48; I² = 20.4%). Cohort studies showed a positive but non-significant association (RR = 1.59; 95% CI: 0.93-2.71). Subgroup analyses showed significant associations within mild, moderate, and severe injury categories and among studies with clearly defined traumatic brain injury exposure. Single head injury was associated with higher odds of ALS (AOR = 1.22; 95% CI: 1.11-1.34).
    CONCLUSION: Head injury was associated with an increased risk of ALS across multiple analyses, including different injury severity levels and exposure definitions. However, the observational nature of available evidence and the possibility of reverse causation and residual confounding limit causal interpretation. Further prospective studies and mechanistic investigations are required to clarify the potential relationship between head injury and ALS development.
    DOI:  https://doi.org/10.1159/ned/adwag050
  21. Eur Neurol. 2026 Oct 15. 1
    Needs and Expectations of ALS Patients and Caregivers: An Integrated Perspective.
    Elisa Bianchi, E Beghi, Anisia Carlino, Federica Cerri, Christian Lunetta, Eugenio Vitelli, Ammar Al-Chalabi, Maurizio A Leone, Elisabetta Pupillo.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease requiring complex multidisciplinary care. As disability advances, patients' and caregivers' needs may diverge.
    OBJECTIVES: to assess needs, priorities and satisfaction with care among people with ALS (pALS) and their caregivers; to examine the association between satisfaction and Quality of life (QoL); to explore differences according to clinical characteristics; to understand the Italian ALS community's willingness to engage in research.
    METHODS: In this cross-sectional multicentre study, 154 pALS and 211 caregivers were recruited (July 2021-November 2022). Structured interviews explored information received, care priorities, research expectations and satisfaction. Answers to the interview were compared between patients and caregivers and between different patients' subgroups with the chi-square or the Fisher's exact test. The scores of QoL questionnaires were compared between satisfied vs. unsatisfied with the Wilcoxon-Mann-Whitney test in patients (ALSAQ-40) and caregivers (SF-36).
    RESULTS: Patients prioritized finding a cure (95%) and overcoming disease-related limitations (72%) over safe and tolerable drugs (55%), similarly to caregivers. Research on psychological and emotional support was rated more important by caregivers (70%) than patients (49%). QoL was higher among satisfied patients, with better ALSAQ-40 scores in mobility, daily activities, communication and emotional domains. Caregivers needing urgent psychological support were fewer among the satisfied (35%) than the not satisfied (50%), and SF-36 mental health scores were also higher in satisfied caregivers.
    CONCLUSIONS: Incorporating both pALS and caregiver perspectives into clinical practice and research planning may enhance patient- and family-centered care, improve QoL, and better align healthcare research and resources with societal needs.
    DOI:  https://doi.org/10.1159/ene/acsag005
  22. bioRxiv. 2026 Oct 02. pii: 2026.09.28.755069. [Epub ahead of print]
    ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways.
    Stephanie Jackvony Infurna, Laraib Ijaz, Evelyn J Hardin, Abulimiti Aikedan, Constance Zhou, Tejabhiram Yadavalli, Minwoo Wendy Jang, Matthew Mahoney, Li Gan, Deepak Shukla, Adam L Orr, Anna G Orr.
      TAR DNA-binding protein-43 (TDP-43) alterations are a key hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. Increasing evidence links these conditions to viral infections, but it is not known if and how viral pathogens may be affected by disease-associated TDP-43. We found that ALS/FTD-linked forms of human TDP-43 prevent infection by herpes simplex virus type-1 (HSV-1), a common neurotropic virus. This cell-autonomous protective effect was conserved across different TDP-43 mutations, sporadic ALS, and C9ORF72 -ALS, in neural and non-neural cell types, and in patient-derived cells and animal models. In addition to restricting infection, TDP-43 mutation prevented inflammatory and cell stress-related responses to HSV-1 exposure. TDP-43 knockdown but not overexpression was sufficient to protect cells from HSV-1 infection, implicating a loss-of-function mechanism. Neurons with TDP-43 mutation had disruptions in adhesion-related pathways and, accordingly, had reduced early-stage viral binding and entry. Further analyses revealed alternative RNA splicing and impairment of focal adhesion kinase (FAK/PTK2), a key mediator of cell-adhesion pathways. Inhibition of FAK was sufficient to decrease HSV-1 infection, and genetic enhancement of functional but not inactive FAK promoted infectivity in cells with TDP-43 mutation. Together, these data indicate that TDP-43 affects virus-host interactions by influencing adhesion pathways required for viral infection.
    DOI:  https://doi.org/10.64898/2026.09.28.755069
  23. Cells. 2026 Oct 01. pii: 1798. [Epub ahead of print]15(19):
    Motor Neuron Disease in a Dish: The Power of Human Induced Pluripotent Stem Cell-Derived Spinal Motor Neurons and Glial Cells.
    Martina Morrone, Chiara F Valori, Liliana Brambilla, Daniela Rossi.
      Induced pluripotent stem cells (iPSCs) have revolutionized disease modelling by providing unprecedented opportunities to investigate complex human disorders. Among others, Amyotrophic Lateral Sclerosis (ALS), the most common adult-onset motor neuron disease, clearly embodies this complexity. This disorder remains particularly challenging not only because of its marked clinical and molecular heterogeneity but also as a consequence of the composite interactions between motor neurons and the neighboring non-neuronal cells, especially astrocytes, which contribute to disease progression. The ability to generate patient-specific spinal motor neurons and astrocytes from human iPSCs has enabled the development of in vitro models that recapitulate key pathological features of ALS, offering valuable platforms to investigate disease mechanisms, to identify therapeutic targets, and to support personalized medicine approaches. In this review, we summarize current iPSC-based strategies for modelling ALS, highlighting their applications in studying disease physiopathology and drug development. In addition, advanced human iPSC-derived technologies, including organoids and organ-on-a-chip systems, are discussed highlighting their potential, current limitations, and future perspectives.
    Keywords:  Amyotrophic Lateral Sclerosis; astrocytes; in vitro models; induced pluripotent stem cells; motor neurons
    DOI:  https://doi.org/10.3390/cells15191798
  24. Front Immunol. 2026 ;17 1928641
    HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.
    Weicai Cai, Yaqiao Yi, Rong Zeng, Yitong Yin, Jiayue Zhao, Jieyang Zhang, Guilong Fu, Hui Xu.
      High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.
    Keywords:  HMGB1; damage-associated molecular patterns; glial-neuronal interactions; neurodegenerative diseases; neuroinflammation; redox regulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1928641
  25. Clin Neurophysiol. 2026 Oct 01. pii: S1388-2457(26)00928-4. [Epub ahead of print]193 2112428
    Serum neurofilament and measures of lower motor neuron dysfunction in amyotrophic lateral sclerosis.
    Aicee Dawn Calma, Nathan Pavey, Yukiko Tsuji, Amirul Ab Ghapar, Bronwen Orden, Grace Lee, Linda Mekhael, Julie Ryder, Cláudia Santos Silva, Parvathi Menon, Steve Vucic.
       OBJECTIVE: Serum neurofilament light chain (NfL) is an emerging diagnostic and prognostic biomarker in amyotrophic lateral sclerosis (ALS). Ulnar far-field potentials (FFP) have also been proposed as a reliable neurophysiological biomarker in ALS. This study examined the relationship between serum NfL levels and neurophysiological biomarkers of lower motor neuron dysfunction in ALS.
    METHODS: This study included 96 ALS participants and 53 participants with ALS-mimicking disorders. All participants underwent serum NfL measurement using a single-molecule array (Simoa) assay, together with peripheral neurophysiological assessment, including ulnar nerve FFP, compound muscle action potential (CMAP), near-field potential (NFP), split-hand index (SI), and neurophysiological index (NI).
    RESULTS: FFP amplitude was reduced in ALS (5.0 ± 3.0 mV) compared with non-ALS participants (7.9 ± 3.2 mV; p < 0.001). Similar reductions were observed for NFP and CMAP amplitudes (p < 0.001). Serum NfL was higher in ALS participants (72.5 pg/mL, IQR 46.5-113.5) compared to ALS-mimicking controls (14 pg/mL, IQR 9-19; p < 0.001). Serum NfL showed weak negative correlations with CMAP (ρ = - 0.23, p = 0.03) and NFP amplitudes (ρ = -0.28, p = 0.01), but no significant correlation with FFP amplitude, SI or NI. After adjusting for disease duration and functional impairment on multiple linear regression, neither CMAP nor NFP amplitudes independently predicted serum NfL levels.
    CONCLUSION: Serum NfL is elevated in ALS and weakly associated with CMAP and NFP amplitudes. The absence of a statistically significant correlation with FFP suggests that these biomarkers may capture distinct aspects of disease biology.
    SIGNIFICANCE: Serum NfL and FFP amplitude may provide complementary diagnostic information in ALS.
    Keywords:  Amyotrophic lateral sclerosis; CMAP; Far-field potential; Near-field potential; Neurofilament light chain
    DOI:  https://doi.org/10.1016/j.clinph.2026.2112428
  26. bioRxiv. 2026 Oct 01. pii: 2026.09.23.753732. [Epub ahead of print]
    Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.
    S MurthyGowda, K Huyghue, B Castillo, F Gugala, W Li, J Dubnau.
      A key pathophysiological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is loss of nuclear localization and abnormal cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43). Upstream factors that trigger the onset and progression of such neurodegenerative diseases are largely unknown. Aging and environmental factors contribute as potential risk factors. But epidemiological evidence suggests psychological stressors such as social isolation and loneliness are also associated with increased risks of neurodegenerative disease [1-8]. We examined the impacts of social isolation on TDP-43 related neurodegeneration. To investigate the potential for causative impact on neurodegeneration, we compared the effects of social isolation versus social enrichment in Drosophila . We utilized an established social isolation paradigm in which flies were either housed alone or in groups as young adults. We found that early-life social isolation acts as a primer to exacerbate the rate of neurodegeneration in response to subsequent induction of pathological levels of TDP-43. Social isolation stress drives more rapid activation of mdg4, an endogenous retrovirus that functionally mediates TDP-43 effects and more aggressive propagation of TDP-43 protein pathology from surface glial cells to nearby neurons. Shortened life span also ensues. We demonstrate that providing isolated flies with visual, olfactory and tactile social cues from conspecifics living behind a divider was insufficient to alleviate these effects of social isolation on neurodegeneration. Our findings have implications for the association between psychological stressors such as loneliness and risk of neurodegenerative diseases in humans and provide a platform to investigate mechanistic underpinnings in animal models.
    DOI:  https://doi.org/10.64898/2026.09.23.753732
  27. Mult Scler Relat Disord. 2026 Oct 08. pii: S2211-0348(26)01008-4. [Epub ahead of print]115 107973
    Multiple sclerosis occurrence with gut microbial metabolites and sex hormones.
    Malihe ParsaSefat, Aisa Bahar, Mohammad Jahanbakhsh Mashhadi, Sedighe Yosefi, Meisam Khazai, Hamed Tahmasebi.
      Multiple sclerosis (MS) is a chronic immune and neurodegenerative condition that affects the central nervous system (CNS). Multiple factors, both genetic (including the HLA gene locus) and environmental (Epstein-Barr virus, low vitamin D levels), may contribute to MS development. Growing evidence supports the importance of the gut-brain axis and hormones in disease pathogenesis and progression. This review focuses on identifying the role of specific gut microbial products (short-chain fatty acids, tryptophan derivatives, bile acids, and polyamines) in this process and how they affect the immune system, blood-brain barrier (BBB), and glial cells. The review will also describe key differences between female and male patients with MS, including the higher prevalence in females and the tendency toward a progressive course in males. Estrogens, progesterone, and androgens have immunomodulatory, neuroprotective, and remyelinating activities, and this review will describe their impact on multiple sclerosis based on preclinical and clinical findings from pregnancy, menopause, and hormone replacement therapy. This paper discusses the intersection of these ideas through the "microgenderome" concept, which describes how hormones influence gut microbiota composition and how the microbiota, in turn, modulates hormone metabolism and levels.
    Keywords:  Gut microbiota; Gut-brain axis; Multiple sclerosis; Neuroinflammation; Sex hormones
    DOI:  https://doi.org/10.1016/j.msard.2026.107973
  28. Mol Biol Rep. 2026 Oct 16. pii: 1742. [Epub ahead of print]53(1):
    Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions.
    Gülfem Erbil, Damla Aykora, Metehan Uzun.
      Neurodegenerative diseases remain largely untreatable at the disease-modifying level, with currently approved therapies providing primarily symptomatic benefits. Small interfering RNA (siRNA) has emerged as a promising therapeutic modality because of its ability to selectively silence disease-associated genes. However, a major obstacle to clinical translation is not the gene-silencing mechanism itself, but the efficient delivery of therapeutic siRNAs to target cells within the central nervous system.This review examines the barriers that limit siRNA-based therapies for neurodegenerative diseases. We adopt a barrier-oriented framework that follows the sequential challenges encountered during siRNA delivery, including extracellular instability, unfavorable pharmacokinetics, immune recognition, limited transport across the blood-brain barrier, inefficient cellular internalization, and endosomal entrapment. Rather than cataloguing available delivery systems, we evaluate how nanocarrier engineering strategies have been developed to address these barriers and assess their impact on delivery. Evidence from Alzheimer's disease, Parkinson's disease, and Huntington's disease is synthesized to distinguish shared limitations from disease-specific challenges and to evaluate the translational performance of lipid-based nanoparticles, polymeric nanocarriers, engineered exosomes, and hybrid platforms.Available evidence indicates that delivery platforms can improve specific aspects of siRNA transport but have not consistently overcome the sequential biological barriers required for therapy. Although nanocarrier engineering has enhanced siRNA stability, brain targeting, intracellular trafficking, and gene-silencing efficiency in preclinical models, manufacturing scalability, biological heterogeneity, long-term safety, reproducibility, and regulatory feasibility remain important barriers to clinical translation. Future progress will likely depend on delivery systems that integrate effective brain transport, endosomal escape, controlled intracellular release, and scalable manufacturing within clinical platforms.
    Keywords:  Blood-Brain Barrier; Drug Delivery Systems; Exosomes; Nanotechnology; Neurodegenerative Diseases; Small Interfering RNA
    DOI:  https://doi.org/10.1007/s11033-026-12937-x
  29. Neuroscience. 2026 Oct 10. pii: S0306-4522(26)00674-3. [Epub ahead of print]
    Partial convergence of alternative polyadenylation changes across ALS-Associated RNA-Binding proteins.
    Changhe Ji.
      Alternative polyadenylation (APA) regulates transcript 3'-end architecture, stability, localization, and translation. Although RNA-binding protein dysfunction is central to amyotrophic lateral sclerosis (ALS), whether different ALS-associated proteins cause shared APA abnormalities remains unclear. We analyzed poly(A)-site usage after TDP-43 knockdown, TDP-43 K263E expression, FUS knockout, FUS P525L expression, and MATR3 knockout. Using false-discovery rate (FDR) < 0.05 as the primary criterion, evidence varied markedly among datasets. FUS knockout produced the strongest response, with 373 significant events affecting 239 genes. Three events involving two genes remained significant after TDP-43 knockdown, and two events involving one gene remained significant in the TDP-43 K263E dataset. No events survived FDR correction after FUS P525L expression or MATR3 knockout, and no FDR-significant events or genes were shared between datasets. We therefore examined nominal events (unadjusted P < 0.05) as an explicitly exploratory layer. Nominal event overlap was enriched in 7 of 10 pairwise comparisons, and nominal gene overlap in 9 of 10. TDP-43 knockdown and TDP-43 K263E showed the strongest directional agreement: 65 nominal events were shared; 25 were directionally classified in both datasets, of which 23 were concordant. FUS knockout and FUS P525L also showed enriched nominal overlap, but without significant directional concordance or correlated ΔPAU responses. Thus, FUS loss induces a robust FDR-supported APA phenotype, whereas evidence is substantially weaker in other contexts. Cross-dataset similarities occur mainly among exploratory nominal targets and do not consistently extend to direction or magnitude. APA responses therefore show partial, context-dependent convergence rather than a universal defect.
    Keywords:  3′UTRremodeling; Alternativepolyadenylation(APA); Amyotrophiclateralsclerosis(ALS); FUS; MATR3; Neurodegeneration; Poly(A)siteusage; RNA-bindingproteins; RNAprocessing; TDP-43
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.10.012
  30. Mol Neurobiol. 2026 Oct 15. pii: 965. [Epub ahead of print]63(1):
    Restoring Neural Homeostasis via Class II HDAC Modulation: Mechanistic Insights and Therapeutic Opportunities.
    Rohan Gupta, Reetesh Kumar, Bhargav Shreevatsa K S, Deepak Kumar Modi, Smita Kumari, Naveen Kumar, Pallavi Singh, Karthikeyan Ravi, Mosleh Mohammad Abomughaid.
      Class II histone deacetylases (HDACs) comprise class IIa enzymes HDAC4, HDAC5, HDAC7, and HDAC9 and class IIb enzymes HDAC6 and HDAC10, which differ substantially in structure, catalytic activity, subcellular localization, and neural function. Class IIa HDACs exhibit weak intrinsic deacetylase activity and function predominantly as signal-responsive scaffolds that couple calcium and kinase signaling to transcription through nucleocytoplasmic shuttling, recruitment of HDAC3-containing NCoR/SMRT corepressor complexes, and interactions with MEF2, CREB, and FOXO. Conversely, HDAC6 is a predominantly cytoplasmic deacetylase that regulates α-tubulin acetylation, cytoskeletal dynamics, axonal transport, autophagy, and proteostasis. Dysregulated class II HDAC signaling contributes to neurodegenerative diseases through convergent mechanisms involving synaptic dysfunction, maladaptive transcriptional repression, mitochondrial impairment, oxidative stress, neuroinflammation, blood-brain barrier disruption, and defective clearance of pathological proteins. Disease-associated substrates include amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and TDP-43/SOD1 in amyotrophic lateral sclerosis. Emerging evidence additionally links aberrant HDAC4/5 signaling to neurodevelopmental disorders through altered synaptic maturation, excitation-inhibition balance, and circuit development. This review integrates the structural and mechanistic biology of class II HDACs with their disease-specific roles and evaluates therapeutic approaches to restore neural homeostasis. Particular emphasis is placed on selective HDAC6 inhibitors, modulation of class IIa protein-protein interactions and subcellular trafficking, natural compounds, and RNA-based strategies. Finally, we discuss major translational challenges, including isoform specificity, brain penetration, context-dependent functions, and the need to distinguish catalytic from non-enzymic mechanisms when developing disease-modifying interventions for neurological disorders while preserving normal essential HDAC functions and minimizing off-target toxicity.
    Keywords:  Histone deacetylases (HDACs); Natural compounds; Neurodegenerative diseases (NDDs); Neuroinflammation; Protein aggregation; Selective inhibitors
    DOI:  https://doi.org/10.1007/s12035-026-06265-1
  31. J Alzheimers Dis Rep. 2026 Jan-Dec;10:10 25424823261437791
    Exploring potential genetic correlation and causality between cathepsins and neurodegenerative diseases: Insight from Mendelian randomization analyses.
    Hui Shu, Rongmao He, Ziting Zhu, Wenlong Zhang, Pingyi Xu.
       Background: Previous research has exhibited a potential association between cathepsins and neurodegenerative diseases (NDDs). Nevertheless, the causal relationships between cathepsins and different types of NDDs remain inadequately clear.
    Objective: We aim to explore the genetically correlation and causality between 4 NDDs and 9 cathepsins based on genome-wide association study platform.
    Methods: Cathepsin B, E, F, G, H, L2, O, S, and Z and four NDDs types, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and dementia with Lewy bodies, were obtained from large-scale genome-wide summary data. To explore potential interactive roles of these cathepsins in the pathogenesis of NDDs, we applied two-sample bidirectional univariable Mendelian randomization (MR) and multivariable MR, with inverse variance weighting as the primary statistical approach.
    Results: The univariable MR analysis revealed one positive and two negative causal effects between genetic liability in nine cathepsins and four NDDs. Reverse univariable MR analysis identified one negative causal link. Furthermore, the multivariable MR analysis not only confirmed two significant associations observed in the univariable analysis but also revealed a new positive effect.
    Conclusions: Our findings demonstrate that several cathepsins are causally associated with different NDDs, offering new insights into the underlying mechanisms of neurodegeneration. These results may contribute to the development of novel diagnostic and therapeutic strategies for managing neurodegeneration.
    Keywords:  Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; cathepsin; dementia with Lewy bodies; neurodegenerative diseases
    DOI:  https://doi.org/10.1177/25424823261437791
  32. Ann Med Surg (Lond). 2026 Oct;88(10): 6221-6224
    Brain-computer interfaces and neuroprostheses for severe speech impairment in amyotrophic lateral sclerosis.
    Syed Tawassul Hassan, Muhammad Shaheer Bin Faheem, Ali Jan Yaqubi, Mohammed Salem Brhaish.
      Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder that frequently culminates in severe dysarthria and anarthria, profoundly isolating patients and diminishing their quality of life. Traditional speech therapy and conventional augmentative and alternative communication devices rely on residual motor control and become ineffective in late-stage ALS. In response, brain-computer interfaces and speech neuroprostheses have emerged as transformative solutions. By decoding neural signals directly from the motor cortex and translating them into synthesized speech, these devices bypass compromised neuromuscular pathways. Recent high-impact clinical trials have demonstrated unprecedented success, achieving high-speed decoding and integrating artificial intelligence-driven voice banking to preserve a patient's unique vocal identity. However, significant translational challenges remain, including signal degradation, surgical risks, high socioeconomic costs, and ethical dilemmas regarding patient autonomy and data privacy. This perspective reviews the current state-of-the-art in speech neuroprosthetics, analyzes the barriers to widespread clinical implementation, and advocates for increased interdisciplinary collaboration and funding to establish these technologies as a standard of care for patients with severe speech impairments.
    Keywords:  amyotrophic lateral sclerosis; anarthria; brain–computer interfaces; neuroprosthetics; speech restoration
    DOI:  https://doi.org/10.1097/MS9.0000000000005542
  33. J Genet Couns. 2026 Oct;35(5): e70307
    Ethical Dilemmas in Predictive Testing for Monozygotic Twins With Hereditary ALS: A Clinical Case Report.
    Miranda Li, Ashley White, Karen Canales, Nellie Fotopoulos.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder typically presenting in midlife and leading to death within 2-5 years of onset. Pathogenic SOD1 variants, inherited in an autosomal dominant manner, account for approximately 20% of hereditary ALS cases. Predictive genetic testing in SOD1-related ALS presents unique ethical challenges, particularly in monozygotic twins who share identical genetic information but hold differing views about testing. We describe an 18-year-old monozygotic twin who requested predictive testing for the familial SOD1 pathogenic variant identified in her father, who died from ALS at age 40. This conferred a 50% a priori risk to both twins. One twin had long expressed the desire to know her genetic status, while the other preferred not to pursue testing. Because a positive result in one twin would automatically reveal the status of the other, the case raised ethical tensions surrounding autonomy, beneficence, non-maleficence, and justice. Institutional ethics consultation and peer supervision were used to navigate these competing ethical imperatives and provided initial recommendations and direction. Additional valuable insights were gained through a peer-supervision framework that brought together genetic counselors across varying levels of experience and specialties. These discussions informed our ethical assessment and supported the decision to proceed with predictive testing, as the benefits were ultimately deemed to outweigh the potential risks. Testing identified the familial SOD1 pathogenic variant, which was disclosed to the patient and her family. Her twin subsequently elected to undergo confirmatory testing and received comprehensive genetic counseling and psychosocial support. Ethical complexities surrounding predictive genetic testing in monozygotic twins with hereditary neurodegenerative diseases, such as ALS, require careful balancing of autonomy, beneficence, non-maleficence, and justice. Structured peer supervision is essential for working through ethical uncertainty, guiding sound clinical decisions, and supporting patient-centered care.
    Keywords:  ALS; ethical dilemma; genetic testing in twins; predictive genetic testing
    DOI:  https://doi.org/10.1002/jgc4.70307
  34. Ann Neurol. 2026 Oct 16.
    Salivary Dim-Light Melatonin Onset is Associated with Functional Decline, Respiratory Symptom Emergence, and Survival in Early Amyotrophic Lateral Sclerosis.
    Alessandro Bombaci, Antonella Iadarola, Alessia Giraudo, Elisa Fattori, Serena Sinagra, Alice Magnino, Maria Falbo, Giovanni De Marco, Andrea Calvo, Adriano Chiò, Alessandro Cicolin.
       OBJECTIVE: Sleep-wake and circadian disturbances are increasingly recognized in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information.
    METHODS: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim-light conditions at 6 predefined time points around habitual sleep onset. Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined when the fitted curve first reached 3 pg/ml. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age- and sex-matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses.
    RESULTS: A total of 50 plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 ± 1:18 vs 20:58 ± 0:50; p = 0.028) despite similar habitual sleep onset and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.11; p = 0.019), and poorer survival/tracheostomy-free outcome. In the resampled subgroup (n = 28), DLMO and melatonin-derived metrics did not change over ~6 months.
    INTERPRETATION: Circadian phase alterations are detectable in early ALS. Baseline DLMO showed exploratory associations with functional, respiratory, and survival outcomes. Larger independent cohorts are required before DLMO can be considered a validated prognostic biomarker. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78398
  35. J Mol Neurosci. 2026 Oct 14. pii: 153. [Epub ahead of print]76(4):
    "Morphological, Functional, and Molecular Progression of Blood-Brain Barrier Dysfunction in Alzheimer's Disease".
    Karen León-Arcia, Humberto Martínez-Orozco, Magdalena Guerra-Crespo, Sofía Y Díaz-Miranda, Luis O Soto-Rojas.
      Blood-brain barrier (BBB) dysfunction is increasingly recognized as an early pathological event in sporadic Alzheimer's disease (AD), which represents over 95% of cases. Vascular risk factors and cerebral insulin resistance are considered potential contributors to its initiation. This review synthesizes evidence available through March 2026 on the temporal progression of morphological, functional, and molecular BBB alterations in AD patients and experimental models. This review emphasizes the proposed role of BBB disruption in perpetuating neurodegeneration through feedback loops involving pericyte damage, hypoxia, perivascular inflammation, and dysregulation of amyloid-β transport systems. By integrating data from neuroimaging, fluid biomarkers, and post-mortem studies, available evidence suggests that BBB alterations can be detected from preclinical stages, most consistently in the hippocampus, and may exhibit sex-specific differences. The review compares findings from familial transgenic models with the more limited characterization available in sporadic AD models (notably the intracerebroventricular streptozotocin model), and highlights key knowledge gaps regarding temporal dynamics. This synthesis supports further exploration of strategies to preserve BBB integrity. An integrated vascular approach may usefully complement current amyloid- and tau-centered therapies, particularly in sporadic AD.
    Keywords:  Alzheimer’s disease; Blood-brain barrier; Brain insulin resistance; Neurovascular unit; Pericytes; Vascular biomarkers
    DOI:  https://doi.org/10.1007/s12031-026-02610-0
  36. Imaging Neurosci (Camb). 2026 ;pii: IMAG.a.1391. [Epub ahead of print]4
    Multimodal MRI insights into glymphatic clearance and blood-brain barrier integrity in healthy aging.
    Anjan Bhattarai, Yufei D Zhu, Barah Albuhwailah, Pauline Maillard, Charles DeCarli, Audrey P Fan.
      Aging is associated with impaired CSF clearance in preclinical models, but its impact on blood-brain barrier (BBB) health and glymphatic function in humans remains unclear. The BBB and glymphatic functions are complementary and may partially overlap, yet their interaction is yet to be fully elucidated. In this study, we aimed to compare BBB integrity, extracellular free water, and glymphatic function between healthy young and older adults, and to examine mechanistic relationships among these measures using multimodal MRI techniques. 30 healthy participants with no known neurological or psychiatric disorders, including 12 younger (26 ± 3 years) and 18 older individuals (75 ± 7 years), underwent MRI scans on a 3T Siemens Prisma scanner. Multimodal MRI techniques were used, including diffusion-prepared arterial spin labeling to measure the water exchange rate (Kw) across the blood-brain barrier (BBB); free water (FW) imaging to quantify extracellular free water in white matter; and diffusion tensor imaging along perivascular spaces (DTI-ALPS) to assess glymphatic function. These measures were compared between younger and older individuals. Mediation analysis was performed to assess the mechanistic relationship between BBB integrity and glymphatic function and to test whether this relationship was mediated by free water. Older individuals showed reduced whole-brain Kw (p = 0.021), increased white matter FW (p = 0.002), and reduced DTI-ALPS (p < 0.001) compared to younger adults. Kw was positively associated with DTI-ALPS (β = 0.402 × 10-2, p = 0.022) and negatively associated with FW (β = -0.676 × 10-3, p = 0.008). DTI-ALPS was negatively associated with FW (β = -3.487, p = 0.001). Significantly reduced Kw was also observed in the cortical grey matter of older adults. Reduced Kw may reflect impaired BBB function, while reduced DTI-ALPS and increased FW indicate impaired glymphatic clearance. FW mediated the relationship between Kw and DTI-ALPS (95% CI [0.00014, 0.00404], p = 0.035), suggesting a potential mechanistic link between BBB function, extracellular water content, and glymphatic clearance efficiency. Overall, this study provides novel multimodal MRI insights into BBB and glymphatic alterations in healthy aging and may inform the development of MRI biomarkers to preserve cognitive health.
    Keywords:  DTI-ALPS; aging; arterial spin labeling; blood–brain barrier; diffusion tensor imaging; free water; glymphatic system; water exchange rate
    DOI:  https://doi.org/10.1162/IMAG.a.1391
  37. Neurol Sci. 2026 Oct 15. pii: 856. [Epub ahead of print]47(11):
    Intracranial metastasis as a mimic of amyloid-related imaging abnormalities.
    Jeongyeon Hwang, Bradley N Delman, Georges Naasan.
      This report describes a 79-year-old woman with biomarker-confirmed Alzheimer's disease who developed progressive vasogenic edema initially interpreted as amyloid-related imaging abnormalities (ARIA) with edema during lecanemab therapy, but was ultimately found to have multifocal intracranial metastases from recurrent papillary thyroid carcinoma. The serial neuroimaging highlights the diagnostic challenge of distinguishing ARIA from alternative causes of vasogenic edema in the era of anti-amyloid monoclonal antibody treatment. In addition, this case raises an important and underexplored question regarding whether anti-amyloid therapies may alter blood-brain barrier integrity in a manner that could influence metastatic spread in susceptible patients.
    Keywords:  Amyloid-related imaging abnormalities (ARIA); Anti-amyloid therapy; Blood-brain barrier; Intracranial metastasis; Vasogenic edema
    DOI:  https://doi.org/10.1007/s10072-026-09449-8
  38. Cell Rep. 2026 Oct 15. pii: S2211-1247(26)01131-9. [Epub ahead of print]45(10): 118053
    Ataxin-2 downregulation rewires neuronal and astrocytic metabolism to protect against TDP-43 toxicity.
    Denise Gastaldo, Stephen Vito, Holly H Black, Oded Foreman, Zhichang Yang, Victoria Pham, Ying Zhu, Meena Choi, Ana Jovičić.
      Ataxin-2 (ATXN2) is a genetic modifier of TDP-43 toxicity and a promising therapeutic target in amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying its neuroprotective effects remain poorly understood. Using global proteomic profiling in yeast and mouse TDP-43 models, we establish that pbp1/ataxin-2 (pbp1 is the yeast ataxin-2 ortholog) reduction confers neuroprotection by activating orthogonal stress-adaptive pathways in neurons and glia, rather than simply reversing TDP-43-induced damage. In neurons, ataxin-2 downregulation activates glycolysis and reductive glutamine carboxylation driven by IDH1, restoring ATP production independently of impaired mitochondria. In astrocytes, it upregulates cholesterol biosynthesis via HMGCS1, enhancing trophic support to neurons. Full neuroprotection requires both mechanisms: neuronal survival is only completely rescued when ataxin-2 is reduced in neuron-astrocyte co-cultures. Importantly, ataxin-2 downregulation protects against both TDP-43 gain- and loss-of-function toxicity, broadening its therapeutic relevance. Collectively, these findings establish ataxin-2 as a regulator of stress-adaptive metabolic resilience.
    Keywords:  ALS; ALS therapy; CP: metabolism; CP: neuroscience; TDP-43; ataxin-2; cholesterol; glutamine reductive carboxylation; glycolysis; mechanisms of neuroprotection; neurodegeneration; neuronal metabolism; neuroprotection
    DOI:  https://doi.org/10.1016/j.celrep.2026.118053
  39. Probiotics Antimicrob Proteins. 2026 Oct 10.
    The Gut-Brain Axis and Neurodegenerative Diseases: From Mechanistic Pathways to Therapeutic Interventions.
    Weilun Lin, Zhiheng Shu, Gang Liu, Jun Fang, Sujuan Ding.
      As the global population ages, the incidence of neurodegenerative diseases (NDDs) has increased. Neurodegenerative diseases have complex pathogenesis and currently lack fundamental treatment methods. The gut-brain axis (GBA) participates in the pathogenesis of NDDs through bidirectional communication between the gut microbiota and the central nervous system (CNS). This review systematically introduces the pathogenic characteristics of representative NDDs such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), as well as the association mechanisms between these diseases and GBA. The pathogenic characteristics of NDDs are closely related to changes in the composition of the gut microbiota and differences in gut microbiota metabolites (such as short-chain fatty acids (SCFAs), neurotransmitters, tryptophan metabolites, etc.). These changes influence the CNS through multiple pathways, including neuroendocrine, vagus nerve, and immune regulation, ultimately contributing to the onset and progression of the diseases. Furthermore, we have collected and summarized preclinical and clinical evidence from recent years regarding therapeutic interventions based on the GBA mechanism, including probiotics, prebiotics, and fecal microbiota transplantation (FMT). Nevertheless, major knowledge gaps remain, particularly regarding causality between gut microbiota changes and NDDs, the underlying molecular mechanisms, and the clinical efficacy of GBA-targeted therapies. This article aims to review the mechanisms of the interaction between the gut microbiota and the brain in neurodegenerative diseases, and based on the existing experimental evidence, provide theoretical basis and future development directions for future prevention and treatment strategies targeting GBA.
    Keywords:  Clinical evidence; Gut-brain axis; Neurodegenerative diseases; Pathogenesis; Therapeutic targets
    DOI:  https://doi.org/10.1007/s12602-026-11246-w
  40. Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2613546123
    An integrative transcriptomic atlas of ALS and aging skeletal muscle defines shared and distinct molecular programs of degeneration.
    Mercedes Grima-Terrén, Megan Rommelfanger, Silvia Campanario, Aina Calls-Cobos, Andrés Cisneros, Ignacio Ramírez-Pardo, Grace Chou, Yuewen Zheng, Nasun Hah, Antonio L Serrano, Eusebio Perdiguero, Joan Isern, Pura Muñoz-Cánoves.
      Skeletal muscle atrophy and weakness resulting from loss of motor neuron innervation are shared hallmarks of amyotrophic lateral sclerosis (ALS) and age-associated sarcopenia. However, muscle wasting in ALS is rapid and severe, whereas sarcopenia progresses gradually over decades, peaking at an advanced age. The molecular mechanisms underlying muscle wasting in these conditions remain incompletely defined. Here, we used the SOD1G93A ALS mouse model and wild-type mice across the lifespan to generate an integrated single-nucleus transcriptomic atlas of skeletal muscle, mapping changes associated with ALS and aging. This atlas is complemented by structural and functional analyses. Our results identify transcriptionally distinct condition-specific myonuclear states, including disease-responsive programs within synaptic myonuclei at the neuromuscular junction, that are shared or distinct between the two conditions. Notably, at early stages, muscle from ALS mice exhibits molecular hallmarks of aged muscle at the myofiber level, indicating premature aging and reinforcing aging as a risk factor in ALS. At advanced disease stages and in old age, myonuclear subpopulations follow similar degenerative pathways in fast glycolytic fibers, consistent with their loss in both conditions. However, a distinct ALS-enriched myonuclei subpopulation displays uniquely regulated genes not observed in aged muscle, potentially underlying the more rapid and severe pathology observed in ALS. This atlas maps shared and divergent mechanisms of muscle degeneration in ALS and sarcopenia and provides a resource for identifying therapeutic targets tailored to each condition.
    Keywords:  aging; amyotrophic lateral sclerosis; atrophy; skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2613546123
  41. Neuromolecular Med. 2026 Oct 11. pii: 54. [Epub ahead of print]28(1):
    Sigma-1 Receptor Mitigates Poly-GR-Associated Redox Dysregulation by Restoring NRF2/HO1 Signaling in C9orf72-Associated ALS.
    Chao-Yi Tsai, Hsuan-Cheng Wu, Tsung-Ping Su, Eddie Feng-Ju Weng, Shao-Ming Wang.
      Hexanucleotide GGGGCC repeat expansions in C9orf72 produce arginine-rich dipeptide repeat proteins, including poly-GR and poly-PR, that contribute to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Although poly-GR has been linked to oxidative stress and mitochondrial dysfunction, the mechanisms that determine whether antioxidant defenses are preserved or suppressed in poly-GR-expressing motor neurons remain incompletely understood. Here, we investigated whether Sigma-1 receptor (Sigma-1R) modulates poly-GR-associated redox dysregulation in cellular and mouse models. In NSC34 cells, both EGFP-PR42 and EGFP-GR50 expression reduced NRF2 protein levels. EGFP-GR50 expression was also associated with reduced NRF1 and HO1 levels and increased reactive oxygen species (ROS) accumulation. Sigma-1R overexpression or pharmacological activation with fluvoxamine or PRE084 restored NRF2 and HO1 expression and attenuated both cellular and mitochondrial oxidative stress in EGFP-GR50-expressing cells. Co-treatment with the Sigma-1R antagonist NE100 attenuated the agonist-induced restoration of NRF2 and HO1. Furthermore, the NRF2 inhibitor ML385 attenuated agonist-mediated HO1 restoration, supporting the involvement of NRF2 activity in this downstream response. In an AAV-mediated EGFP-GR50 mouse model, Sigma-1R deficiency was associated with shortened survival, reduced NeuN-positive neuronal counts, and decreased NRF2 immunoreactivity in the brain. Together, these findings identify Sigma-1R as a modulator of poly-GR-associated redox dysregulation and neuronal vulnerability and support further investigation of Sigma-1R modulation as a potential therapeutic strategy for C9orf72-associated ALS.
    Keywords:   C9orf72 ALS; NRF2; Poly-GR; ROS; Sigma-1R
    DOI:  https://doi.org/10.1007/s12017-026-08951-8
  42. J Mov Disord. 2026 Oct 12.
    Targeting the Gut to Modify Parkinson's Disease: From Mechanisms to Potential Therapeutics.
    Yi-Cheng Tai, Chin-Hsien Lin.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder and its prevalence continues to rise with population aging. Its cardinal motor features arise from the loss of dopaminergic neurons in the substantia nigra, accompanied by intraneuronal α-synuclein aggregates known as Lewy bodies. Neuropathological evidence suggests that, in a subset of patients, α-synuclein pathology first appears in the enteric nervous system and ascends to the brain via the gut-brain axis. Consistent with this "body-first" trajectory, a growing body of work has documented distinct alterations in gut microbial composition and microbiota-derived metabolites in people with PD relative to healthy individuals, with some changes detectable in the prodromal phase. Current management, whether dopaminergic pharmacotherapy or deep brain stimulation, alleviates motor symptoms but does not slow neurodegeneration, and long-term treatment is complicated by motor fluctuations and other adverse effects. Therapies directed at the underlying disease process are therefore urgently needed. Because early perturbations of the gut microenvironment appear to contribute to PD pathogenesis, interventions that restore gut homeostasis represent a rational disease-modifying strategy, particularly for patients whose pathology originates in the gut. This review synthesizes current understanding of how the gut microbiota shapes the gut-brain axis in PD, spanning immune, metabolic, neuroendocrine, and neural pathways, and critically appraises the emerging evidence for microbiota-directed interventions, including fecal microbiota transplantation, probiotics, and prebiotics, as candidate disease-modifying therapies.
    Keywords:  Gut-brain axis; Parkinson’s disease; fecal microbiota transplantation; prebiotics; probiotics
    DOI:  https://doi.org/10.14802/jmd.26285
  43. Phys Act Nutr. 2026 Sep;30(3): 97-113
    Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery.
    Kwangjun Lee, Taejin Kwak, Wonil Park.
       PURPOSE: A key pathological hallmark of amyotrophic lateral sclerosis (ALS) is transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy. Mutations in TARDBP and cellular stress can drive nuclear clearance and cytoplasmic aggregation of TDP-43. TDP-43 is an essential nuclear RNA-binding protein that regulates RNA metabolism, and cytoplasmic TDP-43 aggregation leads to aberrant splicing of essential neuronal transcripts including stathmin-2 (STMN2) and unc-13 homolog A (UNC13A). Dysregulated RNA splicing causes cryptic exon (CE) inclusion in STMN2 and UNC13A mRNA, resulting in non-functional proteins and disruption of axonal regeneration and synaptic integrity. Splice-switching antisense oligonucleotides and gene-editing platforms can correct STMN2 and UNC13A mis-splicing defects. However, restoring STMN2 and UNC13A expression alone is not sufficient to regenerate neuromuscular junctions or reverse skeletal muscle atrophy, both of which are crucial for functional recovery in patients with ALS.
    METHODS: We reviewed gene-targeted treatment strategies and rehabilitative mechanisms that inhibit ALS progression and reverse neuromuscular degeneration by analyzing databases, including Google Scholar, PubMed, and ScienceDirect. We proposed a dual-modality therapeutic approach integrating base-editing-mediated gene therapy with exercise-based rehabilitation.
    RESULTS: Antisense oligonucleotides and genome editing can restore transcript fidelity by preventing cryptic exons inclusion in STMN2 and UNC13A, thereby stabilizing neuronal function. Gene-targeted therapies halt ALS progression; however, these treatments alone are insufficient to reverse neuromuscular degeneration or achieve functional recovery needed for patients with ALS to return to daily life.
    CONCLUSION: Integrated rehabilitation is a crucial step in gene-targeted therapy for ALS. This strategy halts disease progression and restores neuromuscular function, thereby improving the lifespan and quality of life of patients with ALS.
    Keywords:  TDP- 43 proteinopathy; amyotrophic lateral sclerosis (ALS); antisense oligonucleotides (ASOs); exercise rehabilitation; genome editing
    DOI:  https://doi.org/10.20463/pan.2026.0045
  44. Neurotherapeutics. 2026 Oct 12. pii: S1878-7479(26)00266-7. [Epub ahead of print]23(6): e01096
    Immunosenescence as a modifiable driver of neurodegenerative diseases: Pathways and multidimensional emerging strategies for Alzheimer's and Parkinson's diseases.
    Jingyu Zhao, Linzhuo Qu, Hongjian Guan, Huiying Che, Fei Shi, Yang Yang.
      Immunosenescence represents a core upstream driver of Alzheimer's disease (AD) and Parkinson's disease (PD), exerting its pathological effects through four mechanistically interconnected cascades: chronic inflammatory imbalance mediated by the senescence-associated secretory phenotype (SASP), oxidative stress arising from immune-metabolic reprogramming, protein homeostasis dysfunction caused by autophagy-lysosomal failure, and disrupted neuro-immune crosstalk secondary to breakdown of central nervous system (CNS) immune privilege. Current clinical practice remains largely constrained to neurotransmitter-based symptomatic management, which can neither arrest upstream pathological progression nor restore lost neuronal populations. Emerging intervention strategies targeting immunosenescence, including senolytic agents, antioxidant and metabolic modulators, autophagy restoration, and precision-targeted nanocarrier delivery, have demonstrated substantial capacity to delay disease progression in preclinical and early clinical investigations. These strategies act through selective clearance of senescent immune cells, remodeling of the neuroinflammatory microenvironment, and restoration of cellular quality-control mechanisms. The multidimensional treatment strategy approaches from the perspectives of artificial intelligence (AI) guided target discovery, nanocarrier engineering, and gut microbiota intervention to simultaneously address multiple nodes in the immunosenescence network, thereby overcoming the inherent limitations of single-target strategies. This review consolidates current mechanistic evidence and translational data to establish immunosenescence as an actionable therapeutic target and to provide a conceptual framework for precision disease-modifying therapy in AD and PD.
    Keywords:  Combination immunotherapy; Gut microbiota intervention; Immunosenescence; Nanocarrier delivery systems; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.neurot.2026.e01096
  45. J Parkinsons Dis. 2026 Oct 13. 1877718X261499238
    An acoustic-only multivariable diagnostic model for Parkinson's disease using bowel sound acoustic signatures.
    Sicheng Chen, Man Zhang, Surui Fang, Qi Yang, Chuyi Chen, Zhixuan Lei, Yuxia Zhu, Fen Deng, Lijuan Mo, Xi Liu, Changhong Tan, Lifen Chen.
      BackgroundEarly detection of Parkinson's disease (PD) remains challenging due to the lack of reliable prodromal biomarkers. Non-invasive markers of gastrointestinal dysfunction are lacking.ObjectivesTo characterize bowel sound acoustic phenotypes in PD and evaluate their potential as non-invasive diagnostic markers by developing an acoustic-based predictive model.MethodsStandardized 5-min bowel sound recordings were collected from 120 PD patients and 100 controls. Thirteen acoustic features were extracted. LASSO (least absolute shrinkage and selection operator) selected predictors for logistic regression models, internally validated with 1000 bootstrap resamples. The acoustic-only model was evaluated without refitting within the development cohort in 48 patients with Hoehn-Yahr stages 1-2 and 100 controls.ResultsPD patients exhibited fragmented, low-energy bowel sound patterns compared with controls. Acoustic features did not differ significantly by constipation status, while two duration measures differed by Hoehn-Yahr stage. A full-feature model incorporating acoustic and biochemical markers achieved an area under the curve (AUC) of 0.8659. The acoustic-only model containing six predictors, three of which were statistically significant, yielded an AUC of 0.7999 (95% confidence interval [CI], 0.737-0.852). Optimism-corrected AUCs were 0.839 and 0.784, respectively. In the early-stage subgroup, the AUC was 0.728 (95% CI, 0.644-0.806), with 68.75% sensitivity and 66.00% specificity at the fixed probability threshold of 0.50.ConclusionsPD patients exhibit distinct bowel sound acoustic phenotypes. Acoustic features provided discrimination between PD patients and controls, including in early-stage disease. This non-invasive profiling approach offers a promising functional biomarker candidate for multimodal PD assessment.
    Keywords:  Parkinson's disease; acoustic phenotypes; bowel sounds; diagnostic model
    DOI:  https://doi.org/10.1177/1877718X261499238
  46. Chin Med Sci J. 2026 Jun;pii: S1001-9294(26)00013-1. [Epub ahead of print]41(2): 76-83
    Post-traumatic dementia: Advances in understanding neurodegenerative mechanisms.
    Xiao-Jie He, Hui Wang, Yi Zhang.
      Traumatic brain injury can trigger long-term neurodegenerative diseases beyond its devastating acute effects. This narrative review summarizes current understanding of the neurodegenerative mechanisms underlying post-traumatic dementia. Core mechanisms involve multiple pathophysiological processes: long-term dysfunction of the blood-brain barrier, which impairs the clearance of toxic proteins; diffuse axonal injury, leading topersistent disruption of axonal transport, dysregulation of calcium homeostasis, and Wallerian-like degeneration; and the abnormal deposition of key pathological proteins such as amyloid-β, hyperphosphorylation and propagation of tau protein, and dysfunctional TAR DNA-binding protein-43, all of which disrupt protein homeostasis. In addition, chronic neuroinflammation mediated by microglia and astrocytes acts as a critical link, continuously exacerbating synaptic damage and neurodegeneration through the release of pro-inflammatory factors. Genetic factors, such as the APOE4 allele, can significantly amplify these pathological processes. Collectively, this evidence indicates that traumatic brain injury is not an isolated acute event but rather initiates and accelerates a long-term, multifactorial neurodegenerative cascade, ultimately resulting in cognitive dysfunction. These insights provide important targets for the development of targeted intervention strategies.
    Keywords:  Axons; Blood-brain barrier; Dementia; Neuroinflammation; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.cmsj.2026.08.001
  47. Cells. 2026 Sep 29. pii: 1768. [Epub ahead of print]15(19):
    Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.
    Gabriel Burdman, Marco Hanna, Adriana Yndart Arias, Arti Vashist, Madepalli K Lakshmana.
      Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.
    Keywords:  Alzheimer’s disease; CRISPR; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; assembloids; human induced pluripotent stem cells; organoids; translational validation
    DOI:  https://doi.org/10.3390/cells15191768
  48. Zhongguo Zhen Jiu. 2026 Oct 12. 46(10): 1677-1684
    [Effect of electroacupuncture at Jiaji (EX-B2) on disease progression in mice with amyotrophic lateral sclerosis based on NLRP3/Caspase-1/ASC signaling pathway].
    Shilin Wang, Mingyue Wang, Yuanzheng Sun, Guanping Liu, Yingying Li, Wenzhao Zhang, Jia Yao.
       Objective: To explore the underlying mechanism of electroacupuncture (EA) at "Jiaji" (EX-B2) on the disease progression through modulating NOD-like receptor family pyrin domain containing 3 (NLRP3)/cysteine-aspartic acid protease 1 (Caspase-1)/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) signaling pathway in mice with amyotrophic lateral sclerosis.
    Methods: Forty-five mice carrying the human superoxide dismutase 1 G93A (hSOD1G93A) gene were randomly divided into a model group, a Jiaji EA group, and an inhibitor group, 15 mice per group. The other 15 mice without hSOD1G93A gene carried were collected as a wild group. When the mice were aged 60 days, in the Jiaji EA group, EA was operated at "Jiaji" (EX-B2) of L1/L2, L5/L6, with continuous wave, a frequency of 2 Hz and an intensity of 1 mA, retained for 20 min, twice a week; in the inhibitor group, the intraperitoneal injection with NLRP3 inhibitor (10 mg/kg) was administered, twice a week. The interventions lasted for 4 weeks in each group. When the mice were aged 120 days, 9 mice in each group were randomly selected for tissue collection from lumbar spinal cord, and the disease progression and limb function were observed for the remaining 6 mice. The neurological function score was employed to assess the disease progression of mice in each group, and the gait experiment was conducted to observe the gait and stride length; HE staining was used to observe the motor neuron morphology in the anterior horn of the lumbar spinal cord, immunohistochemistry was used to detect the expression of ionic calcium-binding adapter molecule 1 (Iba-1) in the anterior horn of the lumbar spinal cord, and Western blot was used to detect the protein expression of NLRP3, Caspase-1, ASC, interleukin (IL)-18 and IL-1β in lumbar spinal cord.
    Results: Compared with the wild group, in the model group, the disease was worsened progressively, on days 90 and 120 after birth, the stride length of mice was reduced (P<0.05, P<0.01), and the gait was unstable and dragging on 120 days after birth; the motor neurons in the anterior horn of the spinal cord exhibited obvious cellular edema and rupture, marked vacuolization and nuclear pyknosis, along with severe neuron loss; the expression of Iba-1 increased in the anterior horn of the lumbar spinal cord (P<0.01), colored dark brown and densely aggregated; and the protein expression of NLRP3, Caspase-1, ASC, IL-18, IL-1β in lumbar spinal cord was up-regulated (P<0.01). When compared with the model group, in the inhibitor group and the Jiaji EA group, the onset of paresis and the progression of paralysis were delayed and the survival rates increased (P<0.01); stride length was larger in the mice at the age of 120 d (P<0.01); more clear gait was presented, and the ages in days was significantly delayed for gait dragging; the improvements were exhibited in the degree of edema, vacuolization, and nuclear pyknosis observed in the motor neurons of the anterior horn of the lumbar spinal cord; the expression of Iba-1 was reduced in the anterior horn of the lumbar spinal cord (P<0.01), appearing gray-brown, and scattered clusters in small number; and the protein expression of NLRP3, Caspase-1, ASC, IL-18, and IL-1β in lumbar spinal cord was decreased (P<0.05, P<0.01). The protein expression of NLRP3, Caspase-1 and IL-18 in lumbar spinal cord in the Jiaji EA group was up-regulated in comparison with that in the inhibitor group (P<0.05).
    Conclusion: Electroacupuncture at "Jiaji" (EX-B2) can delay the disease progression in mice with amyotrophic lateral sclerosis, which may be related to modulating NLRP3/Caspase-1/ASC signaling pathway and inhibiting the inflammatory response, thereby attenuating the inflammatory injury of lumbar spinal cord.
    Keywords:  NOD-like receptor family pyrin domain containing 3 (NLRP3); Point EX-B2 (Jiaji); amyotrophic lateral sclerosis; electroacupuncture; microglia; neuroinflammatory response
    DOI:  https://doi.org/10.13703/j.0255-2930.20250518-k0001
  49. Molecules. 2026 Oct 07. pii: 3564. [Epub ahead of print]31(19):
    Bee-Derived Products in Neurodegenerative Diseases: Bioactive Constituents, Redox-Modulating Mechanisms, Evidence, and Translational Perspectives.
    Jakub Garbarek, Oskar Hys, Alina Woźniak, Karolina Szewczyk-Golec, Jarosław Nuszkiewicz.
      Oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation are closely interconnected processes involved in the pathogenesis and progression of neurodegenerative diseases. Bee-derived products, including honey, propolis, royal jelly, bee pollen, bee bread, and bee venom, contain diverse bioactive constituents with antioxidant, anti-inflammatory, immunomodulatory, and redox-modulating properties. This narrative review summarizes the major bioactive compounds present in bee-derived products and evaluates their potential relevance to neuroprotection. Particular attention is given to mechanisms involving activation of the Nrf2/ARE antioxidant response, inhibition of NF-κB-dependent inflammatory signaling, modulation of the NLRP3 inflammasome, mitochondrial protection, regulation of apoptosis, and maintenance of proteostasis. Available evidence from cellular and animal models, together with the limited clinical data, is discussed primarily in the context of Alzheimer's and Parkinson's diseases, with additional consideration of amyotrophic lateral sclerosis and other neurodegenerative or neuroinflammatory conditions. Although several bee-derived products and isolated constituents show promising biological effects, their therapeutic translation remains limited by variable chemical composition, insufficient standardization, low or uncertain bioavailability, limited evidence of central nervous system exposure, and safety concerns. Further mechanistic, pharmacokinetic, and well-controlled clinical studies are therefore required before their potential neuroprotective applications can be reliably established.
    Keywords:  NF-κB; Nrf2; bee-derived products; neurodegeneration; neuroinflammation; neuroprotection; oxidative stress; redox signaling
    DOI:  https://doi.org/10.3390/molecules31193564
  50. Biochem Pharmacol. 2026 Oct 13. pii: S0006-2952(26)00887-7. [Epub ahead of print] 118545
    Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.
    Zhi-Yuan Zhang, Bo-Quan Qin, Shi-Zhou Wu, Hui Zhang.
      Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.
    Keywords:  Axonal transport; Charcot–Marie–Tooth disease type 2A; Conformational allocation; Mitochondrial dynamics; Mitofusin 2; Pharmacological modulation
    DOI:  https://doi.org/10.1016/j.bcp.2026.118545
  51. Diagnostics (Basel). 2026 Sep 27. pii: 3143. [Epub ahead of print]16(19):
    An Interpretable Framework for Identifying EEG Spectral Biomarkers of Pathological Brain Aging.
    Yunier Prieur-Coloma, Pavel Prado, Wael El-Deredy, Alejandro Weinstein.
      Background: Normal aging involves gradual declines in brain function, whereas neurodegenerative disorders show accelerated deterioration. Electroencephalography (EEG) captures alterations in brain oscillatory activity, making it promising for detecting neurodegenerative disorders. However, existing approaches often emphasize classification performance over spectral biomarker identification, limiting clinical translation. Methods: We propose an EEG-based framework integrating explainable machine learning, analyses of inter-subject heterogeneity and temporal stability, and probabilistic modeling to identify reproducible spectral biomarkers of pathological brain aging. Two independent public EEG datasets comprising cognitively normal (CN) individuals and patients with Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD) were analyzed. Spectral features from canonical frequency bands were analyzed using SHAP to identify reproducible biomarkers in two datasets. The identified biomarker was subsequently characterized through inter-subject heterogeneity, temporal stability, and empirical distributions to assess disease-related alterations in oscillatory activity. Results: Several spectral features showed consistent disease-related associations across classification tasks. The θ/α ratio emerged as a representative biomarker, showing reduced temporal stability and broader empirical distributions in most neurodegenerative groups than in CN. Conclusions: Reduced temporal stability of reproducible EEG spectral biomarkers may represent an observable signature of disrupted oscillatory brain organization during pathological aging. The proposed framework characterizes a dimension of EEG spectral biomarkers that static summaries discard, offering an interpretable basis on which future longitudinal studies may build diagnostic and monitoring tools.
    Keywords:  EEG biomarkers; brain aging; electroencephalography; explainable machine learning; neurodegenerative disorders
    DOI:  https://doi.org/10.3390/diagnostics16193143
  52. Expert Opin Ther Targets. 2026 Oct 16.
    Targeting the microbiota-gut-brain axis in Alzheimer's and Parkinson´s disease: recent therapeutic approaches.
    Manuela Gries, Karl-Herbert Schäfer, Kristina Endres.
       INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders with limited disease-modifying treatment options. Evidence suggests that the microbiota-gut-brain axis (MGBA) plays a role in these diseases by facilitating communication between the gut and the central nervous system. Associations have been found between altered gut microbiota composition and function, impaired barrier integrity, dysregulated metabolite production, and immune activation to neuroinflammation and progressive neurodegeneration.
    AREAS COVERED: This review summarizes and critically assesses recent studies from the past year to provide an updated overview of therapeutic strategies targeting the MGBA in both diseases. We discuss dietary interventions, probiotics, postbiotics, microbial metabolites, and approaches targeting gut barrier function. We also highlight strategies such as fecal transplantation, photobiomodulation, and PD-targeted metabolism therapies using butyrate and resistant starch.
    EXPERT OPINION: While these interventions have shown promising results in preclinical and early clinical trials, their clinical application is limited by methodological heterogeneity, interindividual variability and a lack of standardized protocols. Successful implementation requires carefully designed clinical trials, particularly longitudinal studies of presymptomatic cohorts, standardized microbiome analyses, and integrated multi-omics approaches to elucidate causal relations and facilitate personalized treatment strategies.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; bacterial metabolites; microbiome; microbiota-gut-brain axis
    DOI:  https://doi.org/10.1080/14728222.2026.2748747
  53. Front Aging. 2026 ;7 1921485
    New insight into Alzheimer's disease: small molecule-Aβ in the brain transport and peripheral organ clearance.
    Tianci Ma, Yongyi Li, Yuting Ding, Shijie Liu, Chuanhao Gao, Xiang Li, Zhiqian Tong, Yan Lv.
      Alzheimer's disease (AD) represents one of the most prevalent neurodegenerative disorders without approved disease-modifying therapies. A major contributing factor is that, for decades, drug development has focused almost exclusively on repairing or removing lesions within the brain itself. Yet a growing body of work now points to AD as a systemic disorder, rooted in a breakdown of whole-body Aβ homeostasis. Nevertheless cerebral Aβ transport and peripheral Aβ clearance are commonly investigated as independent processes, and the coordinated interplay… remains insufficiently characterized. This review bridges the current research gap by systematically elaborating the full trafficking cascade of brain-derived Aβ from intracerebral drainage to peripheral elimination. Four major intracranial clearance pathways are comprehensively summarized, including the blood-brain barrier, blood-cerebrospinal fluid barrier, arachnoid granulation venous outflow, and meningeal lymphatic/glymphatic system. The peripheral clearance processes of circulating Aβ in the blood, liver, kidney, and gastrointestinal tract are further illustrated. A broad spectrum of emerging therapeutic strategies targeting Aβ transport and clearance is also reviewed, including specific pathway modulators, microglia regulators, Aβ aggregation inhibitors, natural multi-target compounds, ultrasound-mediated blood-brain barrier opening, and exosome-based intervention approaches. When we compare the relative contributions of central versus peripheral clearance, Comparative analysis of central and peripheral Aβ clearance indicates that the liver appears to dominate the peripheral elimination of Aβ, yet the real driver of cerebral Aβ deposition is not the failure of any single route, but rather the loss of synergy among multiple pathways. This mechanistic framework explains why purely brain-centric therapeutics are unlikely to correct a systemic Aβ imbalance. Instead, future translational efforts should give higher priority to combination regimens that simultaneously facilitate intracerebral drainage and bolster peripheral organ clearance. This review further discusses current hurdles and emerging opportunities in systemic AD drug discovery, with the aim of offering a unified conceptual framework-one that providing a unified conceptual framework for understanding AD pathogenesis and facilitating the exploration of novel therapeutic paradigms.
    Keywords:  Alzheimer’s disease; brain-peripheral transport and 1 clearance; melecular mechanism; therapeutic drugs; β-Amyloid (Aβ)
    DOI:  https://doi.org/10.3389/fragi.2026.1921485
  54. Psychogeriatrics. 2026 Nov;26(6): e70229
    Association Between Neuropsychological Test Performance and Neuroimaging Findings in Cognitive Impairment: A Retrospective Cohort Study.
    Mehmet Mesut Dorukoğlu, Dilek Evyapan, Cenk Eraslan.
       BACKGROUND: Structural magnetic resonance imaging (MRI) and [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) provide different information about cognitive impairment, but the additional contribution of FDG-PET beyond MRI across cognitive outcomes remains unclear. This study examined associations between neuropsychological performance and MRI/FDG-PET findings.
    METHODS: This retrospective cohort included 200 patients with mild cognitive impairment or dementia. Neuropsychological assessment covered global cognition and memory, executive, visuospatial and language domains. Structural MRI was evaluated using the Modified Visual Magnetic Resonance Rating Scale; FDG-PET data were available for 68 patients. MRI-only, FDG-PET-only and combined models were compared.
    RESULTS: Structural MRI abnormalities showed broad associations with global and domain-level cognitive performance. Sulcal and ventricular atrophy were associated with multiple cognitive domains, while regional FDG-PET findings aligned with corresponding domains. The additional contribution of FDG-PET beyond MRI appeared most evident for global cognition, more modest for executive performance and limited for several other outcomes.
    CONCLUSIONS: Structural MRI showed broad multidomain associations, while regional FDG-PET findings corresponded to cognitive performance. The additional explanatory contribution of FDG-PET appeared to vary across cognitive outcomes, warranting cautious interpretation and further evaluation.
    Keywords:  atrophy; cognitive dysfunction; fluorodeoxyglucose F18; magnetic resonance imaging; neuropsychological tests
    DOI:  https://doi.org/10.1111/psyg.70229
  55. Int Med Case Rep J. 2026 ;19 614180
    Multiple Sclerosis During Pregnancy and the Postpartum Period: Diagnostic and Multidisciplinary Challenges in Two Cases.
    Putri Nadya Syahidah, Setyorini Irianti, Johanes Cornelius Mose, Aih Cahyani, Nabilla Rhamdani.
       Background: Pregnancy may complicate the recognition and evaluation of new neurological symptoms suggestive of a central nervous system demyelinating disease. Diagnostic uncertainty may arise when clinical progression, neuroimaging findings, and supportive investigations are incomplete or inconclusive.
    Case Presentation: We report two pregnant women with progressive focal neurological symptoms and radiological findings suggestive of a demyelinating disease. Case 1 involved a 27-year-old woman with a history of autoimmune spondyloarthritis who developed dizziness, gait instability, asymmetric weakness, paraesthesia, and neuropathic pain during pregnancy. She underwent preterm delivery, and postpartum MRI demonstrated juxtacortical hyperintense lesions. Case 2 involved a 24-year-old woman who developed progressive right-sided weakness, visual disturbances, and headache during pregnancy. MRI demonstrated multiple periventricular and subcortical hyperintense lesions. She subsequently experienced spontaneous preterm labor and neurological worsening during the early postpartum period. In both cases, the available clinical and radiological findings raised concern for a demyelinating disorder; however, incomplete diagnostic investigations precluded retrospective confirmation of a definitive multiple sclerosis phenotype.
    Conclusion: These two cases highlight the diagnostic and clinical challenges associated with neurological symptoms suggestive of demyelinating disease during pregnancy and the postpartum period. Careful interpretation of clinical and radiological findings, continued postpartum surveillance, individualized obstetric decision-making, and multidisciplinary collaboration are essential. These observations should not be interpreted as evidence of causal relationships between suspected demyelinating disease and adverse obstetric outcomes.
    Keywords:  demyelinating disease; diagnostic uncertainty; multidisciplinary care; multiple sclerosis; postpartum period; pregnancy
    DOI:  https://doi.org/10.2147/IMCRJ.S614180
  56. Curr Neuropharmacol. 2026 Oct 02.
    Neuroimmune Dynamics of the Microglia-astrocyte Axis: Implications for Neurodegenerative Disorders as a Double-edged Sword.
    Dhrubajyoti Borah, Piyali Devroy, Asis Bala.
       INTRODUCTION: Maintaining homeostasis in the Central Nervous System (CNS) requires constant, bidirectional molecular interactions between microglia and astrocytes. This intercellular communication, mediated by cytokines, extracellular vesicles, purinergic signals, and connexin hemichannels, synchronizes immune surveillance, neurogenesis, and synaptic pruning under physiological conditions. However, this interaction can drive persistent neuroinflammation in chronic Neurodegenerative Disorders (NDDs) such as Multiple Sclerosis (MS), Parkinson's Disease (PD), and Alzheimer's Disease (AD).
    METHODS: Gene disease association analyses and review of existing literature were employed to identify shared glial regulators and molecular mediators across multiple neurodegenerative disorders, supported by schematic diagrams illustrating intercellular signaling dynamics Results: Deregulated astrocytes sustain microglial activation, creating self-amplifying inflammatory loops, while activated M1 microglia induce the conversion of astrocytes into neurotoxic A1 astrocytes via factors such as IL-1α, TNF-α, and complement C1q. Important mediators, such as prostaglandins, IL-1β, and IL-18, further contribute to demyelination, astrogliosis, and excitotoxicity. A convergent glial activation axis identifies shared regulators across several neurodegenerative disorders, including TREM2, GRN, LRRK2, and BDNF.
    DISCUSSION: Active research targeting reactive astrogliosis and microglial reprogramming towards homeostatic phenotypes shows therapeutic promise. Nevertheless, CNS immune complexity, translational challenge, and inter-patient immunological variability underscore the need for individualized, combinatorial therapeutic strategies and human-relevant experimental models.
    CONCLUSION: The microglia-astrocyte axis plays a dual role in neuro-immune homeostasis and neurodegeneration, representing critical therapeutic targets for NDDs and requiring further mechanistic and translational investigation.
    Keywords:  M1/M2 polarization; Neuroinflammation; astrocytes; cytokines; microglia; microglial reprogramming.; neurodegeneration; neuroimmune crosstalk
    DOI:  https://doi.org/10.2174/011570159X507671260924120425
  57. Front Neurol. 2026 ;17 1943801
    NAD+ signaling in Parkinson's disease: molecular mechanisms and therapeutic perspectives.
    Tianbao Wang, Xue Zhou, Xinhua Chen.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accumulation of α-synuclein (α-syn), mitochondrial dysfunction, and neuroinflammation. Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in cellular energy metabolism, DNA repair, and epigenetic regulation, declines with aging and is markedly reduced in the brains of patients with PD. Emerging evidence suggests that supplementation with NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), exerts neuroprotective effects through multiple mechanisms, such as activation of the mitochondrial unfolded protein response (UPR∧mt), enhancement of autophagy, and suppression of excessive poly(ADP-ribose) polymerase 1 (PARP1) activation. This review summarizes the central role of NAD+ dysregulation in the pathogenesis of PD, with particular emphasis on the interplay between NAD+ depletion, mitochondrial quality control, proteostasis, and neuroinflammation. Furthermore, we discuss recent advances in NAD+-boosting strategies in PD models and clinical studies, highlighting their potential therapeutic implications for PD intervention.
    Keywords:  NAD+; Parkinson's disease; mitochondrial quality control; neuroprotection; nicotinamide riboside
    DOI:  https://doi.org/10.3389/fneur.2026.1943801
  58. J Alzheimers Dis Rep. 2026 Jan-Dec;10:10 25424823261472106
    Artificial intelligence algorithms for the prediction of cognitive decline and dementia: A theoretical-historical narrative review.
    Rubén Sanz-Blasco, Miguel Ángel Fernández-Blázquez, Emilio Verche, José Antonio Muñiz-Casado, Marina Ávila-Villanueva, José María Ruiz-Sánchez de León.
      Population aging has increased the prevalence of neurodegenerative disorders associated with dementia, with Alzheimer's disease remaining the leading cause worldwide. Early identification of individuals at risk of cognitive decline, particularly those with mild cognitive impairment, remains a major clinical and scientific challenge. In this context, artificial intelligence has emerged as a promising framework for prognostic modeling and for the identification of clinically relevant predictors of disease onset and progression. This narrative review provides a theoretical and historical synthesis of the main machine learning and deep learning approaches used to predict cognitive decline and dementia from multimodal data, including biomarkers, clinical and demographic variables, cognitive measures, and neuroimaging markers. The review examines the methodological evolution of the field, from traditional statistical approaches to ensemble methods and deep neural architectures, and discusses the growing role of multimodal and longitudinal data integration. It also highlights major unresolved issues, including limited external validation, reduced interpretability, restricted generalizability, and the gap between predictive performance and clinical implementation. Overall, artificial intelligence has substantially advanced prediction research in cognitive decline and dementia, but its routine clinical adoption will depend on more rigorous validation, improved transparency, and stronger integration between neuroscience, clinical practice, and data science.
    Keywords:  Alzheimer's disease; artificial intelligence; dementia; machine learning; mild cognitive impairment; prognosis; risk assessment
    DOI:  https://doi.org/10.1177/25424823261472106
  59. J Mol Graph Model. 2026 Oct 08. pii: S1093-3263(26)00333-5. [Epub ahead of print]150 109607
    Atomistic simulation of blood-brain barrier permeability of propolis-derived natural compounds.
    Vipul Kumar, Sunil C Kaul, Renu Wadhwa, Durai Sundar.
      The ability of small molecules to cross the blood-brain barrier (BBB) remains a major bottleneck in neurotherapeutic development. While experimental assays and machine learning approaches provide approximate permeability estimates, they lack atomistic insight into the underlying transport mechanisms. Here, we employ all-atom molecular dynamics simulations of a compositionally realistic BBB lipid bilayer to characterize the passive permeation of two bioactive propolis-derived compounds, Caffeic Acid Phenethyl Ester (CAPE) and Artepillin-C (ARC). Using steered molecular dynamics and umbrella sampling, we computed free energy profiles, diffusion coefficients, and permeability metrics across the membrane. CAPE shows an interfacial free-energy well (mean PMF ≈ -4.6 kcal mol-1 at d ≈ 0.8 nm) and favorable passive permeability (logPeff = +0.68). In contrast, ARC exhibits a substantial energetic barrier within the membrane core and strongly unfavorable permeability (logPeff = -6.76). The heterogeneous lipid model reproduces experimentally consistent membrane properties and reveals how lipid composition modulates transport energetics. These findings provide mechanistic insight into BBB permeability and demonstrate the utility of atomistic simulations for guiding the design of neuroactive therapeutics.
    Keywords:  Blood brain barrier (BBB); Lipid bilayer; Molecular dynamics; Natural compounds; Permeability
    DOI:  https://doi.org/10.1016/j.jmgm.2026.109607
  60. IBRO Neurosci Rep. 2026 Dec;21 934-944
    Histopathology-correlated evaluation of magnetic resonance spectroscopy for high-grade glioma prediction: A small-scale neuro-oncology study with exploratory machine learning.
    Nazli Sulaiman, Dost Muhammad, Azmat Ali, Malika Bendechache.
       Background: High-grade gliomas are aggressive primary brain tumours that require timely and accurate preoperative assessment. Magnetic resonance spectroscopy provides non-invasive metabolic information that may support neuro-oncological lesion characterisation. However, its tendency to show good sensitivity but limited specificity, particularly in the presence of metastasis, abscess, and other intracranial mimics, is already recognised. The clinical value of small, fully histopathology-confirmed cohorts lies in clarifying how these limitations appear in real diagnostic practice.
    Objective: This study evaluated the diagnostic performance of magnetic resonance spectroscopy for predicting high-grade glioma in a fully histopathology-confirmed cohort of patients with intracranial lesions. The study also aimed to characterise the false-positive pattern in clinically interpretable terms and to assess, as a secondary exploratory analysis, whether machine learning (ML) could add discriminatory value beyond the radiologist-derived magnetic resonance spectroscopy diagnosis.
    Methods: A retrospective cohort of 53 patients was analysed. All cases had histopathological confirmation, which was used as the reference standard. Patient-level variables included age, sex, magnetic resonance spectroscopy diagnosis, histopathological diagnosis, Cho/NAA, Cho/Cr, NAA/Cr, lactate, lipid, lesion location, enhancement pattern, necrosis, and oedema. Magnetic resonance spectroscopy was treated as the index test. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, F1-score, and balanced accuracy were calculated. Exploratory ML models were assessed using leave-one-out cross-validation.
    Results: The cohort included 31 males and 22 females, with a mean age of 48.1 ± 15.8 years. Histopathology confirmed high-grade glioma in 40 of 53 patients. Magnetic resonance spectroscopy classified 42 cases as high-grade glioma and 11 as non-high-grade glioma. Compared with histopathology, magnetic resonance spectroscopy achieved a sensitivity of 87.5%, specificity of 46.2%, positive predictive value of 83.3%, negative predictive value of 54.5%, accuracy of 77.4%, F1-score of 85.4%, and balanced accuracy of 66.8%. The seven false-positive cases were characterised as metastasis in three cases, abscess in three cases, and other non-high-grade pathology in one case. The best exploratory ML model was Random Forest with magnetic resonance spectroscopy diagnosis included, achieving an accuracy of 73.6% and an AUC of 0.646. However, this did not improve upon the diagnostic performance of radiologist-derived magnetic resonance spectroscopy diagnosis alone.
    Conclusion: In this small fully histopathology-confirmed neuro-oncology cohort, magnetic resonance spectroscopy demonstrated good sensitivity but limited specificity for predicting high-grade glioma. Rather than presenting this pattern as a new diagnostic phenomenon, this study contributes a clinically grounded confirmation with complete tissue verification, a clearly characterised false-positive mimic profile, and a transparent negative ML result. These findings support the use of magnetic resonance spectroscopy as an adjunctive metabolic neuroimaging tool and provide a cautious data point for future larger studies evaluating spectroscopy-guided and ML-supported diagnostic pathways.
    Keywords:  Brain tumour; Diagnostic accuracy; Glioma mimics; High-grade glioma; Histopathology; Intracranial lesions; Machine learning; Magnetic resonance spectroscopy; Metabolic neuroimaging; Neuro-oncology
    DOI:  https://doi.org/10.1016/j.ibneur.2026.09.007
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