bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–10–11
sixty-one papers selected by
Luca Bolliger, lxBio
  1. Lateral sclerosis in amyotrophic lateral sclerosis is an upper motor neuron distal axonopathy ("dying back"): a clinical-neuropathological study.
  2. RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.
  3. Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.
  4. Contrasting clinical trajectories in two ALS patients with rare FUS variants: implications for variant interpretation, penetrance, and trial readiness.
  5. Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.
  6. SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.
  7. Recalibration of the Frontal Behavioural Inventory Cut-Off for Behavioural Screening in Amyotrophic Lateral Sclerosis.
  8. TDP-43 and ALS - what's wrong with my membranes?
  9. Place and cause of death among people with chronic neurological diseases in Munich: a population-based study using death certificates.
  10. Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features.
  11. Neurofilaments support the differentiation of amyotrophic lateral sclerosis from degenerative cervical myelopathy.
  12. Enzymatic N-deacylation is the predicted membrane-disruption switch for sphingomyelin: a falsifiable in-silico framework for sphingolipid vulnerability in ALS.
  13. Genetic testing and counselling of patients with monogenic amyotrophic lateral sclerosis in Northern Finland: a retrospective, single-centre study.
  14. Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.
  15. N-terminal proVGF modifications related to Amyotrophic Lateral Sclerosis.
  16. [Amyotrophic lateral sclerosis: Specific considerations in palliative care].
  17. Fooled by the Heartbeat: Cardioballistic Autotriggering in Amyotrophic Lateral Sclerosis.
  18. Multiple motor proteins regulate TDP-43 anterograde axonal transport.
  19. Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.
  20. TRICALS risk score augments but cannot replace neurofilament as a prognostic biomarker in ALS.
  21. Multisite Anodal Direct Current Stimulation Preserves Motor Function and Modulates Key Cellular Pathways in TDP-43 and SOD1 Mouse Models of Amyotrophic Lateral Sclerosis.
  22. Clinical and genetic characterization of FUS-associated ALS in a tertiary cohort.
  23. Cerebrospinal fluid inflammatory proteomic profiling identifies biomarkers linked to disease progression in amyotrophic lateral sclerosis.
  24. Gut-brain immune dysregulation in Parkinson's disease: a hypothesis-forming narrative review of trained immunity.
  25. Plasma cardiac troponin T as a marker of skeletal muscle involvement in amyotrophic lateral sclerosis.
  26. When the Electromyography (EMG) and the Patient Disagree: Unraveling a Motor Neuron Disease Mimic With Small-Fiber Dysfunction.
  27. Considerations for therapeutic targets for clinical trials in biomarker-characterized prodromal Parkinson's disease populations.
  28. Advances in non-invasive monitoring of drug delivery for neurodegenerative disorders.
  29. The Role of Mast Cells and Their Potential as a Therapeutic Target For Neuroinflammation.
  30. EARLY-ALS: a multicentre study on prodromal amyotrophic lateral sclerosis.
  31. Update on somatic mutations in major neurodegenerative diseases: mutational signatures in neurons and mosaicism.
  32. White matter hyperintensity burden in amyotrophic lateral sclerosis: motor and survival correlates.
  33. Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.
  34. Gene regulatory co-expression networks decipher potential lncRNA-miRNA-mRNA interactions modulating transcription regulation in neurodegeneration.
  35. Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model.
  36. Neuroimaging signatures of facial onset sensory and motor neuronopathy (FOSMN).
  37. Astrocyte Structure-Function Relationship in Senescence and Neurodegeneration.
  38. A Novel Device for Pulmonary Expansion Under Simulated Healthy and Neuromuscular Conditions: A Bench Simulation Study.
  39. [The role of the GSTP1/JNK signaling pathway in regulating oxidative stress and programmed cell death in amyotrophic lateral sclerosis].
  40. Regularization via gradient attribution for multiple sclerosis lesion segmentation.
  41. Pre-diagnostic ALSFRS-R slope provides limited incremental information about the variability in subsequent functional decline in amyotrophic lateral sclerosis: a population-based study.
  42. TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.
  43. Comparison between ultrasound and electromyography for detection of fasciculations in amyotrophic lateral sclerosis: an updated systematic review and meta-analysis.
  44. Immune effects of faecal microbiota transplantation in amyotrophic lateral sclerosis: a pilot multicentre, randomised, masked, sham-controlled, proof-of concept trial.
  45. Tembusu virus neuroinvasion and neuropathogenesis: lessons from blood-brain barrier dysfunction in neurotropic flaviviruses.
  46. One-Year Clinical Course of Patients With Amyotrophic Lateral Sclerosis Admitted to a Home Palliative Care Program: An Extension Study.
  47. AGMNet: an explainable gated multimodal framework integrating MRI heterogeneity and dopaminergic asymmetry for Parkinson's disease classification.
  48. Artificial Intelligence for Gadolinium-Sparing Detection of Active Multiple Sclerosis Lesions: A Structured Narrative Review.
  49. Gut-brain axis dysfunction in Parkinson's disease: a meta-analysis of microbiome dysbiosis and intestinal barrier markers.
  50. Recurrent Sleep Restriction During Aging Induces Early Recognition Memory Impairment, Neuroinflammation, and Blood-Brain Barrier Dysfunction in Female Wistar Rats.
  51. Salivary Extracellular Vesicle Proteome as a Molecular Bridge Between Periodontitis and Neurodegeneration: Mechanisms, Biomarkers, and Therapeutic Opportunities.
  52. Increased CCR2-immunopositive myeloid cells in the putamen and cerebellar white matter with blood-brain barrier disruption in multiple system atrophy.
  53. Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons.
  54. Detailed Analysis of Intraretinal Layers and Their Correlation to Brain Structures in Normal Healthy Aging.
  55. AA and Parkinson's Disease.
  56. Autologous haematopoietic stem cell transplantation affects paramagnetic rim lesions in multiple sclerosis.
  57. Blood-brain barrier opening with focused ultrasound reduces neuromelanin in a non-human primate model.
  58. Early Palliative Care and Structured Serious Illness Communication in a Refugee Patient With Amyotrophic Lateral Sclerosis.
  59. Periodontitis and Parkinson's disease: a narrative review of associations, proposed mechanisms, and clinical considerations.
  60. Artificial Intelligence in the Diagnosis, Treatment, and Management of Rare Diseases: Opportunities and Challenges from a Latin American Perspective.
  61. Long-term trends in selected neurological disorders in Italy (1990-2023): analysis of the global burden of disease (GBD) 2023 data.
  1. Acta Neuropathol. 2026 Oct 09. pii: 48. [Epub ahead of print]152(1):
    Lateral sclerosis in amyotrophic lateral sclerosis is an upper motor neuron distal axonopathy ("dying back"): a clinical-neuropathological study.
    Jianguo Liu, Kailee Ong, Alex Meng, Gorazd B Stokin, Jeffrey A Loeb, John Ravits, Fei Song.
      The hallmark neuropathological feature of upper motor neuron (UMN) degeneration in amyotrophic lateral sclerosis (ALS) is the "sclerosis" of the lateral corticospinal tract (CST)-the major axonal pathway connecting UMNs to lower motor neurons (LMNs). However, few studies since Charcot's original descriptions in the nineteenth century have directly correlated clinical UMN phenotypes with corresponding neuropathological findings. We examined the pathology of the lateral CST at the cervical, thoracic, and lumbar levels of the spinal cord from ALS patients with predominantly UMN (UMN-p) phenotypes and compared it with that in patients with predominantly LMN (LMN-p) phenotypes. We assessed myelin loss, axonal degeneration, neuroinflammation, and TDP-43 pathology. Spinal cords from UMN-p ALS cases exhibited pronounced myelin loss in the lateral CST compared to LMN-p cases and controls, consistent with clinical phenotyping. Quantitative analysis revealed significant axonal loss across all axon diameter ranges in UMN-p ALS, which was more severe than in LMN-p ALS. Importantly, axonal loss was more pronounced in the lumbar than in the cervical spinal cord. We identified a distinct population of foamy, inflammatory microglia localized to regions of severe myelin and axonal loss in UMN-p ALS. TDP-43 was measurably increased in the UMN axons of the lateral and ventral CSTs. In summary, "lateral sclerosis" of ALS correlates to clinically imputed UMN degeneration. It consists of a combination of myelin loss, distal greater than proximal axonal degeneration, inflammatory microglial activation within the CSTs, and abnormally increased axonal TDP-43. The length-dependent gradient of motor axonal loss supports a "dying-back" process. A detailed comparison of "dying-forward" and "dying-forward" is provided in the Discussion. The association of loss of axons and myelin with abnormal microglial activity shows glio-axonal interactions in UMN axon degeneration, the latter CST (lateral sclerosis) across all three spinal cord levels in the ALS UMN-p samples but does not establish a causal relationship.
    Keywords:  Amyotrophic lateral sclerosis; Axon neurodegeneration; Corticospinal tracts; Dying back; Myelin loss; Neuroinflammation
    DOI:  https://doi.org/10.1007/s00401-026-03072-9
  2. Naunyn Schmiedebergs Arch Pharmacol. 2026 Oct 08.
    RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.
    Sonam M Gandhi, Saraswati Patel, Nitin G Haswani, Shadma Wahab, Zia-Ul- Sabah, Devesh U Kapoor.
      Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.
    Keywords:  Blood–brain barrier targeting; Brain-targeted drug delivery; Neurodegenerative diseases; RVG29-functionalized nanocarriers; Receptor-mediated transcytosis
    DOI:  https://doi.org/10.1007/s00210-026-05958-7
  3. J Neuroimmune Pharmacol. 2026 Oct 07. pii: 51. [Epub ahead of print]21(1):
    Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.
    Rohit Kumar Singh, Chandrayee Banerjee, Sidharth Mehan.
      Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.
    Keywords:  Blood-brain barrier (BBB); Clemastine fumarate; Neurodegeneration; Neuroinflammation; Neuroprotection; Remyelination and Oligodendrocyte precursor cells (OPCs)
    DOI:  https://doi.org/10.1007/s11481-026-10321-x
  4. Neurogenetics. 2026 Oct 08. pii: 80. [Epub ahead of print]27(1):
    Contrasting clinical trajectories in two ALS patients with rare FUS variants: implications for variant interpretation, penetrance, and trial readiness.
    Paula V Gaete, Martha Peña Preciado, John Jairo Forero Díaz.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor system. A minority of cases are associated with a genetic variant. Variants in C9orf72, SOD1, TARDBP, and FUS are the most common. Compared with other forms of ALS, ALS presenting with FUS variants is relatively aggressive. However, phenotypic heterogeneity has been reported. We describe two cases of ALS with rare FUS variants with contrasting clinical courses. These cases highlight the importance of the different factors that influence ALS phenotypic presentation and the challenges of variant interpretation in ALS, as outlined in the ACMG Guidelines. It is essential to recognise specific genotype-phenotype relationships and environmental factors that could alter the clinical course of the disease and affect therapeutic agent selection.
    Keywords:  Amyotrophic lateral sclerosis; Case report; FUS; Genetics; Motor neuron disease
    DOI:  https://doi.org/10.1007/s10048-026-00927-x
  5. Expert Opin Ther Targets. 2026 Oct 09.
    Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.
    Arunabh Choudhury, Sneh Prabha, Mohammad Umar Saeed, Md Nayab Sulaimani, Md Imtaiyaz Hassan.
       INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and related proteinopathies are characterized by the misfolding, aggregation, and accumulation of specific proteins that disrupt neuronal homeostasis, leading to neuronal death. Despite major advances in structural biology and molecular neuroscience, identifying and validating druggable targets in neurodegenerative diseases remains challenging. Many involved proteins are intrinsically disordered, exhibit conformational heterogeneity, and form highly dynamic toxic species.
    AREAS COVERED: This review summarizes the mechanisms of protein folding, misfolding, aggregation, and prion-like propagation in major neurodegenerative proteinopathies, including amyloid-beta and tau in Alzheimer's disease, alpha-synuclein in synucleinopathies, TDP-43 and FUS in ALS/FTLD, polyglutamine-expanded proteins, prion proteins, and rare hereditary amyloidosis. We also discuss major barriers to target identification and validation, including conformational flexibility, oligomer toxicity, blood-brain barrier penetration, and target engagement complexity. Finally, we highlight emerging strategies integrating structural biology, computational methods, and improved experimental models to discover small-molecule inhibitors for neurodegenerative diseases.
    EXPERT OPINION: Effective therapeutic discovery will require moving beyond single-target models toward ensemble-based validation strategies. Integrating structural biology, advanced imaging, biomarkers, and computational approaches may improve the identification of druggable targets and support precision-medicine-based interventions for neurodegenerative diseases.
    Keywords:  Intrinsically disordered proteins; Small-molecule inhibitors; neurodegenerative diseases; protein aggregation; protein misfolding
    DOI:  https://doi.org/10.1080/14728222.2026.2747518
  6. Acta Neuropathol. 2026 Oct 06. pii: 43. [Epub ahead of print]152(1):
    SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.
    Evellyn Mayla de Azevedo, Victoria Simões Bernardo, Marcelo M S Lima, Elis Cristina Araujo Eleutherio, Tiago Fleming Outeiro.
      Superoxide dismutase 1 (SOD1), originally regarded as an antioxidant enzyme, is now recognized as a multifunctional protein whose conformational instability and aggregation contribute to neurodegeneration. The emerging evidence suggests that SOD1 pathology extends beyond amyotrophic lateral sclerosis, supporting a role in multiple neurodegenerative diseases. This review summarizes current neuropathological evidence of SOD1 co-pathologies in the human brain, with particular emphasis on its associations with TAR DNA-binding protein 43 (TDP-43), tau, alpha-synuclein, amyloid-β, and other aggregation-prone proteins. We examine the distribution of pathological SOD1 species across neurodegenerative diseases, their coexistence in affected brain regions, and potential mechanisms underlying these interactions, including oxidative stress, impaired proteostasis, aberrant phase separation, and cross-seeding. We also discuss emerging observations of SOD1 pathology in neurological conditions beyond classical neurodegenerative diseases, raising the possibility that SOD1 misfolding represents a broader cellular response to neuronal injury. Collectively, the available evidence supports a shift from viewing SOD1 as a disease-specific protein to considering it a potential participant in interconnected proteopathic networks. Although the functional significance of SOD1 co-pathologies remains incompletely understood, elucidating the molecular basis of aggregation may provide new insights into disease onset and progression, improving our understanding of neurodegenerative mechanisms, and facilitating the development of biomarkers and the identification of therapeutic targets across diverse proteinopathies.
    Keywords:  ALS; Co-pathologies; FTD; Neuropathology; Protein aggregation
    DOI:  https://doi.org/10.1007/s00401-026-03090-7
  7. Eur J Neurol. 2026 Oct;33(10): e70778
    Recalibration of the Frontal Behavioural Inventory Cut-Off for Behavioural Screening in Amyotrophic Lateral Sclerosis.
    Barbara Iazzolino, Francesca Palumbo, Antonio Canosa, Stefano Callegaro, Vita Passidomo, Umberto Manera, Rosario Vasta, Enrico Matteoni, Sara Cabras, Giorgio Pellegrino, Alessandra Maccabeo, Cristina Moglia, Andrea Calvo, Adriano Chiò.
       OBJECTIVE: The Frontal Behavioural Inventory (FBI) was validated in behavioural-variant frontotemporal dementia (bvFTD) with a cut-off of 25. We tested whether this threshold is appropriate in amyotrophic lateral sclerosis (ALS), where behavioural change is milder and partly confounded by motor pathology.
    METHODS: We analysed 506 ALS patients with a valid FBI assessment. Behavioural impairment was defined using two complementary reference standards, to minimise dependence on any single behavioural instrument: a consensus rule (pathology on ≥ 2 of three independent instruments: Edinburgh Cognitive and Behavioural ALS Screen, Frontal Systems Behaviour Scale, Beaumont Behavioural Inventory) and Latent Class Analysis. ROC analysis identified the Youden-optimal cut-off; agreement was quantified by Cohen's κ; internal validity was assessed by stratified 5-fold cross-validation. Total and subscale scores were analysed separately.
    RESULTS: Among 345 complete-case patients, 24.6% met criteria for behavioural impairment. The FBI total discriminated impairment well (AUC 0.855, 95% CI 0.806-0.898). The Youden-optimal cut-off was FBI ≥ 9 (sensitivity 0.87, specificity 0.74), whereas the legacy cut-off of 25 showed sensitivity 0.22. Subscale recalibration yielded cut-offs of FBI-Apathy ≥ 7 (AUC 0.808) and FBI-Disinhibition ≥ 4 (AUC 0.851).
    CONCLUSIONS: In ALS, the bvFTD-derived threshold of 25 misses most patients with behavioural involvement. FBI ≥ 9 is a promising candidate ALS-specific screening threshold, with scores ≥ 15 indicating a higher probability of behavioural involvement; exploratory subscale thresholds of ≥ 7 for Apathy and ≥ 4 for Disinhibition are also proposed. These cut-offs substantially improve sensitivity while maintaining acceptable specificity, but require prospective external validation before replacing current practice.
    Keywords:  Frontal Behavioural Inventory; amyotrophic lateral sclerosis; behavioural impairment; frontotemporal degeneration; psychometric recalibration
    DOI:  https://doi.org/10.1111/ene.70778
  8. Neurobiol Dis. 2026 Oct 05. pii: S0969-9961(26)00376-1. [Epub ahead of print]230 107630
    TDP-43 and ALS - what's wrong with my membranes?
    Regina Dahlhaus, Israfil Yalcin, Julia Tischer, Ralf J Braun.
      In recent years, multiple pathologies of the mRNA binding protein TDP-43 have been linked to the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), in which almost 97% of all ALS patients exhibit TDP-43 abnormalities in affected neurons. Typically, neuronal degeneration first affects alpha motor neurons of the spinal cord and the lower brainstem, before the disease progresses to Betz cells, giant neurons of the primary motor cortex, and subsequently spreads into further brain regions. It is just the Betz cells though, which do not show cytosolic TDP-43 aggregation upon loss of nuclear TDP-43 expression, but instead display membrane defects in organelles such as the Golgi apparatus, the ER and the nuclear envelope. In this review, we will therefore examine connections between TDP-43 and inner membrane systems, with a particular focus on nuclear and the ER membranes. In doing so, we will summarize evidence suggesting that the disease may have an early onset, potentially even prenatally, and describe how interactions between TDP-43 and the lipid metabolism as well as connections with membrane components, may drive cells towards ALS as time goes by.
    Keywords:  Amyotrophic lateral sclerosis; Frontotemporal dementia; LATE; TDP-43 proteinopathy
    DOI:  https://doi.org/10.1016/j.nbd.2026.107630
  9. Neurol Res Pract. 2026 Oct 06. pii: 81. [Epub ahead of print]8(1):
    Place and cause of death among people with chronic neurological diseases in Munich: a population-based study using death certificates.
    Sarah Kristina Bublitz, Claudia Bausewein, Veronika Detter, Berend Feddersen, Matthias Graw, André Klima, Patricia Klotz, Stefan Lorenzl, Sabine Gleich.
       INTRODUCTION: Access to palliative care is often delayed and fragmented for patients with chronic neurological diseases. This study aimed to characterize the place and cause of death among individuals with chronic neurological diseases to help identify potential gaps in palliative care provision.
    METHOD: In this cross-sectional study, all death certificates from the city of Munich, Germany (2020-2023) were reviewed. Cases were included if malignant brain tumours, amyotrophic lateral sclerosis (ALS) or other motor neuron diseases, Parkinson's disease (PD), multiple sclerosis (MS) or other neurodegenerative or neuromuscular diseases were recorded as the cause of death or as a comorbidity.
    RESULTS: Of 60,357 deaths, 2,536 individuals (4.2%) had at least one chronic neurological disease. The most common place of death was the hospital (43.8%), followed by nursing homes (25.9%) and the private home (25.0%), with variations among disease subgroups. Overall, the neurological disease was recorded as the immediate or underlying cause of death in 57.3% of cases, while in the remaining cases it was documented as a comorbidity, reflecting its presence without formal causal attribution to death.
    DISCUSSION: This population-level analysis provides insight into the place and circumstances of death for a large cohort of patients with chronic neurological diseases in a major German metropolitan area and highlights substantial heterogeneity in end-of-life trajectories. The findings indicate that mortality statistics based on death certificates reflect structural limitations in cause-of-death attribution. Nevertheless, place of death remains a robust indicator, showing high hospital utilization and limited hospice use across most diagnostic groups, underscoring potential gaps in goal-concordant care.
    Keywords:  Amyotrophic lateral sclerosis; Death certificates; Goal-concordant care; Neuropalliative care; Palliative care; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s42466-026-00536-x
  10. Cell Rep Med. 2026 Oct 09. pii: S2666-3791(26)00522-7. [Epub ahead of print] 103105
    Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features.
    Kathryn J Citrano, Vidhya Bharathi Maheswari Jawahar, Madison M Reeves, Leonardo Petrucelli, Yari Carlomagno, Mei Yue, Jorge Alaiz Noya, Lillian M Daughrity, Raul Baena Tomé, Karen Jansen-West, Bailey Rawlinson, Michael DeTure, Erica Engelberg-Cook, Alpana Singh, Neill R Graff-Radford, Gregory S Day, Bradley F Boeve, Adam L Boxer, David S Knopman, Keith A Josephs, Ronald C Petersen, Björn Oskarsson, Nicholas J Ashton, Dennis W Dickson, Tania F Gendron, Mercedes Prudencio, Yong-Jie Zhang, Leonard Petrucelli.
      TAR DNA-binding protein (TDP-43) cytoplasmic aggregates and nuclear depletion contribute to TDP-43 dysfunction in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and forms of motor neuron disease (MND), particularly amyotrophic lateral sclerosis (ALS). TDP-43 regulates alternative splicing, but its dysfunction can engender the inclusion of cryptic exons (CEs) during splicing. Transcripts harboring an in-frame CE can generate de novo proteins. One example is the CE variant of hepatoma-derived growth factor-like protein 2 (HDGFL2-CE). To understand HDGFL2-CE as a readout of TDP-43 dysfunction, and its spatial relationship with TDP-43 pathology, we generate anti-HDGFL2-CE polyclonal and monoclonal antibodies and develop sensitive HDGFL2-CE immunoassays. With these tools, we observe that HDGFL2-CE accumulates in neurons with TDP-43 pathology, and that higher frontal cortex HDGFL2-CE in FTLD-TDP and FTLD-TDP/MND associates with greater pathological TDP-43, earlier age of onset, and shorter survival, supporting HDGFL2-CE as a marker tightly linked to TDP-43 dysfunction and clinical disease features.
    Keywords:  HDGFL2-CE; TDP-43; amyotrophic lateral sclerosis; cryptic exon; frontotemporal lobar degeneration; motor neuron disease
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103105
  11. J Neural Transm (Vienna). 2026 Oct 09.
    Neurofilaments support the differentiation of amyotrophic lateral sclerosis from degenerative cervical myelopathy.
    Julia Goebell, Franziska Bachhuber, Jutta Karmann, Veronika Klose, Jan Kassubek, Hans-Peter Müller, Hayrettin Tumani, Albert Ludolph.
      The differential diagnosis between degenerative cervical myelopathy (DCM) and early amyotrophic lateral sclerosis (ALS) is often clinically challenging; laboratory tests that support this distinction could be highly valuable. This study examined the concentrations of neurofilament light chain (NfL) and the phosphorylated neurofilament heavy chain (pNfH), in CSF and serum of carefully selected patients with DCM, spinal canal stenosis (SCS) and ALS, after exclusion of major neurological confounders. Patients were assigned to five groups according to MRI findings and ALS diagnosis. All patients were treated in the Department of Neurology, and were only included if a CSF or serum sample was available for retrospective measurement of neurofilaments. Z-scores were used for age-adjusted interpretation of NfL concentrations in CSF and serum. In addition, the albumin quotient (QAlb), as a marker for the integrity of the blood-CSF barrier, was investigated in the five patient groups. The levels of NfL and pNfH, including Z-score distributions, differed significantly. The groups with diagnosed ALS had elevated neurofilaments both in CSF and Serum. Comparison of neurofilament concentrations between patients with isolated spinal canal stenosis and patients with cervical myelopathy revealed no significant difference. The QAlb showed no clear correlation with elevated neurofilaments and provided limited value for differential diagnosis. In summary, we showed that NfL and pNfH in CSF and serum support the differential diagnosis of cervical SCS with and without myelopathy from ALS in carefully selected cohorts. However, since neurofilaments are not specific, they should be used in context with clinical assessment and imaging for individual diagnostic and treatment decisions.
    Keywords:  ALS; Biomarkers; Myelopathy; NfL pNfH
    DOI:  https://doi.org/10.1007/s00702-026-03277-y
  12. J Mol Graph Model. 2026 Dec;pii: S1093-3263(26)00296-2. [Epub ahead of print]149 109570
    Enzymatic N-deacylation is the predicted membrane-disruption switch for sphingomyelin: a falsifiable in-silico framework for sphingolipid vulnerability in ALS.
    Samarth Basanth.
      Sphingolipid dysregulation is an emerging feature of amyotrophic lateral sclerosis (ALS), but no systematic method separates species that may worsen axon-myelin membrane integrity from matter that may counteract it. We present an in-silico framework classifying sphingolipids and designed derivatives as candidate membrane-disruptive or candidate protective species, scored against real biological referents using externally published tools rather than a bespoke composite. Its central finding concerns a single, chemically defined difference in lipid state. In coarse-grained (MARTINI 3) molecular dynamics with three independent replicates per system, intact palmitoyl-sphingomyelin is indistinguishable from a pure-POPC bilayer (leaflet-mean Δ thickness + 0.001 nm, 95% CI brackets zero), whereas the modeled N-deacylated form thins it in every replicate (Δ=-0.043 nm, [- 0.046, - 0.041]), tracking a lyso-phosphatidylcholine detergent control (-0.083 nm, [- 0.087, - 0.080]) on two concordant estimators. Because only one lyso-sphingolipid is parameterized in public MARTINI 3, N-deacylation is not established here as a class-wide effect. Across eleven ALS studies (2021-2026), six report elevated serine-palmitoyltransferase (SPT) pathway sphingolipids, all in monogenic SPTLC1/SPTLC2 cohorts, whereas sporadic cohorts show disturbance without a shared direction. Because the simulations do not address whether this species is produced, accumulates, or reaches pathological concentrations in ALS tissue, we present the ALS connection as hypothesis-generating rather than direct evidence. Separately, an explicitly exploratory arm reports two designed modulators with predicted target engagement (Boltz-2) and an ADMET triage of their liabilities. The primary contribution is the membrane result with a wet-lab panel that makes it falsifiable.
    Keywords:  Amyotrophic lateral sclerosis; Coarse-grained molecular dynamics; In-silico screening; Membrane biophysics; Sphingolipids; Structure-based affinity prediction
    DOI:  https://doi.org/10.1016/j.jmgm.2026.109570
  13. Eur J Hum Genet. 2026 Oct 08.
    Genetic testing and counselling of patients with monogenic amyotrophic lateral sclerosis in Northern Finland: a retrospective, single-centre study.
    Maari Kytöharju, Jukka S Moilanen, Mika H Martikainen.
      Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease. Its aetiology is complex, but a subset is caused by single-gene pathogenic variants (monogenic ALS). The most common ALS-associated genes are SOD1 and C9orf72. We evaluated the implementation of genetic testing and associated genetic counselling for ALS at a Finnish tertiary-level university hospital. We used the electronic patient records of Oulu University Hospital (Oulu, Finland) to identify patients diagnosed with ALS between 2000 and 2023. Medical records were reviewed for neurological diagnosis and completion of genetic testing and counselling. We identified a total of 387 patients diagnosed with ALS. Of these, 225 patients (58%) were offered genetic testing, and 186 (83%) accepted. The offer for genetic counselling was given to 60 patients, of whom 46 (77%) attended counselling, whilst 13 did not. The proportion of patients who declined counselling did not differ between those with SOD1 and C9orf72 variants. Among the 143 patients tested for SOD1 variants, 36 (25%) were confirmed to harbor the ALS-associated p.Asp91Ala variant in SOD1; 31 were homozygous and 5 were heterozygous. In the 96 analyses of the C9orf72 hexanucleotide expansion, the diagnostic yield was 27 (28%) patients. A positive family history was more common in SOD1-ALS than in C9orf72-ALS (53% vs 33%). Nearly one fifth of patients declined testing and over one fifth of those with genetic ALS did not attend genetic counselling. The reasons for this warrant further investigation.
    DOI:  https://doi.org/10.1038/s41431-026-02246-z
  14. Front Neurosci. 2026 ;20 1941293
    Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.
    Julie Smeyers, Daniel A Mordes.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum characterized by TDP-43 pathology and overlapping genetic risk factors. Loss-of-function variants in TBK1 (TANK-binding kinase 1) represent one of the most common genetic causes of ALS/FTD, highlighting haploinsufficiency for TBK1 as a major contributor to disease pathogenesis. Emerging evidence from iPSC and mouse models suggests that reduced TBK1 activity disrupts interconnected autophagy, endo-lysosomal, and innate immune pathways through both cell-autonomous and non-cell-autonomous mechanisms. In this review, we discuss the multifaceted role of TBK1 as a master regulator of proteostasis and inflammatory pathways, highlight its critical role in maintaining microglial homeostasis, and explore how these convergent functions inform therapeutic strategies for ALS/FTD.
    Keywords:  ALS; FTD; TBK1; cell autonomous; in vivo models; non-cell-autonomous
    DOI:  https://doi.org/10.3389/fnins.2026.1941293
  15. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Oct 07. 1-9
    N-terminal proVGF modifications related to Amyotrophic Lateral Sclerosis.
    Aqsa Anjum, Antonio Luigi Manai, Barbara Noli, Giuseppe Borghero, Marcello Mario Mascia, Mario Meloni, Humaidan Kais, Michela Figorilli, Monica Puligheddu, Cristina Cocco.
      Objective: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunction, for which effective therapies and early diagnostic biomarkers remain limited. This study comprehensively investigated ALS-associated alterations in the N-terminal region of the proVGF precursor protein, evaluating their potential as novel diagnostic and prognostic biomarkers and exploring their precise correlations with clinical severity and plasma neurofilament light chain (NfL), an established indicator of neuroaxonal injury. Methods: N-terminal proVGF levels were quantified using a custom immunoassay using human plasma and lymphocytes as well as motor neuron-like NSC-34 cells subjected to oxidative stress. The clinical cohort comprised 49 ALS patients (28 early-stage, 21 advanced-stage) and 50 age-matched healthy controls. To assess disease specificity, plasma from patients with Parkinson's disease (PD, n = 50), idiopathic dystonia (n = 15), and idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD, n = 21) was analyzed alongside respective age-matched healthy controls (n = 26, 8, and 20). Furthermore, plasma NfL levels were measured and directly correlated with N-terminal proVGF concentrations. Results: N-terminal proVGF levels were significantly increased in both plasma and lymphocytes during the early and advanced stages of ALS. Plasma NfL levels were concomitantly elevated across all ALS patients. In advanced-stage patients, N-terminal proVGF concentrations significantly correlated with both ALSFRS-R scores and NfL levels. No significant N-terminal proVGF alterations were observed in PD, iRBD, or dystonia cohorts. Oxidative stress similarly upregulated N-terminal proVGF levels in vitro within NSC-34 cells. Conclusion: Alterations of the N-terminal region of proVGF are specific to ALS, highlighting their dual value as diagnostic and prognostic biomarkers.
    Keywords:  ALS; N-terminus; VGF peptides; neurodegeneration; oxidative stress
    DOI:  https://doi.org/10.1080/21678421.2026.2742817
  16. MMW Fortschr Med. 2026 Oct;168(17): 51-54
    [Amyotrophic lateral sclerosis: Specific considerations in palliative care].
    Peter Reilich, Florian Schöberl.
      
    DOI:  https://doi.org/10.1007/s15006-026-6225-z
  17. Arch Bronconeumol. 2026 Oct 07. pii: S0300-2896(26)00363-7. [Epub ahead of print]
    Fooled by the Heartbeat: Cardioballistic Autotriggering in Amyotrophic Lateral Sclerosis.
    Eloy Portero-Campillo, Clara Seghers-Carreras, Javier Sayas-Catalán.
      
    DOI:  https://doi.org/10.1016/j.arbres.2026.09.010
  18. Acta Neuropathol. 2026 Oct 09. pii: 47. [Epub ahead of print]152(1):
    Multiple motor proteins regulate TDP-43 anterograde axonal transport.
    Monica Feole, Victorio M Pozo Devoto, Neda Dragišić, Maria Čarna, Katja Klosterman, Clara Limbaek-Stokin, Giancarlo Forte, Kenneth L Moya, Richard A Smith, Clive N Svendsen, Gorazd B Stokin.
      TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein essential for RNA metabolism. Under physiological conditions, it predominantly resides in the nucleus but is also expressed in the cytoplasm, where it regulates mRNA trafficking and local translation. In nearly 97% of amyotrophic lateral sclerosis (ALS) cases, TDP-43 undergoes nuclear depletion and cytoplasmic aggregation. While its nuclear functions are well characterized, its axonal roles remain poorly understood, despite axonal degeneration being a hallmark of ALS pathology. To address this gap, we investigated TDP-43 localization and transport dynamics in axons of H9-derived human neurons. We compared fluorescently labeled TDP-43 with three well-characterized axonal cargoes, ras-related protein Rab5, synaptophysin, and amyloid precursor protein, and examined protein-protein interactions between TDP-43 and the axonal transport machinery. Our analyses revealed that TDP-43 exhibits active anterograde axonal transport and interacts with multiple kinesin motor proteins, including all three KIF5 isoforms, through the adaptor KLC1, and the synaptic vesicles motor KIF1A. This multi-motor engagement suggests a flexible transport system that ensures mRNA delivery to distal axons. In ALS, where TDP-43 accumulates abnormally in the cytoplasm, this flexibility may become compromised, with multiple transport mechanisms simultaneously affected. This could contribute to progressive accumulation of non-functional TDP-43 granules, disrupting mRNA trafficking and local translation. Our findings provide a foundation for understanding how physiological TDP-43 transport mechanisms may be impaired during disease, highlighting axonal TDP-43 transport pathways as potential therapeutic targets.
    Keywords:  Adaptors; Amyotrophic lateral sclerosis; Axonal transport; Cargoes; Motor proteins; TDP-43
    DOI:  https://doi.org/10.1007/s00401-026-03071-w
  19. Front Pharmacol. 2026 ;17 1918967
    Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.
    Mengfan Li, Ronghao Li, Zhe Deng, Liqun Zhang, Shimeng Lv, Jinjing Shi, Haoteng Ma, Wenhui Guan, Han Zhang, Jiamin Li, Jing Teng.
       Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with limited therapeutic options, highlighting the need for multi-target interventions. Traditional Chinese botanical medicine (TCBM) interventions have attracted increasing attention as potential multi-target pharmacological candidates for ALS. In addition, a separate body of evidence derived from selected plant-derived bioactive compounds directly investigated in ALS-specific models provides complementary mechanistic insights into ALS-related pathways. However, the pharmacological mechanisms and translational potential of these two distinct evidence categories remain insufficiently summarized. This review systematically summarizes ALS-related pathological mechanisms and the molecular actions reported within these two distinct evidence categories, together with translational challenges and future research directions.
    Methods: A structured literature search was conducted in PubMed, Web of Science, and ScienceDirect up to May 2026. A total of 198 publications were retained, including 48 ALS-specific original intervention studies forming the core pharmacological evidence set.
    Results: ALS involves interconnected pathological processes, including neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxicity, and neuromuscular junction injury. Evidence across these two categories suggests modulation of multiple ALS-related pathological processes. Reported effects include regulation of inflammatory signaling, enhancement of Nrf2-mediated antioxidant responses, improvement of PGC-1α/MFN2-associated mitochondrial homeostasis, and promotion of protein clearance pathways.
    Conclusion: Together, these distinct but complementary evidence categories highlight the potential for multi-target modulation of ALS-related pathology. However, current evidence remains predominantly preclinical, and clinical efficacy and translational feasibility require further validation.
    Keywords:  amyotrophic lateral sclerosis; molecular mechanisms; neuroprotection; phytochemicals; traditional Chinese botanical medicine; traditional Chinese medicine; translational pharmacology
    DOI:  https://doi.org/10.3389/fphar.2026.1918967
  20. J Neurol. 2026 Oct 06. pii: 643. [Epub ahead of print]273(10):
    TRICALS risk score augments but cannot replace neurofilament as a prognostic biomarker in ALS.
    Ahmad Al Khleifat, Andrea Malaspina, Janine Kirby, Timothy Tree, Pamela J Shaw, P Nigel Leigh, Ammar Al-Chalabi.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with substantial clinical heterogeneity, complicating the design and interpretation of clinical trials. Two strategies have been proposed to address this variability: phenotype-based prognostic modelling and biomarker-based stratification using neurofilaments. We aimed to determine whether a widely used phenotype-based method, the TRICALS risk score, could substitute for neurofilament biomarkers in a clinical trial.
    METHODS: We used data from the MIROCALS phase 2b randomised controlled trial of low-dose interleukin-2 in ALS (n = 220). The TRICALS risk score was calculated for each participant. The published biomarker model includes CSF phosphorylated neurofilament heavy chain (pNFH) and a pNFH × treatment interaction. We analysed the effects of replacing CSF pNFH with the TRICALS risk score and of adding TRICALS score as an additional covariate to the original model. Model performance was assessed using likelihood ratio χ2 statistics and - 2 log likelihood (- 2LL). The primary outcome was survival.
    RESULTS: TRICALS risk score was moderately correlated with CSF pNFH (r = 0.357), explaining 12.7% of shared variance. Substituting CSF pNFH with TRICALS score reduced model performance (- 2LL 928.25 vs 793.36). The TRICALS × treatment interaction was statistically significant (hazard ratio [HR] 0.72, 95% CI 0.54-0.96 p = 0.025), but contributed modestly to model fit (Δχ2 = 4.76), compared with the pNFH × treatment interaction (Δχ2 = 14.24). Incorporating the pNFH × treatment interaction significantly improved model fit and identified a treatment effect (HR 0.28, 95% CI 0.12-0.63; p = 0.002).
    CONCLUSIONS: The TRICALS risk score does not substitute for CSF neurofilament biomarkers as a prognostic or stratification variable but provides complementary information.
    Keywords:  ALS; Amyotrophic lateral sclerosis; Biomarker; Clinical trials
    DOI:  https://doi.org/10.1007/s00415-026-14040-4
  21. Neuromodulation. 2026 Sep 03. pii: S1094-7159(26)01349-8. [Epub ahead of print]
    Multisite Anodal Direct Current Stimulation Preserves Motor Function and Modulates Key Cellular Pathways in TDP-43 and SOD1 Mouse Models of Amyotrophic Lateral Sclerosis.
    Viktoriya Morozova, May Hassieb, Zaghloul Ahmed.
       OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by degeneration of upper and lower motor neurons and disruption of normal motor network excitability. This study aimed to determine whether multi-site direct current stimulation (DCS) can modulate spinal motor circuit excitability in an experimental model of ALS and to evaluate its potential as a neuromodulation approach for preserving motor pathway function.
    MATERIALS AND METHODS: In an initial electrophysiological experiment, corticospinal-evoked muscle contractions were recorded using a force-displacement transducer to compare the effects of different multisite spinal electrode configurations on corticospinal output. Subsequently, two ALS mouse models, SOD1-G93A and TDP-43 A315T, underwent repeated in vivo multisite anodal DCS. Motor function was assessed using grid walking, hindlimb grip strength, and wire-hang tests across five time points. In the TDP-43 A315T model, motor neuron soma size was quantified using choline acetyltransferase immunostaining, whereas heat shock protein 70 (HSP70) expression and TDP-43/phosphorylated TDP-43 (p-TDP-43) aggregation were evaluated using western blotting and confocal imaging.
    RESULTS: Multisite DCS produced the strongest suppression of corticospinal-evoked muscle contractions among all electrode configurations tested, indicating robust modulation of spinal excitability. In SOD1-G93A mice, repeated stimulation preserved motor performance across all behavioral assays, with the clearest differences emerging during later disease stages relative to unstimulated controls. In TDP-43 A315T mice, stimulation was associated with improved motor performance at the final testing point, preservation of motor neuron soma size, increased HSP70 expression, and significant reductions in both the number and size of cytoplasmic TDP-43 and pathological p-TDP-43 aggregates, consistent with enhanced proteostatic capacity and pathological protein clearance.
    CONCLUSIONS: Multisite anodal DCS effectively modulates spinal excitability and preserves motor function in two mechanistically distinct mouse models of ALS. In the TDP-43 A315T model, these functional benefits are accompanied by preservation of motor neuron structure and molecular changes consistent with improved protein homeostasis. Together, these findings support multisite DCS as a promising neuromodulatory strategy for influencing disease-relevant mechanisms and slowing functional decline in ALS.
    Keywords:  Amyotrophic lateral sclerosis; TAR DNA-binding protein 43; motor neurons; multi-site direct current stimulation; neuroprotection
    DOI:  https://doi.org/10.1016/j.neurom.2026.08.007
  22. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Oct 07. 1-4
    Clinical and genetic characterization of FUS-associated ALS in a tertiary cohort.
    Veronica Bettoni, Samir R Nath, Stephen Johnson, Björn Oskarsson, Alissa Bojko, Arash Salmaninejad, Jennifer Tan-Arroyo, Margot A Cousin, Nathan P Staff.
      An understanding of FUS-related ALS is becoming increasingly actionable with the emergence of targeted therapies. We retrospectively reviewed patients with amyotrophic lateral sclerosis and reported FUS variants evaluated across all Mayo Clinic sites between January 2009 and June 2026. Variants were reevaluated according to ACMG/AMP criteria, and clinical and genetic data were abstracted from medical records. The primary cohort included 12 unrelated patients with pathogenic or likely pathogenic (P/LP) FUS variants; 6 patients with variants of uncertain significance were retained descriptively. Pathogenic variants clustered in the C-terminal region, including one previously unreported likely pathogenic frameshift variant, c.1491_1494dup. Patients with pathogenic variants showed early-onset, rapidly progressive disease with frequent bulbar or respiratory onset, predominant lower motor neuron findings, and short survival. Observed phenotypes were broadly consistent with previous variant-specific reports. These findings expand variant-specific natural history data in FUS-ALS and may inform prognosis, patient stratification, and the interpretation of emerging FUS-targeted therapeutic studies.
    Keywords:  Amyotrophic lateral sclerosis; FUS; TLS; fused in sarcoma; motor neuron diseases
    DOI:  https://doi.org/10.1080/21678421.2026.2743446
  23. J Neurol. 2026 Oct 04. pii: 638. [Epub ahead of print]273(10):
    Cerebrospinal fluid inflammatory proteomic profiling identifies biomarkers linked to disease progression in amyotrophic lateral sclerosis.
    Congwen Lv, Wenjia Zhu, Xinmei Wen, Yaye Wang, Nairong Xie, Haoran Liu, Yuting Jiang, Wenlong Zou, Qinyao Liu, Junjiu Gou, Xiaotong Yu, Li Di, Yan Lu, Min Wang, Min Xu, Hai Chen, Jianying Duo, Yue Huang, Yuwei Da.
       BACKGROUND: Neuroinflammation is a key component of amyotrophic lateral sclerosis (ALS), but its association with disease progression heterogeneity remains unclear. We aimed to identify CSF inflammation-related proteins associated with disease progression phenotype in patients with ALS.
    METHODS: Patients with ALS were stratified into slow progressors (SP) and fast progressors (FP) according to the disease progression rate. CSF inflammatory proteins were measured using the Olink Target 96 Inflammation panel. Disease-associated biomarkers were identified using limma package and elastic net (EN) analysis. We assessed the discriminatory power of disease-associated biomarkers using receiver operating characteristic curve analysis and estimated the optimism-adjusted area under the curve (AUC) using the bootstrapping method.
    RESULTS: Among 77 patients (SP: n=40; FP: n=37), limma analysis identified 11 differentially expressed proteins, with functional enrichment in chemokine signaling, TNF-related responses and NF-κB pathways. EN analysis identified 12 candidate proteins, among which CST5, CCL11, SIRT2, CD6, CCL4, MMP-1, TNFRSF9, CCL19, and MCP-4 showed positive associations with the SP phenotype. A model combining SIRT2, MMP-1, BMI, and site of onset yielded an apparent area under the curve of 0.769 (95% CI 0.662 to 0.876) and an optimism-corrected area under the curve of 0.729.
    CONCLUSION: Our study uncovered a CSF inflammatory proteomic signature associated with slow disease progression in ALS. These findings indicate that specific CSF neuroinflammatory protein signatures reflect biological heterogeneity in ALS disease progression rather than non-specific neurodegeneration. SIRT2 and MMP-1 warrant further investigation as components of progression-stratification models, although validation in larger, longitudinal, and independent cohorts is required.
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Disease progression; Inflammation
    DOI:  https://doi.org/10.1007/s00415-026-14178-1
  24. Front Aging Neurosci. 2026 ;18 1973833
    Gut-brain immune dysregulation in Parkinson's disease: a hypothesis-forming narrative review of trained immunity.
    Mingke Tang, Jingxian Li, Chuanzhang Zhang, Ruoxin Tu, Shun Wang.
      Parkinson's disease (PD) is increasingly understood as a multisystem disorder in which gastrointestinal dysfunction, immune remodeling, protein aggregation, and central neurodegeneration interact across the disease course. Although gut microbiota alterations are repeatedly reported in PD, taxonomic differences alone do not explain how peripheral ecological signals acquire neurological relevance. This review therefore focuses on immune translation: the processes through which dysbiosis, microbial metabolites, intestinal barrier stress, and mucosal inflammation may reshape peripheral immunity and lower the threshold for central neuroinflammatory responses. Particular attention is given to trained immunity as a mechanistic framework that may connect repeated low-grade gut-derived stimulation with persistent innate immune reprogramming. Direct evidence that trained immunity drives PD remains limited; the concept is presented as a testable bridge rather than an established causal pathway. We integrate this framework with age-related immunosenescence and inflammaging, enteric nervous system vulnerability, vagal communication, alpha-synuclein pathology, blood-brain barrier signaling, and microglial priming. Human microbiome studies, Parkinsonian animal models, LPS-based innate immune-memory paradigms, and emerging intervention trials are considered according to their evidentiary level and major confounders, including constipation, diet, medication exposure, geography, and disease stage. The resulting model accommodates body-first, brain-first, and mixed trajectories rather than assigning a universal gut origin to PD. Therapeutically, the evidence supports a shift from nonspecific microbiome normalization toward mechanism-matched strategies that combine ecological, immune, metabolic, and clinical biomarkers. Longitudinal prodromal cohorts and integrated multi-omics with immune phenotyping will be essential to determine whether gut-brain immune signatures identify causal pathways, progression markers, or treatment-responsive subgroups.
    Keywords:  Parkinson’s disease; alpha-synuclein; gut microbiota; gut-brain axis; inflammaging; microglia; neuroinflammation; trained immunity
    DOI:  https://doi.org/10.3389/fnagi.2026.1973833
  25. Brain Commun. 2026 ;8(5): fcag358
    Plasma cardiac troponin T as a marker of skeletal muscle involvement in amyotrophic lateral sclerosis.
    Linn Öijerstedt, Jianing Lin, Aditya Singh, Solmaz Yazdani, Annamari M Saarinen, Ulf Kläppe, Alexander Juto, Sanharib Chamoun, Sofia Imrell, Fang Fang, Sebastian A Lewandowski, Caroline Ingre.
      Plasma cardiac troponin T (cTnT) is widely used as a marker of myocardial injury, yet recent studies suggest elevations in amyotrophic lateral sclerosis (ALS). Whether these elevations reflect disease-associated skeletal muscle remodelling remains unresolved. In this translational study, we analysed longitudinal plasma cTnT in a large clinical cohort comprising 496 patients with ALS and 84 with benign fasciculation syndrome (BFS). To investigate the biological origin of circulating cTnT, we examined publicly available skeletal muscle transcriptomes from patients with ALS (n = 28) and healthy controls (n = 17), and quantified troponin isoform expression in skeletal muscle from SOD1G93A mice and wild-type littermates. Plasma cTnT was significantly higher in ALS than in BFS (median 18 versus 6 ng/L, P = 3.6 × 10-27), with 57% of patients with ALS exceeding the cardiologic threshold of 15 ng/L. Diagnostic performance was high [area under the curve (AUC) 0.87], with excellent specificity (94%). Longitudinal modelling revealed a progressive increase in cTnT in ALS whereas levels remained stable in BFS. Skeletal muscle transcriptomics demonstrated robust upregulation of TNNT2, encoding cardiac troponin T, in ALS muscle, while other troponin isoforms were unchanged. In SOD1G93A mice, severely affected gastrocnemius muscle exhibited isoform-specific remodelling, including 20-fold upregulation of Tnnt2 and slow-fibre troponins, alongside downregulation of fast skeletal isoforms. Across clinical, transcriptomic, and experimental data, elevated plasma cTnT in ALS is best explained by disease-associated skeletal muscle remodelling rather than cardiomyocyte injury. Plasma cTnT emerges as a dynamic and accessible biomarker in ALS capturing muscle involvement. Prospective incorporation of cTnT into clinical trials and evaluation across broader neuromuscular differentials are warranted.
    Keywords:  denervation; isoform; longitudinal; motor neuron disease; muscle
    DOI:  https://doi.org/10.1093/braincomms/fcag358
  26. Cureus. 2026 Sep;18(9): e115700
    When the Electromyography (EMG) and the Patient Disagree: Unraveling a Motor Neuron Disease Mimic With Small-Fiber Dysfunction.
    Niyas Khalid Ottu Para.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by upper and lower motor neuron dysfunction. Electromyography (EMG) is central to its evaluation, but neurogenic abnormalities and fasciculations are not specific to ALS and must be interpreted within the clinical phenotype and disease trajectory. This study reports a 52-year-old man with an approximately eight-year history of intermittent muscle twitching, bilateral upper-limb tremor, muscular tightness and warmth, and asymmetric cutaneous hypersensitivity. An initial electrodiagnostic evaluation raised concern for diffuse motor neuron disease, despite preserved strength, normal gait, absence of muscle wasting, and lack of clear upper motor neuron signs. Extensive evaluation for inflammatory, autoimmune, metabolic, toxic, infectious, paraneoplastic, neuromuscular junction, and peripheral nerve hyperexcitability disorders was unrevealing. Serum creatine kinase was mildly and variably elevated, while aldolase and a comprehensive myositis panel were normal. Brain magnetic resonance imaging (MRI) demonstrated no supportive features of ALS. Sudomotor testing showed reduced electrochemical skin conductance (ESC) in the hands, supporting small-fiber/autonomic dysfunction in the context of prominent sensory symptoms. Repeat EMG, performed after interval follow-up with broad muscle sampling, demonstrated focal neurogenic abnormalities involving bilateral ulnar distributions and left L5-S1 radiculopathy but found no electrophysiological evidence of a neurodegenerative disorder. The patient was treated symptomatically with gabapentin and vitamin E and reported approximately 80% improvement after six weeks. This case highlights the importance of clinicophysiological correlation, disease trajectory, sensory phenomenology, and repeat electrophysiology when an initial EMG suggests motor neuron disease but the longitudinal clinical picture is discordant. It also illustrates how small-fiber dysfunction and focal neurogenic abnormalities may coexist and mimic a progressive motor neuron syndrome.
    Keywords:  amyotrophic lateral sclerosis; electromyography; fasciculations; motor neuron disease mimic; peripheral nerve hyperexcitability; radiculopathy; small-fiber dysfunction; sudomotor dysfunction
    DOI:  https://doi.org/10.7759/cureus.115700
  27. J Parkinsons Dis. 2026 Oct 08. 1877718X261493297
    Considerations for therapeutic targets for clinical trials in biomarker-characterized prodromal Parkinson's disease populations.
    R B Schneider, G Skibinski, B Fiske, C M Kopil, K Merchant, T Simuni.
      Parkinson's disease (PD) is a growing public health problem and biologically targeted therapeutics (BTTs) that slow disease progression are urgently needed. However, the development of effective BTTs is challenging as PD is a clinically defined syndrome with pathobiological heterogeneity and the pathobiological process begins many years before the onset of clinically detectable motor symptoms. Testing BTTs in a biomarker-defined population at an earlier stage in the disease course, before a clinical PD diagnosis, may be the key to achieving this objective. The recent emergence of biological definitions of neuronal α-synuclein disease (NSD) and research frameworks for staging disease represent the first step towards testing BTTs in biomarker-defined prodromal populations. While biomarker-defined populations are essential for implementing precision therapeutic approaches, selecting and prioritizing BTTs for testing in early-stage populations is also critical, and requires consideration of biological relevance, safety, and operational feasibility. Here, in preparation for such studies, we review the landscape of publicly available PD BTTs organized by mechanistic pathways and targets, and summarize scientific, safety, and operational considerations relevant to early-stage, biomarker-defined trials targeting NSD participants prior to PD clinical diagnosis. Recognizing that there are shared biological mechanisms across neurodegenerative disorders, we complement this review of the PD therapeutic target landscape with a review of publicly available Alzheimer's dementia and amyotrophic lateral sclerosis BTTs and provide a comprehensive list of agents for reference.
    Keywords:  Parkinson's disease; clinical trials; neurodegenerative diseases
    DOI:  https://doi.org/10.1177/1877718X261493297
  28. Expert Rev Med Devices. 2026 Oct 09.
    Advances in non-invasive monitoring of drug delivery for neurodegenerative disorders.
    Joseph Y Choi, John D Heiss.
       INTRODUCTION: Effective therapies for neurodegenerative disorders remain limited by the blood-brain barrier. However, improving delivery across this barrier is only one part of the challenge. Investigators must also determine whether a therapy reaches the intended brain region, engages its target, and produces a meaningful biological response.
    AREAS COVERED: This narrative review examines emerging approaches for noninvasive monitoring of central nervous system drug delivery. The literature search included PubMed and Web of Science for studies published from 2005 until 2026. Imaging methods such as magnetic resonance imaging, positron emission tomography, and focused ultrasound provide spatial information about blood-brain barrier permeability, regional distribution, and target engagement. Theranostic nanoplatforms and nanocarrier tracking strategies make delivery agents visible, while blood-based biomarkers, biosensors, and wearable technologies offer complementary measures of pharmacodynamic response and functional change. The literature search prioritized peer-reviewed original studies, clinical trials, and recent translational work relevant to delivery verification, biological response, and treatment monitoring.
    EXPERT OPINION: Noninvasive monitoring is shifting CNS drug delivery from a question of blood-brain barrier crossing to a broader framework for evaluating delivery success. Future trials should validate whether multimodal monitoring can guide dosing, patient selection, safety surveillance, and continuation of treatment.
    Keywords:  Drug delivery; focused ultrasound; nanocarrier tracking; neurodegenerative disease; noninvasive monitoring; theranostic nanoplatforms; wearable monitoring
    DOI:  https://doi.org/10.1080/17434440.2026.2743929
  29. J Inflamm Res. 2026 ;19 540890
    The Role of Mast Cells and Their Potential as a Therapeutic Target For Neuroinflammation.
    Sarah Adriana Scuderi, Rossella Basilotta, Laura Cucinotta, Alessio Ardizzone, Emanuela Esposito.
      Neuroinflammation is increasingly recognized as a central mechanism underlying the onset and progression of numerous neurological disorders, including neurodegenerative, autoimmune, and cerebrovascular diseases. Although microglia and astrocytes are traditionally considered the primary mediators of inflammatory responses within the central nervous system (CNS), accumulating evidence has identified mast cells (MCs) as important contributors to neuroimmune regulation. Strategically located at the interface between the peripheral immune system and the CNS, MCs can rapidly respond to a variety of endogenous and exogenous stimuli through the release of bioactive mediators, including histamine, proteases, cytokines, chemokines, and lipid-derived molecules. These mediators influence blood-brain barrier (BBB) integrity, promote glial activation, modulate neuronal signaling, and contribute to the amplification of inflammatory cascades. Increasing experimental and clinical evidence supports the involvement of MCs in the pathogenesis of several neurological conditions, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, migraine, and ischemic brain injury. Consequently, modulation of mast cell activity has emerged as a promising therapeutic approach for limiting neuroinflammatory damage and restoring neuroimmune homeostasis. This review provides an overview of mast cell biology within the CNS, discusses the molecular mechanisms linking MCs to neuroinflammation, examines their contribution to major neurological disorders, and highlights current and emerging therapeutic strategies targeting MCs-mediated pathways. A deeper understanding of mast cell functions in neuroinflammatory processes may facilitate the development of innovative and more effective interventions for neurological diseases.
    Keywords:  CNS; MCs; central nervous system; mast cells; neuroimmune interactions; neuroinflammation; therapeutic targets
    DOI:  https://doi.org/10.2147/JIR.S540890
  30. EBioMedicine. 2026 Oct 09. pii: S2352-3964(26)00389-0. [Epub ahead of print]133 106505
    EARLY-ALS: a multicentre study on prodromal amyotrophic lateral sclerosis.
    Isabell Cordts, Ana Galhoz, Laura Tzeplaeff, Anne Gründel, Florian Kohlmayer, Andreas Schwersenz, Ines Marschalkowski, Bogdan Bjelica, Verena Panitz, Christian Schulze, Martin Svačina, Petra Rau, André C Dorigan, Marcus Deschauer, Simon Witzel, David Brenner, Jochen H Weishaupt, Sarah K Bublitz, Stefan Lorenzl, Andreas Hermann, Tim Hagenacker, Joachim Wolf, Martin Regensburger, Helmar C Lehmann, Maike F Dohrn, Johannes Dorst, René Guenther, André Maier, Thomas Meyer, Daniel Zeller, Christoph Neuwirth, Markus Weber, Jan C Koch, Matthias Boentert, Markus Weiler, Susanne Petri, Ute Weyen, Torsten Grehl, Michael P Menden, Paul Lingor.
       BACKGROUND: Neurodegenerative diseases often feature a prolonged phase of subtle changes preceding diagnosis. In amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and intervention windows.
    METHODS: In this case-control study, 475 patients with ALS and 285 controls from 20 centres in Germany and Switzerland completed a digital questionnaire on prodromal symptoms and health-related factors. Logistic regression included subgroup analyses by sex and clinical strata.
    FINDINGS: Patients with ALS reported a higher burden of prodromal complaints (OR 7.50, 95% CI 4.27-13.17; P < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Before symptom onset, patients consulted neurologists more often (OR 1.26, 1.10-1.44; P < 0.001) and females more often received speech therapy (OR 2.35, 1.05-5.28; P = 0.038). Prodromal herniated discs were more common in males (OR 2.21, 1.04-4.68; P = 0.038) and spinal-onset patients (OR 2.14, 1.25-3.67; P = 0.006). Patients more often had lower secondary education (OR 1.93, 1.24-3.01; P = 0.004), physically demanding occupations (OR 2.21, 1.42-3.43; P < 0.001), and higher consumption habits (P < 0.005). Weight trajectories differed by sex (P = 0.009), with pre-onset weight loss in male patients (P < 0.001).
    INTERPRETATION: Patients with ALS retrospectively reported subtle motor impairment before recognised symptom onset, alongside altered healthcare use and sex- and subgroup-specific patterns. These findings suggest that sporadic ALS may be preceded by a prodromal period and identify mild motor impairment as a potential marker, pending prospective validation.
    FUNDING: DGM e. V.
    Keywords:  Case–control study; Early disease detection; Environmental risk factors; Motor neuron disease; Preclinical neurodegeneration; Sex-specific differences
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106505
  31. Curr Opin Genet Dev. 2026 Oct 08. pii: S0959-437X(26)00116-4. [Epub ahead of print]101 102549
    Update on somatic mutations in major neurodegenerative diseases: mutational signatures in neurons and mosaicism.
    Axel Freischmidt, Jochen H Weishaupt.
      Somatic mutations in major neurodegenerative diseases are poorly understood, but research over the past 2 years provides valuable insights. Single-cell whole-genome sequencing of vulnerable neurons in Alzheimer's disease and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) revealed excess accumulation of single-nucleotide variant signatures and two-bp deletions independent of pathogenic protein aggregation. Increased oxidative DNA damage and possibly impaired DNA damage repair pathways may explain more pronounced signatures in patients. Ultra-deep sequencing of disease-associated genes in relevant tissues in ALS/FTD identified a subset of sporadic patients carrying mosaic variants that cause disease when present in the germline, but the pathogenicity of such mosaic variants at low allele frequencies is unclear. Research on somatic variants in Parkinson's disease remains underrepresented in the literature.
    DOI:  https://doi.org/10.1016/j.gde.2026.102549
  32. Brain. 2026 Oct 08. pii: awag347. [Epub ahead of print]
    White matter hyperintensity burden in amyotrophic lateral sclerosis: motor and survival correlates.
    Alberto De Lorenzo, Alessio Maranzano, Alessandro Cocuzza, Francesco Gentile, Massimiliano Passaretti, Eleonora Colombo, Silvia Torre, Edoardo Nicolò Aiello, Narghes Calcagno, Claudia Gendarini, Marco Olivero, Francesco Scheveger, Valerio Patisso, Jacopo Spagliardi, Alessandro Di Maio, Simone Pierro, Mauro Treddenti, Delia Gagliardi, Giacomo Pietro Comi, Stefania Corti, Joana B Pereira, Pasquale Agosti, Flora Peyvandi, Stefano Messina, Alberto Doretti, Barbara Poletti, Claudia Morelli, Vincenzo Silani, Claudia Mara Cinnante, Federico Verde, Nicola Ticozzi.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Microvascular dysfunction has been implicated by recent research in ALS pathogenesis and motor neuron vulnerability. The aim of this study is to investigate whether MRI markers of white matter hyperintensities (WMHs), reflecting small-vessel disease, are associated with motor and cognitive impairment, disease staging and prognosis in ALS. In this retrospective cohort study MRI scans from 399 ALS patients were evaluated for periventricular and deep white matter hyperintensities (pvWMH and dWMH) using visual grading scales together with semi-automated volumetric quantification of relative WMH volume (WMHrv). The primary outcome was survival. Secondary outcomes included disease staging, functional impairment, motor and cognitive outcome measures. WMH burden was associated with more advanced King's topographic staging [pvWMH (P < 0.001), dWMH (P = 0.002)] and MiToS functional staging [pvWMH (P < 0.001), dWMH (P = 0.017)]. High pvWMH burden was associated with shorter survival [exp(β) = 3.503; 95% CI = 1.131, 10.832; P = 0.030] after adjustment for known prognostic factors. WMH measures correlated with greater functional impairment on ALSFRS-R score [pvWMH (P < 0.001), dWMH (P = 0.003), WMHrv (P = 0.008)]. WMH burden correlated with more severe lower, but not upper, motor neuron impairment, as measured with the MRC sum score [pvWMH (P = 0.002), dWMH (P = 0.024), WMHrv (p=0.030)] and lower motor neuron score [pvWMH (P < 0.001), dWMH (P = 0.001)]. WMH burden was also associated with cognitive deficits on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), as indicated by total [pvWMH (P = 0.007), dWMH (P = 0.009), WMHrv (P = 0.037)] and ALS-specific ECAS scores [pvWMH (P = 0.001), dWMH (P = 0.020), WMHrv (P = 0.022)]. This large-scale MRI study links small-vessel disease to clinical staging, survival and ALS-specific motor (distinctively LMN) and cognitive impairments. These results suggest that WMHs may reflect a diffuse neurovascular pathology spanning cortical and spinal regions and may be relevant to ALS progression. Routine MRI assessment of WMHs could aid patient stratification and inform trial designs. Longitudinal studies are needed to clarify causal relationships and neurovascular-targeted therapeutic implications.
    Keywords:  amyotrophic lateral sclerosis; disease staging; lower motor neuron; small vessel disease; survival; white matter hyperintensities
    DOI:  https://doi.org/10.1093/brain/awag347
  33. Mol Neurodegener Adv. 2026 ;2(1): 41
    Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.
    Masahiro Ohara, Shinsuke Ishigaki, Jonathan K Watts, Ken Yamada, Tsuneya Ikezu, Seiko Ikezu.
      Neurodegenerative disorders have diverse etiologies from monogenic mechanisms such as toxic gain-of-function mutation in subsets of amyotrophic lateral sclerosis (ALS) to multifactorial cascades exemplified by Alzheimer's disease (AD), which feature proteostasis failure, neuroinflammation, mitochondrial dysfunction, or age-associated cellular stress. While small molecules can modulate downstream pathways, nucleic acid therapeutics (NATs) target defined RNA sequences to directly reduce pathogenic gene expression, correct or shift isoform usage via splice modulation, and tune disease-relevant networks, positioning them as promising therapeutic modalities for neurodegenerative disorders. Recent clinical applications of NATs in the central nervous system (CNS) have made significant progress by optimized chemistries, improved tolerability, and established intrathecal administration routes, supporting sustained target engagement in relevant neural and glial compartments. This review summarizes three major NAT platforms-antisense oligonucleotides, small interfering RNAs, and aptamers-by highlighting their mechanisms of action, design principles to enhance their biodistribution, durability, and safety, and emerging novel delivery strategies for CNS targeting. We further discuss emerging translational opportunities across ALS, AD, polyglutamine disorders, prion diseases, and synucleinopathies by integrating disease biology with therapeutic rationale, and by summarizing regulatory approvals, ongoing clinical trials, and next generation NATs in preclinical development.
    Keywords:  Antisense oligonucleotide; Aptamer; Blood brain barrier; Clinical trial; Neurodegenerative disorders; SiRNA
    DOI:  https://doi.org/10.1186/s44477-026-00044-x
  34. Comput Biol Chem. 2026 Oct 02. pii: S1476-9271(26)00589-X. [Epub ahead of print]126(Pt 2): 109462
    Gene regulatory co-expression networks decipher potential lncRNA-miRNA-mRNA interactions modulating transcription regulation in neurodegeneration.
    Amrit Venkatesan, Prashasti Sinha, Jolly Basak, Ranjit Prasad Bahadur.
      Neurodegenerative diseases are complex disorders characterised by progressive neuronal loss and widespread transcriptomic dysregulation. However, understanding the molecular interactions among coding and non-coding RNAs, especially lncRNAs and miRNAs, contributing to disease progression remains elusive. In this study, RNA-Seq datasets from disease-relevant neuronal populations and different brain tissues representing Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are analysed using an integrative network-based framework. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) are combined to identify disease-associated modules and prioritise highly connected hub genes. They are subsequently integrated with curated RNA interaction databases to construct candidate lncRNA-miRNA-mRNA regulatory networks. Functional enrichment and UTR variant analyses are further incorporated to connect the regulatory network framework with biological processes and potential sequence variations. The novelty of the present study lies in the systematic integration of transcriptomic co-expression, post-transcriptional regulation, functional and sequence-level analyses within a single framework. This framework enables the identification of disease-specific and shared regulatory features, and links the candidate regulatory interactions with potential UTR sequence alterations. Across eight tissue-specific samples, 163 hub genes and 4869 candidate lncRNA-miRNA-mRNA interactions are identified. Additionally, we also identify 414 UTR variants associated with the hub genes. Pathways associated with hub genes including axonogenesis, synaptic organization, intracellular transport and RNA regulatory mechanisms are commonly found to be enriched in AD, PD and ALS. These findings provide a quantitative resource for prioritising regulatory interactions between candidate hub genes and associated UTR variants for future experimental validation.
    Keywords:  Functional enrichment; Hub genes; Neurodegenerative diseases; RNA-Seq; lncRNA-miRNA-mRNA interactions
    DOI:  https://doi.org/10.1016/j.compbiolchem.2026.109462
  35. bioRxiv. 2026 Aug 10. pii: 2026.08.07.743573. [Epub ahead of print]
    Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model.
    Paulina Torres, Daniela Becerra, José I Astorga, Matías Fuentealba, Grant Kauwe, Luis Gonzalez, Guillermo Diaz, Vania Morales, Vicente Valenzuela, Cameron Wehrfritz, Yani Y Ngwala, Claudia Sepulveda-Quiñenao, Samah Shah, Joanna Bons, Leonard Petrucelli, Tara E Tracy, Birgit Schilling, Claudio Hetz.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G 4 C 2 ) in the C9ORF72 gene is the most common cause of ALS and FTD, which results in the accumulation of dipeptide-repeat protein aggregates. Regulation of protein synthesis at the level of the initiation factor eIF2α has been suggested as a transversal event contributing to neurodegeneration in ALS and FTD. eIF2α phosphorylation blocks protein synthesis to alleviate protein misfolding overload, but conversely it can reduce the expression of synaptic proteins resulting in neuronal dysfunction. Dibenzoylmethane (DBM) is a small molecule that reverses the translational attenuation mediated by eIF2α phosphorylation which has been shown to alleviate neurodegeneration in prion-infected mice and Tau transgenic animals. Here we investigated the efficacy of the oral administration of DBM in protecting a mouse model of C9ORF72 pathogenesis. Treatment of mice with 0.5% of DBM mixture in powdered food ad libitum was sufficient to prevent cognitive impairment in C9ORF72 mice. Unexpectedly, DBM treatment did not modify the content of poly(GA) and poly(GR) protein inclusion in the hippocampus and brain cortex. Proteomic profiling of brain tissue indicated that DBM administration corrected nearly 70% of the changes in gene expression triggered by expanded G 4 C 2 , where the main pathways modified by DBM were related to cytoskeleton organization, ALS, and metabolic processes. Most proteins corrected by DBM in our C9ORF72 model were also altered in the brain of human FTD/ALS patients. Overall, our results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity.
    DOI:  https://doi.org/10.64898/2026.08.07.743573
  36. J Neurol. 2026 Oct 05. pii: 639. [Epub ahead of print]273(10):
    Neuroimaging signatures of facial onset sensory and motor neuronopathy (FOSMN).
    Angela Rosenbohm, Francisco Herrera-Angeles, Hans-Jürgen Huppertz, Karl Georg Haeusler, Jochen H Weishaupt, Hans-Peter Müller, Jan Kassubek.
      Facial onset sensory and motor neuronopathy (FOSMN) is an exceptionally rare condition characterized by progressive facial paresthesia and the subsequent appearance of bulbar symptoms with rostro-caudal motor and sensory deficits sometimes extending to the hand muscles. The pathophysiological understanding of this disorder is very limited. In order to identify patterns of neuroanatomical involvement within the brain, we applied advanced magnetic resonance imaging-based techniques to a group of six patients with the diagnosis of FOSMN, using unbiased analysis techniques with atlas-based volumetry of volume-rendering T1-weighted data and whole brain-based spatial statistics of diffusion tensor imaging (DTI). The volumetric data showed significant global atrophy with prominent involvement of the medulla oblongata, while DTI demonstrated significant decreases in the right-hemispheric frontal lobe and bilaterally along the superior and inferior longitudinal fasciculi. In summary, this application of volumetry and DTI to a group of FOSMN patients demonstrated, beyond global brain atrophy as a correlate of a systemic disease process, regional atrophy in the brainstem/medulla oblongata, together with tract alterations of polymodal frontotemporoparietal interconnections. Future neuroimaging studies in larger patient groups of FOSMN are needed for detailed phenotype-neuroimaging correlations.
    Keywords:  Amyotrophic lateral sclerosis; Atlas-based volumetry; Diffusion tensor imaging; Facial onset sensory and motor neuronopathy; Magnetic resonance imaging; Motor neuron disease; Neuroimaging
    DOI:  https://doi.org/10.1007/s00415-026-14174-5
  37. Biochemistry (Mosc). 2026 Sep;91(9): 1522-1549
    Astrocyte Structure-Function Relationship in Senescence and Neurodegeneration.
    Daria V Serebryanaya, Ksenia A Kolgaeva, German A Dya, Ivan M Ermakov, Vsevolod V Belousov.
      Astrocytes play a critical role in maintaining brain homeostasis by providing metabolic support to neurons, regulating neurotransmitter levels, modulating synaptic transmission, and preserving the blood-brain barrier (BBB) integrity. Aging is associated with the accumulation of senescent astrocytes - cells that have lost their ability to grow and divide but remained metabolically active and resistant to apoptosis. In neurodegenerative diseases, astrocytes develop a reactive phenotype. Both senescent and reactive astrocytes are characterized by distinct secretory phenotypes known for the production of pro-inflammatory cytokines, chemokines, and metalloproteinases, that considerably overlap in both states of astrocytes. Recent studies indicate that the number of senescent astrocytes in the brain directly correlates with the development of neurodegenerative diseases. However, the relationship between senescence and neurodegeneration remains poorly understood. This review examines the similarities and differences in the structural and functional features of astrocytes in senescent and pro-inflammatory states, explores potential interactions between them, analyzes intermediate functional states, and discusses potential mechanisms by which astrocytes of both phenotypes contribute to the development of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; astrocytes; reactive astrocytes; senescence; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.1134/S000629792660208X
  38. Med Devices (Auckl). 2026 ;19 626538
    A Novel Device for Pulmonary Expansion Under Simulated Healthy and Neuromuscular Conditions: A Bench Simulation Study.
    Alessandra Carneiro Dorça, Letícia de Araújo Morais.
       Background: Amyotrophic Lateral Sclerosis (ALS) leads to a progressive decline in respiratory function, requiring volumetric expansion techniques to prevent hypoventilation. However, the mechanical performance of devices used for this purpose requires evaluation under controlled conditions in bench simulation studies. Devices, such as the manual resuscitator, are commonly used, but present limitations, including high pressures, variable flow, among others. A novel respiratory muscle training device designed to provide controlled flow and pressure (ILLIFE-T) was developed.
    Objective: To evaluate the behavior of the variables pressure, volume, and flow during the volumetric expansion technique, comparing the new device with the manual resuscitator and the manual resuscitator + Positive Expiratory Pressure (PEP), using simulated models of healthy and ALS affected lungs.
    Methods: This bench simulation study used the ASL 5000 simulator, configured with predefined respiratory profiles representing healthy and ALS respiratory conditions. Four repetitions of the volumetric expansion maneuver were performed for each device and simulated respiratory condition, with five insufflations per repetition. One recording was randomly selected from each repetition for analysis, resulting in four observations per device and simulated respiratory condition.
    Results: In the simulation with healthy respiratory conditions, the new device generated higher pressure (23.38±3.81 cmH2O), volume (1991.25 ±174.10 mL), and lower flow variability (-1.47±11.43 L/min) compared with the manual resuscitator (12.25±11.73 cmH2O; 1113.64±131.75 mL; 18.84±61.31 L/min) and the manual resuscitator with PEP valve (16.89±0.64 cmH2O; 1817.25±86.77 mL; -49.49±9.96 L/min), respectively. In ALS simulated models, the new device also achieved higher pressure (23.69±3.29 cmH2O) and volume (2235.28±264.74 mL) compared with the manual resuscitator (8.33±8.34 cmH2O; 563.45±212.03 mL, respectively) and the manual resuscitator with PEP valve (14.89±7.60 cmH2O; 1449.86±153.09 mL, respectively). Flow values were similar among devices: 15.10 ± 18.00 L/min for the new device, 19.28±56.03 L/min for the manual resuscitator, and 0.18±51.67 L/min for the manual resuscitator with PEP valve.
    Conclusion: Pressure and volume were higher with the new device in both simulated models. Flow did not differ significantly among devices, although lower variability was descriptively observed with the new device.
    Keywords:  ALS; lung simulator; respiratory physiotherapy; volume recruitment
    DOI:  https://doi.org/10.2147/MDER.S626538
  39. Zhonghua Nei Ke Za Zhi. 2026 Oct 01. 65(10): 1122-1129
    [The role of the GSTP1/JNK signaling pathway in regulating oxidative stress and programmed cell death in amyotrophic lateral sclerosis].
    H F Wang, B Sun, J Pan, X Y Pang, J M Bai, J L Feng.
      
    DOI:  https://doi.org/10.3760/cma.j.cn112138-20260501-00268
  40. Front Med (Lausanne). 2026 ;13 1907567
    Regularization via gradient attribution for multiple sclerosis lesion segmentation.
    Salvatore Giugliano, Giovanna Sannino.
       Introduction: Accurate segmentation of Multiple Sclerosis (MS) lesions from Magnetic Resonance Imaging (MRI) is fundamental for robust disease monitoring and for the evaluation of therapeutic efficacy. Within Internet of Medical Things (IoMT)-based diagnostic infrastructures, where deep learning models serve as autonomous computational nodes embedded in interconnected clinical workflows, ensuring reliable lesion detection without continuous human supervision is a critical operational and clinical requirement. A persistent methodological challenge is the pronounced class imbalance characteristic of MS neuroimaging datasets. This imbalance causes conventional loss functions to systematically miss small lesions, thereby directly compromising the utility of automated image analysis as an instrument for precision medicine.
    Methods: This work proposes the Regularization via Gradient Attribution (RGA) framework, a module that leverages gradient-based eXplainable Artificial Intelligence (XAI) attribution maps as active supervisory signals during training. Instead of constraining the learning process exclusively at the prediction-output level, RGA imposes additional penalties on the network when false-negative lesion regions have low internal attribution and when false-positive healthy-tissue regions exhibit elevated attribution. The framework is architecturally agnostic, compatible with both convolutional and transformer-based backbone networks, and accommodating arbitrary spatial attribution techniques. RGA was evaluated on two public MS lesion segmentation datasets, MSLesSeg and 3D-MR-MS, using three backbones (nnU-Net, UNETR, TransBTS) and two XAI methods (LayerCAM, Integrated Gradients) in 5-fold cross-validation.
    Results: On both datasets, RGA consistently improved DSC, TPR, and LTPR over the baselines. The best configuration, nnU-Net + RGA achieved a DSC of 0.7056 on MSLesSeg and 0.7466 on 3D-MR-MS, with RGA yielding the highest DSC for all backbones. Qualitative analyses further substantiate these findings by demonstrating a marked reduction in missed-lesion regions across all model architectures, without a corresponding substantial increase in false-positive predictions.
    Discussion: By jointly providing high lesion-level detection completeness, model interpretability, and zero additional inference-time computational cost, RGA represents a methodologically grounded approach compatible with IoMT-oriented precision-medicine pipelines, while requiring dedicated deployment validation before clinical or edge-device implementation.
    Keywords:  deep learning; explainable artificial intelligence; internet of medical things; loss function; multiple sclerosis; precision medicine; segmentation
    DOI:  https://doi.org/10.3389/fmed.2026.1907567
  41. J Neurol. 2026 Oct 08. pii: 651. [Epub ahead of print]273(10):
    Pre-diagnostic ALSFRS-R slope provides limited incremental information about the variability in subsequent functional decline in amyotrophic lateral sclerosis: a population-based study.
    Rosario Vasta, Andrea Calvo, Cristina Moglia, Antonio Canosa, Umberto Manera, Giulia Gianferrari, Elisabetta Zucchi, Ilaria Martinelli, Gabriele Mora, Sara Cabras, Francesca Palumbo, Enrico Matteoni, Alessandra Maccabeo, Giorgio Pellegrino, Emilio Minerva, Daniela Pascariu, Stefano Callegaro, Fabrizio D'Ovidio, Letizia Mazzini, Fabiola De Marchi, Jessica Mandrioli, Adriano Chiò.
       BACKGROUND: The pre-diagnostic ALSFRS-R slope is frequently used in a clinical trial design and clinical practice under the implicit assumption that it reflects subsequent functional decline. We assessed the association between the pre-diagnostic ALSFRS-R slope and subsequent functional decline.
    METHODS: The Piemonte and Valle d'Aosta ALS Registry (PARALS) was used as the primary cohort. The associations between pre- and post-diagnostic slopes at 6, 12, and 18 months were examined using correlation coefficients and multivariable linear regression. Linear and quadratic mixed-effects models used all ALSFRS-R assessments obtained during the first 18 months to evaluate longitudinal trajectories and quantify the incremental contribution of the pre-diagnostic slope. All analyses were replicated in the Emilia Romagna Registry for ALS (ERRALS).
    RESULTS: A total of 2,222 patients from PARALS and 1,543 from ERRALS were included. In PARALS, the pre-diagnostic ALSFRS-R slope showed only a modest monotonic association with post-diagnostic functional decline (Spearman's ρ = 0.19-0.30) and explained 6.1% of its variance at 6 months, with this proportion decreasing thereafter. Quadratic mixed-effects models estimated that, at 12 months, the difference in ALSFRS-R change between patients in the highest and lowest pre-diagnostic slope quartiles was 2.04 points in PARALS (95% CI 1.25-2.83) and 2.47 points in ERRALS (95% CI 1.07-3.86). However, the linear and quadratic interactions together increased the marginal R2 by only 0.43 percentage points in PARALS and 1.68 percentage points in ERRALS.
    CONCLUSIONS: The pre-diagnostic ALSFRS-R slope identifies meaningful average differences in subsequent decline between patient groups but provides limited information for predicting individual trajectories.
    Keywords:  ALSFRS-R; Amyotrophic lateral sclerosis; Clinical trials; Disease progression
    DOI:  https://doi.org/10.1007/s00415-026-14177-2
  42. EMBO Rep. 2026 Oct 05.
    TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.
    Shohei Sakai, Kotaro Oiwa, Yohei Iguchi, Izzet Mehmet Akcay, Seiji Watanabe, Okiru Komine, Noriko Nagata, Mai Horiuchi, Jemeen Sreedharan, Masahisa Katsuno, Koji Yamanaka.
      Loss-of-function mutations in TANK-binding kinase 1 (TBK1) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), characterized by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology, but the mechanisms beyond impaired autophagy remain undefined. Here, we identify a TBK1-IFNβ-immunoproteasome axis as a novel autophagy-independent proteostatic pathway regulating TDP-43 clearance. TBK1 is activated by aggregation-prone monomeric TDP-43 via physical association, and this activation alleviates TDP-43 pathology in neuronal cells. TBK1 subsequently induces IFNβ expression, which upregulates the immunoproteasome to promote degradation of monomeric TDP-43 in neurons, including human iPSC-derived lower motor neurons. Importantly, IFNβ receptor expression is downregulated in spinal motor neurons from ALS patients with TDP-43 pathology. Furthermore, heterozygous Tbk1 deletion in SOD1G93A mice impairs immunoproteasome induction and increases polyubiquitinated protein accumulation in spinal cords, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that impairment of the TBK1-IFNβ-immunoproteasome axis represents an autophagy-independent mechanism contributing to the development of TDP-43 pathology in ALS and FTD.
    DOI:  https://doi.org/10.1038/s44319-026-00953-8
  43. Radiol Bras. 2026 Jan-Dec;59:59 e20260011
    Comparison between ultrasound and electromyography for detection of fasciculations in amyotrophic lateral sclerosis: an updated systematic review and meta-analysis.
    Márcio Luís Duarte, Wagner Iared, Acary Bulle Souza Oliveira, Lucas Ribeiro Dos Santos, Maria Stella Peccin da Silva.
      Fasciculations are a key manifestation of lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). Al-though electromyography is considered the gold-standard method for the detection of fasciculations, its sensitivity for that purpose depends on the muscle sampled and the examination time. Muscle ultrasound has emerged as a dynamic, noninvasive technique with high sensitivity for detecting spontaneous muscle activity. This updated system-atic review compares ultrasound and electromyography in terms of their performance for the detection of muscle fas-ciculations in ALS, with stratification by muscle group and observation time. A comprehensive search of the literature identified studies evaluating both techniques. Data were synthesized descriptively and, when possible, quantitatively. Ultrasound demonstrated higher or comparable detection rates across most muscle groups, particularly in muscles that are large or deep, such as the biceps brachii, tibialis anterior, and vastus lateralis. Longer ultrasound observation times, especially 60 s, were associated with substantially higher detection rates without a loss of specificity. Although electromyography is still essential for electrophysiological characterization, ultrasound offers broader muscle cover-age, excellent reproducibility, and a noninvasive approach. These findings support muscle ultrasound as a valuable complementary tool for the detection and assessment of fasciculations in patients with motor neuron disease.
    Keywords:  Amyotrophic lateral sclerosis; Electromyography; Fasciculation; Motor neuron disease.; Ultrasonography
    DOI:  https://doi.org/10.1590/0100-3984.2026.0011
  44. EBioMedicine. 2026 Oct 08. pii: S2352-3964(26)00393-2. [Epub ahead of print]133 106509
    Immune effects of faecal microbiota transplantation in amyotrophic lateral sclerosis: a pilot multicentre, randomised, masked, sham-controlled, proof-of concept trial.
    FETR-ALS Study Group
       BACKGROUND: The gut microbiota modulates peripheral immunity, which is altered in amyotrophic lateral sclerosis (ALS). Faecal microbiota transplantation (FMT) may exert immunological effects, but its impact in ALS remains unclear.
    METHODS: FETR-ALS was a multicentre, randomised, masked, sham-controlled proof-of-concept trial conducted at four Italian ALS centres. Adults with ALS of 18 months duration or less and forced vital capacity of at least 70% predicted were randomly assigned (2:1) to receive FMT or a sham procedure (SP). The intervention consisted of two nasojejunal administrations of screened-donor faecal suspension at baseline and month 6, without antibiotic preconditioning. The primary endpoint was change in circulating Tregs among CD4+ T cells at 6 months. Secondary endpoints included safety, ALS Functional Rating Scale-Revised slope, respiratory and nutritional measures, survival, and exploratory biomarker profiles. Analyses followed the intention-to-treat principle.
    CLINICALTRIALS: gov identifier: NCT03766321.
    FINDINGS: Between 2020 and 2024, 43 individuals were screened and 42 were enrolled and randomly assigned to FMT (n = 28; mean age 56.1 years [SD 8.2]; 14 [50%] male) or SP (n = 14; 59.6 years [9.1]; eight [57%] male). Overall, 29 participants completed the second procedure and 6-month follow-up, and Treg measurements were available for 28. The primary outcome was not met: at 6 months, 8/18 (44%) participant receiving FMT versus 2/10 (20%) receiving SP achieved a ≥20% increase in circulating Tregs (odds ratio [OR] 3.20, 95% CI 0.59-25.36; p = 0.21). Mean Treg increase was 2.36 percentage points higher with FMT (95% CI 0.19-4.55; p = 0.04). ALSFRS-R declined by -1.07 points/month in the SP group and -0.76 points/month in the FMT group, with a between-group difference in monthly decline of 0.31 points/month favouring FMT (95% CI 0.11-0.51; p = 0.002). Conversely, at month 6, the MRC score was lower in the FMT group than in the SP group (0.75 versus 0.89; mean difference -0.13, 95% CI -0.26 to 0.00; p = 0.042). FMT was associated with 32 adverse events (12.5% severe) versus 14 (28.6% severe) in SP, mostly gastrointestinal or infectious.
    INTERPRETATION: In this exploratory trial, FMT was not associated with major safety concerns. Although the primary endpoint was not met, FMT was associated with a modest increase in circulating Tregs.
    FUNDING: Italian Ministry of Health.
    Keywords:  Amyotrophic lateral sclerosis; Faecal microbiota transplantation; Gut microbiota; Immune modulation; Randomised controlled trial; T regulatory cells
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106509
  45. Front Vet Sci. 2026 ;13 1939599
    Tembusu virus neuroinvasion and neuropathogenesis: lessons from blood-brain barrier dysfunction in neurotropic flaviviruses.
    Zheng Ni, Zicheng Zhang, Ting Zhou, Yinchu Zhu, Suxin Huo, Jionggang Hua, Xuejun Wu, Tao Yun, Liu Chen, Weicheng Ye, Yuan Fu, Zhuanli Wu, Guijun Wang, Zhuangli Bi.
      Central nervous system (CNS) pathogenesis remains a critical but incompletely resolved aspect of flavivirus infection. Neurotropic flaviviruses usually initiate replication in peripheral tissues but can subsequently access the CNS, causing encephalitis, neurological dysfunction, or developmental abnormalities. Because these events occur along a continuum from peripheral infection to CNS injury, their temporal and mechanistic relationships are often difficult to define. In many studies, brain viral detection, blood-brain barrier (BBB) dysfunction, neuroinflammation, and neurological signs are reported together, although they represent different steps in disease progression. Studies of Japanese encephalitis virus, West Nile virus, Zika virus, dengue virus, and tick-borne encephalitis virus show that BBB dysfunction is an important component of flavivirus-associated neurological disease, but no single conserved mechanism applies across flaviviruses. Endothelial activation, cytokine and chemokine signaling, tight junction remodeling, matrix metalloproteinase activity, leukocyte trafficking, glial inflammatory amplification, and viral genetic variation can each shape barrier-related phenotypes, with distinct timing and relative importance depending on virus species and experimental context. Tembusu virus (TMUV) is an evolving avian flavivirus responsible for widespread waterfowl outbreaks, with ongoing genetic diversification and an expanding recognized host and vector range. Increasing evidence of neurological signs, brain lesions, and viral detection in neural tissues indicates that CNS-associated pathogenicity is an important feature of TMUV infection. However, the routes of TMUV CNS entry, the temporal relationship between BBB dysfunction and early brain infection, the viral genetic basis of strain-dependent neurological phenotypes, and the contribution of host inflammation to BBB injury remain unclear. Here, we review current advances in flavivirus-associated BBB dysfunction and use comparative flavivirus evidence to guide a stage-specific interpretation of TMUV neuroinvasion and neuropathogenesis. We argue that TMUV-associated neurological disease should be interpreted along a peripheral-to-CNS sequence that separates CNS access, BBB dysfunction, post-entry brain replication, neuroinflammatory amplification, and clinical disease. By linking CNS-associated phenotypes to defined disease steps, this approach may help explain the emergence of TMUV strains with enhanced neurological pathogenicity and provide a clearer basis for evaluating attenuation and vaccine safety.
    Keywords:  CNS disease; Tembusu virus; blood–brain barrier dysfunction; flavivirus; neuroinflammation; neuroinvasion; neuropathogenesis
    DOI:  https://doi.org/10.3389/fvets.2026.1939599
  46. Muscle Nerve. 2026 Oct 06.
    One-Year Clinical Course of Patients With Amyotrophic Lateral Sclerosis Admitted to a Home Palliative Care Program: An Extension Study.
    Neuro Palliative Care Team of SAMOT
       INTRODUCTION/AIMS: Longer term data on ALS patients receiving home palliative care are scarce. We extended follow-up of a 6-month cohort to 12 months to characterize the trajectory of function, symptoms, vital support (noninvasive ventilation [NIV], gastrostomy, and/or tracheostomy), and advance care planning (ACP).
    METHODS: In this prospective, single-center study, 34 consecutive ALS patients in a home palliative care program (SAMOT, Palermo) were assessed at baseline, 2, 4, 6, and 12 months, using Karnofsky, ALS Functional Rating Scale-Revised (ALSFRS-R), Edinburgh Cognitive and Behavioural ALS Screen (ECAS), Edmonton Symptom Assessment Scale (ESAS), dysphagia, vital support, and advanced care planning (ACP).
    RESULTS: Ten patients (29.4%) died over 12 months (70% at home); 26 completed the 12-month assessment. Karnofsky (34.4-27.7) and ALSFRS-R (27.1-21.7) declined significantly throughout (both p < 0.0005). Total ESAS rose from 15.7 to 23.7 (p < 0.0005); anxiety increased significantly between T4 and T12. NIV use rose from 20.6% to 50.0% (p = 0.014), while tracheostomy remained stable. Documented end-of-life decisions rose to 70.4% at 6 months but plateaued (69.2% at 12 months); no living wills were completed. Cognitive impairment on ECAS was present in about half of patients, unchanged over time. No patient was referred to or admitted to hospice.
    DISCUSSION: Extending follow-up beyond 6 months shows continuous functional decline and rising symptom burden, and highlights late-onset anxiety and early-plateauing ACP. Despite progressive needs, this home palliative care model appeared to support most patients at home until death over 1 year, within this single-center, non-comparative cohort.
    Keywords:  advance care planning; amyotrophic lateral sclerosis; home palliative care; noninvasive ventilation; symptom burden
    DOI:  https://doi.org/10.1002/mus.70429
  47. Front Artif Intell. 2026 ;9 1849408
    AGMNet: an explainable gated multimodal framework integrating MRI heterogeneity and dopaminergic asymmetry for Parkinson's disease classification.
    T Gnana Abinaya, R Sivashankari.
       Introduction: Parkinson's Disease (PD) is a neurological disorder that worsens over time and is marked by interhemispheric asymmetry, dopaminergic degeneration, and structural changes in the brain.
    Methods: This paper presents a novel approach: AGMNet- Adaptive Gated Multimodel Network, which is an explainable gated multimodal deep learning framework that combines structural magnetic resonance imaging (MRI), dopamine transporter (DaT) imaging, asymmetry-aware representations, and biomarker features for robust PD classification. The Grad-CAM method is incorporated with the proposed AGMNet framework to improve the model interpretability by identifying image regions that influence classification decisions. The performance of AGMNet framework was evaluated using five-fold cross-validation and compared with established deep learning architectures, including VGG16, VGG19, InceptionV3, and Xception.
    Results: The proposed AGMNet has achieved 0.8318 of accuracy, 0.8278 of balanced accuracy, sensitivity of 0.8556, specificity of 0.8000, AUC of 0.711, and Matthews correlation coefficient (MCC) of 0.6458. The proposed AGMNet model demonstrated competitive classification performance relative to the evaluated baseline architectures. The combination of DaT imaging, asymmetry-aware features, and biomarker representations in the proposed model, contributed more strongly to the fused representation than MRI features alone.
    Discussion: The findings indicate that adaptive multimodal fusion in the AGMNet framework can improve the integration of complementary structural, functional, asymmetry-related, and biomarker information for PD classification. The learned gate weights further demonstrate the relevance of functional and asymmetry-aware information within the proposed framework, while Grad-CAM provides additional insight into model decision-making. Therefore, the AGMNet framework offers a potentially useful and interpretable framework for multimodal PD classification.
    Keywords:  DAT imaging; MRI; asymmetry analysis; gated fusion network; multi-model deep learning
    DOI:  https://doi.org/10.3389/frai.2026.1849408
  48. Neurol Ther. 2026 Oct 06.
    Artificial Intelligence for Gadolinium-Sparing Detection of Active Multiple Sclerosis Lesions: A Structured Narrative Review.
    Elham Moases Ghaffary, Omid Mirmosayyeb, Saeedeh Mirbagheri.
       INTRODUCTION: Gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI; T1c+) remains the reference standard for identifying active inflammatory lesions in multiple sclerosis (MS). However, cumulative exposure raises concerns regarding tissue deposition, cost, scan duration, and patient burden. Artificial intelligence (AI) has emerged as a potential strategy to reduce reliance on contrast administration.
    METHODS: We conducted a structured narrative review of studies evaluating AI-based approaches for detecting active MS lesions without routine gadolinium use. Eligible studies included those that generated synthetic contrast-equivalent images or directly classified lesion activity using non-contrast MRI. Outcomes included diagnostic test accuracy, reconstruction fidelity, model characteristics, and methodological quality, which were assessed using an adapted QUADAS-2 framework.
    RESULTS: Among studies reporting diagnostic accuracy against a gadolinium reference standard, sensitivity ranged from 72% to 100% and specificity from 66% to 96%. Only one study reported a complete contingency table; a second reported confusion matrices that are not reproduced here, and only one classifier included external multicenter validation. Image-synthesis studies demonstrated visually plausible outputs but were frequently validated against non-gadolinium targets, limiting clinical applicability. Common limitations included lack of prospective validation, limited reporting transparency, and insufficient evaluation of generalizability.
    CONCLUSION: AI-based approaches demonstrate feasibility for gadolinium-sparing MS imaging but are not yet sufficient to replace contrast-enhanced MRI in routine clinical practice. A plausible near-term role is as a triage tool to identify low-risk follow-up examinations in which gadolinium administration may be deferred. Prospective multicenter studies with standardized reporting and true post-contrast reference standards are needed before clinical adoption.
    Keywords:  Deep learning; Gadolinium; Generative adversarial network; Magnetic resonance imaging; Multiple sclerosis
    DOI:  https://doi.org/10.1007/s40120-026-01030-x
  49. Front Med (Lausanne). 2026 ;13 1909087
    Gut-brain axis dysfunction in Parkinson's disease: a meta-analysis of microbiome dysbiosis and intestinal barrier markers.
    Pulkit Mehrotra, K Vengadakrishnan, Puneet Mehrotra, Shubhasis Dan.
       Background: Parkinson's disease (PD) has traditionally been conceptualized as a neurodegenerative disorder centered within the central nervous system. However, growing evidence suggests that gastrointestinal dysfunction, intestinal permeability abnormalities, and gut microbiome dysbiosis may contribute to disease initiation and progression in a subset of patients. While several studies have characterized microbial alterations in PD, the integration of dysbiosis with intestinal barrier dysfunction and emerging phenotype-oriented models remains incompletely synthesized.
    Methods: A systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines. PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases were searched from inception to January 2025 for studies evaluating gut microbiota composition and/or intestinal permeability markers in Parkinson's disease. Random-effects meta-analysis was performed using standardized mean differences (SMDs) with subgroup and sensitivity analyses exploring geographic variation, sequencing methodology, disease duration, and phenotype-specific findings.
    Results: Thirty-four studies were identified; one (an experimental fecal-microbiota-transfer study in mice) was reclassified as preclinical mechanistic evidence rather than a primary human dataset. The remaining 33 human studies comprised 1,588 PD patients and 1,449 healthy controls. Consistent microbial alterations were identified across studies, characterized by depletion of short-chain fatty acid-producing taxa including Prevotellaceae, Faecalibacterium, and Lachnospiraceae, alongside enrichment of Akkermansia, Bifidobacteriaceae, and Christensenellaceae. Elevated fecal calprotectin and zonulin levels suggested concomitant low-grade intestinal inflammation and impaired epithelial barrier integrity. In limited phenotype-stratified subgroup analyses, gut-first PD phenotypes showed potentially more pronounced dysbiosis patterns than brain-first phenotypes; this preliminary observation is based on very few phenotype-stratified studies and requires validation in larger, prospective cohorts. Functional interpretation of the included literature suggested potential alterations in butyrate metabolism, mucosal barrier maintenance, inflammatory signaling, and microbial-host immune interactions.
    Conclusion: Parkinson's disease is associated with reproducible alterations in gut microbial composition together with evidence of intestinal barrier dysfunction. Although causality cannot be established from predominantly observational studies, the findings support a biologically plausible role for gut-related mechanisms in disease pathophysiology, with a preliminary signal for more pronounced involvement in gut-first PD phenotypes that remains to be confirmed. Future longitudinal and mechanistic studies integrating microbiome, metabolomic, and permeability data are required to clarify therapeutic and biomarker implications.
    Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251078511, CRD420251078511.
    Keywords:  Parkinson’s disease; calprotectin; dysbiosis; gut microbiome; gut-brain axis; gut-first Parkinson’s disease; intestinal permeability; zonulin
    DOI:  https://doi.org/10.3389/fmed.2026.1909087
  50. Neurochem Res. 2026 Oct 08. pii: 285. [Epub ahead of print]51(5):
    Recurrent Sleep Restriction During Aging Induces Early Recognition Memory Impairment, Neuroinflammation, and Blood-Brain Barrier Dysfunction in Female Wistar Rats.
    Ana B Ramírez-López, Jessica J Avilez-Avilez, Beatriz Gómez-González, Verónica Salas-Venegas, Ricardo Jair Ramírez-Carreto, Mara A Guzmán-Ruiz, Anahí Chavarria, Mina Konigsberg.
      Sleep restriction is associated with neuroinflammation, blood-brain barrier (BBB) dysfunction, and cognitive impairment. Although reduced sleep duration in women is well recognized and the impact of sleep disorders is correlated with a higher incidence of neurodegenerative diseases, its consequences during female aging remain poorly understood. Hence, the aim of this study was to evaluate whether recurrent sleep restriction in female rats accelerates aging-related processes, compared with aged females with normal sleep patterns. Female Wistar rats were subjected to sleep restriction for 10 consecutive days, every three months from 6 to 18 months of age. An additional group of 3-month-old rats underwent a single sleep restriction episode as control. BBB permeability, neuroinflammation, cellular senescence, and recognition memory were assessed. Recurrent sleep restriction increased BBB permeability in the cerebral cortex to tracers of different molecular weights and induced hippocampal increase in TNF-α and IL-1β. In contrast, senescence markers showed age- and region-dependent changes, with no clear effect of recurrent sleep restriction in aged animals. A single sleep restriction episode was sufficient to impair recognition memory, whereas recurrent sleep restriction accelerated age-related cognitive decline. These findings indicate that the BBB dysfunction and neuroinflammatory alterations during sleep restriction depend on age and brain region, as well as the recurrence of these episodes.
    Keywords:  Declarative memory; aging; Female rats; Sleep restriction
    DOI:  https://doi.org/10.1007/s11064-026-04909-1
  51. ASN Neuro. 2026 ;18(1): 2736964
    Salivary Extracellular Vesicle Proteome as a Molecular Bridge Between Periodontitis and Neurodegeneration: Mechanisms, Biomarkers, and Therapeutic Opportunities.
    Md Azhar, Rishabha Malviya, Vandana, Phool Chandra, Sathvik Belagodu Sridhar, Javedh Shareef, Tarun Wadhwa, Daniel Arockiam.
      Periodontitis is a chronic inflammatory condition associated with systemic inflammation and an increased risk of neurodegenerative disorders. Salivary extracellular vesicles (EVs) carry molecular cargo in an enclosed form and could serve as a non-invasive platform to explore communication between the oral system and the brain. The review analyzes the current evidence on salivary EV proteomes, their mechanistic links to neurodegeneration, and their biomarker potential. This is a narrative review, and PRISMA-2020 reporting was used as a transparency tool only. The following keywords were used to search the databases PubMed/MEDLINE, Scopus, and Web of Science for publications from 2009 to 2026: periodontal disease, periodontitis, salivary EVs, proteomics, neuroinflammation, blood-brain barrier (BBB) dysfunction, and neurodegeneration. After applying the structured screening and eligibility assessment procedure, 112 studies were included in the qualitative synthesis. Synthesized evidence suggests that cytokines, complement proteins, proteases, acute-phase mediators, and oxidative-stress signals are produced during periodontal inflammation and could be detected in salivary EV cargo. These molecular signals converge on TLR2/TLR4-NF-κB, the NLRP3 inflammasome, HMGB1-RAGE, complement C3/C1q, MMP-9-mediated BBB disruption, IL-1β/IL-6/TNF-α signaling, and oxidative stress-mitochondrial injury, potentially leading to endothelial dysfunction, BBB permeability, microglial activation, and neuronal injury. The results indicate that salivary EVs are not only biomarkers but are biologically active, suggesting a possible molecular basis for the link between periodontal inflammation and neurodegenerative processes. This review incorporates the latest data related to salivary EV proteomics, periodontal inflammation, BBB dysfunction, neuroimmune signaling, and biomarker development, with a focus on EV engineering and other emerging strategies as potential avenues for future diagnosis and therapy.
    Keywords:  Biomarkers; EV proteomics; extracellular vesicle cargo; neurodegeneration; neuroinflammation; periodontitis; salivary extracellular vesicles
    DOI:  https://doi.org/10.1080/17590914.2026.2736964
  52. Neurosci Lett. 2026 Oct 03. pii: S0304-3940(26)00250-8. [Epub ahead of print]888 138750
    Increased CCR2-immunopositive myeloid cells in the putamen and cerebellar white matter with blood-brain barrier disruption in multiple system atrophy.
    Nobuhisa Okada, Natsuko Togawa, Tomoyuki Ishimoto, Takashi Ayaki, Takakuni Maki, Riki Matsumoto.
      Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. Recently, a close relationship of neuroinflammation to MSA pathogenesis was identified. Studies in mouse models of MSA have indicated that peripheral-type myeloid cells and endogenous microglia promote neuroinflammation in MSA. However, their distinct roles in MSA pathogenesis remain unknown. We performed immunohistochemical analyses of brain tissues obtained at autopsy from patients with MSA and age-matched controls to examine the putamen and cerebellar white matter with antibodies against CCR2 (a chemokine receptor expressed by monocyte-lineage cells), TMEM119 for microglia, and fibrinogen for blood-brain barrier (BBB) leakage. The CCR2-immunopositive area was significantly increased in both regions in MSA patients compared to controls (putamen, p = 0.0043; cerebellar white matter, p = 0.0438); however, the TMEM119-immunopositive area showed no significant between-group difference (putamen, p = 0.4220; cerebellar white matter, p = 0.8152). The densities of CCR2-immunopositive areas in the putamen and cerebellar white matter were positively correlated (Pearson's r = 0.7325, p = 0.0248). In the putamen, fibrinogen immunoreactivity and perivascular leakage were increased and showed a distribution similar to that of CCR2 immunostaining (p = 0.0398). These findings suggest that CCR2-immunopositive myeloid cell accumulation in regions with BBB dysfunction may involve recruitment of peripheral monocyte-lineage cells.
    Keywords:  Blood–brain barrier; CCR2; Microglia; Multiple system atrophy; Neuroinflammation; Peripheral-type myeloid cells; TMEM119
    DOI:  https://doi.org/10.1016/j.neulet.2026.138750
  53. Nat Neurosci. 2026 Oct 07.
    Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons.
    Maria Stavrou, Áine Bríd Heffernan, Roderick N Carter, Owen Dando, Zoeb Jiwaji, Karen Burr, Jyoti Nanda, David Villarroel-Campos, Alya Masoud Abdelhafid, Justyna Cholewa-Waclaw, Daniel Soong, David Story, Giampietro Schiavo, Giles E Hardingham, Siddharthan Chandran, Bhuvaneish T Selvaraj.
      Disrupted axonal transport and astrocyte dysfunction are implicated in amyotrophic lateral sclerosis (ALS). Here we show these processes are linked-human-induced pluripotent stem-cell-derived astrocytes carrying the C9ORF72 mutation disrupt mitochondrial axonal transport and mitochondrial function in cocultured motor neurons (MNs). Conversely, isogenic gene-corrected astrocytes or boosting astrocytic mitochondrial bioenergetics rescue axonal mitochondrial transport deficits in C9ORF72 MNs. Our results delineate a non-cell-autonomous role for astrocytes in regulating mitochondrial transport along axons in ALS models.
    DOI:  https://doi.org/10.1038/s41593-026-02464-0
  54. Transl Vis Sci Technol. 2026 Oct 05. 15(10): 1
    Detailed Analysis of Intraretinal Layers and Their Correlation to Brain Structures in Normal Healthy Aging.
    Jack Anthony Cipolla, Giovana Rosa Gameiro, William Tackett, Jessica Morgan, Geoffrey Aguirre, Pradip Pattany, Robert O'Brien, Hong Jiang, John A Detre, Jianhua Wang.
       Purpose: The purpose of this study was to investigate the relationships between intraretinal layer volumes and visual cortical thickness in healthy individuals and determine the influence of age on these associations.
    Methods: Fifty-three subjects were recruited. One eye per subject was imaged using optical coherence tomography (OCT) to quantify volumes of total retinal thickness (TRT), retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL), outer nuclear layer (ONL), outer plexiform layer (OPL), and photoreceptor (PR) layer. Brain magnetic resonance imaging (MRI) was performed, and cortical thickness was quantified in 13 visual cortex regions using the Schaefer 2018 atlas.
    Results: TRT, RNFL, and GCIPL volumes were significantly correlated with cortical thickness in multiple visual regions (r = 0.34-0.59, all P < 0.05). These associations were largely attenuated after adjusting for age. In contrast, selected RNFL and INL associations remained significant after age adjustment. OPL, ONL, and PR layer showed no significant correlations with cortical thickness. PR layer volume increased with age (r = 0.38, P < 0.01), unlike the age-related thinning observed in other layers.
    Conclusions: Distinct retinal layers exhibit differential relationships with the visual cortex, with some associations predominantly mediated by age and selected RNFL and INL associations persisting independently of age.
    Translational Relevance: Distinguishing age-mediated from age-independent retinal-cortical relationships may help identify OCT-derived retinal measures that differentiate normal aging from cerebral pathology and support their investigation as noninvasive biomarkers of central nervous system (CNS) integrity.
    DOI:  https://doi.org/10.1167/tvst.15.10.1
  55. Rev Physiol Biochem Pharmacol. 2027 ;188 187-202
    AA and Parkinson's Disease.
    Undurti N Das.
      Parkinson's disease (PD) is due to degeneration of dopaminergic neurons in substantia nigra pars compacta. PD neuropathology is characterized by the presence of Lewy bodies that contain aggregated α-synuclein, which has been implicated in a range of interactions with phospholipid membranes and free fatty acids. I propose that α-synuclein interacts with arachidonic acid (AA) to regulate the function of dopaminergic neurons. α-Synuclein sequesters AA, whereas AA induces the formation of oligomers that are alpha-helical; resistant to fibril formation; more prone to disaggregation, enzymatic digestion, and degradation; and hence less likely to cause neuronal damage and induce PD. In addition, AA interacts with syntaxin to regulate exocytosis of various neurotransmitters, including dopamine. AA has potent anti-inflammatory actions, serves as a mechanotransducer, influences cell membrane fluidity, enhances glucose uptake by neurons, possesses cytoprotective action, and is the precursor of anti-inflammatory lipoxin A4 (LXA4), actions that maintain the integrity of dopaminergic neurons in the substantia nigra pars compacta. The dynamic equilibrium among α-synuclein, syntaxin, AA, exocytosis of dopamine, formation of LXA4, and the inflammatory process is involved in the development of PD. This implies that deficiency of AA can render dopaminergic neurons susceptible to inflammatory neurodegeneration and development of PD. Hence, it is proposed that administration of AA and DHA (that are present in substantial amounts in the brain) can be used in the prevention and management of PD.
    Keywords:  Exocytosis; Fibril; Lewy bodies; Parkinson’s disease; Syntaxin; α-Synuclein
    DOI:  https://doi.org/10.1007/978-981-92-5964-9_8
  56. Mult Scler. 2026 Oct 08. 13524585261489061
    Autologous haematopoietic stem cell transplantation affects paramagnetic rim lesions in multiple sclerosis.
    Alice Mariottini, Andrea Ginestroni, Edoardo Carlesi, Francesca Di Pasquale, Edoardo Simonetti, Linhsia Noferini, Antonella Gozzini, Gaia Costantini, Anna M Repice, Daniel S Reich, Enrico Fainardi, Chiara Nozzoli, Luca Massacesi.
       BACKGROUND: Available literature shows a marginal or no effect of disease-modifying therapies on paramagnetic rim lesions (PRLs), a promising magnetic resonance imaging marker of chronic inflammation in multiple sclerosis.
    OBJECTIVE: To investigate longitudinal changes in PRL count in people with multiple sclerosis treated with autologous haematopoietic stem cell transplantation (AHSCT), exploring their potential as predictors of treatment response.
    METHODS: Monocentric study including 30 AHSCT-treated people with multiple sclerosis who performed at least two brain magnetic resonance imaging scans with susceptibility-weighted imaging either (i) before and after AHSCT (pre/post-AHSCT group; n = 12) or (ii) after AHSCT only (post-AHSCT group; n = 18).
    RESULTS: In the pre/post-AHSCT group, PRL count decreased in 2/5 (40%) PRL-positive cases over a median of 21 (7-74) months; 5/26 (19%) PRL s resolved. In the post-AHSCT group, PRL count decreased in 4/7 (57%) PRL -positive cases over a median of 51 (6-57) months; 10/20 (50%) PRL s resolved. The annualised paramagnetic rim lesion disappearance rate was -0.36 and -0.43 in the two groups, respectively. No new PRL appeared. Baseline PRL count correlated with disability in the pre/post-AHSCT group only (r = 0.741, p = 0.006).
    CONCLUSIONS: Given the reported long persistence of PRLs, these data indicate that AHSCT may accelerate their disappearance, suggesting an effect within the central nervous system on microglia/macrophages. PRLs could predict response to central nervous system-bioavailable treatments.
    Keywords:  biomarker; disease-modifying treatment; hematopoietic stem cell transplantation; magnetic resonance imaging; multiple sclerosis
    DOI:  https://doi.org/10.1177/13524585261489061
  57. Brain. 2026 Oct 05. pii: awag343. [Epub ahead of print]
    Blood-brain barrier opening with focused ultrasound reduces neuromelanin in a non-human primate model.
    Noelia Esteban-García, Carolina Martín-Flórez, José A Pineda-Pardo, Miguel López-Aguirre, Megan Carrillo, Rafael Rodríguez-Rojas, Inés Trigo-Damas, José L Lanciego, Miquel Vila, José A Obeso, Javier Blesa.
      Age-related accumulation of neuromelanin (NM) has been implicated in the intrinsic vulnerability of catecholaminergic neurons in Parkinson's disease. Postmortem studies in Parkinson's disease patients have revealed elevated intracellular and extracellular NM in the substantia nigra pars compacta, whereas experimental enhancement of NM synthesis in animal models disrupts neuronal homeostasis and accelerates neurodegeneration. Low-intensity focused ultrasound combined with microbubbles (LIFU-MB) induces focal opening of the blood-brain barrier. It has been shown to influence protein aggregation and modulate pigment-related processes, thereby raising the possibility that it may also impact NM dynamics in the brain. Here, we investigated the possibility that repeated LIFU-MB-mediated blood-brain barrier opening could modify NM accumulation in a non-human primate model that overexpresses human tyrosinase, leading to elevated NM accumulation in the substantia nigra pars compacta. Comprehensive characterization revealed that these animals exhibit several features compatible with early pathological changes in Parkinson's disease including extracellular NM release, increased iron accumulation, nigral inflammatory changes, and intracellular inclusion formation. Importantly, these alterations occur in the absence of substantial dopaminergic cell loss and behavioral deficits. LIFU-MB-treated animals showed a marked reduction in both intracellular and extracellular NM, accompanied by a trend toward decreased free ferric iron. These results indicate that early, non-invasive LIFU-MB intervention can counteract mechanisms linked to excessive NM accumulation. Moreover, this approach provides a translational framework to explore the broader feasibility of reducing intracellular pigments and pathological aggregates in the brain. Given its clinical safety, capacity to reach deep brain structures, and non-invasive nature, LIFU-MB warrants further investigation as a possible therapeutic approach in Parkinson´s disease and other neurodegenerative disorders.
    Keywords:  Parkinson’s disease; aging; animal models; iron; neuroinflammation; neuromodulation
    DOI:  https://doi.org/10.1093/brain/awag343
  58. Prim Care Companion CNS Disord. 2026 Oct 06. pii: 26cr04223. [Epub ahead of print]28(5):
    Early Palliative Care and Structured Serious Illness Communication in a Refugee Patient With Amyotrophic Lateral Sclerosis.
    Jillian Rankin, Carina Oltmann, Emily Pinto Taylor, Daniel Schachter, Ashima Lal.
      
    DOI:  https://doi.org/10.4088/PCC.26cr04223
  59. Front Oral Health. 2026 ;7 1926663
    Periodontitis and Parkinson's disease: a narrative review of associations, proposed mechanisms, and clinical considerations.
    Jiayi Cheng, Xiaoyue Zhang, Jieyu Zhou, Li Liu, Jin Feng, Lei Zhao.
      Periodontitis is a common chronic inflammatory disease, and oral health problems are frequent in people with Parkinson's disease (PD). Observational studies consistently indicate poorer periodontal status in PD, but evidence that periodontitis increases the incidence or progression of PD is inconsistent and does not establish causality. This narrative review summarizes current evidence on epidemiological associations, biologically plausible mechanisms, and dental management considerations. Human data support an association between PD and greater periodontal disease burden, plausibly related to motor impairment, reduced self-care capacity, salivary dysfunction, and altered oral microbial ecology. By contrast, proposed pathways from periodontitis to PD, including systemic inflammation, blood-brain barrier disruption, microbial products, and the oral-gut-brain axis, are supported mainly by preclinical, indirect, or low-level human evidence and should be regarded as hypotheses rather than established mechanisms. Observational reports of lower PD incidence among individuals receiving dental scaling do not demonstrate a preventive effect of periodontal treatment. In clinical practice, periodontal care should therefore be justified by established oral-health needs and individualized for PD-related motor, swallowing, cognitive, medication, and device-related considerations, rather than presented as a strategy to prevent or modify PD. Better longitudinal studies and interventional trials are needed to clarify temporality, mechanisms, and any neurological effects of periodontal treatment.
    Keywords:  Parkinson's disease; dysbiosis; neuroinflammation; oral health management; oral microbiome; periodontitis
    DOI:  https://doi.org/10.3389/froh.2026.1926663
  60. Arch Med Res. 2026 Oct 07. pii: S0188-4409(26)00140-2. [Epub ahead of print]57(8): 103518
    Artificial Intelligence in the Diagnosis, Treatment, and Management of Rare Diseases: Opportunities and Challenges from a Latin American Perspective.
    Mario A Parra-Vilchis, Asbiel F Garibaldi-Ríos, Martha P Gallegos-Arreola, Adriana Alonzo-Rojo, Gildardo Sánchez-Ante, José Elías García-Ortiz.
      Rare diseases collectively affect between 3.5 and 5.9% of the global population. Yet, patients still endure an average diagnostic interval of five to seven years before receiving an accurate explanation of their condition. Approximately 80% of these disorders have a genetic origin, and nearly 95% lack approved disease-modifying therapies that alter the disease course. This combination places enormous pressure on healthcare systems and affected families. In the last decade, artificial intelligence (AI), particularly machine learning, deep learning, and natural language processing, has emerged as a credible response to these gaps. This narrative review summarizes recent AI contributions across four interrelated dimensions: differential diagnosis and pattern recognition; prognosis and risk stratification; therapeutic discovery and drug repositioning; and the operational organization of rare disease care. Available evidence indicates that AI-based approaches can shorten diagnostic intervals, reduce unnecessary testing, and increase therapeutic options for orphan conditions. Despite these global advances, implementation remains highly unequal. This review foregrounds the Latin American perspective, setting itself apart from broader overviews. The region presents a scenario in which rich genetic diversity and growing collaborative networks coexist with infrastructural bottlenecks and underrepresentation in genomic databases. The integration of AI into rare disease care will depend on federated data infrastructures, transparent and interpretable models, harmonized regulatory frameworks, and sustained investment in workforce training. Patient organizations are essential partners, particularly in emerging economies.
    Keywords:  Artificial intelligence; Deep learning; Diagnosis; Machine learning; Precision medicine; Rare diseases
    DOI:  https://doi.org/10.1016/j.arcmed.2026.103518
  61. Neurol Sci. 2026 Oct 09. pii: 851. [Epub ahead of print]47(11):
    Long-term trends in selected neurological disorders in Italy (1990-2023): analysis of the global burden of disease (GBD) 2023 data.
    Francesco Brigo, Gianni Turcato, Arian Zaboli, Simona Lattanzi.
       BACKGROUND: Neurological disorders are major contributors to disability and premature mortality. We examined long-term trends in selected neurological, cerebrovascular, central nervous system (CNS) infectious, headache, and brain and CNS cancer causes in Italy from 1990 to 2023.
    METHODS: Age-standardized disability-adjusted life year (DALY), years of life lost (YLL), and years lived with disability (YLD) rates were obtained from the GBD 2023 Results Tool. Causes were grouped into clinically coherent clusters. EAPCs were estimated using log-linear models with Newey-West HAC standard errors (lag 1), and Joinpoint regression characterized non-linear patterns. Sex-specific trends, descriptive uncertainty widths, and YLL/YLD ratios were evaluated.
    RESULTS: Overall DALY rates declined (EAPC - 1.01%, 95% CI -1.13 to -0.89). Cerebrovascular and CNS infectious causes showed the largest reductions, whereas multiple sclerosis, Parkinson's disease, idiopathic epilepsy, and motor neuron disease increased. Joinpoint regression identified multi-phase patterns. Migraine, multiple sclerosis, and dementia showed higher female burden, whereas stroke, Parkinson's disease, and brain and CNS cancer showed higher male burden. Uncertainty widths varied across causes; cluster summaries represent mean constituent-cause widths, not uncertainty intervals for aggregated cluster rates. YLL/YLD ratios showed marked heterogeneity between fatal and disability-driven conditions.
    CONCLUSIONS: Italy experienced substantial declines in age-standardized DALY rates across several selected causes from 1990 to 2023, driven predominantly by reductions in cerebrovascular causes, alongside increasing burdens from several chronic neurological conditions. The relative contributions of premature mortality and non-fatal disability varied markedly across individual causes and clusters.
    Keywords:  Burden of disease; DALY; Italy; Neurological disorders; Temporal trends
    DOI:  https://doi.org/10.1007/s10072-026-09457-8
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