bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–08–02
seventy papers selected by
Luca Bolliger, lxBio
  1. Aging-Related Metaflammation and Mitochondrial Dysfunction in Neurodegenerative Diseases.
  2. Amyotrophic Lateral Sclerosis in the Military: A Uniform Risk?
  3. Targeting TDP-43 in ALS: Regulatory hurdles, trial design deficiencies, and the causal evidence gap for CTx1000.
  4. Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.
  5. Microscale dysfunction and mesoscale compensation in degenerating neuronal networks.
  6. Plasma cardiac troponin T complements neurofilament light chain by reflecting disease phase and phenotypic variation in amyotrophic lateral sclerosis.
  7. Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.
  8. A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.
  9. LINE-1 Retrotransposons and Amyotrophic Lateral Sclerosis.
  10. Suicide in neurodegenerative diseases: a systematic review.
  11. Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.
  12. Nanoparticles Navigating the Blood-Brain Barrier for Neurodegenerative Therapy.
  13. Pathology of general proprioception in a canine disease model of amyotrophic lateral sclerosis.
  14. How can we best utilize magnetic resonance for microbubble-mediated drug delivery to the brain.
  15. The aging brain that doesn't fail: how neural resilience masks neurodegeneration.
  16. Introducing Borsantrazole: A Trifunctional Boron-Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice.
  17. Retinal Thickness and Vascular Density Changes in Amyotrophic Lateral Sclerosis Assessed by Optical Coherence Tomography Angiography.
  18. Focal epilepsy expands the phenotype of FUS-associated amyotrophic lateral sclerosis.
  19. Cardiac autonomic dysfunction is associated with advanced stage, fast progression and poor survival in amyotrophic lateral sclerosis.
  20. Influence of micronutrients on anxiety and depression in patients with amyotrophic lateral sclerosis.
  21. Evidence of stage-specific cognitive reserve effects on longitudinal cognition in amyotrophic lateral sclerosis.
  22. Ethical challenges in treatment-goal transitions in invasively ventilated ALS: a case-based topical review.
  23. Hirudin as a Therapeutic and Brain-Delivery Platform: From Stroke to Central Nervous System Disorders.
  24. Toward a Behavioral Reserve Model in Amyotrophic Lateral Sclerosis.
  25. Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models.
  26. Integrative Network Pharmacology and Molecular Docking Analysis Reveals the Multitarget Mechanisms of Pterostilbene in Neurodegenerative Diseases.
  27. Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.
  28. A modified frailty index to identify high-risk groups for amyotrophic lateral sclerosis.
  29. The Kynurenine Pathway: Unraveling Its Role in Neurological Disorders via Mammalian Cellular Models.
  30. Chitosan-based hydrogel for intranasal drug delivery; current advances in the brain diseases treatment.
  31. Cellular Logistics and Synaptic Vesicle Vulnerability in Major Depressive Disorder and Amyotrophic Lateral Sclerosis Comorbidity: Insights From Nicotinamide Mononucleotide Rescue and Transcriptome-Wide Association Study Integration.
  32. Peptide-drug conjugation: a strategy to address blood-brain barrier limitations in central nervous system diseases.
  33. Traumatic Brain Injury and Risk of Amyotrophic Lateral Sclerosis Mortality: A Traumatic Brain Injury Model Systems Study.
  34. Digital Remote Assessment of Motor and Speech Changes in Amyotrophic Lateral Sclerosis: Longitudinal Observational Study.
  35. On-demand, reversible blood-brain barrier opening via electrical activation of piezoelectric nanoparticles for targeted brain drug delivery.
  36. Leaky Blood-Brain Barrier and Chronic Pain: The Neuroinflammatory Link.
  37. Capturing Financial Burden Concerns in an ALS Multidisciplinary Clinic.
  38. Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.
  39. Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.
  40. Pathogenicity Classification of TARDBP Variants of Uncertain Significance: An Integrative Clinical Characterization and Functional Validation.
  41. Blood‒brain barrier permeability assessment: from biomimetic models to multimodal imaging.
  42. Huoling Shengji granule in amyotrophic lateral sclerosis: A multicenter, randomized, double-blind, riluzole-controlled trial.
  43. Mediterranean Diet and Neurodegenerative Diseases: Recent Advances from the Gut-Immune-Brain Axis to Multi-Omics-Guided Precision Nutrition.
  44. Polysaccharide-driven gut microbial metabolism in neurodegenerative brain diseases: from SCFAs and tryptophan catabolites to neuroinflammatory regulation.
  45. Exercise and Pain in Multiple Sclerosis, Parkinson's Disease, Alzheimer's Disease, and Stroke: A Systematic Review and Meta-analysis.
  46. Plasma volume fraction in drug-resistant epilepsy: A DCE-MRI marker of microvascular pathology.
  47. Endothelial-to-mesenchymal Transition at the Blood-brain Barrier: Molecular Mechanisms and Pathological Roles Across Brain Diseases.
  48. Supplementation via DAF-16 and pnk-1 driven pantothenate-coenzyme A flux improves disease related stress resistance in C. elegans.
  49. A Phosphorylation-Induced Micellization Switch in the Low-Complexity Domain of TDP-43.
  50. Association of Military Branch and Rank With Amyotrophic Lateral Sclerosis Incidence Among United States Veterans.
  51. Feasibility Study of Nose-to-Brain Delivery of Galantamine for Alzheimer's Disease: Enhancing Olfactory-Region Deposition to Improve Therapeutic Efficacy.
  52. Boosting Drug Permeability Across the Blood-Brain Barrier Through Supramolecular Macrocyclization.
  53. Intestinal and Blood-Brain Barrier Dysfunction in Lupus: Emerging Mechanisms and Modulation by Cinnamon.
  54. Predictors of Multiple Sclerosis After Clinically Isolated Syndrome: A Systematic Review and Meta-Analysis.
  55. The value of brain age as a transdiagnostic biomarker of neurodegeneration.
  56. Ceruloplasmin and neurodegeneration: A link between copper dysregulation, iron imbalance, and neuronal damage.
  57. Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.
  58. Integrative network pharmacology, transcriptomics, and molecular docking identify candidate Centella asiatica constituents and targets in neurodegenerative diseases.
  59. Neurodegenerative mortality among National Football League Players.
  60. Perfusion as a biomarker of brain dysfunction in dementia (AD, DLB, FTD/PPA, PDD): comparison of CT, MRI (ASL/DSC/DCE), SPECT, and PET with interpretive pitfalls - a narrative review.
  61. Walking as a Window to the Brain: Redefining Gait in Neurology.
  62. Gut-brain axis mechanisms of remote brain dysfunction after traumatic spinal cord injury: immune inflammation, the vagus nerve, and neuroendocrine pathways.
  63. Particulate Matter Induced Neurotoxicity: Interplay of Neuroinflammation and Organelle Dysfunction.
  64. Breaking the Silent Barrier: Engineering Antibodies for Brain-Targeted Rabies Immunotherapy.
  65. Multimodal Assessment of Consciousness with Brain-Computer Interfaces and Artificial Intelligence: From Acquired Brain Injury to Neurodegenerative Disease.
  66. Neuroprotective Effects of Distilled Extract of Zanthoxylum piperitum in Parkinson's Disease Models.
  67. Herbal Bioactives Targeting Rho GTPases: A Multi-Targeted Strategy for Mitigating Neuroinflammation in Alzheimer's and Parkinson's Diseases.
  68. Context-dependent YEATS-domain inhibition enhances neuronal resilience and improves ALS phenotypes.
  69. Regulatory T cells in perioperative neurocognitive disorders: a systematic review with structured narrative synthesis from molecular mechanisms to clinical translation.
  70. Value of Annual MRI Monitoring in Patients With Multiple Sclerosis Treated With Ocrelizumab: A Number Needed to Scan Analysis.
  1. Aging Dis. 2026 Jul 01.
    Aging-Related Metaflammation and Mitochondrial Dysfunction in Neurodegenerative Diseases.
    Wenting Gao, Hye-Yeon Lee, Kyung-Jin Min.
      Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are increasingly recognized as manifestations of aging-associated systemic dysfunction, rather than isolated brain disorders. Central to this dysfunction is the interplay among metaflammation, mitochondrial breakdown, and chronic neuroinflammation. Metaflammation, driven by peripheral metabolic stress, may prime the brain's immune environment through cytokine signaling and blood-brain barrier compromise. This metabolic-inflammatory crosstalk is thought to impair mitochondrial integrity in neurons and glial cells, promoting oxidative stress and the release of pro-inflammatory mitochondrial components. These mitochondrial signals, in turn, may activate microglial and astrocytic innate immune responses, creating a potentially self-reinforcing cycle of neuroinflammation and energy failure that may contribute to neuronal loss. This review outlines a proposed framework linking metaflammation to neurodegeneration, emphasizing shared mechanisms across AD, PD, and ALS. We further examine preclinical and clinical advances in therapeutic strategies that target this axis including anti-inflammatory agents, caloric restriction, mitophagy enhancers, mitochondrial antioxidants, and senescence-targeted therapies. Together, these interventions reflect a shift from symptom management to systemic metabolic and immune modulation, offering a unified framework for understanding and potentially influencing age-related neurodegeneration.
    DOI:  https://doi.org/10.14336/AD.2026.0366
  2. Neurology. 2026 Aug 25. 107(4): e218481
    Amyotrophic Lateral Sclerosis in the Military: A Uniform Risk?
    Orla Hardiman.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000218481
  3. Drug Discov Today. 2026 Jul 29. pii: S1359-6446(26)00157-1. [Epub ahead of print] 104752
    Targeting TDP-43 in ALS: Regulatory hurdles, trial design deficiencies, and the causal evidence gap for CTx1000.
    Michael A S Guth.
      The therapeutic landscape for amyotrophic lateral sclerosis (ALS) has been characterized by decades of clinical trial failures, often attributed to biological heterogeneity, end-point insensitivity, and a profound evidence gap regarding target engagement. With TAR DNA-binding protein 43 (TDP-43) aggregation emerging as a hallmark feature in the vast majority of ALS cases, new precision-medicine modalities - most notably the proteolysis-targeting chimera (PROTAC) CTx1000 - aim to address the underlying causal pathology through selective degradation of mislocalized TDP-43. This review critically evaluates the regulatory hurdles and trial design deficiencies that have historically undermined ALS clinical development, and incorporates the dual sequestration hypothesis as a framework to interpret the convergence of TDP-43 pathology across neurodegenerative diseases. It concludes that it is imperative that the field adopts more rigorous biomarker-led methodologies, and that although target-specific degraders offer a sophisticated technological leap, their success depends on addressing fundamental knowledge gaps in target engagement, age-dependent vector tropism, and trial design architecture.
    Keywords:  14-3-3 protein; AAV9 (adeno-associated virus serotype 9); TDP-43; amyotrophic lateral sclerosis (ALS); biomarker; clinical trial design; gene therapy
    DOI:  https://doi.org/10.1016/j.drudis.2026.104752
  4. Eur J Hum Genet. 2026 Jul 28.
    Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.
    Sean W Willemse, Koen C Demaegd, Wouter Koole, Ruben P A van Eijk, Wouter van Rheenen, Jan H Veldink, Leonard H van den Berg, Michael A van Es.
      The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.
    DOI:  https://doi.org/10.1038/s41431-026-02208-5
  5. Netw Neurosci. 2026 ;10(3): 594-612
    Microscale dysfunction and mesoscale compensation in degenerating neuronal networks.
    Vegard Fiskum, Nicolai Winter-Hjelm, Nicholas Christiansen, Axel Sandvig, Ioanna Sandvig.
      Progressive neurodegenerative diseases involve neuronal dysfunction across cellular, circuit, and whole-brain levels. Despite differences in anatomical origins, vulnerable neuronal subtypes, and specific misfolded proteins, these diseases share key features. In presymptomatic phases, neural networks engage compensatory processes to maintain function, including increased centralization and reliance on a rich-club of hub nodes. While such mechanisms have supporting evidence in some disorders, they remain less established in amyotrophic lateral sclerosis (ALS), limiting understanding of potential shared presymptomatic responses. To address this, we investigated structural and functional properties of ALS patient-derived motor neuron networks compared with healthy controls using longitudinal multielectrode array recordings and graph theory-based analysis. We observed microscale dysfunction marked by TAR DNA-binding protein 43 proteinopathy, hyperactivity, and reduced spike amplitude. Structurally, ALS networks exhibited neurite hypertrophy, suggesting attempts to form new connections. Mesoscale analyses revealed functional reconfigurations, including increased rich-club connectivity and network assortativity, indicating compensatory centralization. Our findings provide novel evidence that ALS network features can be recapitulated in in vitro models, and that these networks progressively become more centralized to preserve computational capacity, imposing growing demands on hub nodes and predisposing them to further damage. These results support models proposing common network reconfiguration mechanisms across neurodegenerative diseases.
    Keywords:  ALS; Functional connectivity; Graph theory; Hyperexcitability; Multielectrode array; Rich club
    DOI:  https://doi.org/10.1162/NETN.a.552
  6. J Neurol. 2026 Jul 27. pii: 494. [Epub ahead of print]273(8):
    Plasma cardiac troponin T complements neurofilament light chain by reflecting disease phase and phenotypic variation in amyotrophic lateral sclerosis.
    Julia Sellin, Linn Öijerstedt, Janina von der Gablentz, Sanharib Chamoun, Ulf Kläppe, Rayomand Press, Kristin Samuelsson, Julian Grosskreutz, Caroline Ingre.
       BACKGROUND: Neurofilament light chain (NfL) is an established marker of neuronal injury and disease aggressiveness in amyotrophic lateral sclerosis (ALS). In contrast, the clinical and biological significance of cardiac troponin T (cTnT) in ALS is not fully understood. We aimed to evaluate the relationship between plasma cTnT and disease aggressiveness, progression stage, and clinical phenotype in comparison with NfL.
    METHODS: Plasma cTnT and cerebrospinal fluid (CSF) NfL were analysed at diagnosis in a population-based cohort of 526 patients with ALS. Disease aggressiveness was modelled using the D50 framework, which quantifies the time taken to lose 50% of functional capacity (ALSFRS-R) and normalises individual disease trajectories. Biomarker associations with disease aggressiveness, phase, and clinical variables were assessed through group comparisons, logistic and linear regression, and receiver operating characteristic analyses.
    RESULTS: Neurofilament light chain in CSF was strongly associated with disease aggressiveness, with higher levels in patients with more aggressive disease. In contrast, plasma hs-cTnT did not correlate with D50. Across disease phases, CSF NfL remained relatively stable, whereas plasma hs-cTnT increased with advancing rD50, suggesting accumulation with disease progression. Plasma hs-cTnT levels were higher in patients with spinal compared to bulbar onset. Combined biomarker models improved sensitivity and negative predictive value for identifying less aggressive disease.
    CONCLUSION: Plasma hs-cTnT and CSF NfL capture distinct but complementary dimensions of ALS pathology. While NfL reflects disease aggressiveness, hs-cTnT aligns with disease phase and clinical phenotype, supporting its use as a complementary biomarker for ALS characterisation and monitoring.
    Keywords:  Amyotrophic lateral sclerosis; D50-Model; Disease aggressiveness; Neurofilament; Progression; Troponin-T
    DOI:  https://doi.org/10.1007/s00415-026-14002-w
  7. Cells. 2026 Jul 09. pii: 1238. [Epub ahead of print]15(14):
    Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.
    Bowen Liu, Lingyun Zhang, Bing Lv, Chunjie Xu, Luyu Han, Qiupeng Yan, Xin Wang.
      Copper is an essential trace element required for numerous enzymatic processes in the brain, including mitochondrial metabolism, antioxidant defense, and gene expression regulation. Recent studies have further implicated copper in a newly defined form of regulated cell death termed cuproptosis, providing a mechanistic framework for copper-dependent cytotoxicity. Increasing evidence indicates that copper dyshomeostasis is a common feature of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), where it is associated with protein misfolding, redox imbalance, and neuronal vulnerability. Nevertheless, the mechanistic link between copper dysregulation and neuronal cell death remains incompletely defined. In this review, we systematically summarize the molecular mechanisms governing copper homeostasis and intracellular copper trafficking, while providing a timely, updated, and in-depth overview of the mechanistic basis and emerging biology of cuproptosis. We further comprehensively evaluate the current evidence linking copper dysregulation and cuproptosis-related pathways to neurodegenerative diseases, with particular emphasis on distinguishing mechanistic causation from pathological correlation. Importantly, we discuss current therapeutic strategies and emerging clinical efforts targeting copper metabolism, while highlighting the major challenges in defining the pathological significance and mechanistic contribution of cuproptosis in neurodegenerative diseases. Collectively, this review provides an updated framework for understanding the pathological significance and translational potential of cuproptosis in neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; copper homeostasis; cuproptosis
    DOI:  https://doi.org/10.3390/cells15141238
  8. J Neuroimmunol. 2026 Jul 24. pii: S0165-5728(26)00177-3. [Epub ahead of print]420 579028
    A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.
    Asmar Ahsan, Ju-Chi Ou, Pritha Majumder, Yung-Hsiao Chiang, Jeffrey K Huang, Chi-Chen Sarah Huang.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS.
    METHODS: A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I2 statistic.
    RESULTS: A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant.
    CONCLUSION: This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder.
    SYSTEMATIC REVIEW REGISTRATION: PROSPERO identifier CRD420251076035.
    Keywords:  Amyotrophic lateral sclerosis; Biomarker; Optical coherence tomography; Retina; Retinal nerve fibre layer
    DOI:  https://doi.org/10.1016/j.jneuroim.2026.579028
  9. Int J Mol Sci. 2026 Jul 14. pii: 6244. [Epub ahead of print]27(14):
    LINE-1 Retrotransposons and Amyotrophic Lateral Sclerosis.
    Tinkara Korošec, Boris Rogelj, Vera Župunski.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. While monogenic causes account for a minority of cases, in most cases, ALS is sporadic and likely arises from multilayer interactions of genetic architecture, aging-associated loss of genome regulation, and inflammatory stress. Long interspersed nuclear element-1 (LINE-1) retrotransposons are endogenous mobile elements that are tightly controlled through various cellular mechanisms under normal conditions. When abnormally active, they are involved in gene inactivation, expression regulation, and genomic instability, leading to cellular processes such as innate immunity and cell death. Here, we present mechanistic links between LINE-1 and ALS. These include evidence that the burden of retrotransposition-competent LINE-1s (RC-L1s) is increased in ALS genomes, positioning RC-L1 load as a candidate contributor to missing heritability in sporadic disease. We also integrate emerging data showing that LINE-1 RNA can be intrinsically toxic independently of new insertions, as it promotes chromatin opening and transcriptional epigenetic noise, particularly when nuclear RNA surveillance pathways fail in TDP-43 pathology. Finally, we review how LINE-1-derived DNA/RNA intermediates can engage innate immune sensors, highlighting the cGAS-STING axis as a plausible route from LINE-1 de-repression to neuroinflammation. Together, these concepts support a model in which genetic RC-L1 load and age-/pathology-driven LINE-1 de-repression converge on nuclear dysfunction and inflammatory amplification, suggesting concrete molecular nodes for therapeutic intervention.
    Keywords:  LINE-1; TDP-43; amyotrophic lateral sclerosis; cGAS–STING; epigenetic dysregulation; neuroinflammation; retrotransposons
    DOI:  https://doi.org/10.3390/ijms27146244
  10. Neurol Sci. 2026 Jul 29. pii: 659. [Epub ahead of print]47(8):
    Suicide in neurodegenerative diseases: a systematic review.
    Sara Abidar, Mohamed Nhiri, Vittorio Bianchi.
       BACKGROUND AND OBJECTIVE: Suicide is a public health issue, which differs from suicidality, the continuum from suicidal ideation to the suicidal act, including suicide attempts and completed suicide. The main goal of the present study is to determine the relationship between Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with suicidality.
    METHODS: This is a systematic review aiming to determine the relationship between AD, PD, ALS, and MS with suicidality following PRISMA 2020 guidelines by collecting cross-sectional, case-control, and cohort studies; case series; case reports; and retrospective and prospective studies from Google Scholar, PubMed, and Cochrane Library. The protocol of this systematic review was registered on PROSPERO; the registration number is CRD420261422354.
    RESULTS: From 2247 records identified from electronic databases, only 24 articles were included: three studies focusing on AD, nine on PD, and six studies focusing on ALS and MS, respectively. These studies exhibited moderate to low risk of bias. Despite the broad differences regarding the neurochemistry, pathophysiology, diagnosis, symptoms, and treatments of the selected diseases, patients are at a higher risk of suicidality. Depression and low social connectivity are the most prevalent risk factors. Suicidality is mainly detected during the first years post-diagnosis in PD, ALS, and MS patients, while the results in AD are confusing.
    CONCLUSIONS: Data about this topic is scarce and largely varying. Further research is required to elucidate this paradigmatic realm, fostering awareness, enhancing therapies, and providing explanations and interpretations of the mechanisms involved.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Multiple sclerosis.; Parkinson’s disease; Suicidality; Suicide
    DOI:  https://doi.org/10.1007/s10072-026-09248-1
  11. Brain Sci. 2026 Jun 27. pii: 675. [Epub ahead of print]16(7):
    Molecular Mechanisms of Neurodegenerative Diseases: Emerging Biomarkers and Therapeutic Targets.
    Sunanda Yogi, Amit Singh.
      Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD's, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies.
    Keywords:  Alzheimer’s disease; Huntington disease; Parkinson disease; amyotrophic lateral sclerosis; biomarkers; molecular mechanism; neurodegenerative disease; therapeutic targets
    DOI:  https://doi.org/10.3390/brainsci16070675
  12. Int J Nanomedicine. 2026 ;21 620793
    Nanoparticles Navigating the Blood-Brain Barrier for Neurodegenerative Therapy.
    Xinming Zhao, Liming Sun, Xiaoman Zhang, Xiaochen Qi, Guangzhen Wu.
      The blood-brain barrier (BBB) blocks most drugs from entering the brain. Over 98% of small-molecule drugs and nearly all biologics fail to cross this barrier. Nanoparticles (NPs) provide multiple ways to bypass the BBB. These include receptor-mediated transcytosis, adsorptive-mediated transport, and intranasal delivery. NPs can also modify disease-related pathways. For example, they promote amyloid-β clearance, reduce tau phosphorylation, and reprogram neuroimmune responses. Many preclinical studies have shown promising results in Alzheimer's, Parkinson's, and Huntington's diseases. However, no NP-based therapy has moved beyond early-stage clinical trials. Several issues remain unresolved. Direct comparisons between different NP platforms are lacking. The long-term toxicity of NPs in the brain is not well understood. Animal models also do not accurately reflect human disease. We suggest that future work should focus on standardized characterization, better predictive models, and clinical trial designs that address NP diversity. Researchers should also compare NP therapies with existing treatments in a rigorous manner.
    Keywords:  blood-brain barrier; clinical translation; drug delivery; nanoparticles; neurodegenerative diseases
    DOI:  https://doi.org/10.2147/IJN.S620793
  13. J Neurol Sci. 2026 Jul 25. pii: S0022-510X(26)00390-4. [Epub ahead of print]489 126108
    Pathology of general proprioception in a canine disease model of amyotrophic lateral sclerosis.
    Brandie R Morgan-Jack, Martin L Katz, Grace R Kick, Gayle C Johnson, Kiara Delgado, Michael Makinen, Joan R Coates.
      Some forms of amyotrophic lateral sclerosis (ALS) are associated with sequence variants in the superoxide dismutase 1 gene (SOD1). The mechanisms by which these variants contribute to ALS disease pathogenesis are poorly understood. Degenerative myelopathy (DM), a naturally occurring canine disease, shares similarities with some forms of SOD1-associated ALS, especially cases with sensory impairment. While motor pathway involvement in ALS has been extensively studied, sensory pathology has received comparatively less attention. To investigate whether pathology in the general proprioceptive pathway is associated with pelvic limb general proprioceptive ataxia, an early DM sign, we examined sensory system components of this pathway from Pembroke Welsh Corgis with early- and late-stage DM and age-matched controls. The disease was characterized by axonal pathology in the spinocerebellar tracts and the fasciculus gracilis, pronounced accumulation of SOD1-positive inclusions in nucleus thoracicus and dorsal root ganglia (DRG) neurons, and altered SOD1 immunolabeling in dorsal and ventral root axons and ensheathing myelin. Axonal pathology was also observed in a pelvic limb sensory nerve. These findings suggest that pathology in the proprioceptive sensory pathways may play a significant role in general proprioceptive ataxia in DM. Some dogs that were homozygous for the SOD1 risk allele did not develop clinical disease or the associated neuropathology, indicating that other factors in addition to the SOD1 mutation influence disease onset and progression.
    Keywords:  Axonal degeneration; Degenerative myelopathy; Dorsal root ganglia; SOD1; Sensory neurons; Spinal cord; Sural nerve
    DOI:  https://doi.org/10.1016/j.jns.2026.126108
  14. Expert Opin Drug Deliv. 2026 Aug 01. 1-12
    How can we best utilize magnetic resonance for microbubble-mediated drug delivery to the brain.
    Yuexi Huang, Kullervo Hynynen.
       INTRODUCTION: Drug delivery to the brain is severely limited by the blood-brain barrier (BBB). Focused ultrasound (FUS) combined with intravenously administered microbubbles (MB) offers a promising noninvasive approach for transient and reversible BBB permeability enhancement.
    AREAS COVERED: Magnetic resonance-guided FUS (MRgFUS) has been well established for thermal ablation, providing precise anatomical targeting and real-time thermometric feedback. Although BBB permeability enhancement does not rely on thermal effects, MRI guidance remains essential. This review highlights the role of MRI in BBB permeability enhancement procedures and summarizes MR sequences used at different stages to optimize targeting accuracy, safety, and therapeutic efficacy.
    EXPERT OPINION: Because substantial temperature elevation is not expected during BBB permeability enhancement, MR thermometry is not routinely informative in this application. Nevertheless, MRI is central to anatomical and functional targeting for treatment planning and monitoring. Contrast-enhanced T1-weighted imaging enables assessment and localization of BBB permeability enhancement, while T2*-weighted imaging helps identify exposures approaching unsafe levels. Future clinical trials incorporating intraoperative MR guidance are needed to refine and standardize cavitation-based feedback control before developing and adopting systems that do not depend on intraoperative MRI.
    Keywords:  Blood-brain barrier; focused ultrasound; image-guided therapy; magnetic resonance imaging; microbubbles; targeted drug delivery
    DOI:  https://doi.org/10.1080/17425247.2026.2711975
  15. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jul 27. 1-15
    The aging brain that doesn't fail: how neural resilience masks neurodegeneration.
    Andrew Eisen, Heather D Durham, Erik Pioro.
      Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease are usually framed as consequences of aging-related pathogenic processes, including impaired proteostasis with protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Yet, most individuals, even into advanced age, do not develop clinically significant neurodegenerative disease. This discrepancy suggests that the nervous system possesses robust and redundant protective mechanisms that maintain neural integrity despite cumulative molecular and cellular stress. In this perspective, we propose that neurodegenerative diseases arise not simply from the presence of pathogenic processes, but when integrated resilience systems fail to maintain homeostasis or when reserve mechanisms no longer compensate for accumulated pathology. We have synthesized a threshold-based model of disease emergence based on evidence across proteostasis, mitochondrial function, neuroimmune regulation, glial biology, network-level compensation, and barrier integrity, while integrating genetic, environmental, developmental, and stochastic modifiers. We distinguish biological resilience, which actively limits or repairs pathology, from reserve, which permits function despite pathology. We further propose that clinical disease emerges only when age-related cumulative stress exceeds the combined capacity of resilience and reserve. Reframing neurodegeneration as a failure of preservation systems offers new directions for prevention and therapeutic development.
    Keywords:  Aging; neurodegeneration; resilience; senescence
    DOI:  https://doi.org/10.1080/21678421.2026.2705693
  16. Adv Sci (Weinh). 2026 Jul 26. e76432
    Introducing Borsantrazole: A Trifunctional Boron-Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice.
    Nitesh Sanghai, Rhonda Kelley, Ying Lao, M Immanuel Reyes Madlangsakay, Prasanta Paul, M Alejandra Llanes-Cuesta, Jun-Feng Wang, René P Zahedi, Jiming Kong, Geoffrey K Tranmer.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is considered a highly complex, heterogeneous, fatal disease with a high unmet medical need that affects multiple pathophysiological pathways and has no known singular cause. Oxidative stress, however, is implicated as a central player in the progression of ALS and other neurodegenerative diseases. To date, only two FDA-approved drugs, Edaravone, an antioxidant, and Riluzole, an antiglutamatergic, have been widely used clinically, albeit with modest effects on the clinical course of ALS disease progression. Additionally, preclinical studies of both drugs in ALS mouse models have not shown any significant survival benefit, although some abatement in disease progression is observed and translated from preclinical animal models to clinical human studies.
    METHODS: Using a trifunctional boron-based drug design strategy, we have synthesized a pyrazole small molecule called Borsantrazole (BSZ) and evaluated BSZ in cell-based experiments, acute and chronic toxicity models, and the SOD1-G37R ALS mouse model. We have also evaluated untargeted global proteomic and phosphoproteomic changes induced by BSZ.
    RESULTS: Borsantrazole (a small molecule that can selectively target oxidative stress) with favorable CNS drug like properties (low ER values of 0.9 and 1.0 at 1 and 10 µm, respectively, suggesting lower Pgp efflux liability and the LogD at pH 7.4 was within the range of 1.2 to 3.1, suggesting BSZ is lipophilic at pH 7.4.) shows no signs of treatment associated toxicity (acute or chronic (120 days)), significantly increases survival (whole animals, 15.1 days (p = 0.0326); males, 16.5 days; females, 13.7 days), rescued weight loss (27.1% control, 18.3% BSZ, p < 0.0001), delays symptom onset (whole animals, 24.9 days (p = 0.0011); males, 23.3 days; females, 26.4 days), delays disease onset (whole animals, 25.5 days (p = 0.0001); males, 21.1 days; females, 29.8 days) and affects global proteomic changes in the SOD1-G37R mouse model of ALS. In total, 51 proteins were found to be significantly differentially expressed (p < 0.05), including Ca3, Gan, Cplx2, Lrp4, Sqstm1, and 29 phosphorylation sites were differentially expressed and considered statistically significant, including T317 and T72 for neurofilaments light and heavy chain, respectively.
    CONCLUSIONS: Herein, we report that BSZ has demonstrated a favorable safety profile and compelling proof-of-concept efficacy in a ALS mouse model and has the potential to become a disease-modifying ALS therapeutic following further clinical development. Within a broader perspective of treatments for neurodegenerative diseases, BSZ offers a new paradigm for trifunctional small molecule targeting of oxidative stress that can mitigate neuronal deterioration and serve as a potential treatment.
    Keywords:  SOD1; SOD1‐G37R ALS animal model; amyotrophic lateral sclerosis; borsantrazole (BSZ); neurodegeneration; oxidative stress; phosphoproteomics; proteomics; superoxide dismutase 1
    DOI:  https://doi.org/10.1002/advs.76432
  17. Biomedicines. 2026 Jul 17. pii: 1612. [Epub ahead of print]14(7):
    Retinal Thickness and Vascular Density Changes in Amyotrophic Lateral Sclerosis Assessed by Optical Coherence Tomography Angiography.
    Abdelilah Assialioui, Mónica Povedano, Marta Senau, Isidro Ferrer, Luis Arias.
      Background: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder involving neurovascular dysfunction. The retina allows in vivo assessment of neurovascular changes. This study evaluated retinal structural and microvascular alterations in ALS using optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A). Methods: This cross-sectional study included 46 participants with ALS and 19 healthy controls. Retinal thickness and vascular density in the superficial and deep retinal capillary plexuses and the choriocapillaris were quantified using OCT and OCT-A. Group comparisons and logistic regression analyses were performed to assess associations with ALS. Subgroup analyses were conducted according to clinical phenotype. Results: In total, 124 eyes were analyzed. ALS was associated with increased average retinal thickness (p = 0.023) and reduced vascular density in the superficial retinal capillary plexus (p = 0.005), deep retinal capillary plexus (p < 0.001), and choriocapillaris (p = 0.004). In logistic regression analyses, retinal thickness was positively associated with ALS status (OR = 1.42, p = 0.023), whereas higher vascular density in the superficial plexus, deep plexus, and choriocapillaris was associated with lower odds of ALS. No significant differences were observed between bulbar- and spinal-onset ALS phenotypes. Conclusions: ALS is associated with structural and microvascular retinal alterations detectable by OCT and OCT-A. These findings support the presence of systemic neurovascular dysfunction and highlight retinal imaging as a promising, non-invasive approach for investigating disease mechanisms and developing potential biomarkers.
    Keywords:  amyotrophic lateral sclerosis; neurovascular dysfunction; optical coherence tomography angiography; retinal imaging; retinal vascular density
    DOI:  https://doi.org/10.3390/biomedicines14071612
  18. Epilepsia. 2026 Jul 25.
    Focal epilepsy expands the phenotype of FUS-associated amyotrophic lateral sclerosis.
    Yu Jia, Bo Cui, Yan Liang, Mengge Zhang, Suobin Wang, Yuping Wang, Hai Chen.
      Epileptic seizures are an exceedingly rare manifestation in classic amyotrophic lateral sclerosis (ALS). Emerging case reports suggest a potential link between ALS associated with FUS gene mutations (FUS-ALS) and seizures, expanding the disease's phenotypic spectrum. A 25-year-old man presented with a 5-month history of rapidly progressive limb weakness, atrophy, and both upper and lower motor neuron signs, consistent with ALS. Notably, he developed two types of epileptic seizures during the disease course, including focal motor seizures and focal seizures evolving to bilateral tonic-clonic seizures. Electroencephalography revealed epileptiform discharges over the right frontotemporal region. Brain 18F-fluorodeoxyglucose positron emission tomography-computed tomography showed focal hypometabolism in the right frontal cortex. Genetic testing identified a de novo pathogenic FUS variant (c.1574C>T, p.Pro525Leu). The patient was diagnosed with FUS-ALS with comorbid focal epilepsy. Treatment with levetiracetam partially controlled the seizures, but motor function continued to deteriorate. This case highlights focal epilepsy as a comorbid feature in FUS-ALS, broadening the recognized phenotypic spectrum. Genetic testing for FUS mutations should be considered in young-onset ALS patients presenting with seizures.
    Keywords:  FUS gene mutation; amyotrophic lateral sclerosis; epileptic seizures; genetic testing; treatment
    DOI:  https://doi.org/10.1002/epi.70409
  19. J Neuromuscul Dis. 2026 Jul 25. 22143602261472982
    Cardiac autonomic dysfunction is associated with advanced stage, fast progression and poor survival in amyotrophic lateral sclerosis.
    Zehui Li, Jingjing Fan, Zhenxiang Gong, Jiahui Tang, Yuan Yang, Fengfei Ding, Li Ba, Mao Liu, Min Zhang.
      ObjectiveTo investigate the association of cardiac autonomic dysfunction with clinical staging and disease progression rate upon diagnosis of amyotrophic lateral sclerosis (ALS), and its impact on survival.Methods24-hour Holter was performed in 95 ALS patients at diagnosis and 39 controls. Patients were grouped by King's Clinical Staging and progression rate (ΔFS, median cut-off 0.67). Heart rate variability parameters were compared across groups. A survival-based cut-point optimization approach was used to determine the cut-off value of standard deviation of all normal-to-normal intervals (SDNN). Kaplan-Meier estimator and multivariable Cox regression analysis were used to evaluate of the effect of SDNN on survival during a median follow-up of 21.5 months.ResultsΔFS in ALS patients in King's Stage 4 upon diagnosis was faster (P=0.007) compared to that of those diagnosed in earlier stages, featuring a higher incidence of respiratory (P<0.001) and bulbar symptoms (P<0.001). In addition, ALS patients in King's Stage 4 exhibited elevated HR-min (P=0.007) and decreased RR intervals (RRI) (P=0.032), SDNN (P=0.004), and standard deviation of the averages of NN intervals in all 5-min segments (SDANN) values (P=0.020) compared to controls. Patients in the ΔFS-fast group had a higher HR-min than those in the ΔFS-slow group (P=0.013) and controls (P=0.003) and lower SDNN (P=0.018) than controls. Both Kaplan-Meier estimator (P=0.03) and multivariable Cox regression analysis (P=0.019) showed that lower SDNN (cut-off value: 111 ms) was associated with poor survival in ALS patients.ConclusionUpon diagnosis, ALS patients in King's Stage 4 and with faster disease progression demonstrated significantly diminished cardiac autonomic control. Lower SDNN was associated with poor survival in ALS.
    Keywords:  amyotrophic lateral sclerosis; autonomic nervous system; heart rate variability; progression rate; survival
    DOI:  https://doi.org/10.1177/22143602261472982
  20. Front Nutr. 2026 ;13 1790327
    Influence of micronutrients on anxiety and depression in patients with amyotrophic lateral sclerosis.
    Sandra Sancho-Castillo, Guillermo Bargues-Navarro, Ruth Gabriela Cárdenas Salazar, Jesús Privado, Elena Sanchis-Sanchis, David Sancho-Cantus, Claudia Emmanuela Sanchis-Sanchis, Laura Cubero-Plazas, Mónica Cano Mateu, José Enrique de la Rubia Ortí.
       Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor function, with respiratory failure representing the leading cause of death. Beyond motor deterioration, ALS involves extramotor manifestations, including prominent anxiety and depression symptoms. The intake of certain micronutrients has been associated with these emotional symptoms, due to their role in monoaminergic and peptidic neurotransmitter synthesis pathways; furthermore, these emotional symptoms can severely reduce patients' quality of life. Therefore, this study aims to analyze the relationship between the intake of key micronutrients related to neurotransmitter activity and anxiety and depression symptoms in ALS patients.
    Methods: A cross-sectional study was conducted with 61 patients with bulbar- or spinal-onset ALS. Dietary micronutrient intake (iodine, magnesium, vitamin B6, vitamin B9, and vitamin C) was assessed using a seven-day dietary record and a Food Frequency Questionnaire. Depression was assessed using the ALS Depression Inventory-12 (ADI-12), while anxiety-related symptoms were assessed using the Beck Anxiety Inventory (BAI).
    Results: A path analysis was conducted to examine the statistical prediction of emotional measures from nutrient intake. The model showed a good fit to the data: NFI = 1.000, GFI = 1.000, and SRMR = 0.001. Considering the magnitude of the effect of the regression weights (β ≥ 0.14), depression scores exhibited exploratory associations with iodine (β = -0.21) and magnesium (β = 0.22), while vitamin B9 (β = -0.32) emerged as an inferentially significant predictor (p < 0.05). Anxiety-related symptom severity (BAI scores) showed exploratory associations with iodine (β = -0.31), vitamin B6 (β = 0.24), and vitamin C (β = -0.15), whereas depression scores (β = 0.51) were an inferentially significant predictor (p < 0.05), with 41% of explained variance.
    Conclusion: In this sample, lower vitamin B9 intake was statistically associated with depression scores in patients with ALS, while lower iodine and higher magnesium intake showed exploratory associations. Regarding anxiety-related symptoms assessed using the Beck Anxiety Inventory (BAI), higher scores were statistically associated with lower iodine and vitamin C intake, higher vitamin B6 intake, and elevated depression scores, and showed exploratory associations with lower iodine and vitamin C intake, and higher vitamin B6 intake.
    Keywords:  amyotrophic lateral sclerosis; anxiety; depression; micronutrients; neurodegenerative disease
    DOI:  https://doi.org/10.3389/fnut.2026.1790327
  21. J Neuropsychol. 2026 Jul 28.
    Evidence of stage-specific cognitive reserve effects on longitudinal cognition in amyotrophic lateral sclerosis.
    Sara Simão, Miguel Oliveira Santos, Marta Gromicho, Isabel Pavão Martins, Mamede de Carvalho.
      About 50% of amyotrophic lateral sclerosis (ALS) patients develop cognitive-behavioural impairment, yet longitudinal studies diverge on onset and extent of decline. Cognitive reserve (CR) may modulate cognitive trajectories, although longitudinal evidence remains limited. We aim to characterize cognitive trajectories in ALS and healthy aging and to examine the role of CR proxies in shaping cognitive change over time. About 268 participants (169 patients, 99 controls) were evaluated twice over 6 to 18 months using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Mixed models were used to predict initial ECAS performance (ECAS1), and cognitive slope (ECAS2-ECAS1) using CR proxies (education, work and leisure), ECAS21-ECAS12 interval, demographics (age, sex, psychiatric medication) and clinical factors (disease duration, onset-region, respiratory capacity, functional decline, C9orf72 mutation and behavioural symptoms). In patients, education (p < .001) and leisure (p < .001) positively predicted ECAS1. However, longitudinally, education and leisure had negative main effects on cognition, protecting against decline through interactions with clinical variables. In controls, more education and leisure predicted better cognition through main effects and interactions. CR appears to exhibit a dynamic, phase-dependent influence in patients and controls, supporting initial cognitive performance and potentially offering subtle protection as disease progresses. The observed non-linear effects of all CR proxies and subgroup-specific effects highlight the importance of considering clinical context, time and initial cognition when evaluating CR's role in ALS.
    Keywords:  amyotrophic lateral sclerosis; cognition; cognitive reserve; healthy aging; longitudinal study
    DOI:  https://doi.org/10.1111/jnp.70066
  22. Neurol Res Pract. 2026 Jul 30. pii: 59. [Epub ahead of print]8(1):
    Ethical challenges in treatment-goal transitions in invasively ventilated ALS: a case-based topical review.
    Sarah K Bublitz, Benedikt Becker, Antonia F Demleitner, Petra Dietz-Laukemann, Paul Lingor, Benno Littger, Stefan Lorenzl, Berend Feddersen.
       INTRODUCTION: In advanced amyotrophic lateral sclerosis (ALS), eye movements often represent the last channel for intentional communication. While oculomotor function has traditionally been considered relatively preserved, emerging evidence indicates progressive impairment in long-term survivors on tracheostomy-invasive ventilation (TIV). As a result, eye-based communication may become increasingly unreliable before complete loss, challenging clinical decision-making and advance care planning (ACP).
    METHODS: We conducted a case-based topical review integrating clinical observation and literature to examine the trajectory of oculomotor decline, its impact on communication, and implications for treatment decisions. Three patients with ALS receiving TIV in a home-care setting illustrate key clinical and ethical challenges.
    RESULTS: Across cases and literature, oculomotor decline followed a gradual trajectory from effective eye-tracking communication to a complete locked-in syndrome. We identify a transitional phase of communicative ambiguity, in which residual ocular signals persist but can no longer be reliably attributed to intentional, patient-controlled communication. This phase is characterized by increasing inconsistency of signals and a divergence between observable responses and their interpretive certainty, creating uncertainty in assessing patient preferences.
    IMPLICATIONS: Communicative ambiguity represents a clinically underrecognized but critical threshold in advanced ALS, marking the transition from direct patient autonomy to interpretative and surrogate-based decision-making. Failure to recognize this phase risks misinterpretation of patient intent and may undermine goal-concordant care. Timely and iterative ACP, initiated before communication becomes unreliable, is essential. We further propose four clinical pathways for treatment goal conversations, highlighting their differing implications for timing, symptom burden, and ethical decision-making.
    Keywords:  Advance Care Planning; Amyotrophic Lateral Sclerosis; Communication; Decisional capacity; Moral distress; Tracheostomy-invasive ventilation
    DOI:  https://doi.org/10.1186/s42466-026-00522-3
  23. Int J Mol Sci. 2026 Jul 18. pii: 6388. [Epub ahead of print]27(14):
    Hirudin as a Therapeutic and Brain-Delivery Platform: From Stroke to Central Nervous System Disorders.
    Yufei Sun, Qiang Fu, Kunyao Deng, Hongjie Zhang, Zhong Zuo, Zhonggui He, Zhijun Yang.
      Crossing the blood-brain barrier (BBB) remains a central obstacle in central nervous system (CNS) therapeutics. Hirudin, a 65-amino acid, disulfide-stabilized, direct thrombin inhibitor with a long history in Traditional Chinese Medicine, has shown compelling efficacy in thrombotic disorders and mounting neuroprotective activity in preclinical stroke models, with supportive clinical signals. Although few studies have directly quantified its BBB permeability, available evidence indicates low but measurable brain exposure under pathological conditions, likely via paracellular leakage rather than receptor-mediated transport. To extend its therapeutic reach in cerebrovascular diseases and mitigate bleeding risk, researchers have engineered hirudin using nanocarrier encapsulation, hydrogel-based delivery systems, prodrug strategies, and other methods to enhance targeting, prolong half-life, and localize activation. These approaches also enable synergistic combinations with established CNS drugs and may facilitate delivery of co-therapeutics to the brain. This review synthesizes current evidence for hirudin in stroke, neurodegeneration, psychiatric disorders, and brain tumors; evaluates its context-dependent BBB access; and outlines a translational agenda centered on quantitative brain pharmacokinetics, pathology-guided targeting, stimulus-responsive formulations, controlled clinical evaluation, and rigorous management of bleeding risk and chemistry, manufacturing, and controls (CMC) readiness.
    Keywords:  CNS translational research; blood–brain barrier; drug delivery; hirudin; peptide therapeutics; stroke
    DOI:  https://doi.org/10.3390/ijms27146388
  24. Ann Neurol. 2026 Jul 30.
    Toward a Behavioral Reserve Model in Amyotrophic Lateral Sclerosis.
    Francesca Palumbo, Barbara Iazzolino, Cristina Moglia, Umberto Manera, Enrico Matteoni, Sara Cabras, Giorgio Pellegrino, Emilio Minerva, Vita Passidomo, Rosario Vasta, Gabriele Mora, Fabrizio D'Ovidio, Antonio Canosa, Andrea Calvo, Adriano Chiò.
       OBJECTIVE: Behavioral impairment is common in amyotrophic lateral sclerosis (ALS) and strongly affects autonomy, caregiver burden, and outcomes, yet predictors of vulnerability remain unclear. We investigated whether premorbid regulatory traits and socio-educational exposures are associated with behavioral phenotypes in ALS within a behavioral reserve framework.
    METHODS: We analyzed 965 consecutively assessed patients with ALS from a prospective tertiary-center cohort. Behavioral impairment was measured using the Frontal Systems Behavior Scale (FrSBe; family-rated before and after onset) and, in a subset (n = 633), the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). Theory-driven hierarchical logistic regression models tested associations between behavioral outcomes and premorbid behavioral regulation, education, occupation, and a Social Interaction Index, including interaction effects. Prespecified sensitivity analyses addressed potential bias in premorbid estimates.
    RESULTS: Premorbid behavioral regulation showed the strongest associations with behavioral impairment across all FrSBe models. Higher combined educational attainment and social exposure were associated with lower odds of impairment, with a significant interaction across multiple behavioral domains. These patterns persisted in restricted sensitivity analyses. Reserve proxies were not significantly associated with ECAS-CI total impairment, although domain-specific effects were observed.
    INTERPRETATION: These findings provide empirical support for a behavioral reserve framework in ALS, in which premorbid regulatory traits and socio-educational exposures are associated with behavioral vulnerability. Although causal inference is limited, reserve-related factors may contribute to non-motor heterogeneity in ALS and may inform future approaches to early behavioral risk stratification. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78315
  25. Neurol Int. 2026 Jul 21. pii: 139. [Epub ahead of print]18(7):
    Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models.
    Chih-Wei Zeng.
      Neurodegenerative diseases represent a major and growing global health burden. Although these disorders are often clinically defined by symptoms and affected brain regions, many are mechanistically linked to abnormal protein accumulation, misfolding, impaired proteostasis, RNA dysregulation, mitochondrial dysfunction, and neuroinflammation. In this Perspective article, I discuss major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, prion diseases, spinocerebellar ataxias, and spinal muscular atrophy, through the lens of disease-associated proteins and experimental modeling. I argue that a protein-centered framework provides a useful approach for understanding disease mechanisms and selecting transgenic mouse models, while recognizing that aging, cellular context, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and other disease modifiers also shape neurodegeneration. Transgenic and genetically engineered mouse models have been essential for dissecting the pathogenic roles of amyloid-β, tau, α-synuclein, TDP-43, SOD1, FUS, C9ORF72-associated dipeptide repeat proteins, mutant huntingtin, prion protein, ataxins, and SMN deficiency. However, these models have important limitations, including artificial overexpression, familial mutation bias, species differences, and incomplete representation of aging-related sporadic diseases. Rather than seeking a single "best" model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation. Such an approach may improve mechanistic insight, strengthen translational relevance, and enhance the predictive value of preclinical neurodegenerative disease research.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; TDP-43; amyotrophic lateral sclerosis; neurodegenerative diseases; neuroinflammation; proteinopathy; tau; transgenic mouse models; α-synuclein
    DOI:  https://doi.org/10.3390/neurolint18070139
  26. Pharmaceuticals (Basel). 2026 Jul 08. pii: 1053. [Epub ahead of print]19(7):
    Integrative Network Pharmacology and Molecular Docking Analysis Reveals the Multitarget Mechanisms of Pterostilbene in Neurodegenerative Diseases.
    Natalia Rosiak, Filip Stojceski, Gabriele Maroni, Bartosz Piontek, Judyta Cielecka-Piontek.
      Background: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), differ in etiology but share several convergent pathological mechanisms. Pterostilbene (PTR) is a natural stilbene with reported antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to prioritize putative PTR-associated targets and biological processes potentially relevant to shared neurodegenerative mechanisms. Methods: An integrative in silico workflow combining network pharmacology, protein-protein interaction (PPI) analysis, GO Biological Process (GO BP) enrichment, molecular docking, and molecular dynamics (MD) simulations was applied. GO BP terms were filtered, focused on neurodegeneration- and neuroprotection-related processes, and subjected to REVIGO-based redundancy reduction. Selected targets were further evaluated by docking and 500 ns MD simulations. Results: A total of 181, 165, 128, and 109 shared PTR-disease targets were identified for AD, PD, HD, and ALS, respectively. Redundancy-reduced GO BP analysis indicated associations with neuroinflammation, oxidative stress and reactive oxygen species-related responses, programmed cell death, MAPK/ERK- and PI3K/AKT-related signaling, ion and calcium transport, and lipid-, steroid-, or hormone-associated regulation. PPI topology prioritized SRC, ESR1, and HSP90AA1 as recurrent hub-bottleneck proteins, whereas MD-based structural interpretation focused on ESR1 and HSP90AA1. MD analyses indicated stable PTR interactions with both proteins, with ESR1 showing the most favorable predicted interaction profile. Conclusions: These findings suggest that PTR may interact with shared neurodegeneration-relevant molecular systems, particularly through ESR1- and HSP90AA1-associated mechanisms. However, the results are exclusively computational and should be interpreted as hypothesis-generating, requiring further experimental validation.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; molecular dynamics; network pharmacology; neuroprotection; pterostilbene
    DOI:  https://doi.org/10.3390/ph19071053
  27. Nat Med. 2026 Jul 27.
    Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.
    Ximing Ran, Joanne Wuu, Zhaohui S Qin, Michael P McDermott, Johnathan Cooper-Knock, Yindi Li, Volkan Granit, Anne-Laure Grignon, Elizabeth Lin, Maria Catalina Fernandez, Danielle Colato, Nathan Carberry, Christina M Lill, Paolo Piazza, Andrea Malaspina, Michael Benatar.
      The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6 years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.
    DOI:  https://doi.org/10.1038/s41591-026-04528-x
  28. Front Neurol. 2026 ;17 1879866
    A modified frailty index to identify high-risk groups for amyotrophic lateral sclerosis.
    Xuecai Gao, Sheng Chen, Sarwara Mahabub, Baokun Cao, Jiahe Deng, Weimin Ye, Haomin Yang, Zhangyu Zou.
       Background: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle weakness and poor prognosis, which requires early detection to optimize therapeutic outcomes. This study aims to develop a risk stratification tools for ALS and to assist in identifying high-risk groups.
    Methods: A prospective cohort study was conducted using the UK Biobank (500,033 participants), which were split into training sets and validation sets. We calculated the frailty index (FI) and modified frailty index (MFI) for the participants and estimated their association with ALS. Finally, two risk stratification tools were constructed and the time-dependent ROC curve was utilized to evaluate the discriminatory performance of each model.
    Results: Among the 49 deficits in FI, we identified five deficits that were significantly associated with ALS, including falls, whole-body pain, long-standing illness, disability or infirmity, self-rated health and tiredness or lethargy in last 2 weeks, which together constructed the MFI. Both the FI and MFI were associated with a higher risk of ALS (HRFI = 4.58, 95% CI = 1.31-16.07, HRMFI = 4.59, 95% CI = 2.79-7.53). Finally, a combination of MFI, gender, age and BMI demonstrated the best discriminative ability. Specifically, on the validation set, it achieved a C-index of 0.696.
    Conclusion: By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease. It could therefore serve as a valuable screening tool for risk stratification in the general population.
    Keywords:  ALS; UK Biobank; frailty; modified frailty index; risk stratification tools
    DOI:  https://doi.org/10.3389/fneur.2026.1879866
  29. Int J Mol Sci. 2026 Jul 16. pii: 6337. [Epub ahead of print]27(14):
    The Kynurenine Pathway: Unraveling Its Role in Neurological Disorders via Mammalian Cellular Models.
    Elizaveta S Podshivalova, Sergey I Kutsev, Aleksandr V Shestopalov.
      The kynurenine pathway (KP) constitutes the primary route of tryptophan catabolism, generating a spectrum of neuroactive metabolites that profoundly influence central nervous system function. Dysregulation of the KP is increasingly recognized as a critical pathogenic mechanism underlying diverse neuropathological conditions. This review critically evaluates the most widely cited mammalian cellular models currently utilized to delineate the causal role of KP alterations in neurological disease. Specifically, this article examines primary cell cultures, immortalized and tumor-derived cell lines, stem cell-derived systems, and ex vivo organotypic brain slices and tissues, highlighting their distinct methodological advantages, translational limitations, and specific enzymatic profiles. Across the described cellular systems, a recurring mechanistic theme emerges: quinolinic acid-driven mitochondrial dysfunction, oxidative stress, and NAD+ depletion converge in neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Conversely, kynurenic acid exhibits disorder-dependent-and at times opposing-roles, attenuating dopaminergic neurotoxicity in Parkinson's disease models while contributing to synaptic pruning deficits in schizophrenia models. Furthermore, cellular models demonstrate that IDO1/TDO induction and downstream metabolite shifts are frequently cell type- and species-dependent, complicating direct extrapolation to human pathology. Because no single experimental system achieves complete physiological fidelity, elucidating the complex dynamics of the KP and identifying novel therapeutic targets requires the integration of data across complementary platforms.
    Keywords:  cellular models; kynurenine pathway; neurodegeneration; neuroinflammation; neurotoxicity; tryptophan metabolism
    DOI:  https://doi.org/10.3390/ijms27146337
  30. Int J Pharm. 2026 Jul 31. pii: S0378-5173(26)00707-6. [Epub ahead of print] 127259
    Chitosan-based hydrogel for intranasal drug delivery; current advances in the brain diseases treatment.
    Omar Abouali, Aysan Mokabber, Saghi Naderpour, Elham Vojoudi, Farshid Sefat, Morvarid Saeinasab, Milad Rahimzadegan, Rahim Nosrati.
      Neurodegenerative diseases represent a growing health concern that is projected to become more prevalent and affect more people in the upcoming decades. One of the most complicated components of recent neurodegenerative disease therapies is the penetration and delivery of therapeutics to the central nervous system (CNS), which are hindered via the blood-brain barrier (BBB). In response, innovative treatment approaches leveraging noninvasive techniques including nanosized drug delivery systems and intranasal (IN) administration with higher treatment efficacy and patient satisfaction are developing as potential options. IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport. Among various IN platforms, chitosan (CS)-based hydrogels have attracted considerable attention because of their excellent biocompatibility, biodegradability, mucoadhesive properties, and ability to enhance drug permeation by prolonging nasal residence time and transiently modulating epithelial tight junctions. This review critically summarizes recent advances in CS-based hydrogels for IN drug delivery for the treatment of brain diseases including Alzheimer's disease (AD), Parkinson's disease (PD), depressive manifestations, ischemia,brain tumors,epilepsy, seizures, and schizophrenia. In addition, the review discusses the relationships between hydrogel design and therapeutic performance, highlights current translational challenges, and outlines future perspectives for the clinical development of CS-based IN hydrogel systems.
    Keywords:  Chitosan; Drug delivery; Hydrogel; Intranasal; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.127259
  31. Cureus. 2026 Jul;18(7): e113549
    Cellular Logistics and Synaptic Vesicle Vulnerability in Major Depressive Disorder and Amyotrophic Lateral Sclerosis Comorbidity: Insights From Nicotinamide Mononucleotide Rescue and Transcriptome-Wide Association Study Integration.
    Ngo Cheung.
       BACKGROUND: Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are usually treated as unrelated, yet depressive symptoms occur in a substantial minority of people with ALS and may appear early. These symptoms are heterogeneous and may reflect syndromal MDD, psychological and functional burden, fatigue, apathy, pseudobulbar affect, frontotemporal involvement, sleep or respiratory disturbance, medication effects, or shared affective vulnerability. A proposed pruning-continuum model suggests both disorders may share vulnerability in microglia-mediated synaptic pruning, with ALS amplified by autophagy and protein-quality-control failure and MDD by RNA-processing, stress, and immune dysregulation. We performed an exploratory secondary transcriptome-wide association study (TWAS)/pathway-integration analysis to test whether predefined nicotinamide mononucleotide (NMN)-nominated pathways map onto this vulnerability.
    METHODS: We integrated precomputed S-PrediXcan outputs for MDD and ALS across available brain-relevant tissues. Ten Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were predefined from a prior re-analysis of NMN-associated transcriptional programs in aged mouse metabolic tissues. Mouse-derived candidates were represented by human ortholog symbols before the human TWAS screen. The analysis tested nominated pathways rather than the 35-gene NMN-robust list as a standalone set. Cross-tissue screening used Stouffer Z aggregation, tissue-level Wilcoxon testing, competitive permutation testing, percentile bootstrap intervals, pairwise disease statistics, Levene variance tests, concordance measures, and leave-one-out sensitivity analysis. No analysis was treated as confirmatory or evidence of causal mediation.
    RESULTS: MDD showed the strongest Stouffer-based exploratory signal in the synaptic vesicle cycle pathway, with a meta-across-tissue Stouffer Z of 3.41 and a wide bootstrap 95% confidence interval of -0.46 to 7.40. This signal did not survive competitive permutation testing (p = 0.1222) or Wilcoxon testing (p = 0.1926). The strongest tissue-level result occurred in the amygdala (Z = 4.057; nominal Wilcoxon p = 0.0093), although tissue-level permutation testing was not performed in the multi-gene-set run. ALS showed no significant meta-across-tissue enrichment among the 10 nominated pathways but displayed candidate gene-level signals in autophagy, endosomal, and vesicle-related genes, including TBK1 and C9orf72. Exploratory Levene tests indicated variance heterogeneity in the regulation of the actin cytoskeleton, endocytosis, and neuroactive ligand-receptor interaction; the actin cytoskeleton and endocytosis remained significant in pooled global false discovery rate (FDR) analysis. Fourteen genes were influential in at least two focus pathways, including EGF, KNG1, FGF8, RAC1, PAK1, PAK2, RAF1, MAPK1, and FGFR1.
    CONCLUSIONS: These findings are hypothesis-generating. MDD and ALS may stress overlapping cellular logistics processes while engaging largely different genes. MDD showed the strongest exploratory pathway-level signal in synaptic vesicle biology, whereas ALS showed candidate gene-level coherence in autophagy and endosomal processes without significant meta-pathway enrichment. NMN/NAD+ repletion is not established as a treatment for MDD, ALS, or their comorbidity. These findings generate hypotheses about NAD+-linked cellular stress pathways for future preclinical and clinical studies.
    Keywords:  amyotrophic lateral sclerosis; autophagy; endocytosis; major depressive disorder; microglia; nad+; nmn; s-predixcan; synaptic pruning; synaptic vesicle cycle
    DOI:  https://doi.org/10.7759/cureus.113549
  32. RSC Med Chem. 2026 Jul 27.
    Peptide-drug conjugation: a strategy to address blood-brain barrier limitations in central nervous system diseases.
    Elvira Passalacqua, Giuseppe Barberi, Pietro Amico, Simona Di Martino, Maria De Rosa.
      Central nervous system diseases are among the most challenging to treat, mainly due to the blood-brain barrier, which restricts the entry of most therapeutics into the brain, preventing them from reaching pharmacological concentrations. Moreover, the multifactorial causes of these diseases require targeting diverse key processes. In this context, peptide-drug conjugates represent a promising strategy and offer a multitargeting regimen platform. In this work, we describe the latest developments of peptide-drug conjugates for glioma, Alzheimer's, and Parkinson's diseases, highlighting how conjugating payloads to specific peptides can offer several therapeutic advantages over conventional approaches. Particular emphasis was given to the chemical nature of the conjugation bonds and to the synthetic reactions to underscore the versatility of the methods used.
    DOI:  https://doi.org/10.1039/d6md00420b
  33. Neurotrauma Rep. 2026 Jan-Dec;7:7 2689288X261450846
    Traumatic Brain Injury and Risk of Amyotrophic Lateral Sclerosis Mortality: A Traumatic Brain Injury Model Systems Study.
    Yi Zhou, Charlotte B Luster, Shanti M Pinto, Evan D Feigel, Sabrina Paganoni, Saef Izzy, Ross D Zafonte, Joseph T Giacino, Flora M Hammond, Daniel H Daneshvar.
      Emerging evidence suggests that amyotrophic lateral sclerosis (ALS) mortality is elevated following traumatic brain injury (TBI), reflecting a consequence of potential prodromal ALS, though the temporal patterns and underlying mechanisms remain unclear. We aimed to evaluate ALS mortality among individuals with TBI and examine temporal patterns. This study leveraged a retrospective cohort study of 20,250 individuals with complicated mild-to-severe TBI enrolled in the TBI Model Systems (TBIMS) from 1987 to 2024, with a cumulative 198,662 person-years (mean [standard deviation] = 9.8 [7.1] years) of follow-up. Standardized mortality ratios (SMRs) were calculated using the National Institute for Occupational Safety and Health Life Table Analysis System R package, adjusting for age, sex, race, and calendar year. Secondary analyses evaluated temporal patterns and injury severity differences in ALS mortality. Among 4,313 decedents in TBIMS, 11 died of ALS, representing significantly elevated mortality from ALS (SMR = 2.39; 95% confidence interval [CI]: 1.19-4.27) compared with the general population. Time-stratified analyses showed elevated ALS mortality within 2 years post-injury (SMR = 4.30; 95% CI: 1.17-11.01), but not after 2 years (SMR = 1.90; 95% CI: 0.76-3.92). Elevated ALS mortality was also observed within 2 years post-injury among those with severe TBI (SMR = 5.00; 95% CI: 1.03-14.61) and when including individuals with ALS at admission (SMR = 6.45; 95% CI: 2.37-14.04). ALS mortality was higher in the TBIMS cohort than in the general population, and this association was confined to within 2 years of injury. This pattern suggests potential reverse causality, whereby some TBIs in the cohort may have occurred in the setting of prodromal or pre-symptomatic ALS. Further investigation into TBI as a sign of subclinical ALS is warranted.
    Keywords:  amyotrophic lateral sclerosis; epidemiology; traumatic brain injury
    DOI:  https://doi.org/10.1177/2689288X261450846
  34. JMIR Form Res. 2026 Jul 30. 10 e85142
    Digital Remote Assessment of Motor and Speech Changes in Amyotrophic Lateral Sclerosis: Longitudinal Observational Study.
    Katherine M Burke, Roland Brown, Narghes Calcagno, Anoopum S Gupta, Krzysztof Z Gajos, Zoe Scheier, Alison Clark, Amrita Iyer, Max P Higgins, Mackenzie Keegan, Timothy B Royse, Evan Remington, Kathryn P Connaghan, Stephen A Johnson, Sheena Chew, M Kelley Erb, James D Berry.
       Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an active trial landscape that relies on the sensitivity of selected clinical trial endpoints. Traditional clinical outcome assessments perform well in trials but lack strong psychometric properties and may not detect small but clinically meaningful disease progression. Digital health technologies offer a promising alternative for tracking ALS disease progression.
    Objective: This study assessed the feasibility of remote digital monitoring in ALS using a comprehensive battery of prescribed home-based assessments via a smartphone, a wearable device, and a computer-based mouse-clicking task.
    Methods: Participants completed weekly remote assessments, including motor and speech tasks via a smartphone app and a computer mouse-clicking task for 24 weeks. They also participated in 3 remote telephone visits in weeks 1, 13, and 25. Reliability, minimal detectable change, and correlations with self-reported ALS Functional Rating Scale-Revised subdomain scores were calculated for 8 features across the speech, fine motor, and gross motor smartphone app tasks and for all 32 features from the computer mouse-clicking task. Sensitivity to longitudinal change was assessed for the 8 smartphone-derived features and for a representative subset of 8 computer mouse-clicking features.
    Results: Forty-two participants (19 with ALS and 23 controls) completed 10,237 smartphone assessments and 459 computer mouse-clicking sessions. Baseline discriminative models differentiated ALS from controls with AUC values of 0.75-0.92. Digital measures correlated strongly with self-reported ALS Functional Rating Scale-Revised subdomain scores. Both participants with ALS and controls demonstrated improvement in fine motor and speech measures, with the exception of nondominant-hand pegboard performance, which declined in the ALS group. Improvements were smaller in participants with ALS, leading to increasing group differences over time, although only one feature showed a statistically significant separation over the 24 weeks. Gait and balance performance declined in both groups, with greater but nonsignificant separation observed for balance measures.
    Conclusions: These findings support the feasibility of digital remote assessments in ALS, demonstrate the ability to discriminate between ALS and controls based on certain features collected from speech, fine, and gross motor tasks, and in some cases, quantify functional decline over time. Further research is necessary to explore the natural history of these features longitudinally in larger cohorts of participants with ALS over extended periods to enable their potential integration into clinical trials.
    Keywords:  amyotrophic lateral sclerosis; digital health; motor function; remote monitoring; speech
    DOI:  https://doi.org/10.2196/85142
  35. bioRxiv. 2026 Jul 22. pii: 2026.07.20.738792. [Epub ahead of print]
    On-demand, reversible blood-brain barrier opening via electrical activation of piezoelectric nanoparticles for targeted brain drug delivery.
    Salona Roy, Umisha Siwakoti, Daniel Alday, Carlos Astete, Ethan McElveen, Ashok Sigdel, Fabio Del Piero, Cristina Sabliov, Elisa Castagnola, Qi Cai.
      Delivering therapeutics to the brain remains one of the most persistent challenges in medicine, because the blood-brain barrier (BBB) excludes over 98% of small-molecule drugs and virtually all biologics from the central nervous system (CNS). We developed electrical BBB modulation (eBBB), an on-demand platform combining vascular-targeting poly-L-lactic acid nanoparticles with high-definition transcranial direct current stimulation to achieve spatially and temporally controlled BBB opening. eBBB produced localized, reversible increases in BBB permeability confined to the stimulated cortex, with the opening area tunable via electrode geometry. This transient window enhanced regional delivery of a small-molecule drug, full-length immunoglobulins, and adeno-associated viral vectors, which are cargo classes otherwise completely excluded by the intact BBB. Neurovascular unit architecture was preserved with no lasting histological damage. Integrating a biodegradable nanomaterial with a clinically evaluated stimulation technology, eBBB offers a programmable, minimally invasive strategy for regional CNS drug delivery across brain malignancies and neurological disorders.
    One sentence summary: Electrical activation of piezoelectric nanoparticles reversibly opens the blood-brain barrier for minimally invasive drug delivery to targeted cortical regions.
    DOI:  https://doi.org/10.64898/2026.07.20.738792
  36. Biology (Basel). 2026 Jul 14. pii: 1145. [Epub ahead of print]15(14):
    Leaky Blood-Brain Barrier and Chronic Pain: The Neuroinflammatory Link.
    Mario García-Domínguez.
      Chronic pain represents a significant clinical challenge and is frequently associated with neuroinflammatory processes. The blood-brain barrier plays a central role in protecting the central nervous system by regulating the passage of molecules and immune cells from the periphery. Emerging evidence indicates that in chronic pain conditions, BBB integrity can be compromised, facilitating the infiltration of pro-inflammatory cytokines, immune cells, and neurotoxic mediators into the CNS. These changes contribute to microglial and astrocyte activation, enhancing central sensitization and the persistence of pain. Animal models and clinical studies suggest that mechanisms including tight junction disruption, oxidative stress, and matrix metalloproteinase release underlie this increased permeability. Understanding BBB modulation in chronic pain not only clarifies disease pathophysiology but also highlights potential therapeutic strategies aimed at preserving or restoring barrier integrity.
    Keywords:  blood–brain barrier; central sensitization; chronic pain; glial activation; neuroinflammation; neurovascular unit; tight junction disruption
    DOI:  https://doi.org/10.3390/biology15141145
  37. Muscle Nerve. 2026 Jul 28.
    Capturing Financial Burden Concerns in an ALS Multidisciplinary Clinic.
    Nikhita Pathapati, Minh Nguyen, Jaden Ju, Mahita Maddukuri, John Kiehl, Elizabeth Kvale, Aaron P Thrift, Sarah Berth, Astrid Grouls.
       INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is associated with substantial financial burden. How financial concerns are documented or addressed in ALS multidisciplinary clinics (MDC) is unclear. We aimed to characterize financial concerns among people living with ALS (pALS) and how they are identified and documented by multidisciplinary clinic staff.
    METHODS: We performed a retrospective electronic medical record (EMR) review for people living with ALS (pALS) attending at least two visits at the MDC, identifying documentation of financial concerns across all MDC notes throughout 2024. Semi-structured interviews with MDC staff explored experiences with financial concern discussions and documentation. Rapid qualitative analysis was used to analyze interview content.
    RESULTS: Among 67 pALS with at least 2 MDC visits, 45 (67.2%) had ≥ 1 documented financial concerns. Financial concerns were most documented in neurology physician notes and portal messages (both 77.8%) and included insurance denials, medication costs, disability/Medicare navigation, caregiving expenses, and home modifications. Social work and patient portal notes provided greater detail than other staff notes. Staff interviews highlighted insurance and equipment costs as frequent financial concerns. Four qualitative themes emerged: insurance challenges and reliance on non-insurance resources, financial barriers limiting care and quality of life, limited proactive conversations/documentation, and the central role of social work.
    DISCUSSION: Financial concerns are common among pALS but are inconsistently discussed and documented in the EMR, often arising through asynchronous communication or social work. Integrating financial screening and promoting proactive multidisciplinary documentation may improve identification of financial concerns and support more equitable, person-centered ALS care.
    Keywords:  amyotrophic lateral sclerosis; cost of care; financial concerns
    DOI:  https://doi.org/10.1002/mus.70364
  38. Biology (Basel). 2026 Jul 17. pii: 1176. [Epub ahead of print]15(14):
    Sex-Dependent Brain Plasticity in Neurological Disease: From Biological Variability to Adaptive, Compensatory, and Maladaptive Trajectories.
    Alessandro Avitabile, Dario Rusciano, Roberta Amato, Ludovica Cannizzaro, Caterina Gagliano.
      Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male-female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient's adaptive state.
    Keywords:  adaptive plasticity; adaptive reserve; biological sex; brain plasticity; compensatory plasticity; epigenetic regulation; maladaptive plasticity; mitochondrial function; neurodegeneration; neurodevelopment; neuroinflammation; rehabilitation; sex and gender; sex differences
    DOI:  https://doi.org/10.3390/biology15141176
  39. Eur J Neurol. 2026 Aug;33(8): e70720
    Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.
    Andrea Calvo, Cristina Moglia, Antonio Canosa, Umberto Manera, Rosario Vasta, Enrico Matteoni, Alessandra Maccabeo, Sara Cabras, Giorgio Pellegrino, Emilio Minerva, Anastasia Dei Giudici, Vita Passidomo, Francesca Palumbo, Barbara Iazzolino, Gabriele Mora, Adriano Chiò.
       OBJECTIVE: Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs).
    METHODS: Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3 months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria.
    RESULTS: Thirty-two PLS patients were included (mean disease duration, 25 months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia.
    INTERPRETATION: Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement.
    DOI:  https://doi.org/10.1111/ene.70720
  40. Cells. 2026 Jul 08. pii: 1232. [Epub ahead of print]15(14):
    Pathogenicity Classification of TARDBP Variants of Uncertain Significance: An Integrative Clinical Characterization and Functional Validation.
    Chao-Sen Yang, Yuan Ma, Jia-Li Xie, Xin-Yan Lou, Yong-Ting Lv, Tan-Xia Wu, Hai-Feng Xu, Sheng-Mei Zou, Zhi-Ying Wu, Hong-Fu Li.
      TAR DNA binding protein (TARDBP) is one of the major causative genes of amyotrophic lateral sclerosis (ALS), which drives disease progression through both gain-of-toxicity (GOT) and loss-of-function (LOF) mechanisms. The mutant TDP-43 exhibits aberrant nucleocytoplasmic distribution and forms cytotoxic hyperphosphorylated aggregates, a process that can be robustly recapitulated in vitro. Thus, functional assays in cell lines serve as a reliable metric for the pathogenicity classification of TARDBP variants. In this study, we performed in vitro experiments to classify the pathogenicity of 28 TARDBP variants of uncertain significance (VUS) among the 172 previously reported TARDBP variants. 22 of these VUS were determined to be functionally abnormal, of which 12 could be further classified as likely pathogenic (LP) variants according to American College of Medical Genetics (ACMG) and the ClinGen Sequence Variant Interpretation (SVI) Working Group guidelines. We also summarized the clinical characteristics of 35 ALS patients carrying 12 variants in the TARDBP gene. Pathogenic missense variants were predominantly clustered in the C-terminal domain (CTD) of TARDBP. Variants in TARDBP exon 6 may lead to an earlier age at onset. ALS caused by TARDBP mutations exhibits marked phenotypic heterogeneity, along with incomplete penetrance in carriers. Patient-derived primary skin fibroblasts serve as a feasible cellular model for the functional assessment of variant pathogenicity. Our findings expand the TARDBP mutation spectrum, and provides a preliminary basis for preclinical research on TARDBP-targeted therapies for ALS.
    Keywords:  TARDBP; amyotrophic lateral sclerosis; clinical characterization; functional validation; pathogenicity
    DOI:  https://doi.org/10.3390/cells15141232
  41. J Zhejiang Univ Sci B. 2026 Jul 15. pii: 1673-1581(2026)07-0715-21. [Epub ahead of print]27(7): 715-735
    Blood‒brain barrier permeability assessment: from biomimetic models to multimodal imaging.
    Miaomiao Wang, Lu Gan, Yiru Fan, Chenxi Duan, Ying Zhu, Shihua Luo, Yanhong Sun.
      The blood‒brain barrier (BBB) is a vital physiological structure that maintains the microenvironmental homeostasis in the central nervous system (CNS). Imbalances in its permeability play a key role in various neurological disorders, including stroke, neurodegenerative diseases, and brain tumors. The development of precise techniques for assessing BBB permeability is therefore paramount for elucidating the mechanisms of neurological diseases, overcoming drug development challenges, and achieving precise diagnosis and treatment of CNS disorders. This review systematically summarizes the latest advances in the assessment of BBB permeability. Regarding in vitro models, platforms have evolved from the traditional transwell system to microfluidic chips incorporating fluid shear forces and subsequently to highly biomimetic brain organoids, with continuous improvements in the ability to simulate the neurovascular unit (NVU) microenvironment. For in vivo assessment, we detail the principles and applications of imaging techniques, including dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), positron emission tomography (PET), near-infrared II (NIR-II) fluorescence imaging (FI), and two-photon microscopy (TPM), highlighting their complementary strengths in macroscopic quantification, molecular targeting, and microscopic dynamic observation. The integration of multi-modal technologies and precise quantitative assessment is a prominent trend. Future investigations will focus on artificial intelligence (AI)-driven personalized permeability assessment, the development of novel intelligent probes, and the dynamic real-time monitoring of the BBB, thereby providing powerful methodological support for neurological disease research.
    Keywords:  Blood‒brain barrier (BBB); Central nervous system (CNS); In vitro BBB model; In vivo imaging; Permeability assessment
    DOI:  https://doi.org/10.1631/jzus.B2500786
  42. Neurotherapeutics. 2026 Jul 27. pii: S1878-7479(26)00123-6. [Epub ahead of print]23(5): e00953
    Huoling Shengji granule in amyotrophic lateral sclerosis: A multicenter, randomized, double-blind, riluzole-controlled trial.
    Xiaolu Liu, Wencheng Fu, Xuanye Cui, Yi Feng, Bin Wen, Lei Shan, Xin Xu, Jian Yang, Jiquan Zhang, Lizhu He, Yingjun Zang, Shengchao Zhao, Xiaoli Yao, Yaling Liu, Mingming Ma, Baoxin Du, Jingxia Dang, Zhangyu Zou, Honglin Feng, Zuneng Lu, Yong Zhang, Zhiying Wu, Huifang Shang, Ping Yin, Dongsheng Fan.
      Currently, no curative therapies exist for Amyotrophic Lateral Sclerosis (ALS). This study aimed to evaluate the efficacy and safety of Huoling Shengji granules (HLSJ), a traditional Chinese medicine (TCM), compared to the standard treatment riluzole. A multicenter, randomized, double-blind, double-dummy, active-controlled Phase II clinical trial was conducted across 11 centers in China. A total of 140 ALS patients were randomly assigned (1:1) to receive either HLSJ or riluzole for 48 weeks. The primary endpoint, analyzed in the full analysis set (FAS), was the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score from baseline to Week 48. Safety profiles were comparable between groups, with no significant difference in adverse events (80.28% vs. 80.56%, P = 0.9671). Analysis using the pre-specified Last Observation Carried Forward (LOCF) method showed a numerical advantage for HLSJ (1.07 points) but lacked statistical superiority. However, a more scientific analysis using the Mixed Model for Repeated Measures (MMRM), recommended for progressive diseases, indicated that HLSJ was significantly superior to riluzole in slowing ALSFRS-R score decline (Least Squares Mean Difference [LSMD]: 2.29 points; 95% confidence interval [CI]: 0.52 to 4.06; P = 0.0114). While the LOCF model showed no statistical difference, the MMRM analysis confirmed that HLSJ demonstrated significant efficacy superior to riluzole with a favorable safety profile. These findings provide a critical basis for conducting pivotal Phase III confirmatory trials of HLSJ for ALS treatment.
    Keywords:  ALSFRS-R; Amyotrophic lateral sclerosis; Huoling Shengji granules; Phase II clinical trial; Riluzole; Traditional Chinese medicine formula
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00953
  43. Cells. 2026 Jul 17. pii: 1287. [Epub ahead of print]15(14):
    Mediterranean Diet and Neurodegenerative Diseases: Recent Advances from the Gut-Immune-Brain Axis to Multi-Omics-Guided Precision Nutrition.
    Jiaxing Dou, Jiahui Wang, Shihan Chen, Elizabeth B Hsueh, Isabella L Scott, Feng Xue.
      Neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) are regarded as systemic illnesses, mainly characterized by long-term neuroinflammation, metabolic dysregulation and barrier dysfunction. All these factors interact through the gut-immune-brain axis. The Mediterranean diet, rich in plant-based foods, olive oil, and fish, has been consistently associated with slower cognitive decline and reduced risk of neurodegeneration in observational studies and some clinical trials. This review provides a systems-level synthesis that distinguishes itself from previous narratives by integrating disease-specific mechanistic frameworks with multi-omics-guided precision nutrition strategies. We summarize recent evidence showing that this dietary pattern can remodel gut microbiota composition and enhance the production of bioactive metabolites such as short-chain fatty acids (SCFAs). These metabolites are associated with improved intestinal barrier integrity, reduced systemic inflammation, and potential modulation of brain functions. Within the central nervous system, diet-related metabolites have been linked to reduced neuroinflammation via modulation of microglial and astrocytic states. They have been linked to protection of mitochondrial function, maintenance of proteostasis, and preservation of blood-brain barrier (BBB) integrity. In AD and PD patients, adherence to this diet is associated with favorable changes in pathological hallmarks, including amyloid-beta (Aβ), tau, and α-synuclein accumulation. Nowadays, multi-omics tools, including single-cell transcriptomics, spatial transcriptomics and microbiome analysis, are widely used in this field, which helps researchers explore these complicated effects more deeply. Importantly, individual responses to the diet vary considerably due to differences in genetic background, gut microbial composition, and metabolic phenotypes, which underscore the need to move from generalized dietary guidelines toward personalized precision nutrition. The Mediterranean diet is not only a dietary pattern but also an effective way to modulate neuro-immune and metabolic networks. However, current evidence remains largely observational, and we critically discuss the need for more randomized controlled trials (RCTs) and standardized multi-omics data analysis frameworks. To sum up, the Mediterranean diet plays a neuroprotective role via the gut-immune-brain axis, and multi-omics techniques promote the development of precision nutrition. More trials and improved multi-omics systems are required to apply these research results in clinical practice.
    Keywords:  gut microbiota; gut–immune–brain axis; mediterranean diet; multi-omics; neurodegenerative diseases; neuroinflammation; precision nutrition; systems biology
    DOI:  https://doi.org/10.3390/cells15141287
  44. Metab Brain Dis. 2026 Jul 31. pii: 179. [Epub ahead of print]41(1):
    Polysaccharide-driven gut microbial metabolism in neurodegenerative brain diseases: from SCFAs and tryptophan catabolites to neuroinflammatory regulation.
    Chengqi Peng, Lingxiao Chen, Zongyao Wu, Cizhen Danzeng, Xiaorui Cheng.
      The gastrointestinal tract constitutes the principal anatomical interface of the microbiota-gut-brain axis (MGBA), orchestrating neuroimmune and metabolic crosstalk. Dysregulation within this network drives neurodegenerative pathogenesis through altered microbial metabolism, peripheral immune activation, and subsequent aggregation of pathological proteins in the central nervous system (CNS). Natural bioactive polysaccharides modulate this axis primarily via indirect, microbiota-dependent mechanisms-acting as fermentable prebiotics that reshape gut ecology and metabolite profiles-rather than through direct CNS penetration of intact macromolecules. These macromolecules promote neuroprotective short-chain fatty acids (SCFAs) that reinforce mucosal and blood-brain barrier (BBB) integrity. At the molecular level, polysaccharide interventions attenuate the TLR4/NF-κB/NLRP3 inflammatory cascade and upregulate Nrf2/BDNF neurotrophic signaling, effects predominantly mediated by microbiota-derived metabolites and peripheral-to-central signaling, with limited evidence for direct CNS entry of low-molecular-weight fractions. This review evaluates the pharmacological mechanisms of natural polysaccharides in neurodegenerative disorders, focusing on microbe-derived metabolic regulation, immune homeostasis, and clearance of neuropathological aggregates. While preclinical efficacy is promising, clinical translation demands rigorous structure-activity relationship mapping and specialized targeted delivery platforms.
    Keywords:  MGBA; Mechanism; Natural bioactive polysaccharides; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s11011-026-01946-1
  45. Sports Med. 2026 Jul 27.
    Exercise and Pain in Multiple Sclerosis, Parkinson's Disease, Alzheimer's Disease, and Stroke: A Systematic Review and Meta-analysis.
    Victor Kornum Baccaro, Lars G Hvid, Rasmus C Jungersen, Martin Langeskov-Christensen.
       BACKGROUND: Pain affects up to 85% of people living with common neurodegenerative diseases, yet evidence on the analgesic effects of exercise remains limited. This systematic review and meta-analysis examined whether exercise reduces pain in people with multiple sclerosis (MS), stroke, Parkinson's disease (PD), and Alzheimer's disease (AD).
    METHODS: A systematic search was conducted across six databases (PubMed, Embase, Cochrane Library, PEDro, CINAHL, and SPORTDiscus) from November 2024 up to November 2025 to identify randomized controlled trials examining the effects of exercise (across different modalities) on pain (across different outcomes) in MS, stroke, PD, or AD. Qualitative and quantitative analyses were performed. Quality was assessed using TESTEX.
    RESULTS: A total of 39 studies were identified, of which 36 were included in the meta-analyses. The overall meta-analysis showed that exercise substantially reduced pain in people with neurodegenerative diseases compared with control conditions (- 0.83 [- 1.10; - 0.57], standardized mean difference [95% CI]). Large comparable effects were observed in MS (22 studies; - 0.63 [- 0.89; - 0.38]) and stroke (12 studies; - 1.07 [- 1.63; - 0.52]). Only one eligible study was found for PD and AD, respectively, highlighting a critical gap in the literature.
    CONCLUSIONS: This review provides strong evidence that exercise alleviates pain in people with MS and stroke and emphasizes its potential as a non-pharmacological analgesic strategy for managing pain in neurodegenerative diseases. More high-quality studies are needed, particularly in PD and AD.
    TRIAL REGISTRY: PROSPERO (CRD42024583498).
    DOI:  https://doi.org/10.1007/s40279-026-02490-9
  46. Neuroimage Clin. 2026 Jul 27. pii: S2213-1582(26)00103-8. [Epub ahead of print]51 104044
    Plasma volume fraction in drug-resistant epilepsy: A DCE-MRI marker of microvascular pathology.
    Amirhossein Talebanpour, Sheida Mirloo, Alireza Aleali, Lyna Kamintsky, Yonatan Serlin, Nir Cafri, Ilan Goldberg, Chris Bowen, Gal Ben-Arie, Theodor Rüber, Felix Benninger, Ben Whatley, Alon Friedman.
       OBJECTIVES: Microvascular remodeling and blood-brain barrier dysfunction (BBBD) are increasingly recognized as contributors to epilepsy. However, commonly used vascular imaging markers are often state-dependent and lack spatial specificity. We aimed to (1) validate plasma volume fraction (vₚ) derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a sensitive marker of microvascular changes; (2) characterize the vₚ alterations in patients with drug-resistant epilepsy (DRE); and (3) assess the spatial relationship between vₚ abnormalities and BBBD.
    METHODS: We analyzed DCE-MRI images from 49 people with epilepsy (PWE) and 68 healthy controls across two sites. vₚ and BBB permeability were quantified using BBBdetect software. Voxel-wise vₚ was estimated using the extended Tofts model, and BBBD was quantified using slope-based permeability mapping. Both measures were summarized using modified z-scores, with suprathreshold abnormality defined as modified z-score > 2. We performed region-wise and lobe-wise analyses restricted to gray matter and trained supervised classifiers to distinguish PWE from controls using regional z-vₚ and z-BBBD features.
    RESULTS: Compared with controls, PWE showed increased voxel-wise and region-wise vₚ abnormality burden, with a non-uniform spatial pattern that includes prominent fronto-temporal elevations and frequent involvement of limbic regions. BBBD was common and spatially diffuse. Restricting analysis to regions with co-occurring suprathreshold vₚ and BBBD reduced spatial diffuseness relative to BBBD alone. Multivariate classification achieved encouraging test performance using vascular and barrier features (balanced accuracy = 0.81), with feature importance suggesting complementary contributions from vₚ and BBBD.
    CONCLUSION: vₚ is a sensitive DCE-MRI-derived marker of microvascular abnormalities in DRE. Integrating vₚ with BBBD enhances the spatial specificity of abnormality patterns and shows encouraging concordance with the clinically suspected epileptogenic territories, warranting prospective validation against clinical reference standards.
    Keywords:  Blood-brain barrier dysfunction (BBBD); Drug-resistant epilepsy (DRE); Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); Epileptogenic zone localization; Microvascular remodeling; Plasma volume fraction (vₚ)
    DOI:  https://doi.org/10.1016/j.nicl.2026.104044
  47. CNS Neurol Disord Drug Targets. 2026 Jul 25.
    Endothelial-to-mesenchymal Transition at the Blood-brain Barrier: Molecular Mechanisms and Pathological Roles Across Brain Diseases.
    Nur Iffah Ishak, Rosfaiizah Siran, Wan Nor I'zzah Wan Mohamad Zain, Nasibah Azme.
      Endothelial-to-Mesenchymal Transition (EndMT) is a significant contributor to Blood- Brain Barrier (BBB) dysfunction in various brain diseases. The majority of current therapies, aimed at reducing BBB dysfunction, focus on preventing inflammation or stabilizing tight junctions. In most cases, these therapies do not provide adequate or long-lasting vascular protection. Endothelial cells undergo phenotypic programming, losing their barrier-forming capacity and developing features of mesenchymal and extracellular matrix-producing cells as the disease progresses. The change leads to chronic vascular leakage, neuroinflammation, microvascular fibrosis, and dysfunctional neurovascular coupling. Several upstream stimuli, including inflammatory cytokines, TGF-β/BMP-Smad signaling, and oxidative damage, converge to drive EndMT within the distinctive, specialized environment of the brain endothelium. Ischemic stroke, multiple sclerosis, cerebral cavernous malformations, arteriovenous malformations, glioblastoma, brain metastasis, and Alzheimer's disease indicate that EndMT is not a rare or unique process but a shared and common pathologic process that may result in disease progression and eventual resistance to treatment. Recent single-cell and spatial transcriptomic data have shown that partial EndMT states exist and may be precursors to irreversible microvascular remodeling. It is necessary to identify therapeutic approaches that go beyond short-term stabilization of the BBB and target the molecular programs underlying the loss of endothelial identity. This review synthesizes mechanistic, disease-related, and therapeutic evidence indicating that EndMT is a leading cause of BBB failure and highlights therapeutic opportunities for targeting this endothelial plasticity in brain diseases.
    Keywords:  Endothelial to mesenchymal transition; blood-brain barrier; brain diseases; pathology; therapeutic; vascular remodeling
    DOI:  https://doi.org/10.2174/0118715273485479260721072747
  48. bioRxiv. 2026 Jul 13. pii: 2026.07.08.737381. [Epub ahead of print]
    Supplementation via DAF-16 and pnk-1 driven pantothenate-coenzyme A flux improves disease related stress resistance in C. elegans.
    Steffi M Jonk, Alan Nicol, Alex Braun, Wenry Wang, James R Tribble, Peter Swoboda, Pete A Williams.
      Metabolic pathways are increasingly recognized as tractable targets in aging and disease. Building on prior work demonstrating that supplementation with low-molecular weight metabolites (amino acids, vitamins, and their intermediates) can extend lifespan in Caenorhabditis elegans , we focused on pantothenate (vitamin B 5 ), which is dysregulated in sarcopenic muscle and in several neurodegenerative and metabolic disorders. Pantothenate is the obligate precursor of coenzyme A through a short, highly conserved biosynthetic pathway in which loss-of-function mutations can cause neurodegeneration with brain iron accumulation. In C. elegans , the longevity curtailing transcription factor DAF-16/FOXO has a conserved binding element in the promoter region of pnk-1 , encoding the first enzyme (PNK-1) in the coenzyme A pathway, and pnk-1 is markedly upregulated in long-lived daf-2 (insulin/-like receptor) mutants, implicating coenzyme A metabolism in longevity. Here, we demonstrate that CoA levels naturally increase during early life and decrease towards older age in C. elegans . Dietary pantothenate supplementation increases coenzyme A levels with minimal effects on lifespan but systemic effects on lipid metabolism, mitochondrial dynamics, and muscle structure under basal conditions. Under DAF-16-associated stress conditions, including heat and oxidative stress, pnk-1 expression is upregulated and pantothenate supplementation robustly extends lifespan and improves mobility. Finally, we demonstrate dysregulation of daf-16 and pnk-1 expression in amyotrophic lateral sclerosis (ALS) models, in which pantothenate supplementation confers both lifespan extension and cholinergic neuroprotection.
    DOI:  https://doi.org/10.64898/2026.07.08.737381
  49. Adv Sci (Weinh). 2026 Jul 28. e76625
    A Phosphorylation-Induced Micellization Switch in the Low-Complexity Domain of TDP-43.
    Rodrigo F Dillenburg, Anastasia Lopatina, Hao Ruan, Tom Scheidt, Simone Mosna, Emre Pekbilir, Julia Bieber, Frank Schäfer-Depoix, Katharina Landfester, Carla Schmidt, Martin M Möckel, Svenja Morsbach, Friederike Schmid, Dorothee Dormann, Lukas Stelzl, Martin Girard, Edward A Lemke.
      Phase separation (PS) of the low-complexity domain (LCD) of TAR DNA-binding protein 43 kDa (TDP-43) is linked to pathogenic aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). Here, we show that extensive phosphorylation of the LCD C-terminus redirects its self-assembly. Coarse-grained Monte Carlo simulations predicted that 12 Ser phosphorylations partition the 148-residue LCD into a hydrophobic N-terminal and highly charged C-terminal block, favouring finite-sized micellization over macroscopic PS. In vitro, LCD phosphorylated by casein kinase 1 delta (CK1δ; mean of 12 phosphorylations by native mass spectrometry) and phosphomimetic 12D/12DD mutants formed spherical nanoparticles (≈ 20-50 nm) above a low-micromolar critical micelle concentration, whereas the unphosphorylated LCD underwent reversible PS that matured into fibrils. Increasing ionic strength shifted the mutants toward anisotropic morphologies (wormlike 12D micelles and rigid 12DD nanocylinders). Turbidity assays and confocal imaging directly visualized the absence of PS in the phosphorylated form. Negative-stain and cryo-electron microscopy (cryo-EM) confirmed the spherical micellar architecture for the phosphorylated LCD and 12D/12DD mimics. Our data identify phosphorylation as a molecular switch tuning macrophase separation and fibril formation of TDP-43 LCD, providing a framework for an aggregation-protective role through microphase separation into size-limited micelles. Whether these assemblies are stable or kinetically trapped on pathological timescales remains unclear.
    Keywords:  TDP‐43; intrinsically disordered proteins; low‐complexity domain; micellization; micro phase separation; protein phosphorylation; wormlike micelles
    DOI:  https://doi.org/10.1002/advs.76625
  50. Neurology. 2026 Aug 25. 107(4): e218303
    Association of Military Branch and Rank With Amyotrophic Lateral Sclerosis Incidence Among United States Veterans.
    Andrea L Roberts, Alexandre D Vilela Braga, Ian W Tang, Ran S Rotem, Lauren R Moo, Donald R Miller, Steven D Shirk, Marc G Weisskopf.
       BACKGROUND AND OBJECTIVES: Military service is one of the most consistent risk factors for the development of amyotrophic lateral sclerosis (ALS), but little is known about what aspects of military service matter. Understanding the distribution of ALS risk in military personnel may help identify key risk factors. We aimed to ascertain the association of United States (US) military branch and rank with incident ALS.
    METHODS: We conducted a longitudinal cohort study including all veterans with a Veterans Health Administration encounter from January 1, 2000, through October 1, 2024, and more than 2 years of follow-up. Incident ALS was identified through medical records. Exposures included military branch (Army, Navy, Air Force, Marine Corps, Coast Guard, or multiple branches), military rank (officer, enlisted, or both), and length of service. Risk was estimated with Cox proportional hazards models, controlled for age, adjusted for race/ethnicity, and stratified by sex.
    RESULTS: The analytic sample comprised 9,157,938 men (13,935 incident ALS cases, mean age = 56.9 years) and 784,941 women (484 cases, mean age = 42.4 at start of follow up). Among men, compared with service in the Army, service in the Air Force (hazard ratio [HR] = 1.29, 95% CI 1.23-1.35), Navy (HR = 1.15, 95% CI 1.10-1.20), and Coast Guard (HR = 1.26, 95% CI 1.06-1.50) was associated with higher rates of ALS and service in the Marines a lower rate (HR = 0.78, 95% CI 0.68-0.88). Officers had higher rates than enlisted personnel (men, HR = 1.64, 95% CI 1.53-1.74; women, HR = 1.72, 95% CI 1.31-2.27). Longer service was associated with lower rates of ALS. In age-stratified models, differences in hazard rates between Army veterans and Air Force, Navy, and Coast Guard veterans were greatest for the youngest men (17-61 years, HR range = 1.26 to 1.51) and smallest for the oldest (>75-104 years, HR range = 0.99 to 1.12).
    DISCUSSION: ALS rates varied considerably by branch and rank in the US military, with larger differences among younger veterans. Officers and those serving in the Air Force, Navy, or Coast Guard may incur exposure to military environments that increase risk of ALS. It is imperative to identify relevant exposures to reduce harm to service members and, potentially, civilians with similar exposures.
    DOI:  https://doi.org/10.1212/WNL.0000000000218303
  51. Pharmaceutics. 2026 Jul 20. pii: 885. [Epub ahead of print]18(7):
    Feasibility Study of Nose-to-Brain Delivery of Galantamine for Alzheimer's Disease: Enhancing Olfactory-Region Deposition to Improve Therapeutic Efficacy.
    Chuangxin Chen, Chunying Leung, Zizhao Zhai, Guanlin Wang, Rui Yang, Qiuyi Hu, Xiao Yue, Zhongxuan Yao, Ziyu Zhao, Xuejuan Zhang.
      Background: Alzheimer's disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood-brain barrier (BBB). Nose-to-brain delivery represents a promising route to bypass the BBB. However, its efficiency remains limited by insufficient drug deposition in the anatomically restricted olfactory region. In this study, we developed a galantamine nasal spray (GNT-NS) with enhanced olfactory region deposition and evaluated its feasibility for nose-to-brain delivery in AD treatment. Methods: We optimized the formulation by systematically investigating the cascade relationship among formulation physicochemical properties, spray performance, and olfactory region deposition. Nasal deposition distribution was quantitatively evaluated using a physiologically realistic 3D-printed human nasal cavity model reconstructed from clinical magnetic resonance imaging (MRI) data. Further, the in vivo biodistribution and therapeutic efficacy of GNT-NS were evaluated in AD rats. Results: The optimized formulation P3 achieved an olfactory region fraction of 23.85%, markedly exceeding that of the unoptimized formulation P0. Subsequent in vivo biodistribution studies showed that P3 produced higher brain drug exposure than both intranasally administered P0 and the commercial oral formulation. Further pharmacodynamic studies demonstrated that GNT-NS significantly improved cognitive and behavioral deficits in AD rats, exhibiting superior therapeutic efficacy over commercially available oral galantamine tablets. Conclusions: Collectively, this study proposes a cascade regulation strategy linking formulation physicochemical properties, spray performance, and olfactory region deposition and demonstrates that optimizing nasal spray properties can enhance olfactory deposition, increase brain exposure and improve therapeutic efficacy. These findings provide a useful reference for the design of nose-to-brain delivery formulations for AD and other central nervous system diseases.
    Keywords:  Alzheimer’s disease; galantamine; nose-to-brain drug delivery; olfactory deposition; spray performance
    DOI:  https://doi.org/10.3390/pharmaceutics18070885
  52. Small. 2026 Jul 28. e74841
    Boosting Drug Permeability Across the Blood-Brain Barrier Through Supramolecular Macrocyclization.
    Wei-Bin Lin, Pei Yu, Batoul Maatouk, Yanying Li, Lukman O Alimi, Basem A Moosa, Gengwu Zhang, Niveen M Khashab.
      Blood-brain barrier (BBB) precisely regulates substance influx and efflux to maintain brain homeostasis and function. Effective CNS targeted therapy necessitates precise cellular targeting and efficient drug delivery across the BBB, which current treatments often fail to achieve. Herein, we report a streamlined one-step macrocyclization strategy for the synthesis of phenothiazine-based macrocycles with enhanced BBB permeability. The macrocyclization process fosters synergistic supramolecular interactions within the macrocyclic cavity, thereby improving BBB permeability and enhancing cellular uptake. As a proof-of-concept, these macrocycles exhibited enhanced anti-glioblastoma (GBM) activity that not only surpassed their small-molecule counterparts but also outperformed a wide range of existing chemotherapeutics and nanomaterials. From a supramolecular perspective, the chemically driven one-step conversion of phenothiazine units into supramolecular macrocycles provides a promising framework for reengineering conventional small-molecule drugs into advanced next-generation therapeutic agents with enhanced BBB permeability and pharmacological properties.
    Keywords:  anti‐glioblastoma; blood‐brain barrier crossing; macrocyclization‐enhanced; organic macrocycles; supramolecular interactions; synergistic effect
    DOI:  https://doi.org/10.1002/smll.74841
  53. Molecules. 2026 Jul 18. pii: 2514. [Epub ahead of print]31(14):
    Intestinal and Blood-Brain Barrier Dysfunction in Lupus: Emerging Mechanisms and Modulation by Cinnamon.
    Georges Maalouly, Georges-Alain Al Tekle, Grisselle Al Achkar, Nassim Fares.
      Systemic lupus erythematosus (SLE) is a complex autoimmune disease with evolving pathogenesis. Biological barriers, especially intestinal and blood-brain barriers (BBBs) with their tight junctions (TJ), are gaining attention in recent years as key players in disease initiation and progression. Among natural products targeting these barriers, cinnamon is emerging as a multi-targeted modulator of TJ. This narrative review integrates current evidence about gut and brain barrier dysfunction in lupus pathogenesis and highlights, on the basis of animal studies, the potential of cinnamon as a therapeutic candidate to restore barrier integrity and attenuate immune and neuroinflammation associated with lupus. Experimental evidence from lupus models supports the role of TJ disruption in disease pathogenesis. The alteration of TJ protein distribution in the epithelial barrier is correlated with an increased permeability of the intestinal barrier and changes in the microbiota composition in lupus, with consequent alteration in the gut-liver axis, liver inflammation and oxidative stress. Pre-clinical studies have demonstrated the restorative effect of cinnamon on gut TJ and permeability, microbiota and the gut-liver axis. Moreover, accumulating data suggest BBB disruption in lupus, correlated with neuroinflammation and behavioral disturbances. A murine model demonstrates the protective effect of cinnamon on BBB, especially via TJ localization, with the alleviation of neuropsychiatric alterations. Future perspectives should focus on cinnamon's effect on the gut-brain axis and translational studies.
    Keywords:  blood–brain barrier; cinnamon; gut permeability; lupus; natural compounds; tight junction
    DOI:  https://doi.org/10.3390/molecules31142514
  54. Eur J Neurol. 2026 Aug;33(8): e70711
    Predictors of Multiple Sclerosis After Clinically Isolated Syndrome: A Systematic Review and Meta-Analysis.
    María Paula Zafra-Sierra, Carolina Ferreira-Atuesta, Daniela Sofía Rodríguez, Jairo Gaitán, Susana Otero, Mar Tintoré, Fred Lublin, Gavin Giovannoni, Jaime Toro, Saúl Reyes.
       BACKGROUND: Most people with multiple sclerosis (MS) present with a clinically isolated syndrome (CIS); however, not all individuals with CIS are subsequently diagnosed with MS.
    METHODS: A systematic literature review was conducted until December 2025. Observational studies of adults with CIS that were later diagnosed with MS were included. Odds ratios (ORs) were pooled using random-effects meta-analysis. Heterogeneity was assessed with I2, sensitivity analyses with leave-one-out procedures, and publication bias with funnel plots and Egger's test. Meta-regression was performed to explore further sources of heterogeneity when appropriate.
    RESULTS: Seventy-two studies with 9915 adults were included. In the meta-analysis, younger age (OR = 1.6, p < 0.01) and multifocal presentation (OR = 1.55, p = 0.02) were associated with a diagnosis of MS after a CIS. Magnetic resonance imaging findings, including a higher number of T2 lesions (OR = 7.46, p = 0.02), periventricular lesions (OR = 4.08, p < 0.01), corpus callosum lesions (OR = 14.89, p = 0.02), infratentorial lesions (OR = 2.16, p = 0.03), spinal cord lesions (OR = 1.4, p = 0.03), and gadolinium-enhancing lesions (OR = 1.91, p = 0.01), as well as cerebrospinal fluid inflammatory markers such as oligoclonal bands (OR = 3.57, p < 0.01) and pleocytosis (OR = 3.34, p = 0.02), were also associated with a subsequent diagnosis of MS.
    CONCLUSIONS: This meta-analysis identified factors associated with an increased likelihood of MS after a CIS. These findings may help identify high-risk individuals and guide personalized treatment strategies.
    Keywords:  clinically isolated syndrome; multiple sclerosis; progression; risk factors
    DOI:  https://doi.org/10.1111/ene.70711
  55. medRxiv. 2026 Jul 22. pii: 2026.07.21.26358569. [Epub ahead of print]
    The value of brain age as a transdiagnostic biomarker of neurodegeneration.
    Lonneke Bos, David R van Nederpelt, James H Cole, Bas Jasperse, Alle Meije Wink, Mario Tranfa, Eva Strijbis, Joep Killestein, Bernard M J Uitdehaag, Frederik Barkhof, Hugo Vrenken, Menno M Schoonheim, Giuseppe Pontillo.
      Progressive structural brain changes are a hallmark of neurodegenerative conditions like Alzheimer's disease (AD), frontotemporal dementia (FTD), multiple sclerosis (MS), and Parkinson's disease (PD). The brain-predicted age difference (brain-PAD) has emerged as a promising biomarker to quantify these alterations, yet its unique clinical contribution relative to conventional measures of global brain atrophy such as the brain parenchymal fraction (BPF) remains underexplored. In this transdiagnostic study across AD, FTD, MS, and PD, we systematically evaluated brain-PAD's capacity to distinguish patients from controls, its cross-sectional and longitudinal associations with cognition, and its voxel-wise structural correlates. We benchmarked brain-PAD against BPF to determine its added explanatory value. Brain-PAD successfully distinguished patients from controls, adding to BPF alone, in AD, FTD, and MS, but not PD. Across disorders, higher brain-PAD correlated with worse cognition, showing clear added value beyond BPF particularly in AD and MS. Baseline brain-PAD also independently predicted subsequent cognitive changes in AD, FTD, and MS, over and above BPF. Voxel-wise analyses revealed spatial features underlying brain-PAD including, beyond global tissue loss, specific regional atrophy matching each disease's characteristic pattern. Collectively, these findings demonstrate that brain-PAD is a clinically meaningful, transdiagnostic biomarker of neurodegeneration that complements conventional volumetric measures like the BPF.
    DOI:  https://doi.org/10.64898/2026.07.21.26358569
  56. J Trace Elem Med Biol. 2026 Jul 21. pii: S0946-672X(26)00115-X. [Epub ahead of print]97 127929
    Ceruloplasmin and neurodegeneration: A link between copper dysregulation, iron imbalance, and neuronal damage.
    Deepika Kunwar, Jayant Kumar, Syed Afroz Ali, Ajay G Namdeo, S J S Flora.
      Ceruloplasmin (Cp) is a multifunctional multicopper oxidase principally produced in the liver and, to a lesser extent, in the central nervous system. It regulates iron homeostasis and oxidative balance, Cp oxidizes ferrous iron (Fe²⁺) to ferric iron (Fe³⁺), thereby enabling its safe integration into transferrin and averting reactive oxygen species formation. Beyond its ferroxidase activity, Cp also serves as a major copper carrier in plasma and contributes to antioxidant defense mechanisms. Although, the imbalance of ceruloplasmin has been gradually recognized as a key marker in the pathogenesis of neurodegenerative disorders. It is associated with neurofibrillary tangles, amyloid plaques, tau hyperphosphorylation, oxidative stress, and mitochondrial dysfunction. In the past, Cp and neuropathology were first established when a decreased level of serum ceruloplasmin was reported as a diagnostic biomarker of Wilson's disease, a disorder characterized by copper build-up triggered by mutations in the ATP7B gene. Furthermore, some studies suggest the absence of Cp was known in aceruloplasminemia, a different neurodegenerative condition characterized by extensive deposition of iron in the brain and progressive neuronal loss. However, several studies have reported that Cp's function and expression undergo important modifications in Alzheimer's, Parkinson's, Wilson's disease, and other neurological conditions. These alterations in Cp are directly linked to disrupted metal homeostasis, alleviating oxidative stress and neuroinflammation. Thus, besides understanding the structural, metabolic, and biological roles of Cp, this review aims at explaining its possible effects on common neurological disorders. The review also focusses on the therapeutic opportunities targeting Cp-mediated pathways, primarily, focusing on how Cp dysfunction interrelates with copper metabolism, iron dysregulation, and neuroinflammatory signalling, as reported in various clinical and experimental studies. Understanding Cp mechanism may highlight novel strategies for overcoming these neurodegenerative diseases.
    Keywords:  Ceruloplasmin; Copper; Copper dysregulations; Iron imbalance; Neurological disorder
    DOI:  https://doi.org/10.1016/j.jtemb.2026.127929
  57. Adv Drug Deliv Rev. 2026 Jul 29. pii: S0169-409X(26)00172-9. [Epub ahead of print] 115938
    Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.
    Katherine Y Bang, Ross Walenga, Steven Chopski, Markham C Luke, Ksenia Blinova, Liang Zhao, Su Guo.
      Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), globally pose a significant challenge with an aging population. Despite the presence of various therapeutic agents, AD and PD treatments with small molecules currently only address the symptoms; certain biologic agents for AD have been approved for their disease-modifying effects, but the risk of intracerebral hemorrhage severely limits their use. Moreover, the bioavailability of orally administered agents in the brain is challenged by the blood-brain barrier, complicating brain-targeted drug development. Extensive efforts are currently underway to develop intranasal platforms with nanoparticles for direct nose-to-brain drug delivery. Additionally, various in vitro designs involving brain organoids, and in vivo models, such as rodents and zebrafish, have been explored to improve the efficiency and accuracy of preclinical models. Efforts to develop sophisticated computational modeling of intranasal drug delivery, including computational fluid dynamics (CFD) deposition and physiologically based pharmacokinetics (PBPK) modeling, also continue to advance the intranasal drug delivery research and potentially improve the feasibility of developing clinically relevant intranasal platforms for neurodegenerative disease.
    Keywords:  Alzheimer's disease; Intranasal drug delivery; Nanoparticles; Neurodegeneration; Nose-to-brain; PBPK; Parkinson's disease; Zebrafish
    DOI:  https://doi.org/10.1016/j.addr.2026.115938
  58. PLoS One. 2026 ;21(7): e0354882
    Integrative network pharmacology, transcriptomics, and molecular docking identify candidate Centella asiatica constituents and targets in neurodegenerative diseases.
    Yuxi Xie, Chong-Teik Lim, Xin-Jieh Lam, Pike-See Cheah, King-Hwa Ling, Tan Huang.
       BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are progressive disorders with limited therapeutic options. Centella asiatica (C. asiatica), a medicinal and edible plant, has been reported to exert neuroprotective and anti-neuroinflammatory properties. Yet, the mechanisms underlying its effects against neurodegenerative diseases remain largely unclear.
    METHODS: We employed an integrative strategy combining network pharmacology, transcriptomic analyses, machine learning and molecular docking to prioritize disease-associated molecular networks and candidate compound-target relationships in AD, PD and HD.
    RESULTS: Sixteen candidate constituents of C. asiatica met the predefined drug-likeness, gastrointestinal absorption and blood-brain barrier permeability criteria, yielding 370 unique predicted targets. Disease-gene mining identified 983 AD-associated genes, 1,103 PD-associated genes, and 3,316 HD-associated genes. Integration of compound targets, disease-associated genes, and transcriptomic profiles prioritized five hub genes in PD (CCKAR, MAPK8, PSEN2, SLC6A3, and TH), four in AD (APP, PGK1, PIK3CA, and TTR), and four in HD (CHRND, HSP90AA1, PRKCQ, and TH). Enrichment analyses highlighted disease-relevant processes involving neurotransmitter signalling, cAMP and calcium pathways, MAPK-related responses and inflammatory regulation. ROC analyses provided additional support for the discriminatory performance of the prioritized genes in independent datasets, whereas molecular docking identified favourable predicted Vina docking scores and structurally plausible interactions between selected compounds and hub targets.
    CONCLUSION: This integrative computational analysis prioritizes candidate C. asiatica constituents, putative disease-associated targets, and molecular pathways in AD, PD, and HD. The findings provide a foundation for subsequent biochemical, cellular, and in vivo validation.
    DOI:  https://doi.org/10.1371/journal.pone.0354882
  59. EClinicalMedicine. 2026 Jul;97 104051
    Neurodegenerative mortality among National Football League Players.
    Charlotte B Luster, Bobak Abdolmohammadi, Michael J Mastrodicasa, Christopher J Nowinski, Evan D Feigel, Brenna Finegan, Adam J White, Eric J Connors, Craig A Rovito, Ross D Zafonte, Michael L Alosco, Ann C McKee, Jesse Mez, Daniel H Daneshvar.
       Background: Empirical research demonstrates elevated neurodegenerative mortality among individuals with repetitive head impact (RHI) exposure, including National Football League (NFL) players. This investigation addressed prior methodological limitations, including selection bias, subjective diagnoses, and retrospective reporting, by analyzing the relationship between RHI exposure and neurodegenerative mortality in a fully enumerated, 5.8-fold larger cohort of NFL players.
    Methods: A population-based retrospective cohort study was conducted comprising all current and former NFL athletes who debuted between 1960 and 2019 and played at least one regular or postseason NFL game, with National Death Index records (1979-2023) matched to Sports Reference, LLC data. Standardized mortality ratios (SMRs) were calculated from National Institute for Occupational Safety and Health data compared to an age-, sex-, race-, and calendar-year-standardized general population. Sensitivity analysis assessed whether the observed excess neurodegenerative mortality could be attributed to competing risks using a cause-specific hazard simulation.
    Findings: A total of 19,824 athletes had a cumulative 518,833 person-years (mean = 26.2 years, SD = 16.2), with 1994 decedents. NFL players exhibited lower all-cause mortality (SMR = 0.70; 95% CI: 0.67-0.74) but higher neurodegenerative mortality (SMR = 3.94; 95% CI: 3.38-4.56), including amyotrophic lateral sclerosis (SMR = 4.55; 95% CI = 3.13-6.38), all-cause dementia (SMR = 3.80; 95% CI = 3.11-4.60), and Parkinson's disease (SMR = 3.88; 95% CI: 2.76-5.30). Cause-specific hazard simulation indicated that competing risks alone would inflate the expected NDD SMR by a factor of 1.30, yielding a residual neurodegenerative SMR of 3.04 (95% CI: 2.63-3.50).
    Interpretation: Neurodegenerative mortality was nearly four times higher in NFL players compared to the general population and remained threefold higher after accounting for competing risks. Together, these findings strengthen the evidence for RHI exposure-related neurodegenerative mortality in NFL players that cannot be explained by differential survivorship.
    Funding: The National Institute of Neurological Disorders and Stroke [U54NS115266; U01NS086659], the National Institute on Aging [P30AG13846; P30AG072978], and the Maloney/Carpenter Trauma-Related Neurodegenerative Disease Research Fund.
    Keywords:  Epidemiology; Neurodegenerative Disease
    DOI:  https://doi.org/10.1016/j.eclinm.2026.104051
  60. Acta Neurol Belg. 2026 Jul 29.
    Perfusion as a biomarker of brain dysfunction in dementia (AD, DLB, FTD/PPA, PDD): comparison of CT, MRI (ASL/DSC/DCE), SPECT, and PET with interpretive pitfalls - a narrative review.
    Katarzyna Sklinda, Jan Bocianski, Tadeusz Budlewski, Malgorzata Kobylecka, Malgorzata Dorobek, Andrzej Gorecki, Bartosz Mruk, Michal Błaszczak, Jerzy Walecki.
      The term 'brain perfusion' is applied in clinical practice to a family of neuroimaging techniques that measure, in reality, quite different physiological quantities in the brain circulation. CT perfusion (CTP) and DSC-MRI track a contrast bolus to derive semi-quantitative haemodynamic parameters. ASL-MRI estimates cerebral blood flow (CBF) without contrast, but the result is sensitive to arterial transit time, haematocrit, and the patient's haemodynamic state on the day of the scan. DCE-MRI quantifies blood-brain barrier (BBB) permeability, a property of the neurovascular unit rather than a flow measurement. Perfusion SPECT provides a relative, normalisation-dependent CBF map that is distorted by cortical atrophy. [¹⁸F]FDG-PET reflects synaptic glucose metabolism, but not blood flow. Because these techniques answer different physiological questions, their results are not interchangeable, and applying a threshold or pattern derived from one modality to interpret another is methodologically unsound - yet this conflation occurs with regularity in clinical practice. This narrative review synthesises the clinical applications, diagnostic performance, and interpretive pitfalls of each technique in Alzheimer's disease (AD)/mild cognitive impairment (MCI-AD), dementia with Lewy bodies (DLB)/Parkinson's disease dementia (PDD), frontotemporal dementia (FTD)/primary progressive aphasia (PPA), and mixed dementia with vascular pathology. Recognised limitations include the narrative study design and the small number of head-to-head multi-modal studies in pathologically confirmed cohorts. A comparative table and practical minimum reporting elements are provided.
    DOI:  https://doi.org/10.1007/s13760-026-03117-6
  61. Med Sci (Basel). 2026 Jun 23. pii: 338. [Epub ahead of print]14(3):
    Walking as a Window to the Brain: Redefining Gait in Neurology.
    Emmanuel Ortega-Robles, Mario Treviño, Elías Manjarrez, Oscar Arias-Carrión.
      Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases-including Parkinson's disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes-gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson's disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a "sixth vital sign" reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology.
    Keywords:  digital biomarkers; gait analysis; mobility outcomes; neurological disorders; precision neurology; translational neuroscience
    DOI:  https://doi.org/10.3390/medsci14030338
  62. Front Cell Neurosci. 2026 ;20 1879641
    Gut-brain axis mechanisms of remote brain dysfunction after traumatic spinal cord injury: immune inflammation, the vagus nerve, and neuroendocrine pathways.
    Yutong Liu, Haifeng Zhang, Bingkai Ren.
      Traumatic spinal cord injury (SCI) has traditionally been regarded as a central nervous system injury mainly confined to the injured segment. However, increasing evidence indicates that SCI can also induce neuroinflammation, cognitive decline, and emotional disorders in remote brain regions, suggesting that its pathological impact is systemic rather than purely local. Remote brain dysfunction after SCI is unlikely to be driven by a single pathway, but may arise from the combined effects of systemic inflammation, autonomic imbalance, neuroendocrine dysregulation, and disruption of intestinal homeostasis. Unlike previous reviews that mainly discuss SCI-associated gut dysbiosis, neuroinflammation, or gut-brain communication separately, this review organizes SCI-related intestinal abnormalities around the concept of "gut-derived pathological signals" and further distinguishes direct SCI evidence from cross-disease mechanistic evidence and proposed mechanistic inference. Specifically, we summarize how intestinal dysmotility, microbial metabolic remodeling, abnormalities in short-chain fatty acids (SCFAs), barrier vulnerability, and mucosal immune imbalance after SCI may generate persistent pathological signals. We then analyze how these signals may affect the central nervous system through an immune-inflammatory main axis, a vagal neural relay branch, and a neuroendocrine modulatory branch, ultimately converging on a common downstream brain effector stage characterized by blood-brain barrier impairment, neuroinflammation, synaptic plasticity deficits, and dysfunction of key brain regions such as the hippocampus and medial prefrontal cortex (mPFC). Based on this cascade, we propose a stratified intervention framework involving upstream restoration of intestinal homeostasis, midstream regulation of interorgan transmission pathways, and downstream protection of brain effector mechanisms. Overall, this review provides an evidence-stratified gut-brain axis framework for understanding remote brain dysfunction after SCI and highlights the need for SCI-specific temporal mapping and pathway-selective causal validation.
    Keywords:  gut-derived pathological signals; gut–brain axis; neuroendocrine dysregulation; neuroinflammation; remote brain dysfunction; spinal cord injury; vagus nerve
    DOI:  https://doi.org/10.3389/fncel.2026.1879641
  63. J Appl Toxicol. 2026 Jul 28.
    Particulate Matter Induced Neurotoxicity: Interplay of Neuroinflammation and Organelle Dysfunction.
    H Abhirami, Amy S Mathew, C Guruvayoorappan.
      Air pollution, composed of several complex particles, is regarded as one of the major causes of adverse health outcomes, and particulate matter (PM), which occurs primarily as PM10, PM2.5, and PM0.1 according to its aerodynamic diameter, is considered to be the most dangerous fraction. It is known to impair the healthy functioning of organ systems, including the cardiovascular system, respiratory system, gastrointestinal system, and reproductive system. Upon inhalation, the respirable fraction of PM can travel through the olfactory bulb and reach the brain, disrupting the blood-brain barrier (BBB), or act through peripheral responses, thereby causing neuroinflammation and oxidative stress in the brain. PM exposure activates unfolded protein response (UPR) and proapoptotic signals like CHOP and caspase-12, which drive brain cell death. It also impairs oxidative phosphorylation, increases ROS, and initiates mitochondrial permeability transition, which results in neuronal energy failure. Upon entering the system, it compromises the autophagic flux and lysosomal integrity, leading to its accumulation. Although the systemic effects of PM are widely recognized, its capacity to penetrate the central nervous system (CNS) poses a significant biological concern. This review maps how PM alters CNS components, leading to neuroinflammation and ultimately neurotoxicity, and examines the upstream and downstream mechanisms underlying these actions.
    Keywords:  PM10; PM2.5; blood–brain barrier; neuroinflammation; oxidative stress; particulate matter
    DOI:  https://doi.org/10.1002/jat.70360
  64. Pharmaceutics. 2026 Jul 12. pii: 848. [Epub ahead of print]18(7):
    Breaking the Silent Barrier: Engineering Antibodies for Brain-Targeted Rabies Immunotherapy.
    Chen Sun, Liang Xiao, Xiao Guo, Wenxin Wang, Kaihong Zhang, Lei Wang, Zhiqiang Lin, Zhaohui Tang.
      Rabies remains one of the clearest therapeutic paradoxes in infectious diseases: it is largely preventable before neuroinvasion, yet once clinical symptoms appear, mortality approaches 100%. This sharp transition reflects more than delayed diagnosis alone. Wild-type rabies virus reaches and spreads within the central nervous system under conditions of relative immune silence, while the blood-brain barrier (BBB) severely restricts the entry of circulating immune effectors, including virus-neutralizing antibodies. As a result, conventional immunotherapy, although highly effective in post-exposure prophylaxis, performs poorly after symptom onset because it no longer reaches the relevant compartment. This review examines whether engineered antibodies can overcome that limitation and provide a realistic path toward brain-targeted rabies immunotherapy. We first outline why symptomatic rabies remains refractory to standard immune intervention, emphasizing the combined roles of viral immune evasion and BBB-mediated anatomical exclusion. We then review recent proof-of-concept studies showing that antibody-based rescue after central nervous system invasion is biologically plausible, particularly when antibodies are delivered directly into the central nervous system (CNS), retain Fc-dependent immune activity, or are modified to improve BBB penetration. Building on these findings, we discuss key design principles for next-generation therapeutics, including epitope breadth, resistance to viral escape, Fc tuning, and delivery modules based on peptide shuttles or receptor-mediated transcytosis platforms such as TfR1- and CD98hc-targeted systems. Finally, we highlight the major translational barriers that still separate experimental rescue from clinical therapy, including the narrow therapeutic window, model limitations, safety concerns, ethical issues, implementation constraints, and the need for standardized endpoints.
    Keywords:  antibody engineering; blood-brain barrier; brain-targeted delivery; immunotherapy; rabies; shuttle antibody
    DOI:  https://doi.org/10.3390/pharmaceutics18070848
  65. J Clin Med. 2026 Jul 09. pii: 5398. [Epub ahead of print]15(14):
    Multimodal Assessment of Consciousness with Brain-Computer Interfaces and Artificial Intelligence: From Acquired Brain Injury to Neurodegenerative Disease.
    Bernard Kordas.
      The assessment of consciousness has been shaped largely by research on acquired disorders of consciousness after acute or chronic brain injury, but similar problems of unreliable behavioral expression increasingly arise in neurodegenerative disease. This translational overlap is especially relevant when preserved cognition, awareness, or intentionality cannot be reliably expressed because of severe motor impairment, fluctuating arousal, cognitive decline, aphasia, apraxia, or impaired cooperation. In neurodegenerative disease, degeneration of arousal systems, large-scale brain networks, cognition, and motor pathways may similarly make observable behavior an unreliable measure of awareness. The challenge is not only to determine if a patient responds, but also to ask if residual awareness, intentionality, or covert cognition can still be detected through physiological signals. This review discusses how contemporary modalities reshape this assessment. Electroencephalography has moved from a descriptive measure of background activity to a bedside tool capable of probing event-related responses, network organization, and cortical complexity. Magnetic resonance methods reveal altered connectivity within thalamocortical and default mode network systems, while functional near-infrared spectroscopy adds a portable hemodynamic approach that may be repeated at the bedside and integrated with active paradigms. Brain-computer interfaces provide a translational step by converting neural responses into evidence of command following or, in selected patients, into communication, and artificial intelligence strengthens these approaches by extracting clinically meaningful patterns from complex neural and hemodynamic data. Additionally, autonomic measures, including heart rate variability and baroreflex indices, are considered as auxiliary physiological context for arousal and engagement, and not as direct markers of awareness. Because the most mature evidence for covert awareness and cognitive-motor dissociation comes from acquired disorders of consciousness, this review treats brain injury literature as a methodological foundation instead of as directly interchangeable evidence for neurodegenerative disease. It then examines how these approaches may be adapted to neurodegenerative contexts, especially ALS, severe dementia, Lewy body disease with fluctuating cognition, and conditions in which communication or motor output becomes unreliable.
    Keywords:  acquired brain injury; artificial intelligence; autonomic measures; brain–computer interface; cognitive-motor dissociation; covert cognition; disorders of consciousness; functional neuroimaging; multimodal assessment; neurodegenerative disease
    DOI:  https://doi.org/10.3390/jcm15145398
  66. Nutrients. 2026 Jul 17. pii: 2350. [Epub ahead of print]18(14):
    Neuroprotective Effects of Distilled Extract of Zanthoxylum piperitum in Parkinson's Disease Models.
    Su Bin Park, Jihun Gong, Gabsik Yang, Ye-Eun Baek, Amjad Khan, Tae Han Yook, Ji Yong Jang, Jong Uk Kim.
      Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. Oxidative stress, neuroinflammation, and α-synuclein aggregation are central pathological features of PD. Zanthoxylum piperitum DC, commonly known as Korean pepper or chopi, is a traditional dietary spice in Eastern Asia and has been reported to possess antioxidant and anti-inflammatory properties. This study investigated the neuroprotective and motor function-enhancing effects of distilled extract of Z. piperitum (deZP) in 1-Methyl-4-phenylpyridinium (MPP+)-treated Caenorhabditis elegans and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models of PD. Methods: In the C. elegans model, dopaminergic neurotoxicity was induced by MPP+, and deZP was tested at 0.25, 0.5, and 1% (v/v) to evaluate neuronal preservation through GFP-labeled dopaminergic neurons and α-synuclein expression. Concurrently, in the MPTP-induced mouse model, deZP was administered intranasally at a fixed dose of 20 μL/mouse, equivalent to 5 mg/mouse. Motor function was assessed using the rota-rod test, pole test, and grip strength test, while dopaminergic neuronal survival was evaluated by tyrosine hydroxylase (TH) immunostaining. Results: In MPP+-treated C. elegans, deZP significantly restored green fluorescent protein (GFP) fluorescence in dopaminergic neurons and reduced α-synuclein expression, with the most pronounced effects observed at 1% (v/v). In the MPTP-induced mouse model, deZP at this fixed intranasal dose significantly improved motor performance and preserved TH-positive neurons in the substantia nigra. Conclusions: These findings suggest that deZP may represent a promising preclinical candidate for further investigation in PD-related neurodegeneration.
    Keywords:  Parkinson’s disease; Zanthoxylum piperitum; neuroprotection
    DOI:  https://doi.org/10.3390/nu18142350
  67. Curr Issues Mol Biol. 2026 Jul 08. pii: 694. [Epub ahead of print]48(7):
    Herbal Bioactives Targeting Rho GTPases: A Multi-Targeted Strategy for Mitigating Neuroinflammation in Alzheimer's and Parkinson's Diseases.
    Tzong-Shi Wang, I-Shiang Tzeng, Yi-Chyan Chen, Mao-Liang Chen.
      Neuroinflammation plays an essential role in the pathogenesis of several associated brain diseases, including neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS)), and traumatic brain injury (TBI). In these diseases, persistent microglial and astrocyte aggregates, elevated proinflammatory cytokines, and oxidative stress drive neuronal injury and cognitive disability. Rho GTPases, in particular the Rho family members Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1), and cell division control protein 42 homolog (CDC42), regulate neuroinflammation, cytoskeletal dynamics, immune responses, and the maintenance of BBB integrity. These proteins are involved in many neuropathological diseases due to dysregulation, making them interesting therapeutic targets. Bioactives used in herbal care have attracted interest for their ability to influence neuroinflammation and even their anti-neurodegenerative activity. Studies show that flavonoids, alkaloids, polyphenols, and other botanical compounds alter Rho GTPase activity, which, in turn, leads to decreased inflammation. This review critically summarizes current evidence regarding phytochemical regulation of Rho GTPase signaling in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), with particular emphasis on the underlying molecular mechanisms, context-dependent signaling responses, and current translational challenges. Furthermore, existing knowledge gaps and future research priorities are discussed to facilitate the development of mechanism-based therapeutic strategies targeting Rho GTPases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; Rho signaling; bioactives; neuroinflammation
    DOI:  https://doi.org/10.3390/cimb48070694
  68. Neurobiol Dis. 2026 Jul 27. pii: S0969-9961(26)00294-9. [Epub ahead of print]228 107549
    Context-dependent YEATS-domain inhibition enhances neuronal resilience and improves ALS phenotypes.
    Luca Lo Piccolo, Chansunee Panto, Ranchana Yeewa, Ruedeemars Yubolphan, Puttachat Poound, Saranyapin Potikanond, Salinee Jantrapirom.
      Neuronal loss in neurodegenerative disease is driven in part by maladaptive stress signaling and impaired adaptation to proteotoxic challenges. ENL and AF9 are YEATS-domain acyl-lysine reader proteins best characterized in leukemia, but their functions in neurons remains unclear. Here, we defined the role of the ENL/AF9 YEATS domain using complementary chemical and genetic perturbations. We applied the selective YEATS inhibitor SR-0813 in differentiated human neurons and modulated ENL/AF9 activity in Drosophila using either SR-0813 or ENL/AF9 knockdown. In flies, SR-0813 phenocopied ENL/AF9 knockdown by extending lifespan and enhancing stress tolerance. To test disease-context specificity, we performed a Drosophila genetic modifier screen across neurodegeneration models. ENL/AF9 reduction was beneficial in UBQLN2P497H and SOD1G94A but showed reduced efficacy or became detrimental in chronic aggregation or mitochondrial stress models such as (GGGGCC)49 and polyQ disease. In human neurons, SR-0813 improved survival across multiple stress conditions, with the strongest protection during endoplasmic reticulum stress. Mechanistically, ENL/AF9 YEATS inhibition dampened PERK-dependent integrated stress response signaling and reduced apoptotic commitment without broadly enhancing proteostasis capacity. Together, these findings identified ENL/AF9 as modulators of neuronal stress-response dynamics and established ENL/AF9 YEATS-domain inhibition as a context-dependent strategy to enhance neuronal resilience with relevance to ALS and related proteotoxic disorders.
    Keywords:  Amyotrophic lateral sclerosis; Chemical probe; Chromatin reader; ENL/AF9; Integrated stress response
    DOI:  https://doi.org/10.1016/j.nbd.2026.107549
  69. Front Mol Neurosci. 2026 ;19 1856316
    Regulatory T cells in perioperative neurocognitive disorders: a systematic review with structured narrative synthesis from molecular mechanisms to clinical translation.
    Yude Zhu, Ke Chai, Chenxu Chou, Xiaoyu Zhang, Yulong Jia, Xiaojun Ge, Xiaguang Duan.
       Background: Perioperative neurocognitive disorders (PND), encompassing postoperative delirium and postoperative cognitive dysfunction, are common complications following anesthesia and surgery, particularly in elderly patients. Neuroinflammation has been identified as a central mechanism underlying PND; however, the contribution of adaptive immune regulation remains incompletely understood. Regulatory T cells (Tregs), as key modulators of immune homeostasis, have recently emerged as potential regulators of perioperative neuroinflammatory responses.
    Objective: This review aimed to comprehensively evaluate current preclinical and clinical evidence regarding the role of regulatory T cells in the development of perioperative neurocognitive disorders, with a focus on molecular mechanisms and translational implications.
    Methods: A systematic literature search was conducted in PubMed, PubMed Central, Web of Science, Scopus, Embase, the Cochrane Library, and ClinicalTrials.gov from inception to 17 May 2026. Original animal and human studies investigating Treg frequency, function, or modulation in relation to perioperative cognitive outcomes were included. Study selection followed PRISMA 2020 guidelines, and methodological quality was assessed using the SYRCLE risk-of-bias tool (animal studies) and the Newcastle-Ottawa Scale (clinical studies).
    Results: The search identified 312 records, of which 10 studies met the inclusion criteria, comprising four animal studies and six clinical studies. Preclinical evidence consistently demonstrated that surgical trauma induces alterations in Treg frequency and suppressive function, particularly in aged models, contributing to exaggerated neuroinflammation, blood-brain barrier disruption, microglial activation, and cognitive impairment. Clinical studies revealed associations between perioperative Treg imbalance-often reflected by an increased Th17/Treg ratio-and the occurrence of postoperative cognitive decline. Moreover, immunomodulatory interventions such as dexmedetomidine were shown to partially preserve Treg balance and reduce the incidence of postoperative cognitive dysfunction, although dexmedetomidine's pleiotropic actions (sympatholysis, opioid-sparing, sedation-related stress reduction) preclude attribution of its cognitive benefit solely to Treg modulation.
    Conclusion: Current evidence supports a critical role for regulatory T cells in the pathophysiology of perioperative neurocognitive disorders. Treg dysfunction contributes to excessive neuroinflammation and cognitive decline after surgery, whereas restoration of Treg-mediated immune regulation confers neuroprotective effects. Targeting regulatory T cells represents a promising translational strategy for the prevention and management of PND, warranting further mechanistic studies and well-designed clinical trials.
    Keywords:  blood brain barrier; immune modulation; neuroinflammation; perioperative neurocognitive disorders; regulatory T cells
    DOI:  https://doi.org/10.3389/fnmol.2026.1856316
  70. Neurology. 2026 Aug 25. 107(4): e218379
    Value of Annual MRI Monitoring in Patients With Multiple Sclerosis Treated With Ocrelizumab: A Number Needed to Scan Analysis.
    Lisa Schoof, Rick Heijnen, Laura Hogenboom, Zoé Léonie Elise Van Kempen, Brigit Alette de Jong, Bob W Van Oosten, Joep Killestein, Frederik Barkhof, Eva M Strijbis.
       BACKGROUND AND OBJECTIVES: Current guidelines recommend annual MRI scans during treatment with disease-modifying therapies, including ocrelizumab, in patients with multiple sclerosis (MS) to monitor treatment effectiveness and safety. However, the low rate of radiologic disease activity during long-term ocrelizumab treatment suggests that this recommendation should be re-evaluated to reduce burden on ocrelizumab-treated patients and the healthcare system. We aimed to describe the frequency of radiologic follow-up and the occurrence of radiologic disease activity in a cohort of ocrelizumab-treated MS patients to provide insight into the clinical value and efficiency of annual MRI monitoring in routine practice.
    METHODS: We included ocrelizumab-treated MS patients from the Amsterdam MS Cohort, who had at least 2 brain MRI scans performed during ≥3 months of treatment. MRI scans were performed as part of routine clinical care and clinical MRI reports issued by radiologist were used. Radiologic activity was defined as either ≥1 contrast-enhancing lesions on a MRI scan performed ≥3 months after ocrelizumab initiation or any new/enlarging T2 lesions on a subsequent MRI scan compared with a scan performed at least ≥3 months after ocrelizumab initiation. The number needed to scan (NNS) was calculated as the inverse of the predicted probability of radiologic disease activity as a function of treatment duration in months, estimated using a mixed-effects logistic regression model.
    RESULTS: A total of 342 patients (mean age at start ocrelizumab 40.3 years (SD 10.8); 65.8% female; 208 relapsing-onset MS and 41 primary progressive MS) were included, contributing 1,639 follow-up MRI scans. Radiologic disease activity was detected in 29 scans in 23 patients (1.8% of scans; 6.7% of patients) over a median treatment duration of 49 months. The NNS increased with treatment duration, especially after 24 months of treatment, reaching 81.3 at month 30 and 152.9 at month 36.
    DISCUSSION: Routine annual MRI monitoring in patients with asymptomatic ocrelizumab-treated MS never led to treatments changes. The increasing NNS over time, especially after 2 years of treatment, indicates that MRI intervals can be safely extended in patients with stable MS treated with ocrelizumab, potentially doubling the interval from treatment year 2 onward (i.e.,; rebaseline, year 1, year 2, year 4, and year 8, etc.).
    DOI:  https://doi.org/10.1212/WNL.0000000000218379
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