bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–07–12
76 papers selected by
Luca Bolliger, lxBio
  1. The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.
  2. Annexin A11 and TDP-43: core players in neurodegeneration.
  3. Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.
  4. Amyotrophic Lateral Sclerosis as a Systemic Disease: Why Integrative and Microbiome-Focused Approaches Deserve Re-Evaluation.
  5. Neuroprotective potential of resveratrol in Parkinson, Huntington, amyotrophic lateral sclerosis, and multiple sclerosis: a comprehensive review.
  6. Value of synaptic proteins as biomarkers in amyotrophic lateral sclerosis.
  7. Dysregulated neuronal mRNA transport and translation in FTD/ALS.
  8. Cholesterol in amyotrophic lateral sclerosis: a bystander, a biomarker, or a target?
  9. Feasibility and sensitivity of a multimodal digital endpoint panel for amyotrophic lateral sclerosis: a prospective cohort study.
  10. Neuroinflammation in neurodegenerative diseases: pathogenic pathways and emerging pharmacotherapeutic targets in Alzheimer's and Parkinson's disease.
  11. Unusual presentation of amyotrophic lateral sclerosis years after a motor-vehicle collision.
  12. Very low-amplitude muscle activity increases probability of motor evoked potentials in healthy individuals and in amyotrophic lateral sclerosis.
  13. The contribution of trapezius and sternocleidomastoideus motor evoked potentials in the diagnosis of Amyotrophic lateral sclerosis.
  14. Quantifying motor unit loss prior to functional impairment in muscles affected by amyotrophic lateral sclerosis.
  15. Gait speed and future ambulatory status in amyotrophic lateral sclerosis: a retrospective observational study with implications for power wheelchair referral.
  16. Cross-disease LC-MS/MS plasma proteomics identifies reproducible shared and disease-enriched biomarker signatures in neurodegenerative disorders.
  17. Association between motor cortex grey matter loss and inability to control an ECoG-based implanted Brain-Computer Interface in ALS.
  18. Neurology® Journal Club: Duration of Current Statin Use and Amyotrophic Lateral Sclerosis Risk.
  19. Sex-associated neuroinflammatory and astrocytic responses in amyotrophic lateral sclerosis: evidence from clinical cohorts and a TDP-43 N390D mouse model.
  20. Perspective and quality of life in amyotrophic lateral sclerosis patients undergoing percutaneous endoscopic gastrostomy.
  21. Role of the Upper Motor Neuron in the Generation of Fasciculations in Early Disease Stages of Amyotrophic Lateral Sclerosis.
  22. Case of concurrent ALS and human T-cell leukaemia virus type 1-associated myositis.
  23. Reduced Soluble Ubiquilin2 in Amyotrophic Lateral Sclerosis Carrying Ubiquilin2 (P494L) Mutation: Clinicopathological and Biochemical Evidence From an Autopsy Case.
  24. Identifying Gastrostomy Care and Home Gastrostomy Tube Feeding-Related Educational Content for Patients With Amyotrophic Lateral Sclerosis and Their Family Caregivers: A Delphi Panel With Professional Stakeholders.
  25. Smoking and the risk of neurodegenerative diseases in a Chinese case-control study.
  26. Transport Across the Blood-Brain Barrier.
  27. Bedside muscle ultrasonography to detect fasciculations and support diagnosis of amyotrophic lateral sclerosis in a mechanically ventilated intensive care unit patient.
  28. Quantitative Spatiotemporal Analysis of Ultrasound Images of Fasciculations in ALS.
  29. A changed landscape: five-year retrospective on the paradigm shift in genetic testing practices for ALS in Canada.
  30. Brain targeting and trafficking of extracellular vesicles in central nervous system diseases: a therapeutic roadmap.
  31. Preliminary Investigation of Myoelectric Control of an Assistive Neck Exoskeleton by Individuals with Amyotrophic Lateral Sclerosis.
  32. Regional wasteosome accumulation across neurodegenerative diseases points to a shared underlying mechanism potentially related to glymphatic insufficiency.
  33. The Role of PGC-1α in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.
  34. RD-OMICS: An Integrative Multi-Omics Data Inventory in Rare Diseases.
  35. Investigating the effect of progressive truncations at the ALS-linked protein TDP-43 RRM2 on its aggregation mechanism.
  36. The autophagy-senescence-inflammasome axis: A novel triad in neurodegenerative diseases?
  37. Clinical studies in 82 individuals with valosin-containing protein (VCP) associated multisystem proteinopathy and literature review.
  38. Fisetin prevents deterioration of cellular functions in amyotrophic lateral sclerosis variants G262R and P438L of SQSTM1 in SH-SY5Y cells.
  39. Striatal neuron dysfunction in C9ORF72-FTD/ALS is driven by AIS and potassium channel dysregulation.
  40. Multi-regional transcriptomic profiling reveals divergent molecular mechanisms in ALS-related neurodegeneration.
  41. Blood-brain barrier permeability in diffuse large B-Cell lymphoma: associations with established risk factors for CNS relapse.
  42. Neurofilament Light Chain as a Biomarker in Neurology.
  43. Frontotemporal Lobar Degeneration-TDP Type C With Striatal Glial Cytoplasmic Inclusions and Motor Neuron Degeneration.
  44. Shared and disease-specific human brain vascular signatures in Alzheimer's disease, frontotemporal dementia, and Huntington's disease.
  45. TOP1MT rs2293925 is an enhancer-active regulatory SNP that shapes mitochondrial R-loop dynamics.
  46. Region-specific features of early glial activation and Aquaporin-4 dysregulation in conditional mouse models of TDP-43 proteinopathies.
  47. Tertiary lymphoid structures in neuroinflammation coordinate neuroimmune homeostasis and pathological progression.
  48. Biological sex differences in neurodegenerative diseases in Africa: a scoping review of evidence and research gaps.
  49. Phase Separation Drives Pathological Aggregation in Neurodegenerative Diseases: A 15-Year Bibliometric Landscape (2009-2024).
  50. Metabolic and epigenetic regulation of microglia memory in neurological disorders.
  51. From the Gut to the Brain: Modeling Intestinal Absorption and Assessing Blood-Brain-Barrier Permeability of Small-Molecule Drugs by IAM Chromatography.
  52. Compound muscle action potential scan dataset in adults with spinal cord injury and healthy controls.
  53. Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation.
  54. 3D OCT-Based Retinal Biomarker Analysis for Automatic Regional-Wise Characterization of Neurodegenerative Diseases.
  55. Cellular, electrophysiological and behavioral improvements in a mouse model of Rett syndrome following gene therapy combined with focused ultrasound-mediated blood-brain barrier opening.
  56. Are T1-weighted and T2-weighted volumetric pipelines interchangeable methodologies for investigating amyotrophic lateral sclerosis pathology in vivo?
  57. Icariin Attenuates Neuroinflammation and Dopaminergic Degeneration in a Rodent Model of Parkinson's Disease by Promoting the Expansion of Regulatory T Cells.
  58. Macropinocytosis mediates neurotropism of Cryptococcus neoformans in a human organoid model of the blood-brain barrier.
  59. Kynurenic Acid, a Key Endogenous Neuroprotective Agent: Role of Its Derivatives in Therapeutics.
  60. Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors.
  61. Refining the link between REM sleep behavior disorder and neurodegeneration: Genetic correlation, Mendelian randomization, and colocalization evidence.
  62. SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
  63. Small molecules targeting ARF1 interaction with C9orf72:SMCR8:WDR41 complexes suppress its overactivation implicated in ALS/FTD.
  64. Human iPSC-Derived Spinal Neurons Carrying the ALS FUS (P525L) Mutation Exhibit Lower Response to Inhibitory Neurotransmitters.
  65. The emerging role of circular RNAs in neurodegenerative diseases and viral infections.
  66. Roles of Microglia in Cerebral Small Vessel Disease.
  67. A nose-to-brain drug delivery system targeting mitochondrial dysfunction: application potential and future prospects of chitosan nanogels in Alzheimer's disease.
  68. Mast Cells in the Developing Brain.
  69. Serum angiogenesis-hypoxia biomarkers in relapsing-remitting multiple sclerosis.
  70. Systematic evaluation of BBB-penetrant AAV capsids in marmosets identifies VCAP-102 as a highly efficient brain-transducing capsid.
  71. ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.
  72. Uric Acid Released from Poly (Lactic-co-Glycolic Acid) Nanoparticles Mitigates Glutamate-Induced Excitotoxicity of Spinal Cord Neurons.
  73. A "three-in-one" nose-to-brain delivery strategy: intranasal vancomycin spray achieves simultaneous clearance of pneumococcal colonization, bacteremia, and meningitis.
  74. Effects of Metabolites of Lactic Acid Bacteria on Nerve Cells of the Microbiota-Gut-Brain Axis.
  75. Spinal cord microglia exhibit a dysfunctional response to myelin damage.
  76. Quantifying cortical lesions in multiple sclerosis MRI datasets using multi-contrast post-processing and deep learning.
  1. J Nanobiotechnology. 2026 Jul 10.
    The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.
    Fengshou Chen, Limei Wang, Hao Liu, Qasim Khan, Bing Tang, Naren Bao.
      Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.
    Keywords:  Alzheimer’s Disease; Artificial Intelligence; Drug Repurposing; Multiple Sclerosis; Neurological Disorders; Parkinson’s Disease
    DOI:  https://doi.org/10.1186/s12951-026-04551-7
  2. Acta Neuropathol. 2026 Jul 07. pii: 4. [Epub ahead of print]152(1):
    Annexin A11 and TDP-43: core players in neurodegeneration.
    Courtney L Smith, John L Robinson, Edward B Lee.
      Annexin A11 (ANXA11) is a Ca2⁺-dependent phospholipid-binding protein that has recently emerged as a key player in neurodegeneration. Rare pathogenic ANXA11 variants were initially identified in cases of amyotrophic lateral sclerosis (ALS). Since then, ANXA11 has been linked to a broader spectrum of related neurodegenerative diseases. Two independent studies demonstrated that ANXA11 co-aggregates with TDP-43 in all cases of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C, with cryo-EM revealing heteromeric ANXA11-TDP-43 filaments. These discoveries support the direct pathological interaction between the two proteins as an important feature of FTLD-TDP type C. We also described secondary ANXA11 pathology in related neurodegenerative diseases, including limbic-predominant age-related TDP-43 encephalopathy (LATE), and more rarely in ALS and FTLD-TDP types A and B. ANXA11 and TDP-43 co-aggregates are also a feature of a FTLD-TDP associated with primary lateral sclerosis. These advances have renewed interest in ANXA11 as a major player in ALS/FTLD pathogenesis in both genetic and sporadic neurodegenerative diseases. In this review, we summarize ANXA11 pathology across genetic and sporadic cases, highlighting its heterogeneous overlap with TDP-43 pathology. We synthesize current knowledge of ANXA11's physiological roles in phase separation, membrane repair, and RNA granule dynamics, integrating emerging evidence on how disruption of these processes may promote pathological aggregation and toxicity. Finally, we outline priorities for future research, with particular emphasis on elucidating ANXA11's mechanistic connection to TDP-43.
    Keywords:  ALS; Annexin A11; FTLD-TDP; Neurodegenerative disease; TDP-43
    DOI:  https://doi.org/10.1007/s00401-026-03043-0
  3. Brain Commun. 2026 ;8(4): fcag241
    Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.
    Stefania Corti, Claudia Alberti, Linda Ottoboni, Giulia Magni, Delia Gagliardi, Filippo Marcotti, Simona Zanotti, Maurizio Moggio, Giacomo Pietro Comi.
      Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by accumulation of the 43-kDa TAR DNA-binding protein (TDP-43). This neuropathological signature has been well documented within the CNS; however, recent findings indicate that the phosphorylated TDP-43 additionally deposits in peripheral tissues, including skeletal muscle and intramuscular nerves. These data warrant a change of view from a neurocentric perspective of amyotrophic lateral sclerosis pathogenesis towards a broader concept of TDP-43 proteinopathy extending both within and beyond the nervous system. In this review, we focus on current evidence supporting the presence of TDP-43 pathology in amyotrophic lateral sclerosis skeletal muscle, examining its topographic distribution, molecular characteristics and associations with intramuscular nerve bundles. We also discuss the susceptibility of intrinsic muscle cells, disrupted axonal transport and impairment in protein quality control. Phosphorylated TDP-43 pathology in muscle biopsies from amyotrophic lateral sclerosis patients has emerged as a promising tool in the early diagnosis of the disease. Moreover, we discuss the relevance of these findings to amyotrophic lateral sclerosis pathogenesis and potential therapeutic implications.
    Keywords:  TDP-43; amyotrophic lateral sclerosis; diagnostic biomarker; peripheral proteinopathy; skeletal muscle
    DOI:  https://doi.org/10.1093/braincomms/fcag241
  4. Front Biosci (Landmark Ed). 2026 Jun 24. 31(6): 52497
    Amyotrophic Lateral Sclerosis as a Systemic Disease: Why Integrative and Microbiome-Focused Approaches Deserve Re-Evaluation.
    Eun Jin Yang.
      Despite decades of intensive research, therapeutic advances in amyotrophic lateral sclerosis (ALS) remain limited. Increasing evidence suggests that ALS is a multisystem disorder involving motor neuron degeneration, immune dysregulation, skeletal muscle pathology, and gastrointestinal dysfunction, thereby challenging the adequacy of current therapeutic strategies. Complementary and alternative medicine (CAM) approaches are widely used by patients with ALS. However, their efficacy remains controversial owing to limited clinical evidence and methodological limitations. The multicomponent herbal medicine and system-level characteristics of CAM conceptually align with the emerging view of ALS as a multisystemic disease. The involvement of gut microbiome dysbiosis in the pathophysiology of ALS has provided a unifying biological framework linking the peripheral, metabolic, and neuroinflammatory processes. These findings suggest that the combination of CAM and conventional therapy may serve as a potential integrative approach to target gut-brain-muscle interactions and systemic disease pathways. This article highlights critical gaps in the existing evidence and proposes that microbiome-focused, biomarker-driven clinical trials are essential to thoroughly evaluate CAM-based interventions in ALS. Embracing a system-oriented therapeutic framework may help address the complexity of ALS beyond traditional neuron-centered approaches.
    Keywords:  amyotrophic lateral sclerosis; complementary and alternative medicine; gut microbiome; multisystem therapy; neuroimmune modulation
    DOI:  https://doi.org/10.31083/FBL52497
  5. Mol Biol Rep. 2026 Jul 04. pii: 1102. [Epub ahead of print]53(1):
    Neuroprotective potential of resveratrol in Parkinson, Huntington, amyotrophic lateral sclerosis, and multiple sclerosis: a comprehensive review.
    Kasra Shahsavari, Omid Yazarlu, Hananeh Ahmadnia, Mahsa Tavakolian Ardakani, Mahnaz Khanavi, Hamidreza Monsef Esfahani, Reza Abdollahzadeh, Aida Sajedi, Hossein Kazemizadeh, Maede Hasanpour.
      Resveratrol shows neuroprotective effects in preclinical studies across a number of neurodegenerative illnesses, including Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's disease (HD), and it enhances mitochondrial function through stimulation of the AMPK/SIRT1/PGC-1α pathway, thereby improving mitochondrial oxidative capacity and ATP generation. The natural polyphenol lowers α-synuclein accumulation and affects autophagy; both markers of PD. Combining nano‑resveratrol formulations with L‑DOPA has shown greater therapeutic efficacy in animal models (MPTP mouse), while co‑administration with EGCG has shown synergistic neuroprotection in vitro (SH‑SY5Y cells). These combination strategies offer potential advantages in neuroprotection and symptom alleviation while minimizing adverse drug effects. Resveratrol activates SIRT1 and AMPK signaling in preclinical models, enhancing mitochondrial biogenesis, lowering apoptosis, and restoring cellular resilience. The effectiveness of various models and dosages varies. The primary mechanism by which resveratrol promotes neuronal survival and remyelination in multiple sclerosis is through SIRT1 activation, which does not directly reduce inflammation. As innovative delivery systems, intranasal nanoparticles and exosomes produced from macrophages have shown improved CNS targeting accuracy. Resveratrol slows down neurodegeneration and improves the prognosis of HD by improving motor function and stimulating mitochondrial biogenesis in addition to activating neuroprotective ERK signaling. All of these results point to resveratrol's several pathways as a strong contender for neurodegenerative disease adjunctive treatment. The current evidence base is insufficient to support clinical use of resveratrol for any of the four diseases. Further rigorous preclinical studies (including TDP-43 models for ALS, SIRT1 knockout studies, and human-feasible dosing) and well-designed clinical trials with pharmacokinetic endpoints are required before any clinical recommendations can be made.
    Keywords:  Amyotrophic Lateral Sclerosis; Huntington’s Disease; Multiple Sclerosis; Neuroprotective; Parkinson’s Disease; Resveratrol
    DOI:  https://doi.org/10.1007/s11033-026-12300-0
  6. Brain Commun. 2026 ;8(4): fcag247
    Value of synaptic proteins as biomarkers in amyotrophic lateral sclerosis.
    Frederik Hobin, Shreyasee Das, Charlotte Lambrechts, Charlotte De Rocker, Jonas Dubin, Fouke Ombelet, Joke De Vocht, Nikita Lamaire, Eugeen Vanmechelen, Koen Poesen, Philip Van Damme.
      Amyotrophic lateral sclerosis is a heterogeneous and rapidly progressing neurodegenerative disorder with limited treatment options. Therefore, there is a critical need for biomarkers that capture the diverse pathophysiological mechanisms underlying disease onset and progression. Emerging evidence suggests that synaptic dysfunction is an early disease mechanism in amyotrophic lateral sclerosis. Using homebrew immunoassays, we explored a panel of pre- and post-synaptic proteins in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (N = 57) and controls (N = 36). The potential value as a biomarker was explored by correlating cerebrospinal fluid levels with clinical parameters and established biomarkers for amyotrophic lateral sclerosis. Higher levels of Neurogranin (NRGN) (P = 0.003) and Vesicle-associated membrane protein 2 (VAMP2) (P = 0.014) were observed in patients with amyotrophic lateral sclerosis compared with controls. VAMP2, Synaptosome-associated protein 25 kDa (SNAP25) and β-synuclein (SNCB) correlated with individual relative disease stage, but none of the biomarkers correlated with disease progression rate. High levels of SNAP25 predicted worse survival in a univariate and stepwise multivariable analysis, but significance did not persist upon including Neurofilament light chain (NfL) levels. Synaptic proteins did not correlate with cerebrospinal fluid levels of neurofilaments or biomarkers of neuroinflammation, suggesting that they reflect different pathological mechanisms in amyotrophic lateral sclerosis. Our findings warrant further investigation to determine whether increased cerebrospinal fluid levels of synaptic proteins reflect synaptic breakdown or active release of synaptic proteins. This will help elucidate how synaptic dysfunction or damage contributes to elevated levels of synaptic markers in amyotrophic lateral sclerosis, and its underlying value as biomarker.
    Keywords:  amyotrophic lateral sclerosis; biomarker; cerebrospinal fluid; prognosis; synapse
    DOI:  https://doi.org/10.1093/braincomms/fcag247
  7. NPJ Dement. 2026 ;2(1): 56
    Dysregulated neuronal mRNA transport and translation in FTD/ALS.
    Emma J Craig, Veronica H Ryan.
      Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, co-occurring neurodegenerative disorders. Dysregulation of mRNA metabolism, transport, and local translation is a significant mechanism contributing to FTD/ALS. Here, we review the processes of neuronal RNA transport and translation, their disruption in FTD/ALS, and mechanistic interplay between the two. Finally, we discuss current progress targeting transport and translation defects and identify potential future directions for therapeutic development.
    Keywords:  Neurology; Neuroscience
    DOI:  https://doi.org/10.1038/s44400-026-00116-5
  8. Atheroscler Plus. 2026 Sep;65 100576
    Cholesterol in amyotrophic lateral sclerosis: a bystander, a biomarker, or a target?
    Matteo Farè, Chiara Comi, Giulia Susanna Ferrero, Gessica Sala, Federica Cerri, Laura Calabresi, Lucio Tremolizzo, Chiara Pavanello.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. In addition to the different pathogenic mechanisms, in recent years, increasing attention has been directed toward the role of lipid metabolism in ALS pathogenesis, although the clinical relevance of lipid alterations in ALS may differ from their well-established role in cardiovascular disease. This review critically examines the multifactorial relationship between cholesterol and ALS through three perspectives: (1) as a risk factor for disease onset, (2) as a prognostic biomarker of disease progression, and (3) as a potential therapeutic target. Epidemiological and genetic studies suggest a complex and sometimes contradictory association between lipid profile and ALS risk. Elevated LDL-cholesterol and total cholesterol have been linked to increased disease susceptibility in some cohorts, with Mendelian randomization studies supporting a potential causal role. Conversely, evidence regarding HDL-cholesterol remains conflicting and may be influenced by sex-specific and metabolic factors. As a prognostic biomarker, hyperlipidemia has been variably associated with prolonged survival in ALS patients; however, these findings often lose significance after adjusting for body mass index and nutritional status, suggesting that lipid levels may reflect systemic metabolic reserve rather than directly modulating disease progression. Pharmacological modulation of cholesterol reveals further complexity. While statins are generally not associated with increased ALS risk in clinical studies, preclinical models show divergent effects: some statins accelerate disease progression, while others like lovastatin may be protective. Other lipid-lowering drugs, including fibrates and PCSK9 inhibitors, may also influence ALS-related pathways beyond cholesterol lowering, although their potential role remains to be clarified.
    Keywords:  Amyotrophic lateral sclerosis; Cholesterol metabolism; Statins
    DOI:  https://doi.org/10.1016/j.athplu.2026.100576
  9. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jul 06. 1-10
    Feasibility and sensitivity of a multimodal digital endpoint panel for amyotrophic lateral sclerosis: a prospective cohort study.
    Lianne C M Botman, Jordi W J van Unnik, Anita Beelen, Jaap N E Bakers, Nina D van der Schoot, Manon A P Gremmen, Sybel van Helm, Leonard H van den Berg, Ruben P A van Eijk.
      Background: The use of digital technology may improve monitoring of amyotrophic lateral sclerosis (ALS) but a multimodal approach is likely required to capture the full disease phenotype. We evaluated the feasibility of a multimodal home monitoring protocol in ALS. Methods: We conducted a 3-month prospective cohort study at the University Medical Center Utrecht, Netherlands, with monthly home assessments of spirometry, accelerometry, speech, and questionnaires on functioning. The primary outcome was protocol adherence, defined as percentage of completed assessments. Secondary outcomes included acceptability ((totally) agree, neutral, (totally) disagree), and perceived burden, ranging from 0 (no burden) to 10 (extremely burdensome). Exploratory analyses were performed to evaluate changes in digital endpoints using linear mixed-effects models. Findings: Fifty patients with ALS were included (January 2023 - June 2025), of whom 47 (94%) completed the 3-month follow-up. Overall adherence was 83.2% (95% CI 76.9-88.6) and did not differ across modalities (p = 0.75). Adherers did not differ from non-adherers in either demographic or disease characteristics. In month 3, 93.0% to 95.3% of patients considered monthly remote assessments as acceptable, with a mean burden score of 2.0 (95% CI 1.7 to 2.3); burden was highest for speech (2.5) and the lowest for questionnaires (1.5). Digital endpoints showed significant change over 3 months (all p < 0.05). Interpretation: This study demonstrates good adherence and acceptability of a multimodal remote monitoring protocol. Digital endpoints offer an innovative approach to capturing disease progression. Future research should assess its long-term feasibility, added value, and integration alongside established clinical outcomes.
    Keywords:  Digital technology; accelerometry; amyotrophic lateral sclerosis; speech analysis; spirometry
    DOI:  https://doi.org/10.1080/21678421.2026.2696382
  10. Inflammopharmacology. 2026 Jul 07.
    Neuroinflammation in neurodegenerative diseases: pathogenic pathways and emerging pharmacotherapeutic targets in Alzheimer's and Parkinson's disease.
    Ravi Ranjan Kumar, Kamaljeet, Sourabh Kosey.
      Neuroinflammation is now widely recognized as a key contributor to the initiation and progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Chronic activation of brain-resident immune cells, including microglia and astrocytes, in response to misfolded protein aggregates such as amyloid-β and tau in AD and α-synuclein in PD, promotes maladaptive immune signaling, sustained cytokine release, and disruption of the blood-brain barrier (BBB). This chronic brain inflammation leads to synaptic dysfunction, neuronal loss and ultimately clinical deterioration. These processes are accompanied by disease-specific factors, such as inflammation of the gut-brain axis in PD and genetic modulators including APOE4, TREM2, and LRRK2. Furthermore, the development of fluid biomarkers together with neuroimaging techniques has improved early detection and monitoring of neuroinflammation leading to personalized therapeutic approaches. Clinical trials targeting microglial phenotypes, cytokine signaling, inflammasome activity, and genetic risk factors are emerging therapeutic strategies. Model limitations and heterogeneity of patients present challenges, but insights into neuroimmune interactions could provide a path forward for disease-modifying strategies. The present review aims to summarize new knowledge about the protective and detrimental aspects of neuroinflammation in AD and PD, providing an analysis on these developing prospects for targeted interventions toward slowing or stopping neurodegeneration.
    Keywords:  Alzheimer's disease (AD); Blood-brain barrier (BBB); Central nervous system (CNS); Cerebrospinal fluid (CSF); Parkinson's disease (PD)
    DOI:  https://doi.org/10.1007/s10787-026-02325-z
  11. BMJ Case Rep. 2026 Jul 09. pii: e272139. [Epub ahead of print]19(7):
    Unusual presentation of amyotrophic lateral sclerosis years after a motor-vehicle collision.
    Dean M Pucciarelli, Radha Patel, Sara Sawicki, Saloni Jain, Patrick Saulino.
      Amyotrophic lateral sclerosis (ALS) is a rare disease caused by the destruction of motor neurons, typically presenting with unilateral lower motor neuron and upper motor neuron symptoms. Here, we report the case of a female in her mid-60s with a complex history of lower extremity weakness following a motor-vehicle collision 3 years before her current presentation with a subacute complaint of right-sided leg weakness. With an atypical symptom course consisting of resolved and recurrent weakness of her left leg, the patient had multi-level chronic, evolving spinal-column damage, severe weight loss, newly discovered rectal neoplasm and longstanding psychiatric pathology. With symptoms concerning for both medical and psychosomatic explanations, several potentially compounded aetiologies were considered. Here, we discuss important considerations for fluctuating chronic and subacute neurological complaints with a broad differential diagnostic spectrum and how a macro-perspective of symptoms over years can aid in the diagnosis of a challenging ALS presentation.
    Keywords:  Amyotrophic Lateral Sclerosis; Colon cancer; Motor neurone disease; Neuromuscular disease; Trauma CNS /PNS
    DOI:  https://doi.org/10.1136/bcr-2026-272139
  12. Exp Physiol. 2026 Jul 05.
    Very low-amplitude muscle activity increases probability of motor evoked potentials in healthy individuals and in amyotrophic lateral sclerosis.
    Séamus O'Sullivan, Yasmine Tadjine, Gabriel R Palma, Narin Suleyman, Eva Woods, Antonio Fasano, Cathal Walsh, Friedemann Awiszus, Orla Hardiman, Richard G Carson, Roisin McMackin.
      Muscle contraction increases motor evoked potential (MEP) amplitude, decreasing motor threshold (MT). Correspondingly, trials where baseline EMG amplitude exceeds a specified threshold are often rejected. We aimed to investigate the influence of motor activity below such a threshold of MEP amplitude. We retrospectively analysed TMS-EMG data collected during resting MT (RMT) measurement in 45 healthy control subjects (1794 data points) and 35 people with amyotrophic lateral sclerosis (ALS; 1229 data points). Trials with de-meaned root mean squared (RMS) EMG amplitude of >10 µV throughout the 200 ms prior to stimulation were rejected. Generalised linear mixed-effects models assessed effects of muscle activity below this rejection threshold on the probability of evoking an MEP with peak-to-peak amplitude of ≥50 µV. Greater sub-rejection-threshold activity significantly increases MEP probability in control subjects and people with ALS. Models predicted a 38%-43% increase in MEP probability when baseline RMS-EMG amplitude increased from 1$\hskip.001pt 1$ to 9 µV. Sub-rejection-threshold baseline activity was significantly greater in ALS than control subjects. Below a typical rejection threshold, greater baseline RMS-EMG amplitudes markedly increase the probability of evoking MEPs with peak-to-peak amplitude of ≥50 µV. Effects of sub-rejection-threshold muscle activity should be accounted for when comparing RMT measures, particularly between cohorts where such activity differs, such as ALS and control subjects.
    Keywords:  amyotrophic lateral sclerosis; resting motor threshold; transcranial magnetic stimulation
    DOI:  https://doi.org/10.1113/EP093429
  13. Clin Neurophysiol. 2026 Jun 30. pii: S1388-2457(26)00831-X. [Epub ahead of print]190 2112331
    The contribution of trapezius and sternocleidomastoideus motor evoked potentials in the diagnosis of Amyotrophic lateral sclerosis.
    Ayşegül Gündüz, Nermin Görkem Şirin, Evren Boran, Sezin Alpaydın Baslo, Mehmet Barış Baslo, Hidayet Reha Kuruoğlu, Elif Kocasoy Orhan, Ali Emre Öge, Fatma Gökçem Yıldız, Onural Tümer, Melih Tütüncü, Ersin Tan, Çağrı Mesut Temuçin, Hilmi Uysal, Nurten Uzun, Bülent Cengiz.
       OBJECTIVE: We aimed to evaluate the role of corticobulbar motor evoked potentials (MEPs) as an objective electrophysiological measure to support clinical assessment of upper motor neurons in amyotrophic lateral sclerosis (ALS).
    METHODS: Seventy-three patients with ALS and 44 healthy individuals with similar age and sex underwent transcranial magnetic stimulation with MEP recordings from the sternocleidomastoideus (SCM), trapezius, and abductor pollicis brevis muscles. Corticobulbar involvement was defined by prolonged cortical MEP latency or central motor conduction time (CMCT) or absence of MEP responses. Awaji-Shima diagnostic categories were evaluated before and after the incorporation of corticobulbar MEP abnormalities.
    RESULTS: Corticobulbar MEP abnormalities were significantly more frequent in patients with ALS than in controls. Prolonged SCM-MEP latency and CMCT were the most sensitive electrophysiological markers of corticobulbar involvement. When interpreted alongside clinical upper motor neuron signs, corticobulbar MEP abnormalities facilitated upward diagnostic reclassification within the Awaji-Shima framework. One-fifth of patients who were initially classified as possible or probable ALS were reclassified as probable ALS and definite ALS, respectively, following inclusion of SCM- and trapezius-MEP abnormalities.
    CONCLUSIONS: Corticobulbar MEP assessment provides objective electrophysiological support for upper motor neuron dysfunction and enhances diagnostic sensitivity when used in conjunction with the Awaji-Shima diagnostic framework.
    SIGNIFICANCE: This study demonstrates that electrophysiological assessment of the corticobulbar pathway using SCM- and trapezius-MEPs provides objective evidence of upper motor neuron dysfunction in ALS.
    Keywords:  Amyotrophic lateral sclerosis; Awaji-Shima criteria; Central motor conduction time; Corticobulbar pathway; Motor evoked potential; Sternocleidomastoideus; Trapezius
    DOI:  https://doi.org/10.1016/j.clinph.2026.2112331
  14. Clin Neurophysiol Pract. 2026 ;11 538-542
    Quantifying motor unit loss prior to functional impairment in muscles affected by amyotrophic lateral sclerosis.
    Boudewijn T H M Sleutjes, Anna Bystrup Jacobsen, Hatice Tankisi, N Gorkem Sirin, A Emre Oge, Robert D Henderson, Pieter A van Doorn, Leonard H van den Berg, Ruben P A van Eijk.
       Objectives: The compound muscle action potential (CMAP) scan is a non-invasive method for deriving motor unit number estimates (MUNE) to track disease progression in muscles affected by amyotrophic lateral sclerosis (ALS). It remains to be established whether and how long motor unit loss precedes functional impairment.
    Methods: In 56 patients with ALS, we compared the longitudinal trajectories of MUNE derived from thenar CMAP scans, and fine motor function (FMF) using a functional rating scale. Linear and sigmoidal disease trajectories were modelled from which time differences were estimated between these measures to reach their half-maximum scores.
    Results: The normalized linear decline per month was 0.02 (95% CI 0.01 to 0.03) for FMF and 0.03 (95% CI 0.03 to 0.04) for MUNE. Half-maximum of FMF was reached after 26.3 months (95% CI 18.9 to 35.1) for the linear model, while MUNE had a shorter time required to reach 50% of its maximum with 13.0 months (95% CI 10.3 to 16.4). The head-to-head comparison between FMF and MUNE showed that MUNE values reached 50% of its maximum 13.1 months (95% CI 7.0-20.8) earlier. Results were similar for sigmoidal disease trajectories.
    Conclusions: Simulated disease trajectories of MUNE values derived from CMAP scans in muscles affected by ALS indicated that MUNE may reach 50% of its maximum in approximately 60% of the time compared to functional impairment.
    Significance: These explorative findings underscore how neurophysiological measures may be of use for early disease monitoring, with relevance for both care and research settings.
    Keywords:  ALS/MND; Clinical trials; Compound muscle action potential scan; Monitoring disease progression; Motor unit number estimation
    DOI:  https://doi.org/10.1016/j.cnp.2026.06.012
  15. Physiother Theory Pract. 2026 Jul 10. 1-12
    Gait speed and future ambulatory status in amyotrophic lateral sclerosis: a retrospective observational study with implications for power wheelchair referral.
    Chelsea E Macpherson, Julie Muccini, Miguel E Blacutt, Meghan Bjalme-Evans, Mary E Lough, Lori Quinn.
       BACKGROUND OR INTRODUCTION: Amyotrophic lateral sclerosis (ALS) causes rapid and progressive loss of ambulation resulting in immobility. A power wheelchair (PWC) increases safety, independence, and quality of life, however, the PWC referral process is lengthy and complex. When the PWC is delayed, immobility complications can occur. One barrier is the lack of a universal predictive "gait speed threshold" to help clinicians determine when to initiate the PWC referral process.
    OBJECTIVE OR PURPOSE: Identify a clinically relevant gait speed threshold associated with future loss of ambulation in people with ALS.
    METHODS: This was a retrospective chart review of a single multidisciplinary ALS Center of Excellence from July 1, 2016 - July 1, 2019 (36-months). Participants were included in this study if they were adults (age >18 years) with clinically definite ALS who were ambulatory at baseline. The primary outcome was gait speed on the 10-meter walk test. Secondary outcomes included the ALS Functional Rating Scale-Revised, forced vital capacity, falls, and ambulation status.
    RESULTS: Of N = 180 people with ALS identified during the study period, n = 72 met inclusion for analysis with a mean age 66.1 ± 11.9 years, 64% male, 76% with an ALS phenotype of spinal onset, and 24% bulbar onset. A gait speed threshold of 0.79 m/s maximized the combined sensitivity and specificity for classifying ambulatory status at the subsequent 6-month visit. Faster gait speeds (>1.2-1.4 m/s) were associated with greater odds of remaining ambulatory at 6-months based on Bayesian logistic regression.
    CONCLUSION: A gait speed threshold of 0.79 m/s was associated with increased likelihood of subsequent loss of ambulation, though modest predictive accuracy limits its use as a stand-alone indicator. Gait speed may serve as one component of clinical decision-making regarding PWC planning and referral in people with ALS. Larger multicenter studies are needed to confirm and generalize results across ALS phenotypes.
    Keywords:  10-meter walk test; Amyotrophic lateral sclerosis; complex rehabilitation technology; gait speed; mobility
    DOI:  https://doi.org/10.1080/09593985.2026.2700400
  16. Acta Neuropathol Commun. 2026 Jul 10.
    Cross-disease LC-MS/MS plasma proteomics identifies reproducible shared and disease-enriched biomarker signatures in neurodegenerative disorders.
    Youngtae Choi, Shinrye Lee, Janbolat Ashim, Wookyung Yu, Eunji Cho, Ho-Won Lee, Jin-Sung Park, Jong Hyuk Yoon, Hyung-Jun Kim, Mookyung Cheon.
      Neurodegenerative diseases (NDDs) exhibit considerable molecular heterogeneity, making it difficult to pinpoint robust, disease-specific biomarkers. Although proteomic studies have deepened our understanding of individual disorders, systematic cross-disease comparisons with cross-platform validation remain scarce, especially for rare conditions like spinal and bulbar muscular atrophy (SBMA). To address this gap, we conducted a comparative plasma proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 264 participants across major neurodegenerative and related diagnostic groups, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), SBMA, and cognitively healthy controls. This unified framework allowed us to capture both disease-specific and shared protein signatures across neurodegenerative conditions. Candidate proteins were then validated in the UK Biobank (Olink Explore) and the Global Neurodegeneration Proteomics Consortium (SomaScan). Of 23 proteins assessed in the UK Biobank, four unique proteins (yielding six disease-protein associations) showed nominally significant and directionally concordant changes; of 20 proteins represented by 27 probes tested in the Global Neurodegeneration Proteomics Consortium, seven proteins reached nominal significance, all with full directional concordance across both cohorts. Notably, IGFBP2 was consistently elevated in AD and PD across independent datasets, pointing to shared metabolic dysregulation, while ADIPOQ showed parallel increases in the same conditions, reinforcing convergent shifts in energy metabolism. By contrast, CRTAC1 and COMP were selectively reduced in motor neuron diseases, suggesting disease-enriched alterations in extracellular matrix composition. Taken together, our findings provide a cross-disease, cross-platform framework for uncovering reproducible proteomic biomarkers and shed light on both overlapping and distinct molecular pathways in neurodegeneration.
    Keywords:  Biomarkers; Cross-platform validation; Global Neurodegeneration Proteomics Consortium; LC–MS/MS; Neurodegenerative diseases; Plasma proteomics; UK Biobank
    DOI:  https://doi.org/10.1186/s40478-026-02377-w
  17. medRxiv. 2026 Jul 01. pii: 2026.06.23.26355654. [Epub ahead of print]
    Association between motor cortex grey matter loss and inability to control an ECoG-based implanted Brain-Computer Interface in ALS.
    Mathijs Raemaekers, Simon H Geukes, Erik J Aarnoutse, Mariana P Branco, Zac V Freudenburg, Anouck Schippers, Nathan E Crone, Sasha Leinders, Julia Berezutskaya, Nick F Ramsey, Mariska J Vansteensel.
       Background: The field of implantable Brain-Computer Interfaces (iBCIs) is rapidly advancing, with individuals with amyotrophic lateral sclerosis (ALS) as key beneficiaries. However, ALS-related cortical degeneration may impair iBCI effectiveness. This study investigated whether structural magnetic resonance imaging (MRI) and functional MRI (fMRI) metrics are associated with the quality of electrocorticography (ECoG) signals critical for iBCI use.
    Methods: Six late-stage ALS participants and 76 controls underwent T1-weighted structural MRI and task-based fMRI during right-hand movement or attempts thereof. ECoG data of ALS participants was benchmarked using ECoG data acquired in epilepsy patients. Grey matter thickness in the sensorimotor cortex and fMRI activation in the motor-hand area were measured.
    Results: Four ALS participants showed >0.4 mm thinning in the precentral gyrus, while the postcentral gyrus was spared. ECoG signal quality was significantly associated with precentral grey matter thickness, but not with fMRI activity.
    Conclusions: These findings suggest that presurgical assessment of precentral grey matter thickness could potentially prove useful for iBCI candidate selection in advanced ALS.
    Plain Language Summary: People with amyotrophic lateral sclerosis (ALS) can lose the ability to move and speak, but their thinking often remains intact. Implantable brain-computer interfaces (iBCIs) can help by translating brain signals into commands for communication devices. However, ALS damages the motor cortex, which may reduce the quality of these signals. In this study, we examined brain scans and electrical recordings from six people with advanced ALS. We found that thinning of the motor cortex was linked to weaker brain signals needed for iBCI control, while functional MRI activity was less predictive. This suggests that measuring motor cortex thickness before surgery could help identify who will benefit most from an iBCI, improving treatment decisions and future clinical trials.
    Two sentence summary: We examine presurgical MRI/fMRI and ECoG recordings from people with advanced ALS receiving implanted brain-computer interfaces. Motor cortex thinning is associated with poorer ECoG signal quality, suggesting cortical thickness may help identify candidates likely to benefit.
    DOI:  https://doi.org/10.64898/2026.06.23.26355654
  18. Neurology. 2026 Aug 11. 107(3): e218358
    Neurology® Journal Club: Duration of Current Statin Use and Amyotrophic Lateral Sclerosis Risk.
    Chia-Yuan Chang, Tiffany R Price, Analisa Jia, Jacquelyn Judith Cragg.
      This article critically appraises the study by Nakken et al., "Duration of Current Statin Use and Amyotrophic Lateral Sclerosis (ALS) Risk." Previous observational studies and Mendelian randomization studies examining statin use and ALS risk have reported mixed results. Millions of adults receive statins for cardiovascular prevention and may be concerned when neuromuscular symptoms suggestive of ALS appear. Using linked nationwide health survey and prescription data, this Norwegian population-based cohort study applied time-dependent models to evaluate statin use and subsequent ALS risk. Short-term statin use was associated with increased ALS risk, whereas long-term use was associated with lower risk. The authors interpreted this as evidence of reverse causation rather than a causal or protective effect of statins. Key strengths of the study include its large population-based design, the use of a negative control, and time-dependent Cox modeling. However, limitations inherent to observational study designs and potential residual confounding should be considered. In this article, we summarize the findings, highlight key statistical concepts, and discuss the study's major strengths and limitations.
    DOI:  https://doi.org/10.1212/WNL.0000000000218358
  19. Brain Behav Immun. 2026 Jul 09. pii: S0889-1591(26)00632-X. [Epub ahead of print] 106884
    Sex-associated neuroinflammatory and astrocytic responses in amyotrophic lateral sclerosis: evidence from clinical cohorts and a TDP-43 N390D mouse model.
    Wenfei Yu, Bing Zhao, Mingjie Ma, Ninglu Gao, Yan Yun, Xiaohan Sun, Kai Shao, Pengfei Lin, Wei Li, Yuying Zhao, Dexin Yu, Cuiping Zhao, Fuchen Liu, Chuanzhu Yan, Shuangwu Liu.
       BACKGROUND: Sex differences are increasingly recognized as important modifiers of neuroimmune processes in neurodegenerative disorders. However, the sex-associated clinical phenotypes and underlying neuroinflammatory mechanisms in amyotrophic lateral sclerosis (ALS) remain poorly understood. This study integrated multimodal clinical assessments, cerebrospinal fluid (CSF) neuroimmune biomarkers, neuroimaging-based glymphatic metrics, and complementary animal analyses to characterize shared and sex-associated alterations in male and female ALS patients.
    METHODS: Two independent cohorts including 158 newly diagnosed ALS patients and 112 healthy controls (HCs) underwent evaluations of motor function, cognition, sleep disturbances, and emotional symptoms. Glymphatic function was assessed using choroid plexus volume (CPV), diffusion-derived analysis along the perivascular space (ALPS) index, and white-matter free-water (FW) fraction. In the original cohort, 12 CSF biomarkers spanning astrocytic activation, neuroinflammation, TDP-43 pathology, synaptic dysfunction, and axonal injury were quantified, and glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), and interleukin-18 (IL-18) were further examined in an independent verification cohort. Complementary neuroimmune alterations were further examined in TDP-43 N390D knock-in mice using ELISA and immunofluorescence.
    RESULTS: Male ALS patients showed markedly elevated CSF GFAP, IL-6, and IL-18 compared with female ALS patients and HCs after false discovery rate correction (q < 0.05). Female ALS patients exhibited increased CSF IL-6 versus HCs, whereas GFAP and IL-18 levels were unchanged. Female ALS patients also demonstrated more severe depressive symptoms and post-traumatic stress disorder than male ALS patients and HCs (p < 0.05). Both sexes displayed glymphatic impairment characterized by increased CPV and FW and reduced ALPS index, as well as pronounced sleep disturbances relative to HCs (all p < 0.05), with no clear sex-related differences. Complementary animal data showed that, at a fixed chronological age, male TDP-43 N390D mice exhibited more severe motor impairment accompanied by higher brain levels of GFAP, IL-6, and IL-18 and more prominent astrocyte-associated IL-6 and IL-18 signals than female mutant mice. Although microglial activation was also observed in TDP-43 N390D mice, no clear sex-related difference was detected at the sampled age.
    CONCLUSIONS: This multimodal clinical-translational study reveals sex-associated neuroinflammatory heterogeneity in ALS. Male patients exhibit a more pronounced GFAP-, IL-6-, and IL-18-related inflammatory profile, whereas female patients display more prominent affective disturbances. Glymphatic dysfunction and sleep impairment emerge as common pathological pathways across sexes. These findings highlight sex as a crucial biological variable shaping ALS heterogeneity and underscore the importance of incorporating sex-stratified analyses in future ALS neuroimmune research and clinical trials.
    Keywords:  ALS; Astrogliosis; Glymphatic dysfunction; Neuroinflammation; Sex differences
    DOI:  https://doi.org/10.1016/j.bbi.2026.106884
  20. Front Nutr. 2026 ;13 1756642
    Perspective and quality of life in amyotrophic lateral sclerosis patients undergoing percutaneous endoscopic gastrostomy.
    Nilo Riva, Enrica Finotto, Paride Schito, Giorgia Donzelli, Tommaso Russo, Teuta Domi, Laura Pozzi, Andrea Tettamanti, Elisa Riboldi, Ignazio Diego Lopez, Angelo Quattrini, George Cremona, Mauro Comola, Massimo Filippi.
       Introduction: Percutaneous endoscopic gastrostomy (PEG) is commonly used to manage dysphagia and nutritional failure, which are among the most frequent and severe complications of amyotrophic lateral sclerosis (ALS). While several studies assessed PEG indications, outcomes, and prognostic factors, there is no evidence regarding ALS patients' perspectives and health-related quality of life (HRQoL) associated with PEG.
    Methods: This study included 48 consecutive ALS patients. At the 1-month follow-up after PEG, patients and their caregivers completed a PEG satisfaction questionnaire regarding their decision to proceed with the PEG-tube placement. HRQoL was assessed using the Gastrointestinal Quality of Life Index (GIQLI) and the Short Form-36 (SF-36).
    Results: In total, 77.1% of patients and 88.9% of caregivers confirmed that they would prefer to have a PEG tube placed again if required (p > 0.001); 93.8% of patients felt that PEG made feeding easier, exerting a positive effect on overall wellbeing (83.3%) and increasing survival rates (93.8%) (p > 0.001); 54.2% felt that PEG was cosmetically acceptable. Consistent positive rates were reported by caregivers. The GIQLI digestion subscale values significantly improved from baseline (28.3; SD = 6.6) to discharge (30.97, SD = 5.84) and were maintained at 1-month follow-up (30.21, SD = 6.7; p = 0.014). Conversely, in follow-up assessments, we observed a significant reduction in the SF-36 physical component summary (PCS) subscale (baseline = 33.3; 1-month follow-up = 28.61; p = 0.032), which was accompanied by a significant worsening in the GIQLI physical dimension subscale (baseline = 9.63; 1-month follow-up = 7.38; p = 0.044).
    Discussion: This study provides preliminary evidence that ALS patients have a positive perspective on PEG positioning, which may also have a beneficial effect on HRQoL related to gastrointestinal function.
    Keywords:  cachexia; dysphagia; motor neuron disease; nutrition; quality of life; rehabilitation; respiratory failure; survival
    DOI:  https://doi.org/10.3389/fnut.2026.1756642
  21. Neurology. 2026 Jul 28. 107(2): e218273
    Role of the Upper Motor Neuron in the Generation of Fasciculations in Early Disease Stages of Amyotrophic Lateral Sclerosis.
    Miguel Oliveira Santos, José Castro, Isabel Castro, Michael Swash, Mamede de Carvalho.
       BACKGROUND AND OBJECTIVES: The origin of fasciculation potentials (FPs) in the early stages of amyotrophic lateral sclerosis (ALS) remains a subject of debate. We investigated the role of the motor cortex in FP generation by comparing resting FP frequency in the first dorsal interosseous (FDI) muscle before and after motor cortex inhibition induced by continuous theta-burst stimulation (cTBS).
    METHODS: We studied patients with early-stage ALS (G1) and a disease-control group (G2) comprising individuals with chronic lower motor neuron (LMN) disorders or benign fasciculation syndrome without upper motor neuron (UMN) involvement. Inclusion required a right FDI strength of MRC grade 4+ or 5. At baseline, we recorded FP frequency and amplitude in the right FDI (3 replicates) and the motor evoked potential (MEP) amplitude. These measures were repeated immediately after cTBS-induced corticomotor inhibition. Statistical significance was set at p < 0.05.
    RESULTS: Twenty-two patients with ALS (14 men; median age 65.5 years; 72.7% spinal onset) were included, with a median disease duration of 6.4 months and a mean ALSFRS-R score of 44. The control group (G2) consisted of 11 participants. Notably, 50% of the ALS cohort showed no neurogenic features on needle EMG of the right FDI at enrollment. Baseline peripheral and cortical amplitudes and left hemisphere motor thresholds were comparable between groups. After cTBS, MEP amplitudes decreased significantly in both G1 (0.93 vs 0.50 mV, p = 0.02) and G2 (1.23 vs 0.38 mV, p = 0.02). However, a significant reduction in FP frequency (39.5%) occurred only in the ALS group (0.43 vs 0.26 Hz, p < 0.001), whereas no change was observed in G2 (0.60 vs 0.77 Hz, p = 0.14). Patients with ALS with a normal FDI EMG demonstrated an even greater reduction in FP frequency (54.5%). FP amplitudes remained stable across both groups after cTBS.
    DISCUSSION: Our findings indicate that in early ALS, LMN excitability is significantly modulated by descending corticospinal input. The reduction in FP frequency after cortical inhibition suggests that FPs in early ALS are driven by a combination of both UMN and LMN hyperexcitability, distinguishing them from fasciculations in other neurogenic disorders.
    DOI:  https://doi.org/10.1212/WNL.0000000000218273
  22. BMJ Case Rep. 2026 Jul 07. pii: e270944. [Epub ahead of print]19(7):
    Case of concurrent ALS and human T-cell leukaemia virus type 1-associated myositis.
    Toshika Hata, Nobuhiro Ogawa, Hiroyuki Yabata, Shuhei Kobashi, Misako Nakayama, Hirohito Ishigaki, Isamu Yamakawa, Yasushi Itoh, Ichizo Nishino, Makoto Urushitani.
      A woman in her late 70s presented with progressive limb weakness, muscle atrophy and hyper-reflexia. Laboratory findings revealed elevated creatine kinase and positive serum human T-cell leukaemia virus type 1 (HTLV-1) antibody. Clinical and electrophysiological findings met revised El Escorial criteria for amyotrophic lateral sclerosis (ALS), but muscle MRI showed inflammatory changes. Muscle biopsy revealed both neurogenic and inflammatory features. While methylprednisolone showed no benefit, intravenous immunoglobulin therapy produced transient improvement in weakness with normalisation of creatine kinase levels. The patient died from respiratory failure 3 years after symptom onset. Autopsy confirmed typical ALS-TDP pathology with phosphorylated TDP-43 inclusions in motor neurons. HTLV-1 Tax-positive lymphocytes infiltrated skeletal muscles but not the central nervous system, establishing dual pathology of ALS-TDP with HTLV-1-associated myositis. The improvement most likely reflected treatment of the HTLV-1-associated myositis rather than the underlying motor neuron disease. This case highlights the importance of evaluating treatable conditions in HTLV-1-seropositive ALS patients.
    Keywords:  Amyotrophic Lateral Sclerosis; Infection (neurology); Motor neurone disease; Muscle disease
    DOI:  https://doi.org/10.1136/bcr-2025-270944
  23. Neuropathol Appl Neurobiol. 2026 Aug;52(4): e70091
    Reduced Soluble Ubiquilin2 in Amyotrophic Lateral Sclerosis Carrying Ubiquilin2 (P494L) Mutation: Clinicopathological and Biochemical Evidence From an Autopsy Case.
    Tadashi Adachi, Toshiya Nakano, Kentaro Yoshida, Yuki Suzuki, Mayuko Sakuwa, Masato Hasegawa, Alfi Raudatil Jannah, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Ritsuko Hanajima.
      We report the clinicopathological and biochemical findings of ALS associated with a UBQLN2 P494L mutation. Autopsy revealed widespread TDP-43 pathology and UBQLN2-positive inclusions. Immunoblot analysis demonstrated a marked reduction of soluble UBQLN2, supporting functional UBQLN2 insufficiency as a pathogenic mechanism underlying TDP-43 aggregation.
    Keywords:  TDP‐43; Ubiquilin2; amyotrophic lateral sclerosis; immunoblotting; intranuclear inclusion
    DOI:  https://doi.org/10.1111/nan.70091
  24. Gastroenterol Nurs. 2026 Jul 09.
    Identifying Gastrostomy Care and Home Gastrostomy Tube Feeding-Related Educational Content for Patients With Amyotrophic Lateral Sclerosis and Their Family Caregivers: A Delphi Panel With Professional Stakeholders.
    Hyeon Sik Chu, Juyeon Oh.
      Enteral nutrition is delivered through a gastrostomy tube to provide nutritional support to patients with amyotrophic lateral sclerosis (ALS) who have developed severe dysphagia at home. Complications may arise from gastrostomy and enteral nutrition when family caregivers do not provide adequate care. This study identifies key areas of educational content that can improve the care of patients with ALS requiring gastrostomy and home enteral nutrition. We conducted a modified three-round e-Delphi survey with health care experts to clarify their perspectives on the educational content regarding gastrostomy and home enteral nutrition disseminated among patients with ALS and their family caregivers. The experts provided their opinions on specific educational content areas, and their responses were analyzed to identify areas of consensus and divergence. Accordingly, in Rounds 1-3 of the survey, 16 experts, including registered nurses (n = 6), advanced practice registered nurses (n = 3), clinical neurologists (n = 3), and dieticians (n = 4), participated. In Round 3, four categories and 39 educational components reached consensus. The results provide a framework for developing educational nursing interventions for family caregivers of patients with ALS receiving home enteral nutrition through gastrostomy tubes and for defining the essential elements of the educational content of such interventions.
    DOI:  https://doi.org/10.1097/SGA.0000000000000937
  25. BMJ Neurol Open. 2026 ;8(2): e001728
    Smoking and the risk of neurodegenerative diseases in a Chinese case-control study.
    Jia Nie, Susan Peters, Calvin B Ge, Lützen Portengen, Nathaniel Rothman, Wei Hu, Ruwei Ou, QianQian Wei, Lingyu Zhang, Yanbing Hou, Qing Lan, Hui-Fang Shang, Roel Vermeulen.
       Background: While smoking is inversely associated with Parkinson's disease (PD) risk, its relationship with amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA) remains unclear, particularly in Asian populations. We investigated these associations in a Chinese case-control study.
    Methods: We recruited newly diagnosed ALS (n=430), MSA (n=271), PD (n=523) cases and hospital-based controls (n=1033) in Sichuan, China. Logistic regression models were used to evaluate associations between smoking and disease risks, adjusting for demographic, lifestyle and occupational factors.
    Results: Compared with never-smokers, the adjusted ORs and 95% CIs of ALS for current and former smokers were 1.00 (0.61 to 1.65) and 1.79 (1.01 to 3.17), respectively. For MSA, ORs were 1.27 (0.73 to 2.23) for current smokers and 2.54 (1.41 to 4.60) for former smokers. Individuals who quit within 4 years before diagnosis showed the highest risk of ALS (OR=1.93, 95% CI 0.96 to 3.88) and MSA (OR=2.09, 95% CI 1.11 to 3.93). For both ALS and MSA, no consistent trend was found with increasing smoking duration or pack-years. In contrast, ever-smokers had a significantly lower PD risk (OR=0.49, 95% CI 0.33 to 0.71), particularly current smokers (OR=0.30, 95% CI 0.19 to 0.48). Longer smoking duration and higher cumulative smoking were also linked to PD risk with clear negative exposure-response patterns (P trend=0.039 and 0.029, respectively).
    Conclusions: Consistent with findings in non-Asian populations, smoking was inversely associated with PD risks in the Chinese population. For ALS and MSA, we found evidence suggestive of positive relationships with cigarette smoking, but no clear exposure-response relationships were observed.
    Keywords:  ALS; MULTISYSTEM ATROPHY; PARKINSON'S DISEASE
    DOI:  https://doi.org/10.1136/bmjno-2026-001728
  26. Adv Exp Med Biol. 2026 ;1512 305-332
    Transport Across the Blood-Brain Barrier.
    Bingmei M Fu, Lyna F Ait Akli.
      The blood-brain barrier (BBB) is a dynamic barrier essential for maintaining the microenvironment of the brain. Although the special anatomical features of the BBB determine its protective role for the central nervous system (CNS) from blood-borne neurotoxins, the BBB extremely limits the therapeutic efficacy of drugs into the CNS, which greatly hinders the treatment of major brain diseases. In addition to describing the unique structures of the BBB, demonstrating a variety of in vivo and in vitro experimental methods for quantification of the transport properties of the BBB, presenting the mathematical model for the paracellular pathway of the BBB, summarizing the modulation of the BBB permeability by chemical and physical stimuli, and proposing drug delivery strategies through specific trans-BBB routes, the updated chapter describes the recently developed 3D in vitro human BBB models, shows a new transcellular model for the transport of therapeutical nanoparticles across the BBB, and presents several clinical studies for systemic drug delivery by MRI (magnetic resonance imaging) guided FUS (focused ultrasound stimulation) for brain diseases.
    Keywords:  Blood-brain barrier (BBB); Drug delivery across the BBB; In vivo and in vitro models; Mathematical models for para- and transcellular transport; Modulation of the BBB; Permeability; Transport pathways
    DOI:  https://doi.org/10.1007/978-3-032-22285-5_15
  27. Acute Crit Care. 2026 Jul 07.
    Bedside muscle ultrasonography to detect fasciculations and support diagnosis of amyotrophic lateral sclerosis in a mechanically ventilated intensive care unit patient.
    Hiroyuki Kida, Taro Kanai, Masayo Morita, Takashi Hasegawa.
      
    DOI:  https://doi.org/10.4266/acc.002080
  28. Muscle Nerve. 2026 Jul 10.
    Quantitative Spatiotemporal Analysis of Ultrasound Images of Fasciculations in ALS.
    Ryosuke Sugisawa, Kenji Sekiguchi, Yoshikatsu Noda, Shun Matoba, Hirotomo Suehiro, Jun Kozuki, Tomoko Tanaka, Norio Chihara.
       INTRODUCTION/AIMS: Fasciculations are a hallmark of amyotrophic lateral sclerosis (ALS), yet quantitative description of individual events on muscle ultrasound (MUS) is limited. We characterized the spatiotemporal kinematics of individual fasciculations to determine whether they differ between ALS and other neurogenic conditions.
    METHODS: We retrospectively analyzed biceps brachii MUS recordings from 680 examinations (January 2020-June 2025), identifying 74 ALS and 40 non-ALS neurogenic recordings with fasciculations (167 and 62 segments). After propensity score matching for age and muscle strength, 62 matched pairs were analyzed. The Lucas-Kanade optical flow algorithm, which estimates frame-to-frame displacement vectors from local intensity gradients, was applied at 1-pixel intervals (57,600 points per 240 × 240 region; ≈60 μm) to quantify twitch durations, peak displacement velocity, and directional anisotropy as a measure of spatial movement coherence.
    RESULTS: ALS fasciculations showed prolonged total duration (582.8 ± 112.8 ms vs. 489.2 ± 128.7 ms, p < 0.001), reduced directional anisotropy (0.534 ± 0.245 vs. 0.627 ± 0.215, p = 0.028), and lower peak displacement velocity (6.55 ± 6.56 vs. 9.53 ± 9.07 μm/ms, p = 0.039). MANOVA showed significant multivariate differences (Pillai's trace = 0.317 ± 0.030, p < 0.001) with moderate group separation (Mahalanobis distance = 1.10 ± 0.05).
    DISCUSSION: ALS fasciculations showed spatially heterogeneous and temporally prolonged contraction patterns, suggesting motor units in a transitional state of incomplete reinnervation, distinct from the more stable architecture of chronic neurogenic disorders. This framework may complement existing ultrasound assessment and aid the study of motor unit pathology in ALS.
    Keywords:  amyotrophic lateral sclerosis; fasciculation; motion tracking; muscle ultrasound; quantitative imaging
    DOI:  https://doi.org/10.1002/mus.70338
  29. Eur J Hum Genet. 2026 Jul 06.
    A changed landscape: five-year retrospective on the paradigm shift in genetic testing practices for ALS in Canada.
    Maya Binet, Gordon Jewett, Ari Breiner, Marvin Chum, Angela Genge, Kerri Schellenberg, Christen Shoesmith, Gerald Pfeffer, Kristiana Salmon.
      Offering genetic testing is increasingly recommended for all individuals with amyotrophic lateral sclerosis (ALS), particularly following the development of gene-targeted therapies, such as tofersen for SOD1-ALS. Historically, testing was routinely offered to those with familial ALS (fALS), but inconsistently to those with sporadic ALS (sALS). We evaluated changes in genetic testing and counseling practices among Canadian ALS physicians over a five-year period spanning pivotal clinical trial results and regulatory approval of tofersen. Members of the Canadian ALS Research Network were surveyed in 2020, 2022, and 2025 about genetic testing practices for symptomatic and asymptomatic individuals, gene panel composition, access to genetic counseling, and perceived drivers of change. Clinics offering genetic testing for sALS increased from 33% of clinics in 2020 and 57% in 2022 to 100% of respondents in 2025. Genetic testing for patients with a family history (fALS) was near-universal across all timepoints. Broader use of multi-gene panel testing increased over time, coinciding with sponsored testing availability. 61% of respondents reported that Health Canada approval of tofersen directly influenced their practice. Predictive testing offerings increased from 37% in 2020 to 61% in 2025. Genetic testing practices in Canada shifted substantially during late-stage clinical development and following regulatory approval of a gene-targeted therapy (tofersen). Proactive planning during the clinical trial phase facilitated rapid, nationwide adoption. This study captures a key turning point in ALS care, illustrating how therapeutic breakthroughs can redefine national clinical standards.
    DOI:  https://doi.org/10.1038/s41431-026-02171-1
  30. Nanomedicine (Lond). 2026 Jul 11. 1-19
    Brain targeting and trafficking of extracellular vesicles in central nervous system diseases: a therapeutic roadmap.
    Blaine Baker, Samuel Emerson, Taylor Tran, Nikita Mohapatra, David Wang, Thant Zaw, Aaleesha Doshi, Juan-Maria Lopez, Dua Hassan, Priyadarsini Kumar, Diana Farmer, Aijun Wang.
      Extracellular vesicles (EVs) mediate intercellular signaling in the central nervous system (CNS) by transferring lipids, proteins, and nucleic acids among neurons, glia, endothelium, and immune cells. Brain targeting depends on a linked sequence: EV ligands and adsorbed protein coronas engage receptor modules, select endocytic routes, determine intracellular fate, and define the therapeutic readouts. These fates include lysosomal degradation, recycling, rare cytosolic delivery, or transport across the blood-brain barrier (BBB). In disease, the same pathways can disseminate proteopathic seeds and amplify neuroinflammation. Heparan sulfate proteoglycans (HSPGs) and LDL receptor family members, including low-density lipoprotein receptor-related protein 1 (LRP1), regulate tau, α-synuclein, and amyloid-β handling. Phosphatidylserine readers and complement shape myeloid sink capture and inflammatory output. Integrin, tetraspanin, and ICAM-1 nanoclusters influence avidity, organotropism, and immune suppression. At the BBB, endothelial HSPGs, LRP1, and transferrin receptor (TfR) support receptor-mediated uptake, motivating engineered ligands such as rabies virus glycoprotein-derived peptides, Angiopep-2, and TfR binders. However, endosomal escape remains a major kinetic barrier to nucleic acid delivery. We synthesize these principles across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, glioblastoma, and demyelinating disease, and outline design and assay standards needed to translate EV biology into safe, manufacturable CNS therapeutics.
    Keywords:  Extracellular vesicles; blood-brain barrier; endosomal escape; microglia; neurodegeneration; protein corona; receptor-mediated transcytosis; uptake logic
    DOI:  https://doi.org/10.1080/17435889.2026.2698782
  31. IEEE Trans Neural Syst Rehabil Eng. 2026 Jul 10. PP
    Preliminary Investigation of Myoelectric Control of an Assistive Neck Exoskeleton by Individuals with Amyotrophic Lateral Sclerosis.
    Monika K Buczak, Joseph Brignone, W Caden Hamrick, Kiley M Cole, Mark B Bromberg, Haohan Zhang, Jacob A George.
      Neck weakness limits head control and quality of life for individuals with Amyotrophic Lateral Sclerosis (ALS). The Utah Neck Exoskeleton can restore neck motion, but current control methods-joystick and gaze tracking-have limited accessibility and reliability. These preliminary offline analyses investigate neck electromyography (EMG) as an alternative control modality from ALS patients. EMG signals were recorded from four male participants with ALS while performing neck flexion/extension, axial rotation, and lateral deviation. The resulting dataset was used to train convolutional neural networks (CNNs) per patient to classify either head position or movement direction from EMG features offline. Position classification significantly outperformed direction classification, with a mean accuracy of 82.5% ± 0.010 across participants. Performance was consistent when controlling one, two, or all three neck degrees of freedom. A subset of participants with sufficient residual motor function also completed neck movements while talking or chewing. Classification accuracy decreased during talking and chewing, although these effects were not statistically significant. Importantly however, training CNNs with diverse data that included periods of talking and chewing improved algorithm robustness across all conditions. These findings suggest that neck EMG signals can reliably predict intended head movements in ALS, even in the presence of weak and often confounding muscle activity. Offline accuracy and real-time computational speed suggest the approach is feasible for future online user-in-the-loop studies. Altogether, this pilot work advances EMG-based assistive technology for individuals with severe motor impairments, laying the groundwork for clinically viable, intuitive control systems.
    DOI:  https://doi.org/10.1109/TNSRE.2026.3712219
  32. Acta Neuropathol Commun. 2026 Jul 04.
    Regional wasteosome accumulation across neurodegenerative diseases points to a shared underlying mechanism potentially related to glymphatic insufficiency.
    Raquel Alsina, Marta Riba, Marina Sartorio, Clara Romera, Jordi Riu, Gerard Vilaplana, Iban Aldecoa, Yaroslau Compta, Raquel Sánchez-Valle, Jaume Del Valle, Carme Pelegrí, Laura Molina-Porcel, Jordi Vilaplana.
      The glymphatic system plays a key role in clearing waste products from the brain and is essential for maintaining brain homeostasis. When dysfunctional, it appears to contribute to pathological changes that exacerbate brain disorders, including neurodegenerative diseases. Additionally, wasteosomes, also known as corpora amylacea, are structures that function as waste containers and are thought to increase in response to chronic glymphatic insufficiency. Hence, in this study, we evaluated whether the accumulation and distribution of wasteosomes are compatible with both the potential role of wasteosomes as a hallmark of the chronic glymphatic insufficiency and the presence of this insufficiency in certain neurodegenerative diseases. Accordingly, brain tissue from 185 donors was analysed, including cases of Alzheimer's disease, amyotrophic lateral sclerosis with TDP-43 proteinopathy, frontotemporal lobar degeneration with TDP-43 or tau proteinopathy, and non-diseased controls. Wasteosomes were examined across 28 brain regions comprised within 5 major brain areas, using region-specific scoring systems. Analysis was conducted through variance and covariance analyses, along with decision tree procedures. The findings reveal that wasteosomes are consistently found in specific critical regions, with a higher burden in donors with neurodegenerative diseases compared with controls. These regions are independent of the regional distribution of the underlying proteinopathy, and are potentially associated with glymphatic drainage pathways. From an integrated perspective, although further studies are required, the increased presence of wasteosomes in these critical regions across all diseased groups is consistent with the potential presence of chronic glymphatic insufficiency in these diseases.
    Keywords:   Corpora amylacea ; Alzheimer's disease; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; Glymphatic system; Wasteosomes
    DOI:  https://doi.org/10.1186/s40478-026-02362-3
  33. Mol Neurobiol. 2026 Jul 10. pii: 755. [Epub ahead of print]63(1):
    The Role of PGC-1α in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.
    Yang You, Daxin Duan, Qian Xiang.
      Neurodegenerative diseases (NDDs) are progressive disorders in which mitochondrial dysfunction, oxidative stress, proteostasis failure, neuroinflammation, and synaptic damage progressively interact to drive neuronal vulnerability. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) links metabolic adaptation to stress-response pathways that are repeatedly disrupted in Alzheimer's disease, Parkinson's disease, Huntington's disease, polyglutamine (PolyQ) disorders, and amyotrophic lateral sclerosis. Rather than providing only an updated catalogue of studies, this review organizes the evidence into a cross-disease rheostat framework that explains why PGC-1α modulation is protective in some settings but incomplete or maladaptive in others. Current findings indicate that PGC-1α supports mitochondrial biogenesis, oxidative phosphorylation, antioxidant defense, mitophagy, autophagy, protein quality control, and inflammatory balance. However, its effects are highly context dependent. In several models, restoration of PGC-1α-related signaling improves mitochondrial function and reduces neuronal injury, whereas broad, sustained, or cell-inappropriate activation may produce limited benefit or undesirable outcomes. These observations suggest that PGC-1α is not a simple neuroprotective switch, but a flexible regulatory hub whose therapeutic value depends on cell type, isoform profile, disease stage, and activation level. Emerging strategies, including small-molecule modulators, gene delivery, antisense-based approaches, nanoparticle systems, and exercise-related interventions, remain largely preclinical and face major barriers related to CNS delivery, pathway selectivity, dose and cell-type control, peripheral safety, and validated target-engagement biomarkers. Nevertheless, clinical translation requires stronger causal validation, reliable target-engagement biomarkers, selective delivery methods, and long-term safety assessment. Future research should focus on precision-based modulation of PGC-1α to determine when and how this pathway can be safely used for disease modification. Such a careful approach may help transform PGC-1α from a broad experimental target into a clinically relevant strategy for well-defined neurodegenerative phenotypes.
    Keywords:  Alzheimer’s disease; Neurodegenerative diseases; PGC-1α; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-026-06029-x
  34. bioRxiv. 2026 Jul 03. pii: 2026.06.29.735296. [Epub ahead of print]
    RD-OMICS: An Integrative Multi-Omics Data Inventory in Rare Diseases.
    Huanfei Wang, Shixue Sun, Ewy A Mathé, Qian Zhu.
      Rare diseases (RD) impact over 30 million individuals in the United States, yet fewer than 5% of the identified conditions have FDA-approved treatments. Progress in RD research is hindered by small patient cohorts, biological heterogeneity, and the fragmented, inconsistently annotated publicly available omics data, which limits integrative analysis and translational discovery. Here, we present RD-OMICS, a data inventory with integrated and structured RD omics data from Gene Expression Omnibus (GEO), in the form of a knowledge graph. We developed a metadata harmonization pipeline that combines rule-based mapping and large language model (LLM)-assisted semantic categorization. The graph-based data model was defined to integrate different types of data including disease conditions, experiments, samples, platforms, projects, and publications into a centralized inventory graph. In this preliminary study, 11,049 GEO series for 126 rare diseases were processed and integrated into RD-OMICS, which includes 375,930 individual biospecimen samples, 1,578 sequencing and array platforms, 10,938 biological projects. Case studies demonstrate the use of RD-OMICS in supporting rare disease research, omics cohort construction, and transcriptome-based drug repurposing for amyotrophic lateral sclerosis (ALS). RD-OMICS provides a scalable foundation for transforming fragmented omics data into a structured, harmonized and interoperable resource, facilitating therapeutic development and other translational discoveries in rare diseases.
    DOI:  https://doi.org/10.64898/2026.06.29.735296
  35. Front Mol Biosci. 2026 ;13 1849627
    Investigating the effect of progressive truncations at the ALS-linked protein TDP-43 RRM2 on its aggregation mechanism.
    Greta Grassmann, Matteo Amadei, Arianna Lardieri, Linda Celeste Montemiglio, Alessandra Anna Passeri, Maurizio Mattarelli, Lorenzo Di Rienzo, Mattia Miotto, Giancarlo Ruocco, Edoardo Milanetti.
      Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by inclusions of TDP-43 protein. C-terminal fragments (CTFs) of TDP-43, generated by cleavage within its second RNA recognition motif (RRM2), have been found forming aggregates in patients. Aggregation has often been attributed to the C-terminal domain, but increasing evidence indicates that RRM2 fragments contribute to pathological inclusions. We performed extensive molecular dynamics simulations to investigate the changes resulting from the truncation that could lead to aggregation. We analyzed the full RRM2 domain (fRRM2, residues 192-261) and two fragments commonly observed in CTFs (tRRM2A, residues 220-261, and tRRM2B, residues 209-261). We found that truncation results in distinct aggregation-prone states. tRRM2B appears to rely on β -sheet elements associated with amyloid-like aggregation, whereas tRRM2A exhibits higher structural variability and a reduced β -content, suggesting a phase separation-like aggregation mechanism. We further simulated an extended fragment of tRRM2A, tRRM2A-l (residues 220-269). Although its predicted aggregation propensity remains largely unchanged, tRRM2A-l exhibits increased structural flexibility, and a stronger exposure of Nuclear Export Signal residues. Our results indicate that subtle differences in RRM2 fragment length influence potential misfolding pathways. Future studies and therapeutic strategies to prevent TDP-43 aggregation should carefully consider the specific domain adopted.
    Keywords:  ALS (Amyotrophic lateral sclerosis); TDP43; aggregation model; molecular dynamics simulation; protein aggragation; protein structure and function
    DOI:  https://doi.org/10.3389/fmolb.2026.1849627
  36. Ageing Res Rev. 2026 Jul 08. pii: S1568-1637(26)00240-0. [Epub ahead of print]121 103248
    The autophagy-senescence-inflammasome axis: A novel triad in neurodegenerative diseases?
    Surendar Ellappan, Punit Prasanna Kujur, Amal Chandra Mondal.
      Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.
    Keywords:  Autophagy; Glial senescence; Inflammasome; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.arr.2026.103248
  37. Neuromuscul Disord. 2026 Jun 17. pii: S0960-8966(26)00137-9. [Epub ahead of print]65 106469
    Clinical studies in 82 individuals with valosin-containing protein (VCP) associated multisystem proteinopathy and literature review.
    Candela Romano, Leepakshi Johar, Keira Hundhausen, Virginia Kimonis.
      Valosin-containing protein (VCP) pathogenic variants cause a multisystem proteinopathy characterized by myopathy, Paget disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis (ALS). We evaluated 82 affected individuals, 14 presymptomatic carriers, and 36 unaffected first-degree relatives from 48 families to identify sensitive measures for disease monitoring. Mean age of onset was ∼42 years for myopathy, Paget disease, or ALS, and 53 years for dementia. Functional assessments included the Inclusion Body Myositis Functional Rating Scale (IBMFRS), ALSFRS-R, Fatigue Severity Scale (FSS), and six-minute walk test (6MWT). Affected individuals demonstrated progressive functional decline, with IBMFRS decreasing 1.9% annually, FSS increasing 4.4%, and 6MWT decreasing 6% annually when modeled against disease duration. Women declined more rapidly on IBMFRS but showed slower ambulatory and fatigue progression. Potential genotype-specific effects were observed, with earlier onset and shorter survival in p.Arg155Cys compared to later onset in p.Arg155His. Strong correlations among IBMFRS, FSS, and 6MWT indicate these as accessible endpoints for longitudinal monitoring and clinical trials. Rapid decline with ALS and dementia necessitates multidisciplinary support, while longer survival after myopathy or Paget onset offers a window for preventive and supportive interventions.
    Keywords:  6-Minute walk test; ALS; ALSFRS-R; Frontotemporal dementia; Genotype; IBMFRS; MSP1; Multisystem proteinopathy; Paget disease; Phenotype; VCP
    DOI:  https://doi.org/10.1016/j.nmd.2026.106469
  38. Toxicol Appl Pharmacol. 2026 Jul 10. pii: S0041-008X(26)00239-5. [Epub ahead of print] 117943
    Fisetin prevents deterioration of cellular functions in amyotrophic lateral sclerosis variants G262R and P438L of SQSTM1 in SH-SY5Y cells.
    Nidhi Singh, James Gomes.
      Oxidative stress is widely accepted as one of the important factors contributing to neurodegeneration, leading to fatal neurodegenerative diseases (NDD) such as Amyotrophic Lateral Sclerosis. Since flavonoids possess antioxidant properties, we investigated whether Fisetin (FS) and Quercetin (QR) protected cells from oxidative stress arising from pathogenic mutations G262R (G > A) and P438L (C > T) of SQSTM1 found in Indian ALS patients. SQSTM1 codes for p62 protein and is involved in multiple signaling pathways through its various domains. We studied changes in cell viability and cellular functions using immunoblotting, confocal microscopy, immunoprecipitation and FACS analysis in the presence and absence of FS and QR. Supplementation with FS and QR in SH-SY5Y cells expressing SQS-wild type and mutants increased cell viability and decreased ROS formation. Also, Nrf2 protein levels increased to offset oxidative stress response. In addition, we studied the effect of FS on the nuclear-cytoplasmic distribution of TDP-43 protein, which serves as a hallmark for ALS. FS corrected the nuclear-cytoplasm translocation of TDP-43 protein and decreased late apoptosis in mutants. Our study illustrates that both FS and QR shield cells from oxidative stress, and that FS imparted better protection against the pathogenic effect of SQSTM1 mutants in SH-SY5Y neuronal cells.
    Keywords:  Amyotrophic lateral sclerosis; Fisetin; Flavonoids; Mutation; Oxidative stress; Quercetin; sequestosome1
    DOI:  https://doi.org/10.1016/j.taap.2026.117943
  39. Cell Rep. 2026 Jul 07. pii: S2211-1247(26)00750-3. [Epub ahead of print]45(7): 117672
    Striatal neuron dysfunction in C9ORF72-FTD/ALS is driven by AIS and potassium channel dysregulation.
    Iris-Stefania Pasniceanu, Manpreet S Atwal, Cleide Dos Santos Souza, Tobias Moll, Marianne King, Connie Treanor, Daniel Cabezas de la Fuente, Ryan J H West, Laura Ferraiuolo, Matthew R Livesey.
      Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) form a neurodegenerative spectrum characterized by progressive cognitive, behavioral, and motor decline, yet the contribution of the striatum to disease pathophysiology remains poorly understood. Here, we generate inhibitory striatal medium spiny neurons (MSNs) from human induced pluripotent stem cells carrying the C9ORF72 repeat expansion, the most common genetic cause of FTD/ALS, and compare them with isogenic-corrected, control, and patient-derived motor neurons. Using whole-cell electrophysiology, pharmacological manipulation, and high-resolution imaging, we identify a vulnerability of C9ORF72 MSNs to develop intrinsic hypoexcitability with linked synaptic dysfunction. These abnormalities are associated with axon initial segment shortening and altered voltage-gated potassium channel function relative to control and isogenic-corrected neurons. Pharmacological modulation partially restores action potential waveform properties, indicating that key electrophysiological abnormalities are reversible. These findings identify the striatum as a critical site of dysfunction in FTD/ALS and highlight striatal excitability as a potential therapeutic target.
    Keywords:  ALS; C9ORF72; CP: neuroscience; FTD; electrophysiology; excitability; inhibitory; neuron; striatal; synaptic
    DOI:  https://doi.org/10.1016/j.celrep.2026.117672
  40. PLoS Genet. 2026 Jul 08. 22(7): e1012225
    Multi-regional transcriptomic profiling reveals divergent molecular mechanisms in ALS-related neurodegeneration.
    Yu-Wen Hsu, Yu-Ning Lu, Mingming Liu, Jiou Wang.
      Neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) remain largely unsolved, with complex etiology yet to be fully elucidated. The most common genetic cause of ALS in both familial and sporadic cases is the expansion of a hexanucleotide repeat in the C9orf72 gene. To systemically dissect the molecular landscape of ALS, we performed integrative transcriptomic analyses across multiple central nervous system regions from ALS patients carrying pathological C9orf72 repeat expansions (ALS-C9) and those without the mutation (ALS-non-C9). In parallel, we performed transcriptome-wide cell-type deconvolution to assess the cellular composition of neuronal and non-neuronal populations. We identified a set of dysregulated molecular pathways that were consistently altered in both ALS-C9 and ALS-non-C9 patients, suggesting shared pathogenic mechanisms. Distinct gene-specific alterations also pointed to divergent subtype-dependent molecular trajectories. Gene-specific alterations were also associated with short clinical duration in ALS-non-C9, highlighting a sex-dependent immunological contribution to disease outcome. Our cross-regional integrative transcriptomic analyses reveal both convergent and divergent molecular and cellular features between ALS-C9 and ALS-non-C9 subgroups, underscoring the clinical heterogeneity of ALS and providing a framework for subtype- and sex-specific therapeutic stratifications.
    DOI:  https://doi.org/10.1371/journal.pgen.1012225
  41. Tissue Barriers. 2026 Jul 04. 2696764
    Blood-brain barrier permeability in diffuse large B-Cell lymphoma: associations with established risk factors for CNS relapse.
    Martine Prütz Nørskov, Elisabeth Præstekjær Cramer, Ulrich Lindberg, Adam Espe Hansen, Jonathan Frederik Carlsen, Peter de Nully Brown, Henrik Bo Wiberg Larsson, Martin Hutchings, Stig Præstekjær Cramer.
      Central nervous system (CNS) relapse is a serious complication of diffuse large B-Cell lymphoma (DLBCL), often associated with poor clinical outcomes. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) enables detection of subtle blood-brain barrier (BBB) leakage. We assessed BBB permeability, using the Patlak model, in 63 patients with DLBCL without CNS involvement and 11 healthy controls using DCE-MRI, and investigated associations with established risk factors for CNS relapse. Patients with high risk of CNS relapse (CNS-IPI  ≥4) demonstrated near-significant increased BBB permeability in cortical gray matter (GM) compared with both low-risk patients (p = 0.053) and healthy controls (p = 0.02). BBB permeability in cortical GM and in cerebral white matter (WM) correlated positively with age (p < 0.001). After adjusting for age, patients with kidney and/or adrenal involvement exhibited significantly higher BBB permeability in cortical GM (p = 0.04). Furthermore, plasma albumin levels were inversely correlated with BBB permeability in both GM (p = 0.003) and WM (p = 0.005). These findings indicate that subclinical BBB dysfunction may contribute to CNS vulnerability in DLBCL, potentially predisposing patients to relapse even before CNS involvement occurs. The observed age-related increase in BBB permeability is consistent with previous reports and may represent an independent risk for CNS relapse. Collectively, these results suggest that BBB imaging could improve CNS risk stratification in DLBCL. Prospective studies are warranted to determine whether early BBB alterations can predict CNS relapse in individual patients.
    Keywords:  Blood-brain barrier; central nervous system; cerebral blood volume; diffuse large B-Cell lymphoma; dynamic contrast-enhanced magnetic resonance imaging
    DOI:  https://doi.org/10.1080/21688370.2026.2696764
  42. Eur Neurol. 2026 Jul 09. 1-18
    Neurofilament Light Chain as a Biomarker in Neurology.
    Emilia Szyłak, Agata Czarnowska, Agnieszka Kulczyńska-Przybik, Jan Kopitelow, Barbara Mroczko, Jan Kochanowicz, Alina Kułakowska.
      Neurofilament light chain (NfL) has emerged as a highly sensitive biomarker of neuroaxonal injury across diverse neurological disorders. This review synthesizes current evidence regarding its diagnostic, prognostic, and therapeutic-monitoring utility, while outlining major clinical limitations and emphasizing the complementary role of glial fibrillary acidic protein (GFAP). NfL concentrations increase following axonal damage and correlate with inflammatory activity, lesion burden, and long-term disability progression in multiple sclerosis. Elevated levels also reflect neurodegeneration in Alzheimer's disease, predict disease severity and survival in amyotrophic lateral sclerosis, and are associated with motor and cognitive decline in Parkinson's disease and multiple system atrophy. In acute neurological conditions, including traumatic brain injury and stroke, NfL serves as a robust indicator of the extent of neuronal injury. Interpretation is constrained, however, by substantial physiological variability related to age, renal function, body mass index, and comorbidities, limiting the utility of absolute cut-off values. GFAP provides complementary information by capturing astrocytic damage, and the GFAP/NfL ratio may aid in differentiating multiple sclerosis from neuromyelitis optica spectrum disorder. Integration of NfL with multimodal biomarkers- such as GFAP, tau proteins, proteomic and metabolomic signatures, and advanced neuroimaging-may enhance diagnostic specificity and prognostic accuracy. Future research priorities include establishing age-adjusted reference intervals, validating longitudinal thresholds, and incorporating NfL into therapeutic monitoring frameworks. Advances in these areas are expected to improve diagnostic precision and support broader clinical implementation of NfL.
    DOI:  https://doi.org/10.1159/000552933
  43. Neuropathol Appl Neurobiol. 2026 Aug;52(4): e70090
    Frontotemporal Lobar Degeneration-TDP Type C With Striatal Glial Cytoplasmic Inclusions and Motor Neuron Degeneration.
    Akiko Uchino, Kazutomi Kanemaru, Airi Tarutani, Masato Hasegawa, Hiroya Naruse, Hiroyuki Ishiura, Shigeo Murayama, Yuko Saito.
      We report an autopsy case of frontotemporal lobar degeneration (FTLD)-TDP type C with severe striatal involvement and annexin A11- and phosphorylated TDP-43-positive glial cytoplasmic inclusions. The patient developed progressive asymmetric rigidity accompanied by marked striatal atrophy and showed both upper and lower motor neuron involvement. These findings expand the clinicopathological spectrum of FTLD-TDP type C and may support the concept of an annexin A11-associated pathogenic continuum linking FTLD and amyotrophic lateral sclerosis.
    Keywords:  TDP‐43; amyotrophic lateral sclerosis; annexin A11; corticobasal syndrome; frontotemporal lobar degeneration; glial cytoplasmic inclusions; motor neuron disease
    DOI:  https://doi.org/10.1111/nan.70090
  44. bioRxiv. 2026 Jul 03. pii: 2026.07.01.735865. [Epub ahead of print]
    Shared and disease-specific human brain vascular signatures in Alzheimer's disease, frontotemporal dementia, and Huntington's disease.
    Patrycja M Forster, Oliver Bracko, Ruslan Rust.
      The blood-brain barrier (BBB) plays a central role in brain function and is increasingly implicated in neurodegenerative disease. Major neurodegenerative disorders, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Huntington's disease (HD), share overlapping pathological features. Yet, the extent to which these diseases converge or diverge at the level of BBB-associated cell types remains poorly understood. Here, we performed a comparative analysis of vessel-enriched human brain transcriptomic datasets across AD, FTD, and HD to define shared and disease-specific neurovascular alterations. We identify a partially conserved transcriptional signature of vascular dysfunction across all three diseases, alongside disease-specific changes in endothelial, pericyte, and perivascular cell populations. Endothelial remodeling was most prominent in capillary and venous segments, highlighting segment-specific vulnerability along the arteriovenous axis. Notably, we identified two molecularly distinct human pericyte subtypes across all three datasets and found a consistent reduction in the matrix-type pericytes (M-peri) fraction, suggesting a selective decline. Cell-cell communication analysis further revealed reorganized endothelial-pericyte signaling networks, with prominent alterations in extracellular matrix-associated pathways, including LAMININ, COLLAGEN, FN1, and NCAM, together with changes in contact-dependent and vascular signaling pathways such as NOTCH and VEGF. Together, our findings define shared and disease-specific neurovascular mechanisms across major neurodegenerative disorders and highlight BBB-associated pathways as central features of neurodegeneration, providing a framework for future diagnostic and therapeutic strategies.
    DOI:  https://doi.org/10.64898/2026.07.01.735865
  45. FEBS J. 2026 Jul 08.
    TOP1MT rs2293925 is an enhancer-active regulatory SNP that shapes mitochondrial R-loop dynamics.
    Dóra Varga, Zsolt Ráduly, Beáta Boros-Oláh, Éva Nagy, Zsolt Karányi, László Halász, Bálint László Bálint, György Vámosi, Emese Tóth, Péter Bai, Serena Santangelo, Patrizia Bossolasco, Antonia Ratti, Vincent Géli, Yves Pommier, Lóránt Székvölgyi.
      Mitochondrial topoisomerase 1 (TOP1MT) regulates mitochondrial DNA (mtDNA) topology during transcription and replication. Perturbed mtDNA maintenance and RNA metabolism have been implicated in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and is associated with increased mitochondrial R-loops (RNA : DNA hybrids). Tissue-dependent expression, quantitative trait locus analysis, chromatin-state annotation, reporter assays, and allele-specific DNA-protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, rs2293925 increased TOP1MT mRNA and protein abundance, and this was accompanied by increased mitochondrial R-loop signal. TOP1MT trapping with lamellarin D supported increased TOP1MT-R525W occupancy at mitochondrial control region sites together with enhanced R-loops, consistent with altered TOP1MT-mtDNA interaction and/or increased TOP1MT abundance. Elevated mitochondrial R-loop signal was also detected in a pilot cohort of sporadic ALS samples carrying rs2293925 and in neural stem cells derived from C9orf72-positive ALS patients. These data support a dual-effect model in which rs2293925 increases TOP1MT expression and is associated with altered mitochondrial R-loop dynamics, linking common genetic variation to mitochondrial nucleic acid stress in disease-relevant contexts.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); DRIP‐seq; R‐loop; TOP1MT; mitochondrion; rs2293925; topoisomerase
    DOI:  https://doi.org/10.1111/febs.70649
  46. Discov Immunol. 2026 ;5(1): kyag011
    Region-specific features of early glial activation and Aquaporin-4 dysregulation in conditional mouse models of TDP-43 proteinopathies.
    Gabriela Nieva, Florencia Vassallu, Amaicha Depino, Vanina Netti, Lionel Muller Igaz.
       Introduction: Aggregation and cytoplasmic mislocalization of TDP-43 are key features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuroinflammatory processes mediated by glial cells play crucial roles in the pathophysiology of these and other diseases, defined as TDP-43 proteinopathies. Here, we characterized region-specific glial activation in two conditional mouse models: hTDP-43-WT (overexpressing nuclear wild-type human TDP-43) and hTDP-43-ΔNLS (expressing cytoplasmic TDP-43 with altered nuclear localization signal) following 1 month of transgene expression.
    Methods and Results: Immunofluorescence analysis revealed distinct patterns of microglial activation across brain regions. hTDP-43-WT mice exhibited significant microgliosis in motor (MC) and somatosensory (SSC) cortices and hippocampal dentate gyrus (DG) with pronounced morphological alterations (i.e. increased soma size). Sholl analysis demonstrated reduced branching length and complexity in MC, SSC, and hippocampal subfields. hTDP-43-ΔNLS mice displayed more pronounced microglial activation in hippocampal regions (CA1, DG) compared to cortical areas, with significant increases in microglial density. Additionally, we observed region-specific cortical astrocytosis in both models, suggesting coordinated glial reactivity. hTDP-43-ΔNLS mice showed decreased polarization of astrocytic water channel Aquaporin-4 (AQP4) around vascular structures in SSC and hippocampal CA1/DG. The changes in AQP4 localization, which is critical for glymphatic function, support the hypothesis that this waste clearance system for the brain is altered in TDP-43 proteinopathies.
    Conclusion: These findings demonstrate that these different animal models of ALS/FTD induce distinct neuroinflammatory signatures, potentially contributing to the region-specific vulnerability observed in these diseases. Our data provide insights into early glial-mediated pathogenic mechanisms that could guide targeted therapeutic strategies for TDP-43 proteinopathies.
    Keywords:  Aquaporin-4; TDP-43; brain; microglia; neuroinflammation
    DOI:  https://doi.org/10.1093/discim/kyag011
  47. J Neuroinflammation. 2026 Jul 10.
    Tertiary lymphoid structures in neuroinflammation coordinate neuroimmune homeostasis and pathological progression.
    Yan Zhang, Peishen Han, Xiaoling Zhang.
      The central nervous system (CNS) has long been considered immune privilege due to the blood-brain barrier, lack of traditional lymphatic drainage, and unique immune microenvironment. However, recent neuroimmunology research has demonstrated that the CNS maintains continuous communication with the peripheral immune system via meningeal lymphatic vessels, lymphoid systems, and border-associated macrophages. This paradigm shift has brought tertiary lymphoid structures (TLSs), ectopic lymphoid aggregates induced by chronic inflammation, infection, or tumors, into focus as key players in neuroimmune interactions. TLSs exert a dual effect in neuroinflammation. In infectious diseases like viral encephalitis, they promote local antibody production and T cell responses, aiding pathogen clearance. In contrast, in multiple sclerosis, autoimmune encephalitis, Alzheimer's disease, and Parkinson's disease, TLSs may sustain chronic inflammation, drive autoantibody production, and accelerate neurodegeneration. This review systematically summarizes the composition, induction mechanisms, and functional heterogeneity of TLSs across neurological diseases. We discuss their protective versus pathogenic roles in neuroinflammation and highlight their diagnostic value and therapeutic potential, aiming to provide new insights for precision intervention in neuroimmunological disorders.
    Keywords:  Disease progression; Neuroimmune homeostasis; Neuroimmune interaction; Neuroinflammation; Tertiary lymphoid structures
    DOI:  https://doi.org/10.1186/s12974-026-03961-6
  48. BMC Neurol. 2026 Jul 07.
    Biological sex differences in neurodegenerative diseases in Africa: a scoping review of evidence and research gaps.
    Mundih Noelar Njohjam, Mark Olivier Ngoule, Tiffany Falonne Niakam.
       BACKGROUND: Biological sex is a well-established determinant of risk, progression, and therapeutic response in neurodegenerative diseases (NDs). However, current evidence on sex differences in NDs is from high-income Western populations. This review aims to map and synthesize evidence on biological sex differences in NDs in Africa, and to identify key research gaps.
    METHODS: This scoping review was conducted in accordance with the Joanna Briggs Institute methodology and reported in accordance with the PRISMA-ScR guidelines. A literature search was conducted on PubMed, African Journals Online, Sabinet Journals, ScienceDirect, and Google Scholar. We included studies conducted in African countries that reported sex disaggregated data or examined biological sex differences in at least one ND. Data were synthesized descriptively.
    RESULTS: All included studies reported sex distribution, but most (about 84%) did so only descriptively. Approximately 17% conducted sex-stratified analyses beyond prevalence. Similar to global epidemiological trends, several studies suggested a higher prevalence or odds of dementia and multiple sclerosis among females, while male predominance was observed in Parkinson's disease and Amyotrophic lateral sclerosis studies. An earlier onset and a higher mutation frequency in LRRK2-G2019S were reported in females with Parkinson's disease in some studies, while another study reported a higher mortality rate in females with dementia. No study evaluated sex specific biomarker profiles, disease progression, or treatment response.
    CONCLUSIONS: Evidence on biological sex differences in NDs in Africa remains limited and is largely descriptive. Mechanistic, longitudinal, and biomarker-based investigations are largely absent.
    Keywords:  Africa; Neurodegenerative disease; Sex differences
    DOI:  https://doi.org/10.1186/s12883-026-05123-w
  49. Ann N Y Acad Sci. 2026 Jul;1561(1): e70311
    Phase Separation Drives Pathological Aggregation in Neurodegenerative Diseases: A 15-Year Bibliometric Landscape (2009-2024).
    Chanyuan Zhang, Siyao Chen, He Zhao, Yan Wang, Lingyan Zhou, Haixia Fan, Yan Sun.
      Liquid-liquid phase separation (LLPS), a biophysical driver of membraneless organelle assembly, is central to pathological aggregation in neurodegenerative diseases. Initially linked to amyotrophic lateral sclerosis (ALS), LLPS dysregulation has now been implicated in Alzheimer's, Parkinson's, and frontotemporal dementia, where aberrant transitions convert dynamic condensates into insoluble fibrils. To systematically map this landscape, we employed CiteSpace-based bibliometrics to analyze 784 Web of Science articles from 2009 to 2024. Our analyses reveal dominant contributions from the United States, China, and Germany, with collaborative networks focusing on protein dynamics. Key hotspots include LLPS-driven aggregation of TARDBP (TDP-43), FUS, and α-synuclein, alongside stress granule dysfunction and nucleocytoplasmic transport defects. Emerging frontiers highlight therapeutic strategies targeting pathological condensates utilizing small-molecule chaperones and posttranslational modification modulators to restore cellular homeostasis. Our findings underscore LLPS as a critical axis bridging molecular pathology and translational innovation. The field is rapidly shifting from mechanistic exploration to therapeutic applications, emphasizing interventions to halt or reverse aggregation. By delineating global trends and changing priorities, our study highlights the transformative potential of phase-targeted interventions and provides a roadmap of groundbreaking interdisciplinary research into neurodegenerative disorders.
    Keywords:  Alzheimer's disease; bibliometric analysis; liquid–liquid phase separation; neurodegenerative diseases; pathological aggregation
    DOI:  https://doi.org/10.1111/nyas.70311
  50. J Leukoc Biol. 2026 Jul 03. pii: qiag085. [Epub ahead of print]118(7):
    Metabolic and epigenetic regulation of microglia memory in neurological disorders.
    Xiaoya Wang, Yunpeng Jia, Xinyi Yan, Youwei Wang.
      As tissue-resident innate immune cells of the central nervous system, microglia are capable of acquiring innate immune memory-a persistent state of functional reprogramming triggered by prior stimuli. This memory typically manifests as 3 distinct phenotypes: trained immunity, immune tolerance, and immune exhaustion. In this review, we synthesize current knowledge on the metabolic and epigenetic mechanisms that govern these 3 forms of microglial innate immune memory. We further summarize and discuss how each phenotype is induced in microglia and its respective pathophysiological roles in neurological disorders. Owing to their slow turnover and unique tissue-resident characteristics, microglia sustain long-lasting memory states that can profoundly influence the trajectory of neuroinflammation and neurodegeneration. Finally, we highlight the bidirectional effects of microglial immune memory on disease progression, discuss emerging therapeutic strategies aimed at modulating these memory states, and outline key translational challenges that remain to be addressed.
    Keywords:  epigenetic reprogramming; innate immune memory; microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.1093/jleuko/qiag085
  51. ACS Omega. 2026 Jul 07. 11(26): 38581-38593
    From the Gut to the Brain: Modeling Intestinal Absorption and Assessing Blood-Brain-Barrier Permeability of Small-Molecule Drugs by IAM Chromatography.
    Stefan Simić, Predrag Kalaba, Judith Wackerlig, Thierry Langer.
      Designing small-molecule compounds and delivery systems capable of crossing the blood-brain barrier (BBB) remains a major obstacle in central nervous system (CNS) drug development. This challenge is compounded by the lack of robust, rapid, and cost-effective methods for early-stage assessment of BBB permeability. In this study, we addressed this gap by evaluating immobilized artificial membrane (IAM) chromatography as a high-throughput screening tool using a set of 50 marketed drugs with diverse chemical structures and well-documented CNS penetration profiles (both positive and negative). The strong correlation between IAM retention parameters (k IAM) and passive diffusion-based permeability confirms the ability of this biomimetic method to simulate drug-membrane interactions, establishing IAM chromatography as a reliable and economical alternative to more complex cell-based and in vivo models. Additionally, the integration of IAM data with in silico molecular descriptors yields a predictive model for intestinal absorption, offering a powerful tool for early permeability profiling in drug discovery.
    DOI:  https://doi.org/10.1021/acsomega.6c00701
  52. Sci Data. 2026 Jul 11.
    Compound muscle action potential scan dataset in adults with spinal cord injury and healthy controls.
    Junjun Chen, Peipei Xu, Maoqi Chen, Zhiyuan Lu, Xiaoyan Li, Argyrios Stampas, Ya Zong, Ping Zhou.
      Certain neurological conditions, such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), result in motor unit loss in muscles. The stimulus-evoked compound muscle action potential (CMAP) scan captures comprehensive information on motor unit recruitment that enables rapid and non-invasive assessment of motor unit status. However, few publicly available CMAP scan datasets exist to support research on motor unit number estimation (MUNE). To address this gap, we collected CMAP scan data from the first dorsal interosseous (FDI) muscle of 13 individuals with SCI and 13 healthy participants, and established a dedicated CMAP scan dataset. The dataset includes CMAP waveforms evoked by each nerve stimulus from which CMAP scan curve and typical parameters were extracted for direct use. All SCI participants underwent multiple clinical assessments and exhibited a spectrum of impairment severity from mild to severe, resulting in diverse CMAP features. We anticipate that this dataset will facilitate the development of advanced CMAP scan-based assessment techniques and aid in the investigation of neuromuscular impairment.
    DOI:  https://doi.org/10.1038/s41597-026-07864-2
  53. Front Immunol. 2026 ;17 1837643
    Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation.
    Hui Guo, Ziyu Yang, Long Cheng.
      Neuroinflammation is increasingly recognized as a core pathological process in various neurological diseases, including neurodegenerative disorders, stroke, autoimmune demyelinating diseases, and acute brain dysfunction associated with systemic inflammation. Among its regulatory mechanisms, the cholinergic anti-inflammatory pathway links neural activity with immune regulation. However, its neurological relevance extends beyond the classical peripheral vagus nerve-mediated inflammatory reflex. Within the central nervous system, cholinergic signaling interacts with resident immune cells, particularly microglia, and influences inflammatory tone, neuronal vulnerability, and tissue repair. Recent advances in immunometabolism further suggest that metabolic reprogramming may bridge cholinergic signaling and microglial inflammatory phenotypes. In this review, we discuss the role of cholinergic regulation of neuroinflammation from three interrelated perspectives: microglia as the hub of core cells, immune metabolism as the basis of mechanism, and neural regulation as the frontier of transformation. We first reviewed the cholinergic system and its role in neuroimmune communication, then discussed how cholinergic signals shape microglial state and metabolic process, and finally evaluated its disease-specific evidence in Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and acute inflammatory brain dysfunction. We will also discuss pharmacological and bioelectronic methods, including targeting cholinergic receptors and vagus nerve stimulation, as emerging therapeutic strategies. By integrating cholinergic biology, microglial heterogeneity, and metabolic reprogramming, this review proposes an updated framework for understanding neuroinflammation in neurology, and highlights the future opportunities for precise neuroimmune intervention.
    Keywords:  cholinergic signaling; immunometabolism; microglia; neuroinflammation; vagus nerve stimulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1837643
  54. J Imaging Inform Med. 2026 Jul 07.
    3D OCT-Based Retinal Biomarker Analysis for Automatic Regional-Wise Characterization of Neurodegenerative Diseases.
    Lorena Álvarez-Rodríguez, Carlota Vázquez, Beatriz Cordón, Elena Garcia-Martin, Joaquim de Moura, Jorge Novo, Marcos Ortega.
      Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), essential tremor (ET), multiple sclerosis (MS), and Parkinson's disease (PD) are complex disorders that often exhibit overlapping symptoms, leading to diagnostic challenges. Given the increasing interest in retinal imaging as a non-invasive biomarker for neurodegeneration, this study proposes a fully automated machine learning pipeline for disease characterization using optical coherence tomography (OCT). We analyze macular thickness patterns across three key and relevant retinal elements: retinal nerve fibre layer (RNFL), ganglion cell layer to Bruch's membrane (GCL-BM), and the total retina. These are processed by two complementary regional layouts: the standard ETDRS scheme and a custom 3 × 3 quadrant grid. These measurements are used to train multiple classifiers to distinguish between healthy controls and NDDs either collectively or individually. The proposed method processes 34,375 OCT B-scans from 353 subjects and highlights disease-specific thickness patterns with a pathological distinction score ranging up to 0.71 depending on the retinal region, disease, and classifier. Sector-based grids generally outperform quadrant-based ones, revealing highly localized pathological signatures. Our findings demonstrate that each disease manifests distinct retinal alterations, aligning with current clinical literature while offering novel insights for ET and PD. The study reinforces the potential of grid-based OCT analysis as a discriminative and fully automatic screening tool, paving the way for improved early diagnosis and differential analysis of NDDs through retinal biomarkers.
    Keywords:  Artificial intelligence; Machine learning; Neurodegenerative diseases; Optical coherence tomography; Retinal Imaging
    DOI:  https://doi.org/10.1007/s10278-026-02098-5
  55. Exp Neurol. 2026 Jul 10. pii: S0014-4886(26)00273-6. [Epub ahead of print] 115908
    Cellular, electrophysiological and behavioral improvements in a mouse model of Rett syndrome following gene therapy combined with focused ultrasound-mediated blood-brain barrier opening.
    Marie-Solenne Felix, Léna Bourcin, Emilie Borloz, Khaled Metwally, Benoit Larrat, Serge Mensah, Yasmine Belaidouni, Jean-Luc Gaiarsa, Anthony Novell, Laurent Villard, Jean-Christophe Roux.
      Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder due to pathogenic variants in the methyl CpG binding protein 2 gene (MECP2). The discovery that deficits resulting from Mecp2 loss are reversible in mice has increased interest in gene therapy as a potential cure for RTT. We have previously evaluated the efficacy of a self-complementary AAV9 vector expressing a codon-optimized version of Mecp2 (scAAV9-MCO) delivered via a systemic approach in early symptomatic Mecp2-knock-out male (KO) mice. In the present study, focused ultrasound (FUS) was used to transiently disrupt the blood-brain barrier (BBB) in a RTT mouse model, thereby facilitating enhanced AAV delivery to the central nervous system (CNS). Our findings demonstrate that scAAV9-MCO administration, when combined with FUS, significantly improves survival, body weight, respiratory function, and locomotor activity, while restoring the excitatory-inhibitory synaptic balance in hippocampal neurons in treated KO mice relative to untreated animals. Quantification of the brain infection level revealed that 20-40% of cells are Mecp2-positive in the brain of KO mice following the treatment with scAAV9-MCO and FUS. This is a significant improvement compared to prior results without FUS. The evaluation of the protein levels indicates a possible overdose of Mecp2 protein in the brain cells. Nevertheless, these results demonstrate that using FUS following systemic administration of an AAV9 vector represents a significant improvement over classical gene therapy protocol for RTT.
    Keywords:  Blood brain barrier; Brain distribution; Breathing; Focused ultrasound; Gene therapy; Locomotion; Mecp2; RTT
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115908
  56. Brain Res Bull. 2026 Jul 07. pii: S0361-9230(26)00323-0. [Epub ahead of print]243 112036
    Are T1-weighted and T2-weighted volumetric pipelines interchangeable methodologies for investigating amyotrophic lateral sclerosis pathology in vivo?
    Sana Mohammadi, Francesca Trojsi, Sadegh Ghaderi.
       PURPOSE: To test the hypothesis that T1-w and T2-w volumetric pipelines are not interchangeable, particularly regarding their differential sensitivity to physiological traits and disease effects in the red nucleus (RN) and substantia nigra (SN).
    METHODS: Thirty-one patients with ALS (mean age: 59.39 ± 8.73 years; 23 males) and 21 non-neurodegenerative controls (mean age: 53.43 ± 10.01 years; 16 males). Bilateral RN and SN volumes were automatically extracted using deep learning pipelines optimized for T1-w (OpenMAP-T1) and T2-w (pBrain) images. Volumes were normalized to total intracranial volume. A 2 × 2 × 2 repeated-measures general linear model (GLM) assessed interactions between Method, Region, Side, and Group, controlling for age, sex, BMI, and handedness.
    RESULTS: There was no significant main effect of the disease group (p = 0.829) or Method × Group interaction (p = 0.682), indicating both pipelines agreed on the absence of disease-specific macrostructural atrophy. However, a significant four-way Method × Region × Side × Age interaction (P = 0.031) was observed. In the RN, the T2-w pipeline detected robust age-related atrophy (Left: Slope = -1.84 × 10-6; Right: Slope = -1.70 ×10⁻⁶), whereas the T1-w pipeline did not (p > 0.05). Conversely, in the SN, T1-w consistently identified bilateral age-related loss, whereas T2-w yielded lateralized results (Right: p = 0.011; Left: P = 0.465).
    CONCLUSIONS: T1-w and T2-w pipelines are not interchangeable. Though both confirm the absence of gross atrophy in this ALS cohort, their differing sensitivity to physiological aging highlights their distinct biological tissue properties, requiring method-specific interpretation.
    Keywords:  Aging; Imaging Technique; Motor Neuron Disease; Structural MRI, Amyotrophic Lateral Sclerosis
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.112036
  57. Front Biosci (Landmark Ed). 2026 Jun 26. 31(6): 47325
    Icariin Attenuates Neuroinflammation and Dopaminergic Degeneration in a Rodent Model of Parkinson's Disease by Promoting the Expansion of Regulatory T Cells.
    Sicong Xu, Li Jiang, Hao Zhang, Ping Zhang, Zhao Pan.
       BACKGROUND: Icariin, a bioactive flavonoid, exhibits significant neuroprotective properties and has emerged as a promising candidate for preventing neurodegenerative diseases, including Parkinson's disease (PD). However, the mechanism underlying its action is not fully understood. Enhancing the function and frequency of peripheral regulatory T cells (Tregs) may mitigate dopaminergic degeneration. This study investigates the role of Tregs in icariin's neuroprotective effects in a rodent model of PD.
    METHODS: PD was induced in mice via stereotactic injection of 6-hydroxydopamine (6-OHDA). Mice underwent pretreatment with saline, icariin, an androgen receptor inhibitor (ARI), or a combination of icariin and ARI. Motor function was assessed in each experimental group, and dopaminergic neuronal injury was evaluated using immunohistochemistry (IHC) staining for tyrosine-hydroxylase (TH) in the substantia nigra (SN) and striatum. IHC was used to quantify CD4+ T-cell infiltration in the SN. Neuroinflammation was assessed through mRNA levels of the pro-inflammatory M1 phenotype of microglia, the anti-inflammatory M2 phenotype of microglia, and the levels of indicated pro-inflammatory cytokines in the SN. The frequency of Tregs among peripheral blood mononuclear cells (PBMCs) was analyzed by flow cytometry, and with Tregs were depleted using PC61 monoclonal antibodies. In vitro androgen receptor (AR) knockdown using shRNA in naïve CD4+ T cells was performed to validate the AR-dependent mechanism.
    RESULTS: The results revealed that icariin significantly alleviated dopaminergic degeneration. Mechanistically, icariin promotes the expansion of peripheral neuroprotective and immunosuppressive Tregs, thereby restricting CD4+ T cell migration into the SN. This improvement in the inflammatory microenvironment reduced neuroinflammation and mitigated neurodegeneration. However, the neuroprotective and anti-inflammatory effects of icariin were lost when combined with ARI. Additionally, Treg depletion before 6-OHDA injection reversed the positive effects observed in the PD model.
    CONCLUSIONS: Icariin protects against neurodegeneration and neuroinflammation by boosting Tregs expansion in an androgen receptor-dependent manner.
    Keywords:  Parkinson’s disease; androgen receptor; icariin; regulatory T cell
    DOI:  https://doi.org/10.31083/FBL47325
  58. Commun Biol. 2026 Jul 07.
    Macropinocytosis mediates neurotropism of Cryptococcus neoformans in a human organoid model of the blood-brain barrier.
    Amelia B Bennett, Dylan M Lanser, Kiem Vu, Amita R Sahoo, Matthias Buck, Angie Gelli.
      The opportunistic and neuroinvasive fungus, Cryptococcus neoformans (Cn), causes a life-threatening brain infection that despite treatment can cause long-term cognitive deficiencies. Studies have shown that Cn can infiltrate the central nervous system (CNS) through a transcellular route across the brain endothelium, however, the molecular process that drives brain endothelial cells to internalize Cn remains poorly defined. Here we examine the molecular interactions between fungal cells and the brain endothelium by utilizing a human 3D organoid model of the blood-brain barrier (BBB). We show that Cn exploits the process of macropinocytosis as the mechanism of endocytosis into brain endothelial cells by recruiting CD44 and EphA2 as a molecular complex. We identified two predicted binding sites on EphA2, suggesting that the two structurally distinct regions may provide a molecular basis for cooperative signaling in brain endothelial cells that stimulate macropinocytosis as the mode of entry for Cn.
    DOI:  https://doi.org/10.1038/s42003-026-10597-y
  59. ACS Chem Neurosci. 2026 Jul 07.
    Kynurenic Acid, a Key Endogenous Neuroprotective Agent: Role of Its Derivatives in Therapeutics.
    Swati Verma, Ramesh Ambatwar, Ashok Kumar Datusalia, Gopal L Khatik.
      Kynurenic acid (KYNA) is an endogenous molecule that acts as a nonselective antagonist of ionotropic glutamate receptors and has been shown to have neuroprotective properties. Although KYNA has shown considerable therapeutic potential in neurodegenerative disorders, its limited permeability across the blood-brain barrier restricts its direct clinical application. To overcome this limitation, various ester and amide derivatives have been developed as prodrugs to enhance brain delivery and subsequently release KYNA within the central nervous system. Beyond serving as prodrugs, KYNA derivatives have attracted substantial interest in medicinal chemistry due to their ability to interact with multiple molecular targets. Additionally, these compounds exhibit a wide range of biological activities, including potential treatments for Alzheimer's disease, Parkinson's disease, Huntington's disease, and psychiatric disorders. Therefore, kynurenic acid-based scaffolds have prompted further research into their derivatives, leading to a range of structurally distinct products. Here, we discuss the neuroprotective role of KYNA and its derivatives, which exhibit diverse bioactivities.
    Keywords:  Alzheimer’s disease; kynurenic acid; neurodegenerative disease; neuroprotective
    DOI:  https://doi.org/10.1021/acschemneuro.6c00081
  60. JAMA Neurol. 2026 Jul 06.
    Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors.
    Amanda J Guise, Monica Thanawala Sellon, Shanu F Roemer, Michael Monine, Nicole T Comfort Harris, Dan Bartlett, Eric David, Shanqin Xu, Luke Jandreski, Sohail Malek, Steve Garafalo, Ivan Nestorov, Margaret D Ireland, Andrew King, Robert P Bowser, Vladislav Korobeynikov, John Ravits, Pamela J Shaw, J Robin Highley, Toby A Ferguson, Stephanie Fradette, Danielle L Graham, Eric J Sorenson, Björn Oskarsson, R Ross Reichard, Dennis W Dickson, Sabrina Paganoni, Suma Babu, Derek H Oakley, Matthew P Frosch, Timothy M Miller, Robert C Bucelli, Richard J Perrin, Cindy V Ly, Edward D Plowey.
       Importance: Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1-amyotrophic lateral sclerosis (SOD1-ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues.
    Objectives: To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues.
    Design, Setting, and Participants: This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1-ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026.
    Exposures: Participants received multiple intrathecal 20- to 100-mg tofersen doses.
    Main Outcomes and Measures: Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study's recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1-ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays.
    Results: In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1-ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses.
    Conclusions and Relevance: This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.
    DOI:  https://doi.org/10.1001/jamaneurol.2026.2195
  61. Medicine (Baltimore). 2026 Jul 10. 105(28): e48922
    Refining the link between REM sleep behavior disorder and neurodegeneration: Genetic correlation, Mendelian randomization, and colocalization evidence.
    Hong Ye, Jia-Li Wang, Qiu-Han Xu, Yu-Liang Gao.
      Observational studies have proposed a link between isolated rapid eye movement sleep behavior disorder (iRBD) and several neurodegenerative diseases. We employed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analysis to assess the causal links between iRBD and these neurodegenerative conditions. iRBD demonstrated a positive causal association with Alzheimer disease (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.00-1.03, P = 1.10E-02), Parkinson disease (OR = 1.10, 95% CI: 1.03-1.16, P = 2.96E-03), and multiple sclerosis (OR = 1.09, 95% CI: 1.02-1.17, P = 1.61E-02). A strong positive genetic correlation with dementia with Lewy bodies was observed (rg = 1.6313, P = .0002), along with a causal association (OR = 1.45, 95% CI: 1.03-2.06, P = 3.53E-02), further supported by colocalization analysis. No significant causal relationship was identified between iRBD and amyotrophic lateral sclerosis (all P > .05). Additionally, reverse Mendelian randomization analyses did not reveal any causal relationships between the neurodegenerative diseases studied and iRBD. Our findings provide robust genetic evidence supporting a causal relationship between iRBD and the risk of multiple neurodegenerative diseases, highlighting the potential for shared pathophysiological mechanisms.
    Keywords:  Mendelian randomization; causal relationship; colocalization analysis; isolated REM sleep behavior disorder; linkage disequilibrium score regression; neurodegenerative diseases
    DOI:  https://doi.org/10.1097/MD.0000000000048922
  62. Mol Neurobiol. 2026 Jul 10. pii: 753. [Epub ahead of print]63(1):
    SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
    Qingya Wu, Dengying Fan, Jianhui Ren, Yafang Xing, Zhengzheng Chen, Haochen Jin, Yisheng Lu, Xiaopeng Wang, Hua Zheng.
      Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Neurodegenerative diseases; SUMOylation
    DOI:  https://doi.org/10.1007/s12035-026-06050-0
  63. bioRxiv. 2026 Jul 01. pii: 2026.01.24.701325. [Epub ahead of print]
    Small molecules targeting ARF1 interaction with C9orf72:SMCR8:WDR41 complexes suppress its overactivation implicated in ALS/FTD.
    Emma Dixon, Fereshteh Azimian, Angelina Joby Chacko, Rodney Tatum, Christi Boykin, Yan-Hua Chen, Qun Lu.
      The hexanucleotide repeat expansion in C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). The C9orf72 protein forms a complex with SMCR8 and WDR41 (CSW), which functions as a GTPase-activating protein (GAP) regulating ARF1 and RAB small GTPases. While these findings implicated ARF1-GAP dysregulation in ALS/FTD and supported ARF1 suppression as potential intervention, small molecules that modulate ARF1-CSW interactions are lacking. In this study, we demonstrated upregulation of tyrosine-phosphorylated (Tyr-782) ASAP1 (also known as AMAP1, DDEF1, or Centaurin β4), an ARF-GAP, in human motor cortex of both sporadic ALS and ALS with C9orf72 mutations. Ectopic C9orf72 expression partially mimicked the effects of a known ARF1 inhibitor brefeldin A to disperse Golgi apparatus. Computer-aided rational drug design with high-throughput in-silico screening identified MCULE-5095997944 (Named as SCC944) as a ARF1-CSW modulator. SCC944 binds directly to ARF1 and reduced GTP-bound ARF1 levels upon ARF1 activation. SCC944 demonstrated brefeldin A-like ARF1-dependent alteration of organelle organization including Golgi, microtubules, and mitochondria, but also a protein trafficking pattern that is distinct from brefeldin A mechanism. These studies identified the first small molecule targeting ARF1-CSW interaction and further support ARF1 modulation as a potential therapeutic approach for ALS/FTD.
    DOI:  https://doi.org/10.64898/2026.01.24.701325
  64. Cell Mol Neurobiol. 2026 Jul 10.
    Human iPSC-Derived Spinal Neurons Carrying the ALS FUS (P525L) Mutation Exhibit Lower Response to Inhibitory Neurotransmitters.
    Tiziano D'Andrea, Maria Cristina Benedetti, Michela Mochi, Valeria De Turris, Alessandro Rosa, Sergio Fucile.
      Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder characterized by motoneurons degeneration. Functional studies have linked ALS to hyperexcitability and excitotoxicity, but the cause of the disease is unknown, though familial ALS cases are linked to pathogenic variants in several genes, including SOD1, TARDBP and FUS. Here we focused on the effect of the severe FUS (P525L) mutation on the functional properties of human spinal neurons derived from induced pluripotent stem cells (hiPSCs). This mutation delayed functional maturation, as revealed by the observation that mutated neurons showed alterations of membrane potential, reduced spontaneous synaptic activity, and altered action potentials at early differentiation stages. FUS (P525L) mutation was associated with a significant alteration of inhibitory signalling transmission: mutated neurons showed a significantly lower current response to GABA and glycine compared to control isogenic WT neurons of the same age. Also, glutamatergic currents exhibited a different temporal evolution in control and mutated neurons, but at a lower extent in comparison to inhibitory neurotransmitters. The decrease in the glycine-evoked currents was confirmed by the reduction of the expression of the α1 subunit of glycine receptor, measured by immunofluorescence assay. Similar functional alterations were measured in spinal neurons differentiated form a second hiPSC line, confirming the causative role of the FUS (P525L) mutation. Our data indicate that the FUS (P525L) mutation reduces the maturation rates and the function of hiPSC-derived spinal neurons, with a strong decrease of inhibitory transmission, which may affect the excitatory/inhibitory balance, possibly predisposing to excitotoxicity and neurodegeneration.
    Keywords:  Excitotoxicity; Glycinergic transmission; Inhibitory/excitatory balance; Neurodegeneration; Neurotransmission
    DOI:  https://doi.org/10.1007/s10571-026-01773-z
  65. J Neurovirol. 2026 Jul 10. pii: 28. [Epub ahead of print]32(4):
    The emerging role of circular RNAs in neurodegenerative diseases and viral infections.
    Finley Medina, Anna Bellizzi.
      Circular RNAs (circRNAs) represent a class of highly stable, covalently closed RNA molecules increasingly recognized as important regulators of brain aging and neurodegenerative disease. Growing evidence also implies circRNAs in viral infection, suggesting a potential intersection between viral neuropathogenesis and neurodegeneration. However, no studies have yet directly integrated circRNAs, neurotropic viral infections, and neurodegenerative disorders within a single mechanistic framework. To date, specific circRNAs have been linked to the progression of Alzheimer's disease and Parkinson's disease, where they regulate central pathological processes including amyloid-β clearance, neuroinflammation, synaptic plasticity, neuronal apoptosis, and oxidative stress. Moreover, it has been established that both host cells and viruses produce circRNAs during infection. Virus-derived circRNAs can enhance viral replication, promote immune evasion, and support latency. In contrast, host circRNAs contribute to antiviral defense by acting as microRNA sponges, interacting with viral proteins, or encoding peptides with antiviral activity, mechanisms particularly explored in viral oncogenesis. In this review, we will evaluate the most updated research evidence on the role of circRNAs in major neurodegenerative diseases and neurotropic viral infections. Considering the growing concern regarding the long-term neurological consequences of viral infections, including chronic neuroinflammation, viral reactivation, and post-viral syndromes, dysregulated circRNAs may represent a mechanistic link between viral infection and associated neurodegenerative processes. Finally, we will discuss future directions for identifying circRNAs-based biomarkers and developing circRNAs-targeted therapeutic strategies for age-related and virus-associated neurological disorders.
    Keywords:  Biomarkers; Circular RNAs; Neurodegenerative diseases; Viral infections; circRNAs therapeutics
    DOI:  https://doi.org/10.1007/s13365-026-01324-8
  66. CNS Neurosci Ther. 2026 Jul;32(7): e71007
    Roles of Microglia in Cerebral Small Vessel Disease.
    Chenyang Jin, Xiaoqian Song, Yuewen Sun, Yilong Peng, Jing Zhou, Liyan Wang, Xinbao Yin, Xueping Zheng.
       BACKGROUNDS: Cerebral small vessel disease (CSVD) is a major cause of vascular dementia, characterized by heterogeneous pathologies affecting the brain's microvasculature. In recent years, researchers have recognized the significant role of neuroinflammation and increased permeability of the blood-brain barrier (BBB) in the development of CSVD. Within this framework, microglia exert multifaceted roles.
    METHODS: This review synthesizes current evidence on microglial involvement in CSVD, covering their heterogeneity, associations with neuroimaging markers, pathogenic mechanisms, and the translational prospects of microglia-directed therapies.
    RESULTS: Chronic cerebral hypoperfusion drives microglial activation toward pro-inflammatory phenotypes, triggering oxidative stress, inflammatory mediator release, and BBB disruption. These pathological changes correlate spatially with white matter hyperintensities, enlarged perivascular spaces, and lacunes. Microglia also interact with other glial cells to modulate disease progression. Preclinical studies have shown that modulating microglial phenotypes can be beneficial, though clinical translation remains challenging.
    CONCLUSION: Microglia serve as pivotal double-edged players, central to both neuroinflammation and BBB dysfunction in CSVD.Understanding the intricate relationship between microglia and CSVD is essential for elucidating the underlying mechanisms and paves the way for novel therapeutic approaches.
    Keywords:  BBB; CSVD; immunoregulation; microglia; neuroinflammation
    DOI:  https://doi.org/10.1002/cns.71007
  67. Biomater Sci. 2026 Jul 09.
    A nose-to-brain drug delivery system targeting mitochondrial dysfunction: application potential and future prospects of chitosan nanogels in Alzheimer's disease.
    Qucheng Huang, YuanYuan Zuo, Yining Xie, Zhenye Liu, Leiyi Wang, Hewei Xu, Miao Yu, Chang Liu.
      Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal degeneration and cognitive impairment. One of its core pathologies involves energy metabolism disruption and oxidative stress resulting from mitochondrial dysfunction. Traditional drugs struggle to effectively cross the blood-brain barrier (BBB), while the nasal-brain drug delivery system offers a novel approach for achieving direct brain access. Chitosan, a biodegradable natural polymer with strong mucosal adhesion properties, has been extensively utilized in recent years to construct nanogel carriers. This approach enhances drug retention and absorption in the nasal epithelium, enabling targeted delivery to the brain via the olfactory or trigeminal nerve pathways. This paper provides a systematic review of research progress on chitosan nanogel-based naso-cerebral drug delivery systems targeting mitochondrial dysfunction, focusing on their molecular mechanisms in improving mitochondrial energy metabolism, scavenging excess reactive oxygen species (ROS), suppressing neuroinflammation, and regulating apoptosis. Additionally, this paper analyzes the design principles of various modification strategies-such as triphenylphosphine (TPP) modification, pH/ROS responsiveness, and drug-loaded nanozyme complexes-along with their efficacy validation in AD models. It further explores the future development trends of chitosan nanogel-mediated multi-target intervention and smart-responsive nasal-brain delivery systems, offering new directions for precision treatment of AD.
    DOI:  https://doi.org/10.1039/d6bm00624h
  68. J Neurosci. 2026 Jul 08. pii: e0452262026. [Epub ahead of print]46(27):
    Mast Cells in the Developing Brain.
    Matthew R Bruce, Anna A Maximova, Kaliroi J Engel, Andrew W Allee, Margaret M McCarthy.
      Brain development requires the coordination of numerous cell types including neurons, glia, and immune cells. Mast cells (MCs) are tissue-resident innate immune cells canonically known for their role in allergic responses and anaphylaxis. In the central nervous system (CNS), MCs populate the meninges and brain parenchyma, exhibiting dynamic, age- and region-dependent changes during neurodevelopment. Emerging evidence indicates that CNS-resident MCs may influence key neurodevelopmental processes through bidirectional cross talk with microglia, regulation of blood-brain barrier permeability, and orchestration of peripheral immune cell recruitment to the developing brain. However, significant challenges exist regarding tools to precisely dissect the contribution of MCs in these processes. Clinically, MC-derived mediators including interleukin 6 and histamine have been implicated in neurodevelopmental disorder (NDD) etiology, with epidemiological links between allergic disease and elevated risk for NDD. This review synthesizes current knowledge of MC biology in the developing brain and highlights critical gaps requiring further investigation to understand their role in neurodevelopment and neurological disease susceptibility.
    Keywords:  NDD; mast cells; microglia; neuroimmune; rodent models
    DOI:  https://doi.org/10.1523/JNEUROSCI.0452-26.2026
  69. Mult Scler Relat Disord. 2026 Jun 29. pii: S2211-0348(26)00392-5. [Epub ahead of print]113 107356
    Serum angiogenesis-hypoxia biomarkers in relapsing-remitting multiple sclerosis.
    Heather Y F Yong, Nicholas J Batty, Serena Phillips, Mankarman Ghuman, Yunyan Zhang, Carlos Camara-Lemarroy.
       BACKGROUND: Studies have demonstrated that the hypoxia-angiogenic axis is dysregulated in progressive multiple sclerosis (MS), with an upregulation of hypoxic biomarkers with a paradoxical reduction of angiogenic biomarkers. In this study, we postulated that the hypoxia-angiogenic axis would be relatively preserved in relapsing-remitting MS (RRMS; a predominantly neuroinflammatory driven process) as opposed to its progressive counterpart (predominantly neurodegenerative driven).
    METHODS: Serum samples were collected from RRMS participants screened for a randomized pilot trial of domperidone as adjunct therapy, prior to initiation of the study drug (n=122), and matched to healthy controls (n=78). Angiogenic factors were measured with a commercially available bead-based multiplex assay and hypoxia biomarkers were measured with a custom bead-based multiplex assay. Publicly available transcriptomic databases of the RRMS brain were utilized to investigation the expression of selected hypoxia/angiogenic markers in the central nervous system (CNS).
    RESULTS: Circulating hypoxic markers (hypoxia inducible factor-1-a, heme oxygenase-1, and heat shock protein-90) were increased in the serum and CNS of people with RRMS. Conversely, brain derived neurotrophic factor was reduced. Lysyl oxidase levels correlated with lesion texture (r=(-)0.28) and brain volume (r=(-)0.24). Angiogenic markers were not significantly dysregulated.
    CONCLUSION: Hypoxic factors are upregulated in RRMS serum and CNS, while angiogenesis factors are unchanged. This may suggest preservation of the hypoxia-angiogenic axis in RRMS as compared to the dysregulation seen in progressive MS.
    Keywords:  Angiogenesis; Hypoxia; Multiple sclerosis; RRMS; Relapsing-remitting multiple sclerosis
    DOI:  https://doi.org/10.1016/j.msard.2026.107356
  70. Mol Ther Adv. 2026 Sep 10. 34(3): 201783
    Systematic evaluation of BBB-penetrant AAV capsids in marmosets identifies VCAP-102 as a highly efficient brain-transducing capsid.
    Yasunori Matsuzaki, Ayumu Konno, Kenji Sakamoto, Yasuo Uchida, Tetsuya Terasaki, Hirokazu Hirai.
      Recent advances in engineering adeno-associated virus (AAV) capsids capable of crossing the blood-brain barrier (BBB) have led to the development of numerous variants aimed at enhancing central nervous system gene delivery. Over the past decade, as new BBB-penetrant capsids were reported or independently identified through our own capsid library screening, we systematically evaluated their performance in adult marmosets, using a standardized experimental framework. Here, we present a cross-comparison of eleven AAV variants, predominantly AAV9-derived, alongside native AAV9 following systemic administration. Whole-brain reporter expression was quantitatively assessed using uniform imaging and analysis pipelines to enable relative comparison across animals. Under these conditions, most previously reported and newly identified BBB-penetrant variants-including those obtained through our own screening efforts-did not exhibit brain transduction levels clearly distinguishable from those of AAV9 based on whole-brain fluorescence intensity. In contrast, VCAP-102 consistently produced markedly higher brain-wide reporter expression across animals, accompanied by substantially increased vector genome copy numbers in the marmoset cortex, with most GFP-positive cells corresponding to neurons. These findings provide a systematic benchmark for evaluating BBB-penetrant AAV capsids in non-human primates and identify VCAP-102 as a highly efficient vector for systemic brain gene delivery.
    Keywords:  adeno-associated virus; blood-brain barrier; brain microvascular endothelial cell; capsid engineering; central nervous system gene delivery; comparative evaluation; gene therapy; marmoset; non-human primate; tissue-nonspecific alkaline phosphatase ALPL
    DOI:  https://doi.org/10.1016/j.omta.2026.201783
  71. Mol Neurodegener. 2026 Jul 07.
    ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.
    Michael R Strickland, David M Holtzman.
      Apolipoprotein E (ApoE) is highly expressed in the central nervous system (CNS) where it plays a critical role in lipid homeostasis and in the etiology of Alzheimer's disease (AD) and related diseases. ApoE associates with lipids to form discoidal and spherical lipoproteins that carry lipid and protein cargo throughout the brain. In this review, we focus on the significance of ApoE as a lipoprotein and how this impacts the function of ApoE in homeostasis and disease. In the CNS, ApoE is primarily secreted by astrocytes, though other cells, including microglia, secrete ApoE under certain conditions. ApoE lipoproteins (LpE) secreted by different cell types carry unique lipids and proteins which alter its function. The lipidation state of ApoE alters its conformation and binding to different receptors and, consequently, its ultimate impact on AD pathology. Most dramatically, nonlipidated ApoE has minimal binding to the low density lipoprotein receptor (LDLR), while lipidation of ApoE restores high affinity binding to LDLR. Furthermore, the degree of ApoE lipidation also impacts ApoE receptor binding through changes in protein conformation and stoichiometry of ApoE molecules per lipoprotein. The lipidation state of ApoE also alters its interaction with amyloid-β and tau, the proteins involved in forming amyloid plaques and neurofibrillary tangles, the pathological hallmarks of AD. LpE also carry lipids and proteins that alter the function of ApoE. Understanding how the lipid and protein content of LpE interacts with the conformational changes that occur with lipidation and maturation are essential to mechanistically understanding the role of ApoE in homeostasis and disease pathogenesis. In this review, we highlight the current understanding of LpE biology in the CNS and delineate important areas of future research.
    Keywords:  Alzheimer’s disease; Apolipoprotein; Apolipoprotein E; Central nervous system; Lipoprotein
    DOI:  https://doi.org/10.1186/s13024-026-00970-0
  72. ASN Neuro. 2026 ;18(1): 2696824
    Uric Acid Released from Poly (Lactic-co-Glycolic Acid) Nanoparticles Mitigates Glutamate-Induced Excitotoxicity of Spinal Cord Neurons.
    Kaavyashri Anbumani, Brandon J Vaglio, Agam Aviv, Courtney M Stains, Katie Lynch, Rene S Schloss, Bonnie L Firestein.
      Spinal cord injury (SCI) is often compounded by secondary damage caused by glutamate-induced excitotoxicity (GIE), where excessive glutamate release results in neuronal damage by overstimulation of glutamate receptors. This process leads to mitochondrial dysfunction, oxidative stress, and neuronal death. Uric acid (UA) has been identified as a potential neuroprotective molecule due to its antioxidant properties, but its limited solubility poses challenges for clinical use. To address this issue, we encapsulated UA in poly (lactic-co-glycolic acid) nanoparticles (UA-NPs) using a modified double emulsion technique to enhance stability and delivery of UA. Spinal cord cultures were subjected to GIE, followed by treatment with UA-NPs or empty nanoparticles. Neuronal survival was assessed with immunocytochemistry for the neuronal marker microtubule-associated protein 2 (MAP2), which revealed that treatment with UA-NPs resulted in significantly higher cell survival compared to cultures treated with empty nanoparticles. These findings suggest that UA-NPs provide neuroprotection to spinal cord neurons in vitro and may serve as a promising localized drug delivery system for SCI treatment, offering a targeted approach to mitigate secondary injury.
    Keywords:  Glutamate-induced excitotoxicity; nanoparticles; neuronal culture; neuroprotection; spinal cord neurons; uric acid
    DOI:  https://doi.org/10.1080/17590914.2026.2696824
  73. Int J Pharm. 2026 Jul 04. pii: S0378-5173(26)00596-X. [Epub ahead of print]701 127148
    A "three-in-one" nose-to-brain delivery strategy: intranasal vancomycin spray achieves simultaneous clearance of pneumococcal colonization, bacteremia, and meningitis.
    Guanlin Wang, Huagui Yi, Xi Kong, Junge Ou, Yue Zhou, Xuan Tang, Kaiqing Zhang, Wenhao Wang, Ziyu Zhao, Ying Huang, Xin Pan, Chuanbin Wu, Xuejuan Zhang.
      Bacterial meningitis caused by Streptococcus pneumoniae is a lethal central nervous system infection, yet conventional intravenous vancomycin struggles to cross the blood-brain barrier effectively. Interestingly, the natural pathology of this pathogen originates from nasopharyngeal colonization, disseminates into systemic bacteremia, and ultimately breaches the meninges. Inspired by this sequential invasion, we hypothesized that administering vancomycin directly at the exact starting point via a nasal spray could achieve a simultaneous "three-in-one" eradication of all infection stages. To realize this goal and overcome the bottleneck of nasal delivery, we developed a vancomycin nasal spray using hydroxypropyl methylcellulose as a viscosity modifier. By systematically tuning the formulation viscosity, we achieved a synchronous optimization of the macroscopic spray morphology and microscopic droplet behavior. This aerodynamic balance minimized premature droplet impaction at the anterior nasal valve and prevented excessive gravitational settling in the main nasal meatus. Quantitative analysis in a 3D-printed human nasal cast demonstrated that the optimized formulation F4 maximized target site coverage, achieving a total nasal meatus deposition of 2491.7 μg and a peak olfactory deposition fraction of 5.06%. The optimized spray increased cerebrospinal fluid bioavailability by 2.93-fold and drastically reduced peripheral renal exposure by 74.93% compared to intravenous injection. In a pneumococcal infection rat model, the intranasal therapy demonstrated superior multidimensional bactericidal efficacy, clearing 89.81% of the local nasopharyngeal colonies, 97.11% of the systemic bacteremia, and 93.83% of the intracerebral bacterial load. This robust pathogen clearance was accompanied by the prompt resolution of localized neuroinflammation, systemic procalcitonin levels, and circulating leukocyte abnormalities. Ultimately, this aerodynamically engineered formulation provides an anatomically inspired and highly effective intervention paradigm for managing complex central nervous system infections.
    Keywords:  Blood-brain barrier; Nasal spray; Nose-to-brain drug delivery; Pneumococcal meningitis; Vancomycin
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.127148
  74. Biochemistry (Mosc). 2026 Jun;91(6): 867-892
    Effects of Metabolites of Lactic Acid Bacteria on Nerve Cells of the Microbiota-Gut-Brain Axis.
    Konstantin V Sobol.
      This review examines the key pathways of bidirectional communication between the gut and brain along the microbiota-gut-brain axis, with particular emphasis on the effects of metabolites of lactic acid bacteria (metLABs) on neurons of the enteric and central nervous systems. Special attention is given to the role of metLABs in intracellular signaling. The review further explores the direct effects of metLABs on mitochondrial function in nervous tissue, neuronal plasticity, and neuritogenesis. Potential mechanisms for the release of neurotrophic factors in both cells and host organism following exposure to metLABs or probiotic products are analyzed. Although clinical evidence remains limited, existing studies suggest that regular consumption of metLAB-containing fermented foods may positively influence brain functions through modulation of the microbiota-gut-brain axis. At least two ongoing clinical trials currently investigate whether normalization of the gut microbiota through probiotic interventions can slow the progression of Alzheimer's disease. As this field continues to advance rapidly, further studies are expected to provide important insights into the therapeutic potential of microbiota-targeted strategies for neurological health.
    Keywords:  central nervous system; enteric nervous system; gut–brain; lactic acid bacteria; microbiota; microbiota metabolites; mitochondria; neurons; neuroplasticity; neurotrophic factors; oxidative stress
    DOI:  https://doi.org/10.1134/S0006297926600377
  75. J Neuroimmunol. 2026 Jul 02. pii: S0165-5728(26)00171-2. [Epub ahead of print]419 579022
    Spinal cord microglia exhibit a dysfunctional response to myelin damage.
    Matthew C Zupan, Jack M Petersen, Addison C Stover, Corbin A Fairchild, Nishama De Silva Mohotti, Meredith D Hartley.
      Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that affects both the brain and spinal cord, although the brain has historically received greater attention. In the inducible, oligodendrocyte-specific knockout model of Myrf, which results in white matter damage to both the brain and spinal cord, our laboratory previously demonstrated that the brain undergoes remyelination following white matter damage, whereas the spinal cord has limited remyelination. We also observed that brain microglia display a much stronger activation than spinal cord microglia. Microglia regulate remyelination by clearing myelin debris, processing resulting lipids, and modulating the inflammation response. Therefore, we hypothesized that microglia are involved in limiting spinal cord remyelination in this model, either by having a limited phagocytosis response or by causing neuroinflammation. To test our hypothesis, we characterized microglial phenotypes during demyelination in both brain and spinal cord in the Myrf demyelination model. The brain exhibited an earlier microglial activation response and showed a higher percentage of microglia expressing phagocytic markers, suggesting a primed state for responding to damage. In contrast, spinal cord microglia showed a delayed increase in cells expressing phagocytic markers, sustained inflammation, and a predominately ameboid morphology during demyelination. Together, these findings in the Myrf demyelination model indicate that brain microglia mount a timely and coordinated response to demyelination that supports remyelination, whereas spinal cord microglia adopt a dysfunctional phenotype that likely contributes to reduced myelin repair.
    Keywords:  Brain; Demyelination; Inflammation; Microglia; Phagocytosis; Spinal cord
    DOI:  https://doi.org/10.1016/j.jneuroim.2026.579022
  76. Commun Med (Lond). 2026 Jul 07. pii: 365. [Epub ahead of print]6(1):
    Quantifying cortical lesions in multiple sclerosis MRI datasets using multi-contrast post-processing and deep learning.
    Michael G Dwyer, Niels Bergsland, Alexander Bartnik, Dejan Jakimovski, Samantha Noteboom, Menno M Schoonheim, Martijn D Steenwijk, Jinglan Pei, David Clayton, Robert Zivadinov.
       BACKGROUND: Multiple sclerosis (MS) is a chronic neurological disease affecting both white and gray matter of the central nervous system. Despite the well-established involvement of cortical lesions in MS, feasibility limitations in their visualization on typical magnetic resonance imaging (MRI) protocols prevent their evaluation in nearly all clinical trials. Recently, several post-processing methods, including synthetic contrasts and artificial intelligence (AI)-based approaches, have shown potential for enhancing cortical lesion detection on conventional MRI data. These methods have the potential to reanalyze existing clinical-trial data to answer key mechanistic questions about both MS development and about treatment effects.
    METHODS: We sought to evaluate the feasibility of combining and extending existing methods into a unified framework for analysis using the data from the large, multicenter, phase 3 ORATORIO trial (full n = 732, age=44.6 ± 8.0; development subset n = 80, age=46.6 ± 7.1). We specifically evaluated three of the most promising of them - fluid-attenuated inversion recovery squared (FLAIR2), T1/T2 ratio, and artificial intelligence-derived double inversion recovery (AI-DIR) - and introduced a new combined contrast called multi-modal cortical lesion enhanced (MMCLE). We also harnessed transformer-based semantic segmentation to improve automated detection and delineation of these lesions.
    RESULTS: At baseline, we detected 14.8 + /-20.72 lesions per participant, with 86.0% true positive rate and 8.4% false positive rate across subjects for blinded MMCLE, using simultaneous review of all contrasts as the reference. High reproducibility was observed across field strengths and acquisition types (ICC 88.8-92.5%).
    CONCLUSIONS: We confirmed that cortical lesions can be clearly visualized and quantified with these methods. Using deep learning, we also confirmed that the simultaneous use of multiple contrasts improves quantification.
    DOI:  https://doi.org/10.1038/s43856-026-01683-7
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