bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–07–05
53 papers selected by
Luca Bolliger, lxBio
  1. TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.
  2. Unravelling the Significance of Cystatin C and Bunina Bodies in Amyotrophic Lateral Sclerosis Pathogenesis.
  3. Microbiome and metabolites impact enteric and central nervous systems in ALS.
  4. Neurodegenerative diseases and environmental risk factors: an overview of the available scientific evidence.
  5. Distal Motor Latency in Amyotrophic Lateral Sclerosis: A Robust and Reliable Prognostic Marker.
  6. Adaptive immunity in the pathogenesis of neurodegeneration.
  7. Neural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis.
  8. Mutant superoxide dismutase 1-catalyzed hydrogen therapy for amyotrophic lateral sclerosis achieved by intercepting oxidative stress-neuroinflammation crosstalk.
  9. The Target ALS Global Natural History Study: Cross-platform proteomics to accelerate biofluid biomarker and drug target discovery in amyotrophic lateral sclerosis.
  10. Role of Toll-like receptors and oral-gut-brain axis in neurodegenerative and neuropsychiatric disorders.
  11. Preparing Amyotrophic Lateral Sclerosis Clinics to Provide Longitudinal Care for Individuals Carrying ALS Risk Variants.
  12. Quantification of amyotrophic lateral sclerosis (ALS) disease accumulation with T1-weighted high-resolution magnetic resonance imaging: validation in an independent cohort.
  13. Simultaneous ultrasound and needle electromyography recording of fasciculations in amyotrophic lateral sclerosis.
  14. A case study of comprehensive association analysis and risk prediction of amyotrophic lateral sclerosis in a Chinese population.
  15. Assessing upper motor neuron dysfunction in ALS: from TMS-EEG and EMG neurophysiology to a combined tFUS-TMS translational framework.
  16. Elevated urea levels in human frontotemporal dementia and amyotrophic lateral sclerosis post-mortem brain tissue: Evidence of a multi-dementia pathogenic mechanism.
  17. Radiologically inserted gastrostomy in advanced amyotrophic lateral sclerosis: clinical outcomes.
  18. Understanding patients' experiences and needs around decision-making for bulbar symptom management at a multidisciplinary ALS clinic.
  19. Occurrence of amyotrophic lateral sclerosis during TNF inhibitor treatment in inflammatory rheumatic disease. What are the relationships?
  20. Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.
  21. SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.
  22. An open-label Phase 2a study of fasudil in amyotrophic lateral sclerosis: safety and exploratory endpoints.
  23. Genome-wide spectrum of coding DNA variations in Indian patients with amyotrophic lateral sclerosis.
  24. Beyond neurofilaments: a multidimensional blood signature for amyotrophic lateral sclerosis.
  25. Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes.
  26. Nanoscale morphological and structural analysis of round and donut oligomers formed by C-terminal domain of TDP-43.
  27. The SQSTM1 L341V Variant Associated With Sporadic ALS Promotes the Accumulation of Enlarged Ubiquitin-Positive SQSTM1 Bodies.
  28. The role of SUMOylation in regulating proteins that drive neuronal disease progression.
  29. Structural-functional network decoupling in early stage amyotrophic lateral sclerosis reveals cell-type specific transcriptional signatures.
  30. Innate immune signaling and functions in astrocytes.
  31. The impedance mismatch theory: A non-equilibrium thermodynamic framework for a shared energetic stress pathway in neurodegeneration.
  32. Comparative Analysis of Regional Blood-Brain Barrier Permeability in Humans and Rodents: An Evolutionary Perspective.
  33. Global epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.
  34. Could anticholinergics accelerate ALS progression? A critical perspective on drug safety and disease vulnerability.
  35. At-Home Versus in-Clinic Vital Capacity Measurement: Insights From the HEALEY ALS Platform Trial.
  36. Focused ultrasound-mediated blood-brain barrier opening enhances delivery of Rg3 ginseng nanoparticles in a Parkinson's disease mouse model.
  37. Dexamethasone restores blood-brain barrier integrity in an in vitro heatstroke model.
  38. Macrophage inclusions in patients undergoing antisense oligonucleotide therapy for ALS or SMA: A retrospective and transversal study.
  39. Safety, feasibility and preliminary effects of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis: a prospective ABA pilot study.
  40. Decremental responses following repetitive nerve stimulation in spinal and bulbar muscular atrophy.
  41. A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.
  42. A Brain-Targeted DNA Delivery Nanocarrier Modulator for Synergistic Therapy of Parkinson's Disease.
  43. A single Citrobacter rodentium infection in Pink1 knockout and wild-type mice leads to regional blood-brain-barrier perturbation and limited microglial activation without dopamine neuron axon terminal loss.
  44. Focused ultrasound-mediated blood-brain barrier opening to enhance temozolomide delivery in glioblastoma: a systematic review of preclinical and early clinical evidence.
  45. Glucose metabolic reprogramming: mechanisms and therapeutic implications in neuroinflammation.
  46. A Cross-Neurotype Analysis of Camouflaging and Illness Perceptions in People with Central Sensitivity Syndromes.
  47. Advances in neural organoids: structural organization, disease modeling, and applications in gene therapy.
  48. From cellular heterogeneity to precision medicine: single-cell multi-omics in CNS disease research.
  49. F-waves in primary lateral sclerosis: a window into spinal motoneuron hyperexcitability.
  50. Border-Associated Macrophages in CNS Health and Disease: A Comprehensive Review of Ontogeny, Heterogeneity, and Functional Plasticity at Neural Interfaces.
  51. Autoimmune GFAP astrocytopathy with eosinophils on cerebrospinal fluid cytology and isolated spinal cord lesions on MRI: a case report.
  52. Beyond Viral Control: Tenofovir's Hidden Impact on Blood-Brain Barrier Endothelial Cells.
  53. Novel strategies to overcome the blood-brain barrier in triple-negative breast cancer brain metastases.
  1. Biochem Soc Trans. 2026 Jul 29. 54(7): 901-913
    TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.
    Eleni Christoforidou, Emily McFagan, Martha McLaughlin, Majid Hafezparast.
      Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease, characterised by the degeneration of upper and lower motor neurons. The cytoplasmic aggregation of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein, is considered a hallmark of ALS pathology, found in nearly all postmortem cases of ALS. TDP-43 is normally primarily nuclear, where it has a widespread role in gene regulation. Mutations, extrinsic stressors, and alterations in RNA homeostasis in ALS lead to nuclear depletion of TDP-43 and the formation of cytosolic TDP-43 aggregates. This causes multiple downstream effects on neuronal function and degeneration as well as gene expression. TDP-43 is a promising target as a biomarker, as it is found to be elevated in the biofluids of ALS patients, and its cytoplasmic aggregation can also be observed in peripheral tissues; however, methodological variability and technical limitations currently preclude the establishment of TDP-43 as a standalone biomarker. There are also promising therapeutic strategies in development targeting TDP-43 pathology, but a critical challenge that remains is achieving a balance between eliminating toxic aggregates and preserving the essential functions of TDP-43. In summary, with further research, considering TDP-43 pathology in ALS gives hope for finding future novel diagnostics and therapeutics for ALS.
    Keywords:  ALS; Amyotrophic Lateral Sclerosis; MND; Motor Neuron Disease; TARDBP; TDP-43
    DOI:  https://doi.org/10.1042/BST20260896
  2. Neuropathol Appl Neurobiol. 2026 08;52(4): e70083
    Unravelling the Significance of Cystatin C and Bunina Bodies in Amyotrophic Lateral Sclerosis Pathogenesis.
    Sarah M Granger, Rosemary A Staniforth, Asbjorg Osk Snorradottir, Johnathan Cooper-Knock, Kurt J De Vos, J Robin Highley.
      Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal neurodegenerative disease primarily affecting motor neurons. Two key protein inclusions found in lower motor neurons serve as neuropathological hallmarks of the disease in human tissue: the TDP43-positive inclusion and the cystatin C-positive Bunina body. Despite their diagnostic specificity and presence in most sporadic and familial ALS cases, Bunina bodies remain poorly understood, and their true prevalence is likely underestimated. The co-occurrence of the Bunina body and the TDP43 inclusion may provide valuable insights into the development of TDP43 pathology in ALS. Thorough characterisation of the Bunina body is needed to understand this interplay and the broader pathomechanisms of disease. This review examines our current knowledge of Bunina bodies and the biochemical properties of cystatin C that may promote its aggregation. Sequestration and aggregation of cystatin C into Bunina bodies may diminish its neuroprotective functions, including cysteine protease inhibition, autophagy induction and anti-amyloidogenic activity, thereby contributing to ALS pathogenesis. This review also evaluates findings from human post-mortem tissue and ALS disease models, discussing the value and limitations of these models in the context of Bunina bodies and TDP43 pathology. Finally, we discuss cystatin C's use as a biomarker and its therapeutic potential. A deeper understanding of cystatin C biology, its relationship with TDP43 pathology and improved ALS models will be essential for determining whether targeting cystatin C could provide a viable avenue for future ALS therapies.
    Keywords:  Bunina bodies; amyotrophic lateral sclerosis; cystatin C; motor neuron disease
    DOI:  https://doi.org/10.1111/nan.70083
  3. Gut Microbes. 2026 Dec 31. 18(1): 2692737
    Microbiome and metabolites impact enteric and central nervous systems in ALS.
    Erykah I Walton, Jun Sun.
      Amyotrophic lateral sclerosis (ALS) has been linked to gastrointestinal symptoms and alterations in the gut microbiota. The enteric nervous system (ENS) coordinates intestinal function and sits at the host-microbe interface. The mechanisms by which luminal changes relay to the central nervous system (CNS), where motor neurons reside, have yet to be completely defined. In this narrative review, we first present evidence from ALS patient cohorts and preclinical models alongside mechanistic studies of infection, dysbiosis, and related neurodegenerative diseases to discuss how the microbiota and its metabolites may affect the ENS and CNS in ALS. Next, we propose a plausible mechanism of ALS pathogenesis through the gut-microbiome-brain axis. We further offer a summary of clinical trials that have studied the impacts of the microbiota on human ALS. Finally, we discuss future directions for studies of microbiota-ENS-CNS interactions in ALS. Better understanding of the dynamic interactions among the microbiota, microbial metabolites, neuroactive metabolites, and inflammation through the ENS/CNS in ALS will provide innovative insights into ALS prevention and treatment.
    Keywords:  ALS; dysbiosis; enteric nervous system; central nervous system; inflammation; gut–microbiota–brain–axis; microbial metabolites; microbiome; microbiota; neurodegenerative diseases
    DOI:  https://doi.org/10.1080/19490976.2026.2692737
  4. J Neural Transm (Vienna). 2026 Jun 29.
    Neurodegenerative diseases and environmental risk factors: an overview of the available scientific evidence.
    Giuseppe Stipa, Carlo Colosimo, Nicola Vanacore.
      Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are among the most well-known and prevalent neurodegenerative disorders. These diseases result from an interaction between the environment and genetically predisposed individuals. This review examines the evidence available in the literature underlying this multifaceted interaction, focusing on various chemical substances such as metals, fertilizers, and herbicides, as well as toxic agents of microbiological origin, including cyanobacteria and their neurotoxins. In addition, the pathways through which toxic substances can enter the human body are discussed, such as air and water, which may lead to absorption through the lungs, the gastrointestinal tract, the skin, and mucosae. The routes by which neurotoxic substances gain access to the human body may help explain the increased risk of developing neurodegenerative diseases observed in sports played on soil and grass surfaces, such as soccer, American football, and golf.
    Keywords:  Air pollution; Environmental exposure; Neurodegenerative diseases; Raw water; Sport
    DOI:  https://doi.org/10.1007/s00702-026-03202-3
  5. Mymensingh Med J. 2026 Jul;35(3): 924-931
    Distal Motor Latency in Amyotrophic Lateral Sclerosis: A Robust and Reliable Prognostic Marker.
    S H Siddik, M B A Miah, S K M Alam, T S Sumaiya, D Debnath, S M A Haque.
      An electrophysiological test is routinely done to confirm Amyotrophic Lateral Sclerosis (ALS) and rule out differentials. Distal Motor Latency (DML) is a simple electrophysiological measure that is always done in a primary setting. It can be used as an excellent prognostic marker for ALS so that we can know ALS better and formulate precise management plans. This longitudinal study was conducted in the Neurology Department of Bangladesh Medical University (BMU), Dhaka, Bangladesh from April 2022 to October 2023. In this study a total of 34 subjects, 17 ALS patients with normal DML and 17 ALS patients with prolonged DML, were enrolled. Severity was assessed by the ALS functional rating scale-revised (ALSFRS-R). The study's endpoints were determined as death during this 6-month follow-up or reaching an advanced stage (ALSFRS-R <20). Then, an electrophysiological test was used to measure DML in all four commonly tested nerves. ALSFRS-R was significantly reduced (p<0.025) at 6 months in ALS patients with prolonged DML than normal DML. It was found that having a higher odd (p<0.012, OR=20.718), prolonged DML had a significant impact on the outcome of ALS patients than that of normal DML. In multivariate analysis, lower ALSFRS-R at diagnosis (B= -0.124, p<0.001, HR=0.883) and prolonged DML (B=1.412, p<0.031, HR=4.104) were associated with poor outcomes. ALS patients with prolonged DML also had a poorer prognosis than patients with normal DML (log-rank test, p<0.045). In this study, patients with prolonged DML had a significant functional decline, rapid disease progression and poor prognosis than patients with normal DML. So, prolonged DML can be used as a robust prognostic marker for patients with ALS.
  6. Nat Immunol. 2026 Jul;27(7): 1375-1389
    Adaptive immunity in the pathogenesis of neurodegeneration.
    Yongyi Li, Jason D Ulrich, David M Holtzman.
      Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and others, are a group of neurological disorders characterized by progressive neuronal loss in the central nervous system (CNS) and the deterioration of CNS function. Multiple lines of evidence have highlighted activation of innate immune cells in the CNS, namely microglia and astrocytes, as hallmark pathological features in neurodegeneration and key drivers of disease progression. Advances in genetic, neuropathological and experimental studies also underscore the potential role of the adaptive immune system in disease pathogenesis. Here we summarize the current understanding of how adaptive immunity can shape the progression of neurodegenerative diseases and highlight cross-disease parallels and potentially shared mechanisms. We also examine cellular events leading to the recruitment of peripheral immune cells to the CNS, as well as candidate antigens driving the adaptive immune response. Last, we discuss potential therapeutic strategies to treat neurodegeneration via the manipulation of adaptive immune cells.
    DOI:  https://doi.org/10.1038/s41590-026-02538-y
  7. J Neurochem. 2026 Jul;170(7): e70513
    Neural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis.
    Kristel N Eigenhuis, Roberto Montoro Ferrer, R Jeroen Pasterkamp.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons leading to muscle wasting. However, structural and molecular abnormalities, including cortical thinning and TDP-43 pathology, extend into frontal, parietal, and temporal areas, pointing to defects across broader cortical regions. The advent of human induced pluripotent stem cell (hiPSC) technology has enabled the generation of human-specific brain cell types in vitro. Here, we provide an overview of the three-dimensional (3D) hiPSC-derived neural organoid platforms used to model cortical structures and to study cortical ALS-associated phenotypes. We review which pathological hallmarks have been recapitulated in these organoids and discuss disease phenotypes reported to date. Further, we comprehensively cover different neural organoid models and experimental strategies, including patient-derived hiPSC models and exogenous pathology induction, while addressing current technical challenges. Together, these advances position neural organoids as an emerging tool to study cell-type-specific and circuit-level mechanisms related to cortical changes in ALS.
    DOI:  https://doi.org/10.1111/jnc.70513
  8. Acta Biomater. 2026 Jul 03. pii: S1742-7061(26)00441-1. [Epub ahead of print]
    Mutant superoxide dismutase 1-catalyzed hydrogen therapy for amyotrophic lateral sclerosis achieved by intercepting oxidative stress-neuroinflammation crosstalk.
    Yihui Sun, Yingshuai Wang, Qianbo He, Min Zhao, Jiaru Guo, Chunjie Xu, Qiupeng Yan, Yanchun Chen, Bingqiang Zhang, Hongmei Du, Jing Huo, Yong Zhang, Haoyun Zhang, Yingjun Guan, Qianjun He.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord, with mutant superoxide dismutase 1 (SOD1) induced oxidative stress and neuroinflammation as key pathogenic drivers. Here, we uncover that mutant SOD1 is both a Fenton-like agent able for catalytical generation of ·OH and a hydrogenation catalyst for H2 scavenging reactive oxygen species. To enhance the bioavailability of H2, we develop an orally administered Mg2Si nanosheets based feed for sustained release of high-amount H2. On an ALS model of hSOD1G93A transgenic mice, Mg2Si feed remarkably delays ALS progression, improves the motor performance of ALS mice, and extends their lifespan. Histopathologically, oral Mg2Si treatment ameliorates motor neuron degeneration, misfolded SOD1 aggregation and reactive gliosis in spinal cord, while protecting neuromuscular junctions and ameliorating muscle atrophy during disease progression. Transcriptomic analysis demonstrates the H2-mediated down-regulation of both oxidative stress and neuroinflammatory pathways in response to the suppression of NLRP3 inflammasome activation. The proposed strategy of catalyzed hydrogen therapy offers an inspiration for metalloproteases-related neurodegenerative diseases treatment. STATEMENT OF SIGNIFICANCE: Amyotrophic lateral sclerosis (ALS) is an incurable and devastating neurodegenerative disease lacking effective clinical interventions. Although hydrogen gas (H2) exhibits promising neuroprotective potential, conventional H2 therapy is severely limited by unstable and transient H2 release, failing to sustain long-term treatment requirements for chronic ALS pathogenesis. To overcome this bottleneck, we engineer oral administrable Mg2Si nanosheets that enable sustained H2 release via gastrointestinal retention, achieving stable long-term hydrogen supplementation in vivo. Mechanistically, Mg2Si-derived H2 efficiently eliminates excess free radicals triggered by toxic mutant SOD1, and further disrupts the pathological crosstalk between oxidative stress and neuroinflammation in ALS. In transgenic ALS mice, dietary Mg2Si intervention markedly ameliorates motor dysfunction and effectively delays disease progression. Collectively, this study firstly applies Mg2Si nanomaterial-based sustained hydrogen therapy for ALS treatment, establishes a novel gastrointestinal hydrogen delivery strategy, and provides an innovative and clinically translatable paradigm for the design of hydrogen delivery systems against neurodegenerative disorders.
    Keywords:  Amyotrophic lateral sclerosis; Hydrogen therapy; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1016/j.actbio.2026.07.004
  9. medRxiv. 2026 Jun 23. pii: 2026.06.13.26355379. [Epub ahead of print]
    The Target ALS Global Natural History Study: Cross-platform proteomics to accelerate biofluid biomarker and drug target discovery in amyotrophic lateral sclerosis.
    Daisuke Yasui, Daniel Weatherill, Laura Dugom, Sophia Weiner, Lathika Gopalakrishnan, Huy Tran, Björn Oskarsson, Kyra Nagle, Timothy Miller, Gilbert Gutierrez, John Ravits, Benjamin Hoover, Matthew Harms, Neil Shneider, Lizzi Neylon, Whitney Dailey, Shafeeq Ladha, Cassandra Holmes, Joseph Lee, Nicholas Streicher, Shakti Nayar, Brent T Harris, Manish Raisinghani, Henrik Zetterberg, Johan Gobom, Amy Easton, Robert Bowser, Cindy V Ly.
      Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.
    DOI:  https://doi.org/10.64898/2026.06.13.26355379
  10. Rev Neurosci. 2026 Jul 02.
    Role of Toll-like receptors and oral-gut-brain axis in neurodegenerative and neuropsychiatric disorders.
    Erfan Sabouri, Tara Shahmoradi, Nazanin Zahra Keshvari, Pegah Khodaee, Kiarash Saleki, Nima Rezaei.
      The oral-gut-brain axis is a path connecting the gastrointestinal tract and the central nervous system (CNS). The gut microbiota influences the immune system, metabolism, and nerve cells through the production of neurotransmitters and microbial metabolites that can cross the blood-brain barrier (BBB). The interplay between neuroinflammation and altered oral and gut microbiota is a bidirectional complex path modulated by inflammatory mediators. Recent studies suggest a potential role for Toll-like receptor (TLR) signaling pathways in the induction of neuroinflammation via the oral-gut-brain axis. As neuroinflammation is one of the key elements in the pathophysiology of neurodegenerative and neuropsychiatric disorders, this review was conducted to reflect on the pathophysiological pathways and clinical evidence on the role of TLR and inflammasome signaling pathways via oral-gut-brain axis in neurodegenerative diseases such as cognitive impairment, Alzheimer's disease, Multiple sclerosis, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis, and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, bipolar disorders, and Autism spectrum disorders. Because the contributing factors have not been fully understood yet, further studies could help provide novel therapeutic opportunities.
    Keywords:  Toll-like receptors; neurodegenerative disease; neuroinflammation; oral-gut-brain axis; psychiatric disorders
    DOI:  https://doi.org/10.1515/revneuro-2026-0064
  11. Neurol Genet. 2026 Aug;12(4): e200406
    Preparing Amyotrophic Lateral Sclerosis Clinics to Provide Longitudinal Care for Individuals Carrying ALS Risk Variants.
    Jennifer Morganroth, Julia Yasek, Matthew Harms.
       Background and Objectives: Emerging genetic therapies and the expansion of genetic testing are identifying individuals carrying amyotrophic lateral sclerosis (ALS) risk variants who would benefit from surveillance and early intervention. Anticipating the geographic distribution and clinical needs of this population is essential for optimizing care delivery and ensuring readiness as new therapies become available. We estimate the number of individuals in the United States carrying ALS risk variants and project the clinical engagement required to support this population. This is especially timely because ALS clinics are already grappling with rising numbers of patients with symptomatic ALS and deep funding cuts.
    Methods: We developed a population model to estimate the number of symptomatic individuals with gene-positive ALS and asymptomatic gene carriers across US states over the next decade (year 1: 2026). State-level ALS prevalence and incidence were calculated using 2 approaches: (1) race-adjusted ALS rates from the Atlanta metropolitan study applied to 2023 Census demographics and (2) observed state-level ALS case counts from the National ALS Registry (2011-2018). Gene-positive cases were estimated using published frequencies of SOD1, C9orf72, FUS, and TARDBP pathogenic variants. At-risk relatives were modeled assuming autosomal-dominant inheritance with ∼5 first-degree and ∼7 second-degree living relatives per proband, and broad uptake of cascade genetic testing. Surveillance needs were modeled as 1 annual visit per asymptomatic carrier, which was normalized by the number of ALS centers per state.
    Results: In year 1 (2026), the model estimated 2,704 symptomatic gene-positive ALS carriers. With an average of 4.25 carrier relatives per proband, 10,944 asymptomatic carriers were projected nationwide. Most states required <50 additional visits per clinic annually, with 12 states in the 50-99 range and none exceeding 100. By year 10 (2035), the model projected 7,474 symptomatic and 26,111 asymptomatic carriers. State-level demand shifted substantially: only 6 states remained below 50 visits per clinic annually; 22 reached 50-99; 18 reached 100-199; and 3 exceeded 200.
    Discussion: Gene-targeted testing is projected to substantially increase ALS clinic visits among asymptomatic gene carriers. While current infrastructure may accommodate the initial rise, within a decade, most states will require significant expansion. Anticipating and planning for this growth now is essential to ensure seamless integration of gene-positive individuals into ALS care.
    DOI:  https://doi.org/10.1212/NXG.0000000000200406
  12. J Neurol. 2026 Jun 29. pii: 429. [Epub ahead of print]273(7):
    Quantification of amyotrophic lateral sclerosis (ALS) disease accumulation with T1-weighted high-resolution magnetic resonance imaging: validation in an independent cohort.
    Philip Alexander Gremmler, Janina von der Gablentz, Julia Meyer, Benjamin Ilse, Behnaz Farahi Ghasraboonasr, Sophie Dalbert, Isabelle Jana Buchholz, Julian Grosskreutz, Robert Steinbach.
       BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease with multifaceted phenotypic presentation thus obstructing objective disease staging. The D50 disease progression model is a framework to comprehensively dissect biomarker-signals towards their relevance regarding disease accumulation/phase (rD50), or disease aggressiveness (D50). Based on previous findings using 1.5-Tesla Magnetic-Resonance-Imaging (MRI), this study hypothesized that high-resolution MRI markers of Grey-Matter (GM) structural integrity would enable quantification of disease accumulation, independent of aggressiveness.
    METHODS: A separate cohort of 75 patients with ALS and 73 Healthy Controls (HC) underwent T1-weighted 3-Tesla MRI. Voxel-Based-Morphometry measured GM and White-Matter (WM) density and Surface-Based-Morphometry assessed Cortical Thickness (CT). Non-parametric Threshold-Free-Cluster-Enhancement with 5000 permutations was applied for inter-group and regression contrasts, whilst correcting for possibly interfering co-variates and applying Family-Wise-Error-adjustment.
    RESULTS: Compared with HC, the ALS cohort showed widespread decreases of CT and GM/WM density (p < 0.001). These case-control effects were driven by patients scanned during rD50-defined disease Phase 2 (p < 0.001). Within the ALS-cohort, direct Phase 2 versus Phase 1 contrasts revealed spatially-distributed decreases, reflecting higher disease accumulation (p < 0.05). These were independent of disease aggressiveness (and onset-region), as corrected for in the models. Accordingly, all contrasts assessing aggressiveness did not yield significant results.
    CONCLUSIONS: These semi-automated analyses of T1-weighted-images captured disease accumulation related GM structural integrity-loss in this cohort scanned with 3-Tesla MRI, independent of the underlying disease aggressiveness. This principle was validated across different scanners and field strengths, supporting its application for objective and non-invasive staging of patients with ALS, whereby true longitudinal studies are necessary.
    Keywords:  Amyotrophic laterals sclerosis; Biomarker; Cortical thickness; D50-model; Magnetic-Resonance-Imaging (MRI); Voxel-Based-Morphometry (VBM)
    DOI:  https://doi.org/10.1007/s00415-026-13937-4
  13. Clin Neurophysiol Pract. 2026 ;11 448-452
    Simultaneous ultrasound and needle electromyography recording of fasciculations in amyotrophic lateral sclerosis.
    Takamichi Sugimoto, Keisuke Tachiyama, Akemi Hironaka, Hiroyuki Naito, Masahiro Nakamori, Shiro Aoki, Yu Yamazaki, Hirofumi Maruyama.
       Objective: Fasciculations can be detected using both muscle ultrasonography and needle electromyography, yet the correspondence between ultrasonographically observed fasciculations (U-fas) and needle electromyography-detected fasciculation potentials (N-fas) has not been clarified. This study investigated their correspondence using fully synchronized recordings.
    Methods: Adult patients showing fasciculation-like contractions on muscle ultrasonography were enrolled; all were subsequently diagnosed with amyotrophic lateral sclerosis. Ultrasound and needle electromyography were recorded simultaneously in up to three muscles per patient, with a recording duration of 3 min per muscle. For each ultrasonographically observed fasciculation, the presence of a corresponding electromyographic event and contraction duration assessed by M-mode imaging were evaluated.
    Results: Ten patients with amyotrophic lateral sclerosis were included. A total of 472 focused U-fas events were analyzed. Corresponding N-fas were detected in 437 events, yielding an overall concordance rate of 92.6% (95% confidence interval, 90.2-95.0%). U-fas contraction duration ranged from 343 to 971 ms, whereas N-fas duration ranged from 10.9 to 76.4 ms. The number of phases of N-fas observed during U-fas events ranged from 1 to 10.
    Conclusions: Most ultrasonographically observed fasciculations corresponded to electromyography-detected events on simultaneous recording.
    Significance: Ultrasonographically detected fasciculations may serve as a supplementary indicator of lower motor neuron involvement in amyotrophic lateral sclerosis.
    Keywords:  Amyotrophic lateral sclerosis; Electromyography; Fasciculation; Motor neuron disease; Ultrasonography
    DOI:  https://doi.org/10.1016/j.cnp.2026.06.008
  14. Mol Biol Rep. 2026 Jul 03. pii: 1090. [Epub ahead of print]53(1):
    A case study of comprehensive association analysis and risk prediction of amyotrophic lateral sclerosis in a Chinese population.
    Xueying Xie, Xiaoqing Jiao, Ke Yang, Qianqian Zhang.
       BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with significant genetic heterogeneity. While large-scale studies have characterized its genetic architecture in European populations, the genetic basis of ALS in the Chinese population remains under-explored.
    METHODS AND RESULTS: To address this gap, we conducted a comprehensive genetic analysis on a cohort of 40 Chinese individuals (32 ALS patients and 8 controls) using whole genome sequencing. We employed the Phenotype-Covariate Genetic Correlation method to estimate SNP-based heritability on the liability scale and utilized LDAK-KVIK for gene-based association analysis. Our analysis revealed a SNP-based heritability (h2SNP) of approximately 25.1% in this Chinese cohort, with a positive correlation between minor allele frequency and heritability, highlighting the substantial contribution of common variants. Gene-based analysis prioritized candidate risk genes, including MIB1, TMED2, and DOC2B, which implicate ubiquitin-mediated protein degradation and intracellular vesicle trafficking in ALS pathogenesis. In risk prediction models, the BOLT-LMM approach achieved a robust mean Area Under the Curve (AUC) of 0.883.
    CONCLUSIONS: This study provides the first comprehensive estimate of SNP-based heritability in a sequenced Chinese ALS cohort and supports the "polygenic background" hypothesis. The identification of candidate risk genes and the preliminary validation of polygenic risk scoring highlight the potential for future genetic stratification in Chinese patients.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); Genome-Wide Association Study (GWAS); Heritability; Polygenic Risk Score (PRS)
    DOI:  https://doi.org/10.1007/s11033-026-12221-y
  15. Front Neurol. 2026 ;17 1798525
    Assessing upper motor neuron dysfunction in ALS: from TMS-EEG and EMG neurophysiology to a combined tFUS-TMS translational framework.
    Ahmadreza Keihani, Mahsa Hassani, Seyed Saman Sajadi, Seyedeh Atena Modarresi, Marziyeh Khoshkholgh, Mahdi Haresabadi, Kiana Amani, Zahra Jourahmad, Fabio Ferrarelli.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of upper motor neurons (UMNs) and lower motor neurons (LMNs). Despite significant advances in molecular and neuroimaging biomarkers, the initial site of pathology and the causal contribution of UMN dysfunction to disease progression remain undetermined. Accumulating neurophysiological evidence points to cortical hyperexcitability as an early and potentially upstream mechanism, raising the possibility that UMN pathology drives LMN degeneration through an anterograde dying-forward process. In this review, we synthesize findings from noninvasive brain stimulation (NIBS) studies, with particular emphasis on transcranial magnetic stimulation (TMS)-based neurophysiological markers of UMN dysfunction. We review evidence from TMS-electromyography (TMS-EMG) and TMS-electroencephalography (TMS-EEG) paradigms demonstrating cortical disinhibition and excitatory-inhibitory imbalance in ALS, consistent with impaired GABAergic interneuronal dysfunction and supportive of a cortical onset hypothesis. Finally, we propose integrating transcranial focused ultrasound (tFUS) with TMS as a novel experimental and translational framework to directly examine and modulate cortical hyperexcitability and test the causal role of UMN dysfunction in ALS. The combination of targeted neuromodulation with sensitive neurophysiological readouts in controlled experimental designs offers a promising avenue to advance mechanistic insight, refine biomarkers, and inform mechanism-based therapeutic strategies. Together, these approaches position noninvasive neurophysiology as a powerful tool for elucidating UMN dysfunction in ALS.
    Keywords:  ALS; TMS; cortical onset theory; hyperexcitability; tFUS; upper motor neuron
    DOI:  https://doi.org/10.3389/fneur.2026.1798525
  16. Mol Omics. 2026 Jul 02. pii: aaiag019. [Epub ahead of print]
    Elevated urea levels in human frontotemporal dementia and amyotrophic lateral sclerosis post-mortem brain tissue: Evidence of a multi-dementia pathogenic mechanism.
    Sasha A Philbert, Stephanie J Church, Richard D Unwin, Garth J S Cooper.
      Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent two neurodegenerative diseases on opposite sides of a movement disorder continuum. However, like many other neurodegenerative diseases, the molecular pathogenesis of FTD and ALS is not fully understood. Our group has previously reported evidence for a pervasive elevation of brain urea levels in five other dementia-causing diseases. However, brain urea levels have yet to be measured in ALS and FTD. Here, we employed ultra-high-performance liquid chromatography-tandem mass spectrometry to characterise brain urea differences between control (n = 14/12) and ALS/FTD (FTD: n = 8/9; ALS: n = 13/14) cases in post-mortem tissue from two brain regions with different levels of neuropathological burden (high versus low). Elevated urea levels were observed in both the frontal cortex (high neuropathological burden) and primary visual cortex (low neuropathological burden) in cases with FTD. Contrastingly, in cases with ALS, elevated urea was observed in the primary motor cortex (high neuropathological burden), but not the dentate nucleus (low neuropathological burden). These results not only suggest that elevated urea levels are also present in ALS and FTD but imply that elevated brain urea is linked to a multi-dementia pathogenic mechanism. In contrast to ALS, the observation of elevated urea in regions of both high and low neuropathological burden in FTD implies that this phenotype is likely widespread and, therefore, may play a larger role in the pathogenesis of disease. Such a mechanism could offer new directions for developing treatments targeting this underlying pathology.
    Keywords:  amyotrophic lateral sclerosis (ALS); carbamoylation; frontotemporal dementia (FTD); liquid chromatography–mass spectrometry; metabolomics; urea
    DOI:  https://doi.org/10.1093/molecular-omics/aaiag019
  17. BMJ Support Palliat Care. 2026 Jul 03. pii: spcare-2026-006126. [Epub ahead of print]
    Radiologically inserted gastrostomy in advanced amyotrophic lateral sclerosis: clinical outcomes.
    María Varela-Cerdeira, Laura Urraco Nieto, Maria Antonia Gomez Mendieta, Ana Santiago Recuerda, Yolanda Moran Benito, Pilar Carbajo Gullon, Alberto Alonso-Babarro.
       OBJECTIVES: To evaluate survival and clinical outcomes in patients with amyotrophic lateral sclerosis (ALS) undergoing radiologically inserted gastrostomy (RIG) and to describe outcomes in patients in whom gastrostomy was indicated but not performed.
    METHODS: This retrospective observational cohort study included patients with ALS followed by a multidisciplinary palliative care team between 2018 and 2020. Patients were classified according to gastrostomy status (RIG vs no RIG). Clinical data, respiratory support, nutritional status and survival outcomes were collected from medical records. Survival was analysed from gastrostomy indication using Kaplan-Meier curves stratified by baseline non-invasive ventilation (NIV) use.
    RESULTS: Among 155 patients with ALS, RIG was indicated in 53 and performed in 45; eight patients died before the procedure. 65 patients did not undergo gastrostomy. Median survival after RIG was 14.7 months, compared with 8 months in non-RIG patients who died. Baseline NIV use was associated with longer survival. No major safety concerns were identified.
    CONCLUSIONS: RIG appears to be a safe and feasible option in advanced ALS. Multidisciplinary care with integrated palliative involvement may facilitate referral, optimise nutritional support and support shared decision-making aligned with patients' goals of care. Further prospective studies are needed to confirm benefits and identify intervention timing.
    Keywords:  Clinical assessment; Dysphagia; Neurological conditions; Palliative Care; Survivorship
    DOI:  https://doi.org/10.1136/spcare-2026-006126
  18. Disabil Rehabil. 2026 Jul 01. 1-16
    Understanding patients' experiences and needs around decision-making for bulbar symptom management at a multidisciplinary ALS clinic.
    Anna Huynh, Lisa Cranley, Carolina Barnett-Tapia, Agessandro Abrahao, Lorne Zinman, Yana Yunusova.
       PURPOSE: This study explored the decision-making experiences of people living with amyotrophic lateral sclerosis (ALS) for managing bulbar symptoms and their perceived needs for decision-making support from healthcare professionals.
    METHODS: An interpretive, descriptive qualitative study was conducted. We recruited adult patients with ALS with and without any bulbar symptoms from a multidisciplinary ALS clinic in Central Canada. Patients were interviewed using a semi-structured guide. Reflexive thematic analysis was used to analyze study data. Recruitment ceased when information power was reached.
    RESULTS: Twelve participants were interviewed. Three themes were identified for patient's decision-making experiences and needs: (1) Disease uncertainty hinders decision-making; (2) Quality information triggers decision-making; and (3) Personal values and beliefs inform decision-making.
    CONCLUSIONS: To reduce psychological consequences of disease uncertainty and complexity on bulbar-related decision-making, patients emphasized the need for specific and contextualized information and healthcare professional supports aligned with their decision-making styles and approaches, highlighting the importance of a person- and family-centred approach to ALS care.
    Keywords:  Amyotrophic lateral sclerosis; decision-making; motor neurone disease; multidisciplinary care; patient experience; patient needs; qualitative research
    DOI:  https://doi.org/10.1080/09638288.2026.2693395
  19. EULAR Rheumatol Open. 2025 Oct;1(4): 475-477
    Occurrence of amyotrophic lateral sclerosis during TNF inhibitor treatment in inflammatory rheumatic disease. What are the relationships?
    Eric Toussirot, Laurent Tatu, Matthieu Bereau.
      Neurological adverse events have been reported in patients receiving tumor necrosis factor inhibitors (TNFi) for the treatment of inflammatory rheumatic diseases. The occurrence of amyotrophic lateral sclerosis (ALS) during TNFi therapy is rare but raises the question of a possible relationship. We report 2 cases of ALS diagnosed during TNFi treatment: the first in a patient with spondyloarthritis treated with adalimumab and the second in a patient with seronegative polyarthritis treated with infliximab. Tumor necrosis factor alpha (TNFα) has been implicated in ALS pathogenesis and is considered to exert both neuroprotective and neurotoxic effects, depending on the differential expression of its receptors in distinct regions of the central nervous system. We also review data from pharmacovigilance databases and discuss the potential influence of TNFα inhibition on ALS development.
    DOI:  https://doi.org/10.1016/j.ero.2025.11.019
  20. Nat Aging. 2026 Jul 03.
    Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.
    Ju Gao, Devanshi Shukla, Mao Ding, Siyue Qin, Fan Tang, Evelyn Guerrero, Lauren Vicuna, Jiawei Xu, Hongling Li, Masaru Miyagi, Pan P Li, Jingjing Liang, Xinglong Wang.
      Autosomal dominant mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), cause amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is a hallmark of multiple aging-associated neurodegenerative diseases. Despite its pathological role, effective therapies remain limited by the lack of safe, potent molecules targeting TDP-43 neurotoxicity. Here we show that the conserved α-helical region spanning residues 320-340 (conserved region or CR) is a therapeutically actionable target for TDP-43 neurotoxicity. Deletion of CR markedly suppressed TDP-43-induced neuronal death. Structure-based virtual screening identified XL20, a brain-penetrant small molecule that engages CR and confers neuroprotection without affecting TDP-43 splicing activity. XL20 alleviated motor neuron loss, extended survival in TDP-43 p.Ala315Thr ALS mice and enhanced neuronal function in p.Gln331Lys induced pluripotent stem cell-derived human ALS motor neurons. Mechanistically, targeting CR suppressed TDP-43 mitochondrial localization and restored mitochondrial function, likely through liquid-liquid phase separation. Our findings highlight CR as a therapeutic target for TDP-43-associated neurodegeneration and support CR-binding small molecules as therapeutic candidates.
    DOI:  https://doi.org/10.1038/s43587-026-01166-3
  21. J Neuroinflammation. 2026 Jul 02.
    SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.
    Meijun He, Chaoran Wu, Mengqiu Hu, Xiayi Shi, Ruiqi Liu, Yujie Tong, Heng Wang, Haoran Hu, Hong Liao.
      Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic activity during disease progression remain unclear. In this study, we observed stage-dependent alterations in microglial phagocytic activity during disease progression in SOD1G93A mice. Single-cell RNA sequencing suggested that this change was associated with a reduced abundance of microglial subpopulations enriched for phagocytosis-related pathways. Transcriptomic analysis identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a potential mediator of this process. Notably, sgk1 knockout in SOD1G93A mice was associated with improved microglial clearance of myelin debris and reduced aberrant engulfment of neuronal material after disease onset. Our results further showed that, after disease onset, the accumulation of myelin debris and apoptotic neurons induced SGK1 upregulation in microglia from SOD1G93A mice. Mechanistically, SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris. Moreover, pharmacological inhibition of SGK1 with GSK650394 attenuated motor deficits and prolonged survival in SOD1G93A mice. Together, our findings provide evidence for a previously unrecognized role of SGK1 in regulating microglial phagocytosis in ALS models and support SGK1 as a potential therapeutic target in SOD1 mutation-associated ALS models.
    Keywords:  ALS; Lysosomal dysfunction; Microglia; Motor deficits; Phagocytic activity; SGK1
    DOI:  https://doi.org/10.1186/s12974-026-03925-w
  22. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 29. 1-8
    An open-label Phase 2a study of fasudil in amyotrophic lateral sclerosis: safety and exploratory endpoints.
    Claudia Pena, Casey Barker, Allison N Grossberg, Ibrahim Mian, Sabrina Williams, Thomas MacAllister, Tuan Vu, Daniel A Linseman.
       OBJECTIVES: The primary objective was to assess the safety of oral fasudil in amyotrophic lateral sclerosis (ALS) patients. Changes in serum neurofilament light (NfL) levels and the ratio of phosphorylated to total AKT (pAKT/tAKT) were exploratory endpoints.
    METHODS: This was a multicenter, open-label study. Two 31-patient cohorts were sequentially enrolled and treated with either 180 mg or 300 mg per day of oral fasudil for 24 weeks. The primary endpoint was safety. Secondary endpoints evaluated changes in the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity, and muscle strength. We also assessed changes in serum NfL and pAKT/tAKT ratios in plasma (neuron-derived) and CSF (total) extracellular vesicles (EVs).
    RESULTS: Eighty-one percent (25/31) and 71% (22/31) of patients completed 24 weeks of treatment in the 180 and 300 mg cohort, respectively. Fasudil was safe and well tolerated, with predominantly mild drug-related adverse events. Secondary endpoints, though not statistically significant, were directionally consistent with a treatment effect. Exploratory analyses showed a 15.4% reduction in serum NfL at 24 weeks (p = 0.001) in the 180 mg cohort, with no change in the 300 mg cohort (-0.4%, p = 0.990). The NfL reduction was inversely correlated with ALSFRS-R decline (Spearman = -0.45, p = 0.028). Ratios of pAKT/tAKT, a pharmacodynamic marker of rho kinase (ROCK) inhibition, were significantly increased at 24 weeks in plasma (neuron-derived) and CSF EVs.
    CONCLUSIONS: Oral fasudil is safe and well-tolerated in ALS patients. The reduction in NfL and demonstration of CNS target engagement, supports studying the 180 mg dose in a double-blind placebo-controlled study.
    Keywords:  AKT; Amyotrophic lateral sclerosis; exosomes; fasudil; neurofilament light chain (NfL); rho kinase (ROCK)
    DOI:  https://doi.org/10.1080/21678421.2026.2694507
  23. J Neurol. 2026 Jul 01. pii: 435. [Epub ahead of print]273(7):
    Genome-wide spectrum of coding DNA variations in Indian patients with amyotrophic lateral sclerosis.
    Ananthapadmanabha Kotambail, Gautham Arunachal, Muddasu Suhasini Keerthipriya, R Mahima, Ramya Sukrutha, M B Ramyashree, Madhusudhan Deekshitha, Bhoomika M Rao, Purbasha Biswas, Kiran Polavarapu, Veeramani Preethish-Kumar, Pradeep Reddy, Olivia Gray, Kaja A Wasik, Anne-Katrin Emde, Sanjana Angadi, Bhaswar Bhattacharya, Marsha Zacharia, K V Jeevitha, Koneti Deepak Kumar, Naveen H Masaraddi, Saraswati Nashi, G K Chetan, Seena Vengalil, Atchayaram Nalini.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapies, emphasizing the need for deeper understanding of disease pathogenesis. While more than 40 ALS-associated genes have been identified, their contribution varies significantly across populations and the data from the Indian population remains scarce. We aimed to comprehensively characterize the spectrum of coding DNA variations in ALS-associated genes and identify novel genetic contributors in an Indian cohort. Whole-exome sequencing on 761 ALS patients and 917 in-house healthy controls and repeat-primed PCR for expansions (C9orf72, ATXN2, NOTCH2NLC, NOP56) were performed. Variants were classified using ACMG guidelines, and rare variant association testing was conducted. Overall diagnostic yield was 15.90%, with pathogenic/likely pathogenic variants. Familial ALS showed higher diagnostic yield (36.95%) than sporadic ALS (12.96%). SOD1 dominated familial cases (53.85%), while OPTN, SOD1 and FIG4 were prevalent in sporadic cases. Homozygous SOD1 variants in six patients correlated with juvenile/young onset (< 30 years). C9orf72 expansions (4%) and ATXN2 repeats (1.7%) were identified at frequencies comparable with Asian cohorts. Rare variant analysis identified JAK2 as a novel genome-wide significant signal (FDR = 3.5 × 10-5). This first large-scale genomic survey of Indian ALS patients showed SOD1 being the predominant cause of fALS, while OPTN, FIG4, and other genes drive disease amidst low C9orf72 frequency. The novel JAK2 association suggests a potential neuroinflammatory mechanism, highlighting the importance of studying diverse populations to uncover distinct genetic etiologies.
    Keywords:   SOD1 ; Amyotrophic lateral sclerosis; Exome sequencing; Genetic variation; Neurodegenerative disease
    DOI:  https://doi.org/10.1007/s00415-026-13819-9
  24. Brain Commun. 2026 ;8(3): fcag231
    Beyond neurofilaments: a multidimensional blood signature for amyotrophic lateral sclerosis.
    Eleanor V Thomas, Devesh C Pant.
      This scientific commentary refers to 'Blood-based biomarker discovery in motor neuron disease using nucleic acid-linked immuno-sandwich assay', by Bozkurt et al. (https://doi.org/10.1093/braincomms/fcag180).
    DOI:  https://doi.org/10.1093/braincomms/fcag231
  25. Life Sci Alliance. 2026 Sep;pii: e202503605. [Epub ahead of print]9(9):
    Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes.
    Devesh C Pant, Museer A Lone, Janani Parameswaran, Fuying Ma, Nicole Ziak, Prisha Dutta, Zitong Wang, Daniel Pun, Sumit Verma, Thorsten Hornemann, Jie Jiang.
      Mutations in the human SPTLC1 gene have recently been linked to early-onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2, and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel knock-in mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings provide valuable insights into SPTLC1 exon 2 biology and serve as a useful resource for future mechanistic studies.
    DOI:  https://doi.org/10.26508/lsa.202503605
  26. Phys Chem Chem Phys. 2026 Jul 02.
    Nanoscale morphological and structural analysis of round and donut oligomers formed by C-terminal domain of TDP-43.
    Davis Pickett, Yana Purvinsh, Joshua T Skrehot, Daniel Warren, Dmitry Kurouski.
      Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), limbic predominant age-related TDP-43 encephalopathy (LATE), and Parkinson's disease are associated with an abrupt aggregation of TAR DNA-binding protein 43 (TDP-43). Although molecular mechanisms of this pathological aggregation remain unclear, accumulated evidence suggests that the C-terminus domain (C-terminal domain (CTD)) is the trigger of TDP-43 self-assembly into toxic oligomers and fibrils. While the secondary structure and morphology of protein fibrils have been well documented, very little is known about TDP-43 oligomers. This is primarily because of the transient nature and low concentrations of these protein species. In the current study, we utilize nano-infrared spectroscopy, also known as atomic force microscopy-infrared (AFM-IR) spectroscopy, to investigate the morphology and secondary structure of CTD of TDP-43 oligomers formed at the early and middle stages of protein aggregation. This innovative technique allows us to resolve both morphology and secondary structure of individual protein aggregates. We found that at the early stage of protein aggregation, CTD of TDP-43 formed two morphologically different protein aggregates: donut-like (DO) and round (RO) oligomers. DO yielded fibrillar species, while RO persisted throughout the entire course of CTD TDP-43 self-assembly.
    DOI:  https://doi.org/10.1039/d6cp01760f
  27. Genes Cells. 2026 Jul;31(4): e70134
    The SQSTM1 L341V Variant Associated With Sporadic ALS Promotes the Accumulation of Enlarged Ubiquitin-Positive SQSTM1 Bodies.
    Kento Shimakura, Akira Oka, Haruka Yudahira, Yutaro Hama, Asako Otomo, Shinji Hadano.
      SQSTM1 is one of the causative genes of neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The SQSTM1 protein regulates the degradation of polyubiquitinated proteins and autophagosome formation through its interaction with microtubule-associated protein light chain 3 (MAP1LC3/LC3). However, the molecular mechanisms by which SQSTM1-LC3 binding regulates the autophagy-endolysosomal system (APELS) remain unclear. To elucidate the spatiotemporal role of SQSTM1, we transiently expressed wild-type SQSTM1 or missense mutants carrying mutations in the LC3-interacting region (LIR), fused with the photoconvertible fluorescent protein Dendra2. Live-cell fluorescence imaging and co-localization analyses with markers of the APELS were then performed. Particle analysis of photoconverted or non-photoconverted SQSTM1-positive structures in live cells revealed that the pathogenic L341V variant formed larger structures than the wild-type. Co-localization analyses further showed that both the L341V and artificial LIR3A mutants accumulated in large ubiquitin-positive structures, likely due to impaired localization to autophagosomes. These results suggest that mutations within the LIR differentially affect autophagosome formation and cargo degradation within APELS-related compartments, highlighting the importance of SQSTM1 structural integrity in ALS/FTD pathogenesis.
    Keywords:  ALS; Dendra2; FTD; LC3; SQSTM1; autophagy‐endolysosomal system (APELS)
    DOI:  https://doi.org/10.1111/gtc.70134
  28. Biochem Biophys Rep. 2026 Sep;47 102687
    The role of SUMOylation in regulating proteins that drive neuronal disease progression.
    Aditya Sidharth, Daesung Shin.
      SUMOylation is a post-translational modification in which a Small Ubiquitin-like Modifier (SUMO) protein is reversibly attached to a lysine residue on a target protein in an ATP-dependent process. This modification can affect the function of target proteins by enhancing their stability or changing cellular translocation, thereby making SUMOylation a critical regulator in the pathogenesis of multiple diseases. The functional consequences of SUMOylation, however, are highly context dependent. In Alzheimer's disease, SUMOylation stabilizes proteins that drive disease progression and enhances neurotoxicity, thereby exacerbating these conditions. Similarly, in Progressive Supranuclear Palsy, SUMO-1 conjugation stabilizes truncated tau and blocks its ubiquitination, whereas SUMO-2/3 conjugation promotes Tau clearance and recovery from neuroinflammation, illustrating how distinct SUMO paralogues can exert opposing effects within the same disease. Conversely, increased SUMOylation can be neuroprotective in cerebral ischemia and Parkinson's disease by promoting autophagic clearance of pathogenic proteins. Beyond alterations in protein stability, aberrant SUMOylation can also lead to mis-localization of target proteins, which has been identified as a pathogenic mechanism in disorders such as Huntington's disease and Amyotrophic Lateral Sclerosis that results in impaired clearance and pathogenic buildup, which results in neuronal death. From a therapeutic standpoint, the SUMO inhibitor TAK-981 has shown promise in both Multiple Sclerosis and in pre-clinical glioblastoma models, underscoring the translational potential of targeting of this pathway. This review examines the multifaceted role of SUMOylation across diverse neurological conditions, evaluates the therapeutic potential of SUMO inhibitors and activators, and highlights the opportunities and challenges of modulating this pathway in currently incurable neurological disorders.
    Keywords:  Alzheimer's disease; Amyotrophic lateral sclerosis; Huntington's disease; Multiple sclerosis; Parkinson's disease; Posttranslational modification; Progressive supranuclear palsy; SUMOylation
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102687
  29. BMC Med. 2026 Jul 02.
    Structural-functional network decoupling in early stage amyotrophic lateral sclerosis reveals cell-type specific transcriptional signatures.
    Jixin Luan, Yan Yun, Yichang Jiao, Yao Wang, Mingjie Ma, Didi Shan, Hongxu Wang, Xinbo Ji, Yao Tang, Jianing Li, Zexin Zhan, Xiaohan Sun, Ninglu Gao, Pengfei Lin, Chuanzhu Yan, Dexin Yu, Shuangwu Liu, Fuchen Liu.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) involves widespread brain network dysfunction, yet the molecular mechanisms linked to these alterations remain poorly understood. We investigated macroscopic structural-functional coupling abnormalities in early-stage ALS (ALS-ES) and their underlying transcriptomic signatures.
    METHODS: We analyzed multimodal MRI data from 73 patients with sporadic ALS-ES and 74 age- and sex-matched healthy controls. Structural-functional (SC-FC) coupling was quantified using diffusion tensor imaging and resting-state functional MRI. Machine learning models were constructed to distinguish patients from controls based on network features. Coupling alterations were spatially correlated with neurotransmitter receptor maps and gene expression profiles from the Allen Human Brain Atlas. Key transcriptomic findings were validated using independent single-cell RNA sequencing datasets.
    RESULTS: While structural connectivity remained largely preserved, functional connectivity was significantly reduced in the somatomotor network (SMN). This mismatch manifested as significant SC-FC network decoupling, particularly within the SMN (pFDR = 0.001). A gradient boosting machine model accurately classified patients, identifying SC-FC coupling in the left precentral gyrus as a primary statistical contributor to the classification model. Decoupling spatially correlated with 5-HT2A and mGluR5 receptor distributions. Imaging-transcriptomics linked network failure to a gene signature enriched for synaptic pathways and microglial markers. Single-cell analysis identified FMN1 as a candidate gene whose glial expression spatially associates with network decoupling.
    CONCLUSIONS: Early-stage ALS is characterized by significant structural-functional network decoupling, primarily in motor systems. This macroscopic failure is linked to specific microglial dysregulation, particularly FMN1 downregulation, providing a multiscale framework bridges statistical neuroimaging signatures with potential cellular pathology.
    Keywords:  Amyotrophic lateral sclerosis; Microglia; Single cell; Structural-functional coupling; Transcriptional patterns
    DOI:  https://doi.org/10.1186/s12916-026-04932-7
  30. Nat Immunol. 2026 Jul;27(7): 1364-1374
    Innate immune signaling and functions in astrocytes.
    Amy X Guo, Theodore M Fisher, Natacha Comandante-Lou, Philip L De Jager, Shane A Liddelow.
      Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.
    DOI:  https://doi.org/10.1038/s41590-026-02561-z
  31. Biosystems. 2026 Jun 27. pii: S0303-2647(26)00172-3. [Epub ahead of print]266 105862
    The impedance mismatch theory: A non-equilibrium thermodynamic framework for a shared energetic stress pathway in neurodegeneration.
    Kevin Thorsen Baird.
      Current neurobiological models of Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's Disease (HD) utilize multi-omic interactome analyses to map cascades of proteinopathy. While essential, these approaches often overlook the macroscopic thermodynamic limits of the neural substrate as an information processing system. We propose the Impedance Mismatch Theory, a theoretical biophysical model and quantitative framework for the thermodynamic limits of neural computation, positing that these distinct pathologies converge as a shared energetic stress pathway. We introduce the Neurophysiological Load Index (NLI)-a dimensionless parameter quantifying the mismatch between electrical computational drive, topological network impedance, and the local structural and microvascular dissipation capacity. Drawing on the Pennes Bioheat Transfer Equation and insights from multiplex network theory, we hypothesize that pathology initiates as localized thermal runaway, where resistive metabolic heat exceeds convective blood perfusion and thermal conduction, inducing acute decompensation. We outline cross-translational disease-network mechanisms, address the inverse cancer comorbidity paradox via speculative bioelectric attractor states, and propose falsifiable predictions involving high-resolution in vivo proton magnetic resonance spectroscopy thermometry (1H-MRS-t) and phosphorus-31 magnetic resonance spectroscopy (31P-MRS).
    Keywords:  Amyotrophic lateral sclerosis; Information processing; Neuroenergetics; Pennes bioheat equation; Theoretical biology; Thermal runaway
    DOI:  https://doi.org/10.1016/j.biosystems.2026.105862
  32. Res Sq. 2026 Jun 15. pii: rs.3.rs-9869051. [Epub ahead of print]
    Comparative Analysis of Regional Blood-Brain Barrier Permeability in Humans and Rodents: An Evolutionary Perspective.
    Sheida Mirloo, Lyna Kamintsky, Shayna Cort, Jamil Muradov, Saara Mansoor, Laith Alhadeed, Alaa Abu Ahmad, Basim Shafiq, Amirhossein Talebanpour, Rotem Saar -Ashkenazy, Yonatan Serlin, Alon Friedman.
      Background The blood-brain barrier (BBB) serves a critical function in regulating transport between the blood and the brain, with its dysfunction being implicated in numerous neurological diseases such as neurodegenerative disorders, epilepsy, stroke, traumatic brain injury, and brain tumors. Understanding the regional heterogeneity in BBB properties in healthy individuals remains limited. This study aims to characterize regional BBB permeability variations in the healthy brain using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and explore differences related to sex and age. Methods We retrospectively analyzed DCE-MRI scans from 102 healthy participants aged 19-85 (55.8% female), assessing BBB permeability to a Gadolinium-based contrast agent and plasma volume fraction across 124 brain regions. We examined the effects of sex and age on BBB permeability and plasma volume fraction. Additional studies were conducted on 11-week-old Sprague Dawley rats using DCE-MRI and fluorescent microscopy following peripheral injection of Evans blue dye. Results We show that BBB permeability varies across brain regions, being lower in more recently evolved cortical regions, such as the frontal cortex, compared to the phylogenetically older brainstem and subcortical areas. Plasma volume fraction showed the opposite trend with higher vascularization in cortex compared to brainstem. Age-related analysis revealed an increase in BBB permeability (normalized to plasma volume fraction) that was more pronounced in males than females. Conclusions This study underscores an evolutionary perspective in BBB properties, highlighting a gradient from higher permeability in evolutionarily older brain regions (e.g. brainstem) to lower permeability in evolutionarily younger regions (e.g. frontal cortex). These permeability differences accentuate with age, particularly in males.
    DOI:  https://doi.org/10.21203/rs.3.rs-9869051/v1
  33. J Neurol Neurosurg Psychiatry. 2026 Jul 03. pii: jnnp-2026-338675. [Epub ahead of print]
    Global epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.
    Ru-Yin Liu, Wei-Ming Su, Qing-Qing Duan, Xiang-Jin Wen, Sheng-Yi He, Nan Zhang, Bei Cao, Yong-Ping Chen.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with the global epidemiological profile remaining incompletely understood. While previous systematic reviews existed, an updated comprehensive synthesis is needed to delineate the disease burden.
    METHODS: We searched PubMed, Embase, Scopus, Web of Science and Cochrane databases from inception to 18 February 2025, for studies reporting the incidence, prevalence or mortality of ALS in the general population. Pooled estimates with 95% CIs were calculated, and subgroup analyses were performed.
    RESULTS: Of 29 110 articles initially screened, 142 were included. Global pooled incidence was 1.65 per 100 000 person-years (95% CI 1.43 to 1.91), prevalence was 5.05 per 100 000 population (95% CI 4.26 to 5.99) and mortality was 1.26 per 100 000 person-years (95% CI 0.94 to 1.69). Both incidence rate ratio (IRR=0.74) and prevalence rate ratio (PRR=0.69) indicated significantly lower disease burden in females than in males. The burden of disease exhibited a marked age-dependent pattern, peaking at ages 70-79. Temporal trend analyses revealed a consistent increase in prevalence from 1963 to 1999 onwards, while incidence peaked in 2014-2017. Geographically, incidence and prevalence were highest in Europe, North America and Oceania and lowest in Asia and South America. The disease burden was significantly higher in high-income countries compared with both upper-middle-income and lower-middle-income countries.
    CONCLUSION: This systematic review provides updated global ALS burden estimates, showing variations by sex, age, time and geography and underscoring the complex interplay of genetic, environmental and socioeconomic factors, with implications for health planning, resource allocation and etiological research.
    DOI:  https://doi.org/10.1136/jnnp-2026-338675
  34. Expert Opin Drug Saf. 2026 Jun 30. 1-16
    Could anticholinergics accelerate ALS progression? A critical perspective on drug safety and disease vulnerability.
    Tiffany R Price, Chia-Yuan Chang, Kirya Skinner, Michael Dinneny, Parmida Nafezi, Lisa Kuramoto, Mary A De Vera, Neil R Cashman, Jacquelyn J Cragg.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited treatment options and diverse symptoms necessitating active management. Anticholinergic medications are frequently used in ALS care, particularly for sialorrhea and mood disturbances. Their cumulative effects, termed anticholinergic burden, may pose underrecognized risks in this neurologically vulnerable population. This review highlights a plausible safety signal and outlines priorities for future research.
    AREAS COVERED: This narrative review synthesizes evidence from non-ALS populations reporting associations between higher anticholinergic burden and cognitive decline, respiratory complications, functional deterioration, and mortality. Evidence was identified through targeted PubMed/MEDLINE and Embase searches with reference chaining, emphasizing recent and seminal studies. Mechanistic overlap with ALS pathophysiology, including neuromuscular junction disruption, impaired cholinergic signaling, and neuroinflammation, supports biological plausibility for harm. Current ALS guidelines do not address cumulative anticholinergic exposure, leaving clinicians without a framework for evaluating risk or deprescribing.
    EXPERT OPINION: This article proposes a testable hypothesis that anticholinergic burden may represent a clinically relevant yet unmeasured risk factor in ALS. Emerging pharmacoepidemiologic methods and validated burden tools offer approaches to quantify exposure and evaluate relationships with ALS outcomes, supporting safer symptomatic management. Prioritizing longitudinal studies and integrating burden assessment into multidisciplinary care may help clarify risk.
    Keywords:  Amyotrophic lateral sclerosis; anticholinergic burden; disease progression; drug safety; neurodegeneration; neuromuscular junction; pharmacoepidemiology; polypharmacy
    DOI:  https://doi.org/10.1080/14740338.2026.2687628
  35. Muscle Nerve. 2026 Jun 28.
    At-Home Versus in-Clinic Vital Capacity Measurement: Insights From the HEALEY ALS Platform Trial.
    HEALEY ALS Platform Trial Study Group
       INTRODUCTION/AIMS: Respiratory weakness, typically monitored as vital capacity (VC), is a central feature of amyotrophic lateral sclerosis (ALS). VC is increasingly measured remotely in participants' homes, although in-clinic assessment remains the standard. We tested concordance between at-home and in-clinic VC to determine trial eligibility, track progression, and predict survival in a large ALS trial.
    METHODS: At-home and in-clinic VC were assessed at baseline and approximately every 8 weeks for a year in the first four regimens of the HEALEY ALS Platform Trial. At-home assessments were coached via live videoconference and centrally reviewed. VC measurements, expressed as percent of predicted normal (%PN), were compared cross-sectionally, longitudinally, and for predicting survival time. Data from 233 participants with 3-8 paired at-home and in-clinic VC assessments completed < 14 days apart were analyzed.
    RESULTS: At-home and in-clinic VC were well correlated (Lin's rc = 0.82) with no systematic bias. At-home VC ≥ 60%PN predicted in-clinic VC ≥ 60%PN with a positive predictive value of 91% and a negative predictive value of 65%. VC slopes were moderately correlated (rc = 0.68). At-home VC progressed 28% faster than in-clinic VC with proportionately less variance (at-home [SE] = -1.882 [0.153] %PN/month, in-clinic = -1.476 [0.131] %PN/month). Slopes of at-home and in-clinic VC explained 15% and 17% of variation in future survival time, respectively.
    DISCUSSION: At-home and in-clinic VC were well correlated cross-sectionally. At-home VC performed well tracking longitudinal change and predicting survival. The reduced participant burden of assessment and concordance with in-clinic measurement support use of at-home monitoring of VC.
    Keywords:  amyotrophic lateral sclerosis; remote patient monitoring; spirometry; validation studies as topic
    DOI:  https://doi.org/10.1002/mus.70322
  36. Int J Pharm X. 2026 Dec;12 100583
    Focused ultrasound-mediated blood-brain barrier opening enhances delivery of Rg3 ginseng nanoparticles in a Parkinson's disease mouse model.
    Cynthia Imtiaz, Changsoo Kim, Dong-Guk Paeng.
      The blood-brain barrier (BBB) severely restricts the delivery of neuroprotective compounds to the brain, limiting therapeutic strategies for Parkinson's disease (PD). Ginsenoside Rg3, a bioactive component of ginseng, has demonstrated neuroprotective potential, but its efficacy is constrained by poor BBB permeability. Here, we evaluated focused ultrasound (FUS)-mediated BBB opening (FUS BBBO) to enhance delivery of Rg3-loaded nanoparticles in a rotenone-induced mouse model of PD. Localized FUS sonications were applied to induce transient BBB disruption, followed by intraperitoneal administration of FITC-labeled Rg3 nanoparticles. In vivo and Ex vivo fluorescence imaging confirmed a significant increase in brain accumulation of nanoparticles after FUS BBBO. While Rg3 nanoparticle treatment alone showed moderate increases in ATP levels and Complex I activity, FUS alone produced comparable trends with slightly higher recovery. The combination treatment with FUS-mediated BBBO demonstrated higher mean values (ATP: 0.27 ± 0.06; Complex I: 1.98 ± 0.41) compared to the PD group, along with improvements in motor performance. These findings suggest that FUS-BBBO may enhance the delivery of Rg3 nanoparticles to the brain and support mitochondrial function. Overall, the combination approach showed a trend toward improved outcomes; however, further studies are required to confirm these effects and establish therapeutic potential for solid statistical analysis.
    Keywords:  Blood–brain barrier disruption; Focused ultrasound; Mitochondrial function; Parkinson's disease; Rg3 ginsenoside nanoparticles
    DOI:  https://doi.org/10.1016/j.ijpx.2026.100583
  37. PLoS One. 2026 ;21(6): e0352334
    Dexamethasone restores blood-brain barrier integrity in an in vitro heatstroke model.
    Kazuaki Okamura, Karoline Pichlerova, Takayuki Matsuo, Daisuke Watanabe, William D Cutts, Brandon J Kim, Yoichi Morofuji.
      Heat-related diseases and their treatments are becoming the center of focus due to global warming resulting in rising global temperatures. Heatstroke is the most hazardous condition of heat-related diseases, which when left untreated leads to death. One of the main characteristics of heatstroke is the dysfunction of the central nervous system. In this study, we established an in vitro heatstroke model of the blood-brain barrier (BBB) consisting of endothelial cells and pericytes. Following heat exposure at 43°C for 3 h, the model failed to recover during the subsequent 24 h regeneration period. The damage was shown by decreased transendothelial resistance (p < 0,0001) and confirmed by permeability assays and immunohistochemistry with in silico analysis. We subsequently evaluated the effect of dexamethasone in our heatstroke model. Administration of dexamethasone post-heatstroke alleviated BBB damage during the regeneration period, by increasing transendothelial electrical resistance and ZO-1 expression while reducing BBB permeability. Our findings suggest that dexamethasone reduces heatstroke damage at the BBB in in vitro conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0352334
  38. Rev Neurol (Paris). 2026 Jul 03. pii: S0035-3787(26)00556-4. [Epub ahead of print]
    Macrophage inclusions in patients undergoing antisense oligonucleotide therapy for ALS or SMA: A retrospective and transversal study.
    R Demeret, D Vieles Marais, E Treiner, B Acket, V Fabry, T Levade, L Nogueira, J-C Pages, P Cintas.
       BACKGROUND: Intrathecal antisense oligonucleotides (ASOs) have revolutionized the management of genetic motor neuron diseases. Nusinersen is approved for spinal muscular atrophy (SMA) caused by SMN1 mutations, and tofersen for amyotrophic lateral sclerosis (ALS) linked to SOD1 mutations. Since their approval, some studies reported the presence of macrophagic inclusions in cerebrospinal fluid (CSF) of patients treated with ASOs, first in nusinersen-treated patients and more recently in those receiving tofersen. These findings remain poorly characterized, and their clinical significance is unclear.
    METHODS: We first conducted a retrospective study in 21 patients (132 CSF samples): six treated with tofersen (every 4 weeks) and 15 with nusinersen (every 4 months). CSF samples were analyzed for macrophagic inclusions, their time of onset, and persistence over time. To assess clinical and inflammatory correlates of macrophagic inclusions, we then performed an analysis of CSF inflammatory biomarkers and serum ferritin and neurofilament light chain tests in 18 of these patients still under treatment.
    RESULTS: In tofersen-treated patients, macrophagic inclusions were consistently observed and persisted over time, except in one case. In nusinersen-treated patients, inclusions were rare and transient. An inflammatory CSF profile was associated with the presence of inclusions, but their cellular nature remained undetermined. Notably, tofersen-treated patients with "tofersenophages" exhibited favorable clinical responses.
    DISCUSSION: Macrophagic inclusions appear more frequent in the CSF of tofersen-treated patients than previously reported. While their origin remains unclear, they seem linked to CSF inflammation without precluding a beneficial therapeutic response.
    Keywords:  ALS; Antisense oligonucleotide; Macrophages with inclusions; Nusinersen; SMA; Tofersen
    DOI:  https://doi.org/10.1016/j.neurol.2026.05.005
  39. J Neuroeng Rehabil. 2026 Jul 01.
    Safety, feasibility and preliminary effects of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis: a prospective ABA pilot study.
    Ghida Trad, Timothée Lenglet, Isabelle Ledoux, Giorgia Querin, Sophie Blancho, Véronique Marchand-Pauvert, Jean-Yves Hogrel, Pierre-François Pradat.
       BACKGROUND: In amyotrophic lateral sclerosis (ALS), progressive weakness makes walking practice increasingly unsafe and difficult, accelerating loss of mobility and autonomy. Lower-limb exoskeletons could preserve task-specific stepping in a controlled setting, but evidence in ALS remains scarce. This study evaluated the safety of an intensive Atalante exoskeleton gait-training program and explored its effects on walking and related clinical outcomes.
    METHODS: In this prospective, monocentric ABA pilot study, 10 ambulatory persons with ALS underwent three consecutive 6-week phases over 18 weeks: A1 (baseline, usual care), B (intervention: Atalante exoskeleton gait training added to usual care; 18 sessions, 3 times/week), and A2 (withdrawal, usual care), with repeated assessments every 3 weeks. The primary endpoint was safety, assessed by adverse events (AE). Secondary endpoints included ALS Functional Rating Scale-Revised, forced vital capacity, standardized walking tests (6-minute walk test, 10-meter walk test, Timed Up and Go test), Berg Balance Scale, postural control on a force platform, lower-limb strength with dynamometry, spasticity with isokinetic dynamometer, Fatigue Severity Scale, Modified Fatigue Impact Scale, ALS Assessment Questionnaire-40, and Hospital Anxiety and Depression Scale. Exoskeleton-specific patient-reported outcomes (PROs) included intrinsic motivation, participants' attitudes toward the intervention, perceived subjective impact of the training, perceived efficacy and interactivity of the exoskeleton. The results were analyzed with linear mixed-effects models.
    RESULTS: No serious AE occurred, and one mild AE was certainly related to the intervention. No outcome showed significant phase-specific slopes or slope contrasts, although several measures displayed directionally consistent trends compatible with attenuated decline during phase B and a return toward a less favorable trajectory after withdrawal. Exoskeleton-specific PROs indicated high intrinsic motivation and acceptability (usefulness for standing, perceived safety, ease of participation, and ease of installation/uninstallation rated very highly), with perceived gait-training efficacy generally positive. Participants frequently reported reduced immobility and increased accomplishment (80% each) and postural improvement (70%), and the Net Promoter Score of recommendation was + 40.
    CONCLUSIONS: Atalante exoskeleton gait training was safe and feasible in ambulatory ALS. These pilot data can guide the optimization of future studies to test whether it preserves function. Trial registration ClinicalTrials.gov, NCT06199284. Registered on 29/12/2023.
    Keywords:  Amyotrophic lateral sclerosis; Atalante exoskeleton; Rehabilitation; Robot-assisted gait training
    DOI:  https://doi.org/10.1186/s12984-026-02046-y
  40. Clin Neurophysiol Pract. 2026 ;11 522-527
    Decremental responses following repetitive nerve stimulation in spinal and bulbar muscular atrophy.
    Keisuke Tachiyama, Masahiro Nakamori, Yuki Fujii, Keiichi Hokkoku, Dai Agari, Shoji Hemmi, Eiichi Nomura, Yuki Hatanaka, Katsumi Kurokawa, Masahiro Sonoo, Hirofumi Maruyama.
       Objective: The presence of decremental responses following repetitive nerve stimulation (RNS) in amyotrophic lateral sclerosis (ALS) is well established. However, in spinal and bulbar muscular atrophy (SBMA), a rare X-linked recessive lower motor neuron disease, the incidence and distribution of decremental responses across different muscles have not been thoroughly investigated.
    Methods: Patients with SBMA were retrospectively identified in our database. RNS at a frequency of 3 Hz was performed on five muscles: the abductor pollicis brevis (APB), abductor digiti minimi (ADM), upper trapezius, deltoid, and facial muscles (frontalis or nasalis).
    Results: A total of forty patients were identified. A significant (> 5%) decremental response in at least one muscle was observed in all patients. It was observed more frequently in proximal muscles than in distal muscles: deltoid (86%), trapezius (70%), facial muscles (44%), APB (37%) and ADM (25%). The magnitude of the decremental response in the deltoid was significantly higher than that in the other muscles.
    Conclusions: Our results demonstrated that decremental responses were frequently observed in patients with SBMA, with a distribution pattern similar to that in ALS. The fact that the decremental responses are observed in SBMA having an extremely chronic course would be relevant for the pathophysiological mechanism of the decremental response.
    Significance: The RNS findings provide valuable insights into the pathological mechanisms of SBMA and may contribute to the development of future treatments.
    Keywords:  Decremental response; Repetitive nerve stimulation; Spinal and bulbar muscular atrophy
    DOI:  https://doi.org/10.1016/j.cnp.2026.06.011
  41. Front Neurol. 2026 ;17 1824840
    A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.
    Louisa Leone, Tighe J Kiernan, Satoshi Kuwabara, Michael Barnett, Emma Devenney, Rebekah M Ahmed, Cindy Shin-Yi Lin.
      Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.
    Keywords:  dementia; diabetes mellitus; insulin resistance; neurodegeneration; neuroimmune disease; neuroinflammation; peripheral neuropathy
    DOI:  https://doi.org/10.3389/fneur.2026.1824840
  42. ACS Appl Mater Interfaces. 2026 Jul 02.
    A Brain-Targeted DNA Delivery Nanocarrier Modulator for Synergistic Therapy of Parkinson's Disease.
    Yuxue Cheng, Limin Zhai, Haoyuan Wang, Beining Liao, Jingfeng Che, Kuo Ma, Guowei Huang, Shengjun Pan, Hao Yang, Yan-Qing Guan.
      The pathological characteristics of Parkinson's Disease (PD) are multifactorial, encompassing the aggregation of α-synuclein, mitochondrial dysfunction, and oxidative stress, necessitating the adoption of multitarget therapeutic strategies. In this study, a borneol-modified carboxymethyl chitosan nanoparticle system (BC/P/HCR NPs) was developed, aiming to codeliver curcumin, rosmarinic acid, and plasmid DNA (pDNA) targeting the SNCA gene for synergistic therapeutic intervention in PD. Borneol is capable of enhancing the permeability of the blood-brain barrier (BBB), while carboxymethyl chitosan contributes to improving the solubility of curcumin and preventing premature drug release. In a C57BL/6 mouse model of PD, BC/P/HCR NPs demonstrated enhanced penetration through the BBB, effectively alleviating motor dysfunction and reducing neuronal damage by downregulating the expression of α-synuclein, restoring mitochondrial function, and mitigating oxidative stress. These findings underscore the potential of BC/P/HCR NPs as a multifunctional nanotherapeutic platform for addressing the complex pathological features of PD.
    Keywords:  blood-brain barrier (BBB); borneol; gene therapy; nanoparticles; parkinson’s disease; synergistic therapy
    DOI:  https://doi.org/10.1021/acsami.6c06170
  43. PLoS Pathog. 2026 Jun;22(6): e1014315
    A single Citrobacter rodentium infection in Pink1 knockout and wild-type mice leads to regional blood-brain-barrier perturbation and limited microglial activation without dopamine neuron axon terminal loss.
    Sriparna Mukherjee, Vladimir Grouza, Alex Tchung, Amandine Even, Moein Yaqubi, Marius Tuznik, Tyler Cannon, Sherilyn Junelle Recinto, Christina Gavino, Marie-Josée Bourque, Nicolas Giguère, Heidi McBride, Michel Desjardins, Samantha Gruenheid, Jo Anne Stratton, David A Rudko, Louis-Eric Trudeau.
      A growing body of research suggests a link between immune system activation and the development of Parkinson's disease (PD). Previous work showed that repeated gastrointestinal infection with Citrobacter rodentium can induce PD-like motor dysfunction in Pink1 knockout (KO) mice, along with immune cell infiltration into the brain. To better understand mechanisms underlying immune-mediated brain attack in this model, we tested whether mild infections are sufficient to increase blood-brain barrier (BBB) permeability and trigger brain inflammation. Pink1 wild-type (WT) and KO mice were infected with C. rodentium, and gadolinium-enhanced magnetic resonance imaging (MRI) was performed at days 13 and 26 post-infection to assess BBB integrity. Quantitative MRI analysis revealed increased BBB permeability at day 26 in both WT and KO mice, particularly in the striatum, dentate gyrus, somatosensory cortex, and thalamus. Notably, this permeability was not associated with changes in tight junction protein expression or dopamine system markers in the striatum at either time point. However, persistent microglial activation was observed at day 26 post-infection, along with elevated levels of inflammatory mediators such as eotaxin, IFN-γ, CXCL9, IL-17, and MIP-2 in the striatum. Additionally, serum levels of IL-17 and CXCL1 were increased in infected Pink1 KO mice. Flow cytometry revealed neutrophil infiltration in the brain at day 26 post-infection. Finally, a bulk RNA-seq transcriptome analysis revealed that gene sets related to synaptic function were particularly influenced by the infection and that inflammation-related genes were upregulated by the infection in the Pink1 KO mice. These findings support the hypothesis that even mild gastrointestinal infections can increase BBB permeability, disrupt brain homeostasis, and promote chronic neuroinflammation. In genetically susceptible individuals, such as those with Pink1 deficiency, this may represent a first hit that contributes to subsequent induction of PD pathology with aging.
    DOI:  https://doi.org/10.1371/journal.ppat.1014315
  44. Neurosurg Rev. 2026 Jul 04. pii: 466. [Epub ahead of print]49(1):
    Focused ultrasound-mediated blood-brain barrier opening to enhance temozolomide delivery in glioblastoma: a systematic review of preclinical and early clinical evidence.
    Joyce Campos, Max Schreiber, Nikki Barrington, Bryanna Rather Eguh, Shoaib A Syed, John A Boockvar, Randy S D'Amico.
      Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults, with persistently poor survival despite chemoradiation and temozolomide (TMZ). Limited intratumoral drug delivery imposed by the blood-brain barrier (BBB), along with intrinsic and acquired resistance mechanisms, constrains TMZ efficacy. Focused ultrasound (FUS)-mediated BBB opening (BBBO) has emerged as a noninvasive strategy to transiently and locally enhance central nervous system drug delivery. To systematically synthesize preclinical and early clinical evidence evaluating the feasibility, safety, and therapeutic impact of FUS-enhanced TMZ delivery in GBM, and to identify key methodological and translational gaps informing future study design. A systematic search of PubMed, Cochrane Library, ClinicalTrials.gov, Embase, and Scopus was conducted from inception through December 2025. Eligible studies combined FUS-mediated BBBO with systemic TMZ in preclinical GBM models or human patients and reported pharmacologic, therapeutic, or safety outcomes. Nine studies (6 preclinical, 3 clinical) met inclusion criteria. All studies employed microbubbles to facilitate BBBO. Preclinical studies consistently demonstrated increased intratumoral TMZ delivery, improved tumor control, and prolonged survival with FUS plus TMZ compared with TMZ alone. Two studies directly quantified enhanced intratumoral drug exposure. Clinical studies demonstrated reproducible, MR-guided BBBO with favorable safety profiles and no procedure-related neurological complications. However, survival and pharmacokinetic endpoints remain preliminary. Focused ultrasound-mediated BBBO is a feasible and well-tolerated strategy to augment TMZ delivery in GBM. While preclinical evidence supports enhanced intratumoral drug exposure and therapeutic benefit, clinical efficacy remains unproven. Future studies should prioritize standardized protocols, direct pharmacokinetic validation, and adequately powered trials incorporating molecular stratification and clinically meaningful endpoints.
    Keywords:  Blood-brain-barrier; Focused ultrasound; Glioblastoma; Microbubbles; Temozolomide
    DOI:  https://doi.org/10.1007/s10143-026-04367-x
  45. Front Immunol. 2026 ;17 1737175
    Glucose metabolic reprogramming: mechanisms and therapeutic implications in neuroinflammation.
    Lan Zhang, Xinyue Yang, Xiaolin Ai.
      Microglia play dual and context-dependent roles in the central nervous system, contributing both to the maintenance of brain homeostasis and the propagation of neuroinflammatory responses. Under pathological conditions, microglia undergo profound glycolytic reprogramming, characterized by a shift from oxidative phosphorylation to enhanced aerobic glycolysis. This review focuses on the glucose-glycolysis-lactate metabolic axis and its pivotal role in microglial immunometabolism. We elucidated how key glycolytic enzymes (e.g., HK2, PKM2) and metabolites (e.g., lactate, pyruvate, ATP) regulate microglial function through both metabolic and non-metabolic mechanisms. Furthermore, therapeutic strategies that target this glycolytic shift to alleviate neuroinflammation were discussed. A deeper understanding of microglial glycolytic reprogramming may provide critical insights for developing novel therapies for neurodegenerative diseases.
    Keywords:  glycolysis; metabolic reprogramming; microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1737175
  46. Autism Adulthood. 2026 Aug;8(4): 646-663
    A Cross-Neurotype Analysis of Camouflaging and Illness Perceptions in People with Central Sensitivity Syndromes.
    Sarah Grant, Sam Norton, Rosa A Hoekstra.
       Background: Central sensitivity syndromes (CSS) are a group of conditions, including fibromyalgia, migraine, and others, that are thought to share a common mechanism of central sensitization-that is, pain and hypersensitivity that originate in the central nervous system. Research suggests that autistic adults may be more likely to have a CSS, and that autistic traits, sensory sensitivity and anxiety, all contribute to an association. This study aimed to explore whether autistic camouflaging could also be related to CSS symptoms in autistic and nonautistic adults. In addition, we completed an analysis of illness perceptions to determine whether autistic and nonautistic people may experience chronic illness differently.
    Methods: The sample comprised 504 adults (88 men, 416 women) with clinical diagnoses of autism, CSS, both diagnoses or neither (i.e., a comparison group), who completed online self-report validated questionnaires, including the Autism Spectrum Quotient, Central Sensitization Inventory, Sensory Perception Quotient, the Camouflaging Autistic Traits Questionnaire, the Brief Illness Perceptions Questionnaire, the Patient Health Questionaire-9, and Generalized Anxiety Disorder-7.
    Results: Camouflaging significantly predicted CSS symptoms in this sample. Autistic people with a CSS had higher camouflaging scores (mean: 130.28) than the other diagnostic groups, with a significant difference between the comparison and the CSS-only group (p < 0.001). The autism-only and CSS-only groups had significantly higher camouflaging scores than the comparison group (p < 001) but not from each other (119.35 vs. 107.94). Autistic people reported a significantly more negative effect of chronic illness on their life (f (1333) = 5.289 p = 0.022); there were few other differences in illness perceptions between autistic and nonautistic people with a CSS.
    Conclusion: Autistic camouflaging is associated with CSS symptoms. Autistic people who receive a CSS diagnosis are particularly at risk for greater illness-related disability, including poorer quality of life and mental health.
    Community Brief: Why is this an important issue?: Lots of research has demonstrated that autistic adults are more vulnerable to poor physical health and chronic illness. Autistic people seem to be more likely to have central sensitivity syndromes (CSS). Conditions listed under the CSS umbrella include fibromyalgia, irritable bowel syndrome, and migraine. These conditions are considered to share a common mechanism of "central sensitization," in which the neural signals in a person's brain and spinal cord become amplified, causing several symptoms, including pain and sensory hypersensitivity, fatigue, and brain fog. We do not have a good understanding of why CSSs are common in autistic people, or what impact CSSs have on autistic people's lives.What was the purpose of this study?: We wanted to explore how some psychological or social factors in people's lives might differ between autistic and nonautistic people with and without a CSS. We were particularly interested in whether there was a relationship between camouflaging, which is when people use social strategies and techniques to hide their autistic traits, and CSS symptoms. We also wanted to explore whether autistic and nonautistic people think about and perceive chronic illness differently.What did the researchers do?: We used data from 504 online survey participants to compare social camouflaging scores between autistic and nonautistic people with and without a CSS. We also explored group differences in autistic and nonautistic illness beliefs between a subset of people who all had a CSS diagnosis.What were the results of the study?: While autistic people camouflaged the most, nonautistic people with a CSS had higher camouflaging scores than the comparison group (nonautistic people without a CSS). This could suggest that the CAT-Q, the measure used to explore camouflaging, may also be capturing techniques that nonautistic people use in everyday life to manage others' impressions of them, such as through concealing symptoms and effects of chronic illness. Alternatively, it could suggest that a significant number of autistic people receive a CSS diagnosis before autism is recognized, and that diagnostic overshadowing could be happening-that is, traits and experiences related to autism could be missed or misattributed by clinicians to an already diagnosed CSS. Autistic people with a CSS also reported a greater impact of illness on their life, even though the number of symptoms they experienced did not differ significantly from nonautistic people with a CSS. This could mean that, in addition to autistic people being more likely to experience chronic illness, the impact of chronic illness may be greater on autistic people than for nonautistic people.What do these findings add to what was already known?: While it is known that autistic people are more prone to physical ill health, these findings add to our understanding of the association between autism and CSS. They also suggest that underdiagnosis of autism and/or diagnostic overshadowing could occur in people with both CSS symptoms and autistic traits, and emphasize the heavy impact of chronic illness on autistic quality of life.What are potential weaknesses in the study?: The participants were recruited online with a large proportion of women responding, and more nonautistic people with a CSS than autistic people.How will these findings help autistic adults now or in the future?: These findings draw attention to the experience of autistic people with a chronic illness and suggest future directions for research into autism and co-occurring conditions.
    Keywords:  autism; camouflaging; central sensitization; chronic pain; fatigue; fibromyalgia; illness perceptions
    DOI:  https://doi.org/10.1089/aut.2024.0186
  47. Mol Biol Rep. 2026 Jun 30. pii: 1064. [Epub ahead of print]53(1):
    Advances in neural organoids: structural organization, disease modeling, and applications in gene therapy.
    Evelina Nasybullina, Elvira Akhmetzyanova, Albert Rizvanov, Yana Mukhamedshina.
      Neural organoids and assembloids have emerged as advanced in vitro models that reproduce the cytoarchitecture and functional complexity of the human brain. This review focuses on recent applications of these three-dimensional systems for modeling neurodegenerative diseases and assessing the efficacy of gene therapy, particularly using adeno-associated viral vectors. The development of induced pluripotent stem cell technology enables the creation of patient-specific organoids that reflect individual genetic backgrounds and disease phenotypes. Neural organoids have been used to model Alzheimer's, Parkinson's, and Huntington's diseases, reproducing hallmark features such as protein aggregation, neuroinflammation, and synaptic dysfunction. They have also served as test systems for evaluating AAV-mediated gene delivery, revealing serotype-specific tropism and supporting optimization of vector design and gene expression. Further advances include integration of immune and vascular components and the construction of multi-regional assembloids that replicate inter-regional neuronal communication and complex network dynamics. Ongoing standardization and scalability of neural organoid systems, combined with bioengineering and analytical innovations, are expected to enhance reproducibility and translational relevance. The convergence of organoid models with gene therapy testing frameworks may accelerate preclinical validation and contribute to the development of precision approaches in neurology.
    Keywords:  AAV vectors; Assembloids; Gene therapy; Neural organoids; Neurodegeneration; iPSCs models
    DOI:  https://doi.org/10.1007/s11033-026-12236-5
  48. Front Cell Neurosci. 2026 ;20 1848558
    From cellular heterogeneity to precision medicine: single-cell multi-omics in CNS disease research.
    Tingyu Liu, Yan Zhang, Wei Hou, Hui Hao, Anqi Geng, Gang Zhao, Yingying Zhang.
      Single-cell sequencing and multi-omics technologies are revolutionizing research on central nervous system (CNS) diseases by enabling high-resolution analysis of cellular heterogeneity and molecular dynamics. Traditional technologies (e.g., bulk sequencing, routine histology) often lack cellular resolution, fail to capture heterogeneity among individual cells, and struggle to reveal subtle molecular changes in early pathogenesis, limiting their ability to clarify complex CNS disease mechanisms and develop precise diagnostic tools. This review comprehensively summarizes the latest advances in single-cell multi-omics methodologies, including genomics, transcriptomics, proteomics, metabolomics, and spatial omics, and their applications in elucidating the pathogenesis, diagnosis, and treatment of common CNS disorders. Representative diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, viral meningitis, bacterial meningitis, multiple sclerosis, autism spectrum disorder, and depression are used as examples to discuss the current status and future prospects of single-cell multi-omics technologies in CNS disease research. Currently, these technologies have enabled the identification of rare pathogenic cell subsets, the mapping of cell-specific molecular pathways, and the discovery of potential diagnostic biomarkers in several common CNS disorders, though their clinical translation is still hindered by technical costs and standardization issues. In the future, the integration of single-cell multi-omics with spatial transcriptomics, artificial intelligence, and clinical data is expected to further decode the complex pathogenesis of CNS disorders, accelerate the development of targeted therapies, and promote the shift toward personalized medicine in CNS disease management-aligning with translational goals of neuropsychopharmacology.
    Keywords:  cellular heterogeneity; central nervous system diseases; multi-omics; precision medicine; single-cell sequencing
    DOI:  https://doi.org/10.3389/fncel.2026.1848558
  49. Clin Neurophysiol. 2026 Jun 27. pii: S1388-2457(26)00817-5. [Epub ahead of print] 2112317
    F-waves in primary lateral sclerosis: a window into spinal motoneuron hyperexcitability.
    Steve Vucic.
      
    DOI:  https://doi.org/10.1016/j.clinph.2026.2112317
  50. ASN Neuro. 2026 Jun 11. 18(1): 2687503
    Border-Associated Macrophages in CNS Health and Disease: A Comprehensive Review of Ontogeny, Heterogeneity, and Functional Plasticity at Neural Interfaces.
    Xueting Liu, Mingyue Li, Zengrong Wei, Tong Shang, Wei Zou.
      Border-associated macrophages (BAMs) represent a specialized population of tissue-resident immune cells strategically positioned at the critical interfaces between the central nervous system (CNS) and peripheral circulation, including the meninges, choroid plexus, and perivascular spaces. As frontline sentinels of the neuroimmune system, BAMs perform essential functions in immune surveillance, barrier integrity maintenance, and homeostatic regulation, yet their unique biology and disease-associated roles remain incompletely characterized compared to parenchymal microglia. This review aims to synthesize current knowledge on BAM ontogenetic origins, compartment-specific heterogeneity, transcriptional programs, and functional outputs in both health and neurological disorders. We conducted a comprehensive literature analysis integrating findings from lineage tracing studies, single-cell RNA sequencing, spatial transcriptomics, and functional interrogation in animal models of disease. The results reveal that BAMs exhibit remarkable cellular diversity shaped by distinct ontogenetic origins-primarily yolk sac-derived erythro-myeloid progenitors with variable contributions from fetal liver and postnatal monocytes depending on anatomical compartment. Compartment-specific marker combinations (CD206, LYVE1, CD163, MHCII) define functionally distinct subsets, and core transcriptional regulators including PU.1 and IRF8 maintain BAM identity while CSF-1/IL-34-CSF1R signaling governs survival and renewal. In neurological disorders including ischemic stroke, Alzheimer's disease, multiple sclerosis, and brain tumors, BAMs display pronounced double-edged roles, transitioning from protective homeostatic guardians to pathogenic drivers depending on disease stage and microenvironmental context. This comprehensive analysis establishes a unified framework for understanding BAM biology and identifies critical opportunities for developing subset-specific therapeutic strategies targeting these interface macrophages in neurological diseases.
    Keywords:  Border-associated macrophages; microglia; neuroimmunology; neuroinflammation; single-cell transcriptomics
    DOI:  https://doi.org/10.1080/17590914.2026.2687503
  51. Front Immunol. 2026 ;17 1865920
    Autoimmune GFAP astrocytopathy with eosinophils on cerebrospinal fluid cytology and isolated spinal cord lesions on MRI: a case report.
    Dongdong Zhang, Yahan Song, Yongjie Bai, Junqiang Yan, Ruile Shen.
       Background: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an autoimmune inflammatory disorder of the central nervous system associated with GFAP-IgG. It most commonly presents as meningoencephalitis, myelitis, or meningoencephalomyelitis. Although MRI abnormalities in the brain and spinal cord are common, isolated spinal cord lesions without corresponding brain MRI abnormalities are uncommon and may pose a diagnostic challenge. Eosinophils identified on cerebrospinal fluid cytology have rarely been reported in this disorder.
    Case presentation: A 31-year-old woman presented with fever, headache, urinary retention, and meningeal irritation signs. Despite these findings, brain magnetic resonance imaging (MRI) was unremarkable, whereas spinal MRI revealed discontinuous patchy long-segment intramedullary lesions in the thoracic cord. Cerebrospinal fluid (CSF) analysis showed elevated opening pressure, pleocytosis, increased protein, and 10% eosinophils on cytological examination. Infectious studies, including CSF culture and metagenomic next-generation sequencing, were negative. Serum and CSF antibodies against aquaporin-4, myelin oligodendrocyte glycoprotein, and myelin basic protein were negative, whereas CSF GFAP-IgG was positive at a titer of 1:32, while serum GFAP-IgG was negative. Following high-dose intravenous methylprednisolone and an oral prednisone taper, the patient showed marked clinical, CSF, and radiological improvement, with complete resolution of thoracic cord lesions on follow-up MRI.
    Conclusion: Isolated spinal cord lesions on MRI may represent an important clue to autoimmune GFAP astrocytopathy and should prompt consideration of this diagnosis even in the absence of brain MRI abnormalities. The presence of eosinophils on cerebrospinal fluid cytology may further suggest a distinct inflammatory profile and offer insight into the pathophysiology of the disease.
    Keywords:  autoimmune GFAP astrocytopathy; case report; cerebrospinal fluid cytology; cerebrospinal fluid eosinophilia; isolated spinal cord lesions; myelitis
    DOI:  https://doi.org/10.3389/fimmu.2026.1865920
  52. Microcirculation. 2026 Jul;33(5): e70079
    Beyond Viral Control: Tenofovir's Hidden Impact on Blood-Brain Barrier Endothelial Cells.
    Saarah Behardien, Khayelihle Brian Makhathini, Chontrelle Willemse, David Fisher.
      The blood-brain barrier (BBB) is a dynamic endothelial interface that protects the brain from harmful agents while regulating molecular exchange. Human immunodeficiency virus (HIV) compromises BBB integrity, promoting neurological damage. Antiretroviral (ARV) therapies suppress HIV replication, preventing immune system deterioration and progression to AIDS. Although Tenofovir-based ARV regimens are vital for HIV treatment and prevention, their impact on cerebrovascular function remains unclear.
    AIM: This study examined Tenofovir's effects on murine brain endothelial cells using an in vitro BBB model.
    METHODS: Brain endothelial cells (bEnd.5) were treated with Tenofovir Disoproxil Fumarate (TDF; 9.8-98 ng/mL) or Tenofovir Alafenamide (TAF; 1-10 ng/mL) for 24-96 h. Cell proliferation, cell cycle progression (via flow cytometry) and monolayer permeability (via Transendothelial Electrical Resistance) were evaluated.
    RESULTS: Both TDF and TAF treatments suppressed cell division by S-phase disruption of the cell cycle and increased monolayer permeability.
    CONCLUSION: These findings suggest that prolonged TDF or TAF exposure compromises BBB integrity by inhibiting endothelial cell division and altering barrier function, which could have implications for HIV-ARV-induced neurodegeneration in individuals receiving long-term Tenofovir-based therapy.
    Keywords:  TAF; TDF; blood–brain barrier; human immunodeficiency virus; pre‐exposure prophylaxis; suppression
    DOI:  https://doi.org/10.1111/micc.70079
  53. Lancet Oncol. 2026 Jul;pii: S1470-2045(26)00146-4. [Epub ahead of print]27(7): e325-e338
    Novel strategies to overcome the blood-brain barrier in triple-negative breast cancer brain metastases.
    Yu Fan, Huiru Zhang, Shan Tang, Masakazu Toi.
      Triple-negative breast cancer-the most aggressive breast cancer subtype-has a high propensity for brain metastases, with limited treatments and poor prognosis. The blood-brain barrier, long viewed as an impermeable therapeutic sanctuary, is the core barrier to effective care. This Review advocates a key paradigm shift for clinical and translational research: from merely circumventing the blood-brain barrier to actively targeting and exploiting its biology. We delineate triple-negative breast cancer-specific mechanisms of blood-brain barrier breach and evaluate emerging therapies via a clinically actionable three-pillar framework: physical and focal blood-brain barrier disruption, biological blood-brain barrier exploitation, and microenvironmental modulation. We also summarise advances in preclinical models for blood-brain barrier-targeted drug development. Synthesising the latest preclinical and clinical evidence, this Review provides a translational roadmap for unmet clinical needs, emphasising that integrated, blood-brain barrier-centric strategies are crucial to improving patient outcomes.
    DOI:  https://doi.org/10.1016/S1470-2045(26)00146-4
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒05 at 11:33.