bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–04–26
38 papers selected by
Luca Bolliger, lxBio
  1. The Cat is Out of the Bag: Confronting False-Positive Risks in Amyotrophic Lateral Sclerosis Clinical Trials.
  2. Death certificate data of patients with amyotrophic lateral sclerosis in easternmost Finland.
  3. Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics.
  4. A nomogram for estimating baseline respiratory insufficiency in patients with amyotrophic lateral sclerosis.
  5. Alcohol and neurodegenerative diseases: a review of mechanistic insights and disease specific effects.
  6. C3 and C5 Complement Cascade Activation in Brain Injury and Disease: Molecular Mechanisms, Pathological Roles, and Therapeutic Implications.
  7. Modeling ALS in a dish: how organoids are transforming research.
  8. Treatment pathway, healthcare resource utilization and direct cost of ALS in France: A nationwide claims database study.
  9. Prevalence and determinants of anxiety in amyotrophic lateral sclerosis.
  10. [Amyotrophic lateral sclerosis (ALS): current perspectives and the Swiss ALS Registry].
  11. Association between statin use and survival in patients with ALS: A propensity score-matched analysis.
  12. BDNF insufficiency exacerbates ALS progression.
  13. Predicting amyotrophic lateral sclerosis stage based on multi-parameter ultrasound: development and validation of an interpretable machine learning model.
  14. Opportunities and challenges related to participant stratification and cohort enrichment in ALS clinical trials.
  15. A pipeline to characterize spinal cord pathology in neurological disorders combining magnetic resonance microscopy and histopathology.
  16. How effective does a new drug for Amyotrophic Lateral Sclerosis need to be - the patient perspective: a letter in response to "Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND" published in vol. 26, pp. 249-258.
  17. Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.
  18. When Rare Is Not Small: Amyotrophic Lateral Sclerosis Initiatives and Therapy.
  19. Monoclonal antibodies against nitrated nerve growth factor reveal an oxidation-dependent pathogenic hallmark in ALS.
  20. Synaptic Plasticity Fragility Underlies a Microglial Pruning Continuum in Major Depressive Disorder and Amyotrophic Lateral Sclerosis.
  21. Protein misfolding enteropathy predicts and prognosticates neurodegenerative disease years before symptom onset.
  22. Subtype-specific associations between serum lipid profiles and disease severity in patients with amyotrophic lateral sclerosis.
  23. Speech and swallow outcome measures for ALS and perspectives on remote monitoring: an international survey of speech & language therapists.
  24. Beyond the Leak: Advanced MRI Assessment of the Blood-Brain Barrier in Neurodegeneration.
  25. Heterogeneity in the Analysis of the ALSFRS-R in ALS Clinical Trials and its Effect on the Validity and Precision of Trial Conclusions.
  26. Medicinal chemistry strategies to breach the blood-brain barrier: structural design principles for brain-targeted therapeutics.
  27. Role of the WNT signalling pathway in physiological and pathological blood-brain barrier.
  28. Chitosan-Based Nanoparticles for Nose-to-Brain Drug Delivery: A Real Path toward Effective CNS Therapy?
  29. Ultrastructural organization of the neurovascular unit: Nanoscale perspectives on blood-brain barrier architecture.
  30. Navigating the cholesterol maze: Key insights on use of statins in neurodegenerative disorders.
  31. Development and characterization of 3D spinal cord organoids to advance the study of amyotrophic lateral sclerosis.
  32. Peptide-Based Therapeutics for Alzheimer's Disease: Medicinal Chemistry, AI-Guided Computational Design, and Blood-Brain Barrier Delivery.
  33. Luteolin as a dietary flavonoid for brain health: modulating neuroinflammation and cognitive decline in neurodegenerative disorders.
  34. Blood-Brain Barrier Permeability in Cases of Post-operative Delirium Is Associated with Central Nervous System Phosphatidylcholine Imbalances.
  35. Risk of Multiple Sclerosis Among Persons with Epstein Barr Virus-Positive Mononucleosis: A Population-Based Study.
  36. Advancing Brain Age Estimation: Normative Deviation Mapping (NDM) for Sensitive Detection of Pathological Aging.
  37. Targeting pyroptosis in tauopathies: A redox-driven axis of neuroinflammation and neurodegeneration.
  38. Transneuronal cytokine delivery promotes functional recovery across spinal cord contusion severities via descending circuit plasticity.
  1. Neurology. 2026 May 12. 106(9): e218029
    The Cat is Out of the Bag: Confronting False-Positive Risks in Amyotrophic Lateral Sclerosis Clinical Trials.
    Mamede de Carvalho.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000218029
  2. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Apr 24. 1-3
    Death certificate data of patients with amyotrophic lateral sclerosis in easternmost Finland.
    Jussi Sipilä, Eino Solje, Sanna Ahola, Leena Surakka, Manu Jokela.
      Objective: Topical data on causes of death and death certificate (DC) accuracy in patients with amyotrophic lateral sclerosis (ALS) are constantly needed. Methods: Data on a previously published ALS cohort from North Karelia in easternmost Finland was updated by extracting DC information from the electronic health records. Results: Death certificate data were available for 91% of the deceased. In all cases, ALS had been coded as a cause of death. In four cases, it had been inserted as a contributory cause of death. In three cases, ALS was indicated but incorrect coding was used. Three of the four cases in which ALS had not been deemed the underlying or immediate cause of death were cardiovascular deaths. One or more contributory causes of death had been recorded in 28% of DCs (54% of these were cardiovascular disorders), although comorbidities had not always been coded in the DC. In individual cases, the death had been sudden and unexpected, resembling a cardiovascular death, but this had not been coded. Conclusion: Finnish DC data remain a very reliable data source for ALS epidemiology, albeit with the caveat that data need to be obtained rigorously. Comorbidities are incompletely recorded as may be some immediate causes of death.
    Keywords:  Amyotrophic lateral sclerosis; cause of death; comorbidity; death certificate; epidemiology
    DOI:  https://doi.org/10.1080/21678421.2026.2662015
  3. Annu Rev Genomics Hum Genet. 2026 Apr 21.
    Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics.
    Sara Emad El-Agamy, Francesca Mattedi, Pietro Fratta.
      TDP-43 is an RNA-binding protein that regulates multiple aspects of RNA processing, and its mislocalization from the nucleus to the cytoplasm is a defining feature of amyotrophic lateral sclerosis (ALS). While both loss- and gain-of-function mechanisms contribute to disease, the discovery of cryptic splicing has shed light on the downstream consequences of TDP-43 nuclear clearance for neuronal health. Here, we highlight how loss of nuclear TDP-43 can drive a cascade of events that lead to the impairment of cellular proteostasis and result in a positive feedback loop that perpetuates neuronal dysfunction. This sustains the appearance of cryptic splicing events in genes that are involved in key pathways for the maintenance of axonal homeostasis and synaptic transmission. In contrast to their detrimental effects on neuronal health, cryptic splicing mechanisms may be harnessed to develop novel therapeutic strategies, unprecedentedly expanding the availability of therapeutic avenues for TDP-43 proteinopathies.
    DOI:  https://doi.org/10.1146/annurev-genom-022024-011307
  4. Ann Med. 2026 Dec;58(1): 2654938
    A nomogram for estimating baseline respiratory insufficiency in patients with amyotrophic lateral sclerosis.
    Huifen Wang, Guanxi Li, Feng Liang, Xiaoqian Xia, Wei Zhang, Zhelu Fan.
       OBJECTIVES: To develop and validate a nomogram for estimating the risk of baseline respiratory insufficiency in patients with amyotrophic lateral sclerosis (ALS). This also aims to analyze the association between readily available clinical predictors and pulmonary function.
    MATERIALS AND METHODS: This retrospective study assessed 142 ALS patients treated at the First Hospital of Shanxi Medical University from August 2020 to June 2023. ALS was diagnosed based on revised El Escorial criteria with Awaji modifications. Clinical data and pulmonary function tests (PFTs) were performed during a single hospital stay. Respiratory insufficiency was marked as forced vital capacity (FVC) < 80% of predicted. Muscle strength of neck and limbs was measured with the Medical Research Council (MRC) scale. Multivariable logistic regression evaluated independent predictors of respiratory insufficiency. A nomogram was created and internally validated using bootstrap resampling (1,000 iterations). Model performance was assessed with ROC curve analysis, calibration curve analysis, and decision curve analysis (DCA).
    RESULTS: Of the 142 patients, 30 (21.1%) presented with baseline respiratory insufficiency. In the multivariable analysis, neck flexor muscle strength (OR = 0.497, 95% CI: 0.321-0.769; p = 0.002) and bulbar onset (OR = 4.392, 95% CI: 1.674-11.521; p = 0.003) were independent predictors in the multivariable analysis. The nomogram showed good discrimination and calibration (AUC = 0.823, 95% CI: 0.739-0.907).
    CONCLUSIONS: Weakness of neck flexors and bulbar onset are independently associated with baseline respiratory insufficiency in ALS patients. The proposed nomogram may serve as a useful tool for baseline screening and risk stratification. External validation in larger multicenter cohorts is warranted before clinical application.
    Keywords:  Amyotrophic lateral sclerosis; bulbar onset; forced vital capacity; neck muscle strength; nomogram; respiratory insufficiency
    DOI:  https://doi.org/10.1080/07853890.2026.2654938
  5. Am J Drug Alcohol Abuse. 2026 Apr 23. 1-16
    Alcohol and neurodegenerative diseases: a review of mechanistic insights and disease specific effects.
    Juan Mei, Meng Xia, Lin Peng, Xuezhi Li.
      Background: Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) represent a significant global public health problem. Alcohol consumption is a common lifestyle factor that has been implicated as both a risk factor and potential modifier of disease progression.Objectives: This review integrates evidence from human and experimental studies to characterize the effects of alcohol consumption on the onset and progression of major neurodegenerative diseases.Methods: A narrative review was undertaken examining the pathophysiological effects of alcohol on the brain and its disease-specific effects on neurodegenerative disorders, integrating findings from human cohort studies and mechanistic investigations in preclinical models.Results: Experimental evidence indicates that chronic alcohol consumption exacerbates neurodegeneration through multiple converging mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, inflammatory signaling, disruption of neurotrophic pathways, impairment of dopaminergic neurotransmission, and alcohol-induced gut microbiota dysbiosis with blood-brain barrier compromise. Epidemiological data suggest dose-dependent and disease-specific associations, with heavy and sustained consumption more consistently linked to increased risk or accelerated progression of AD and PD, while evidence in ALS and HD remains inconsistent.Conclusion: Alcohol exerts a multifaceted and context-dependent influence on neurodegenerative diseases. Accumulating evidence supports that long-term heavy alcohol consumption is associated with enhanced neurodegeneration. Minimizing alcohol consumption may present a pragmatic opportunity to reduce neurodegenerative risk.
    Keywords:  Alcohol consumption; gut microbiota dysbiosis; neurodegenerative diseases; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.1080/00952990.2026.2645215
  6. Neurochem Int. 2026 Apr 21. pii: S0197-0186(26)00052-5. [Epub ahead of print] 106161
    C3 and C5 Complement Cascade Activation in Brain Injury and Disease: Molecular Mechanisms, Pathological Roles, and Therapeutic Implications.
    Geoffrey E Woodard.
      The complement system represents a crucial component of innate immunity with increasingly recognized roles in central nervous system pathology and homeostasis. Complement components C3 and C5 serve as central molecular hubs in the complement cascade, orchestrating inflammatory responses, synaptic pruning, and neuronal injury across diverse neurological conditions. This comprehensive review examines the molecular mechanisms underlying C3 and C5 activation in the brain, their pathological contributions to acute brain injuries including traumatic brain injury and ischemic stroke, and their complex involvement in chronic neurodegenerative diseases such as Alzheimer disease, multiple sclerosis, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Emerging evidence demonstrates that complement activation in the central nervous system extends beyond traditional immune functions to encompass critical roles in neurodevelopment, synaptic plasticity, and neural circuit refinement. The dual nature of complement function in the brain, exhibiting both neuroprotective and neurodegenerative properties depending on context and activation levels, presents unique therapeutic challenges and opportunities. This review synthesizes current understanding of complement-mediated neuroinflammation, discusses validated and emerging therapeutic strategies targeting C3 and C5, evaluates complement biomarkers for disease diagnosis and monitoring, and identifies critical knowledge gaps requiring future investigation. Understanding the nuanced roles of C3 and C5 in neurological disease provides essential foundations for developing targeted immunomodulatory therapies that preserve beneficial complement functions while mitigating pathological activation.
    DOI:  https://doi.org/10.1016/j.neuint.2026.106161
  7. Front Med (Lausanne). 2026 ;13 1792336
    Modeling ALS in a dish: how organoids are transforming research.
    Gaia Galluzzi, Giancarlo Ruocco, Ersilia Fornetti, Ilaria Genovese.
      Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. The multifactorial etiology of ALS, encompassing genetic mutations, protein aggregation, oxidative stress, excitotoxicity, and dysregulated RNA metabolism, has hindered the development of effective therapies. Traditional animal and 2D cell models have provided important mechanistic insights but often fail to fully capture the human-specific and multicellular aspects of disease pathophysiology. Recent advances in induced pluripotent stem cell (iPSC)-derived organoids offer a promising human-based platform for ALS research, enabling the generation of disease-relevant neural and neuromuscular subtypes in three-dimensional architectures. These models recapitulate key pathological features, including protein mis-localization, neuromuscular junction defects, synaptic impairments, and glial contributions to motor neuron degeneration, while also serving as platforms for drug screening and mechanistic studies. Importantly, spinal and neuromuscular organoids bridge the gap between simplified in vitro systems and the complex human nervous system, providing a unique framework to study ALS pathogenesis. This review provides a comprehensive overview of the various differentiation protocols, experimental strategies and key results obtained to date, with a primary focus on validating and benchmarking organoid models, while also highlighting their limitations, emerging clinical applications, translational potential, and opportunities for personalized therapeutic discovery.
    Keywords:  ALS; disease modeling; neuromuscular organoids; spinal organoids; tridimensional cell cultures
    DOI:  https://doi.org/10.3389/fmed.2026.1792336
  8. Rev Neurol (Paris). 2026 Apr 17. pii: S0035-3787(26)00503-5. [Epub ahead of print]
    Treatment pathway, healthcare resource utilization and direct cost of ALS in France: A nationwide claims database study.
    C Desnuelle, P Couratier, P Corcia, A Duburcq, E Torreton, S Baffert, C Nevoret, S Turgeman.
       OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a severe, progressive disease, associated with high clinical burden. The aim of this study was to estimate ALS-related healthcare resource utilization (HCRU), associated direct costs and their determinants in France.
    METHODS: A retrospective cohort study was conducted among newly diagnosed patients with ALS identified between 2012 and 2022 (11 years) in the French National Health Data System (SNDS) through a validated algorithm. This incident population was compared with non-ALS controls (1:2) matched on age, sex, and region. Direct all-cause healthcare reimbursable costs were estimated. Survival, HCRU and direct costs were analyzed over the first five years after diagnostic.
    RESULTS: A total of 16,814 newly diagnosed ALS patients were identified who could be matched with 33,628 non-ALS controls. The median age was 68.0 year and 55.3% were males. Over the first year after diagnosis, the direct all-cause medical cost per patient was €19,497 of which 47.2% was related to inpatient care, compared to €4,921 for controls which led to an ALS-attributable cost of €14,474 per patient per year. ALS patients had significantly (P<0.0001) higher HCRU than controls in all items of inpatient and outpatient care but especially for utilization of medical devices, frequencies of nurse and physiotherapist visits and acute care hospitalizations. The annual direct cost per patient who survived the successive annual period after diagnosis increased during the second, third and fourth year to €22,358, €22,276 and €21,372 respectively and then declined in year 5 to €19,720. These results largely underestimated the real cost of the management of ALS by not considering the out-of-pocket expenses associated with informal care and home renovation as well as productivity loss.
    CONCLUSIONS: Patients with ALS had higher HCRU and direct medical cost, compared with controls. The economic burden of ALS was substantial even when restricted to the medical costs covered by the public health insurance system. There is an important need for novel therapies that might lower disease progression in early disease stages.
    Keywords:  Amyotrophic lateral sclerosis; Burden; Claims database; Direct cost; Healthcare resource utilization
    DOI:  https://doi.org/10.1016/j.neurol.2026.02.159
  9. BJPsych Open. 2026 Apr 24. 12(3): e114
    Prevalence and determinants of anxiety in amyotrophic lateral sclerosis.
    Edoardo Nicolò Aiello, Giulia De Luca, Beatrice Curti, Silvia Torre, Claudia Gendarini, Alessandro Cocuzza, Eleonora Colombo, Angelica De Sandi, Denise Mellace, Roberta Ferrucci, Sergio Barbieri, Alessio Maranzano, Federico Verde, Stefano Messina, Alberto Doretti, Claudia Morelli, Vincenzo Silani, Nicola Ticozzi, Barbara Poletti.
       BACKGROUND: Clinically relevant anxiety can be detected in patients with amyotrophic lateral sclerosis (ALS), but its prevalence and determinants have not yet been fully assessed.
    AIMS: This study aimed at assessing the prevalence and clinical underpinnings of anxiety in ALS.
    METHOD: Non-demented ALS patients (N = 433) and healthy controls (N = 313) were administered the State- and Trait-Anxiety Inventory - Form Y (STAI-Y1 for state-anxiety and STAI-Y2 for trait-anxiety) and the Beck Depression Inventory (BDI). Patients were further assessed for cognition (Edinburgh Cognitive and Behavioural ALS Screen), behaviour (Frontal Behavioural Inventory) and motor status (disease duration, ALS Functional Rating Scale-Revised and progression rate). The prevalence of clinically significant state- and trait-anxiety were estimated by applying age-stratified cut-offs to STAI-Y1/-Y2 t-scores. Linear and logistic regressions were run to test the determinants of STAI-Y1/-Y2 scores.
    RESULTS: STAI-Y1 and -Y2 scores above cut-off were detected in 18.2 and 13.9% of patients, respectively - with proportions being higher in cases versus controls (ps < 0.001). BDI, but neither cognitive/behavioural nor motor variables, was identified as a significant predictor of STAI-Y1/-Y2 scores (ps < 0.003). The cognitive-affective subscale of BDI was the sole predictor of scores above cut-off on both STAI-Y1 and STAI-Y2 (ps < 0.001).
    CONCLUSIONS: Clinically significant levels of state- and trait-anxiety occur in ∼18 and ∼14% of non-demented ALS patients, respectively, mostly driven by cognitive and affective facets of depression, and are independent of motor and cognitive/behavioural features.
    Keywords:  Amyotrophic lateral sclerosis; anxiety; depression; psychiatry
    DOI:  https://doi.org/10.1192/bjo.2026.11025
  10. Praxis (Bern 1994). 2026 Apr;115(4): 100-106
    [Amyotrophic lateral sclerosis (ALS): current perspectives and the Swiss ALS Registry].
    Sasha Mukhija, Franz Lehner, Hans H Jung.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease leading to muscle weakness, atrophy, and ultimately death. In addition to mutations in ALS-related genes, environmental and lifestyle factors may increase disease risk. Diagnosis is based on clinical evaluation, supplemented by electroneuromyography, imaging, and molecular genetic testing. No curative therapy exists, but Riluzole and Edaravone can slow progression, and genetic therapies offer promising perspectives in certain genetically determined forms. In practice, diagnosis is often delayed. The Swiss ALS Registry collects comprehensive data on environmental, lifestyle, clinical, genetic, and biomarker factors, aiming to improve understanding of risk, disease progression, and therapeutic approaches.
    Keywords:  ALS Registry; Amyotrophic lateral sclerosis; neurodegeneration; therapy
    DOI:  https://doi.org/10.23785/PRAXIS.2026.04.003
  11. J Neurol Sci. 2026 Apr 19. pii: S0022-510X(26)00198-X. [Epub ahead of print]486 125916
    Association between statin use and survival in patients with ALS: A propensity score-matched analysis.
    Pooled Resource Open-Access ALS Clinical Trials Consortium
       OBJECTIVE: To evaluate the association between statin use, disease progression, and survival in patients with amyotrophic lateral sclerosis (ALS) using data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.
    METHODS: We conducted a retrospective cohort study of adults (≥18 years) diagnosed with ALS and included in the PRO-ACT database. Statin exposure was defined as any statin use at cohort entry. Statin users were matched 1:1 to non-users using propensity score matching based on age, baseline ALS Functional Rating Scale (ALSFRS), disease duration, ethnicity, bulbar onset, riluzole use, and cardiovascular or metabolic comorbidities. Participants were followed from cohort entry or statin initiation until death, end of follow-up (36 months), or loss to follow-up. The primary outcome was all-cause mortality at three years. The secondary outcome was disease progression, defined as time to a four-point decline in ALSFRS score. Cox proportional hazards models were used to estimate hazard ratios (HRs).
    RESULTS: Among 3439 eligible participants, 131 statin users (mean age 63.1 years; 34% female) were identified and matched to 131 non-users. Statin use was not associated with all-cause mortality at three years (HR 0.97; 95% CI 0.66-1.44; P = 0.89). Disease progression was also similar between statin users and non-users (HR 1.02; 95% CI 0.80-1.31; P = 0.90).
    CONCLUSIONS: In this large observational cohort, statin use was not associated with survival or disease progression in ALS. These findings do not support statin initiation or discontinuation based solely on ALS diagnosis or disease course.
    Keywords:  Amyotrophic lateral sclerosis; Disease progression; Propensity score matching; Statins; Survival analysis
    DOI:  https://doi.org/10.1016/j.jns.2026.125916
  12. Cell Rep Med. 2026 Apr 20. pii: S2666-3791(26)00175-8. [Epub ahead of print] 102758
    BDNF insufficiency exacerbates ALS progression.
    Yihua Xu, Ji He, Shudan Wang, Yijun Ge, Yichang Jia, Wei Guo, Chen Lv, Xinmeng Yao, Yingying Mao, Fan Mei, Dongsheng Fan, Peng Yuan, Bai Lu.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUSR521C, we demonstrate that BDNF haploinsufficiency leads to shortened lifespan, accelerated motor dysfunctions, and exacerbated motor neuron death. Importantly, activation of the BDNF receptor TrkB by an agonistic antibody effectively rescues these ALS-associated phenotypes. In additional ALS mouse models, TrkB activation antibody also shows superior therapeutic effects compared to current ALS medication riluzole. Our data indicate that insufficient BDNF could be a crucial contributing factor for ALS progression, and activation of BDNF-TrkB pathway may represent a promising therapeutic strategy against ALS.
    Keywords:  ALS, BDNF, V66M, FUS, TrkB antibody, B90-1
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102758
  13. BMC Med. 2026 Apr 22.
    Predicting amyotrophic lateral sclerosis stage based on multi-parameter ultrasound: development and validation of an interpretable machine learning model.
    Tianhua Yang, Ying Wang, Nan Dong, Junling Ding, Xinyi Yan, Jialei Luo, Peijun Chen, Yuxuan Qiu, Ting Lin, Jiahui Tong, Jiayi Mao, Yunyi Dai, Haojie Shentu, Shizhen Tang, Li Sheng, Min Zhao, Gaoyi Yang.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) lacks sensitive, objective staging tools to guide clinical management and trials. Existing methods have limited granularity and rely on subjective assessment, while biomarker and imaging approaches can be invasive or impractical for serial use. Ultrasound is a safe, portable imaging modality that can detect neuromuscular changes, but it has not yet been applied to ALS staging. We developed and validated an interpretable ultrasound model for clinical staging and risk stratification in ALS.
    METHODS: We enrolled 300 ALS patients, classified as early-stage (King's stages 1-2; n = 148) or late-stage (3-4; n = 152). Each patient underwent ultrasound of key muscle groups, including the diaphragm (excursion and thickening), geniohyoid (shear-wave velocity), and peripheral skeletal muscles (thickness and cross-sectional area). Six machine learning models were trained to predict early vs late stage from these ultrasound metrics combined with clinical factors. Performance was evaluated on a test set using area under the curve (AUC), F1 score and Brier score. Feature importance was analyzed with SHapley Additive exPlanation (SHAP) values.
    RESULTS: In the test set, the random forest achieved an AUC of 0.843, an F1 score of 0.727, and a Brier score of 0.177, with sensitivity 0.80 and specificity 0.68. SHAP analysis identified diaphragm excursion during deep breathing (DEDB) as the top predictor, followed by masseter muscle thickness (MMT) and geniohyoid shear-wave velocity (GHSWVmean). Higher DEDB, MMT and GHSWVmean values predicted earlier stage, whereas lower peripheral muscle thickness and older age indicated late-stage disease.
    CONCLUSIONS: Multiparameter ultrasound combined with machine learning offers a non-invasive, bedside tool for ALS staging. The model's accuracy and interpretability enable objective tracking of disease progression and may support timely interventions and patient stratification in clinical practice and trials. Leveraging widely accessible ultrasound technology, this approach is feasible for routine ALS care and research.
    Keywords:  ALS; Machine learning; Motor neuron disease; Neuromuscular; Ultrasound
    DOI:  https://doi.org/10.1186/s12916-026-04871-3
  14. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Apr 25. 1-10
    Opportunities and challenges related to participant stratification and cohort enrichment in ALS clinical trials.
    Sabrina Yusuf, Matti D Allen, HyungMo Kang, Daniel E Phillips, Angela Genge.
      Amyotrophic lateral sclerosis (ALS) is marked by substantial clinical heterogeneity. This heterogeneity has impacted clinical trials by obscuring treatment effects and causing inefficiency. In this review, we summarize potential approaches for addressing heterogeneity in ALS via patient stratification and cohort enrichment methods and highlight potential challenges and limitations. These categories include stratification based on genetics, clinical characteristics (e.g. pattern of weakness, ALS Functional Rating Scale rates of progression), wet biomarkers (e.g. neurofilament light chain), neuroimaging, and novel methods employing statistical modeling or machine learning. These stratification methods have yet to be fully leveraged in clinical trial design. But these strategies must be employed thoughtfully and judiciously due to potential issues stratification can introduce. Future clinical trials should explore how participant stratification and cohort enrichment strategies may improve our ability to identify treatment effects, which may ultimately aid in the quest to establish more personalized medicine for persons with ALS.
    Keywords:  Amyotrophic lateral sclerosis; clinical research; clinical trials; motor neuron disease; pharmacotherapy
    DOI:  https://doi.org/10.1080/21678421.2026.2659128
  15. Commun Med (Lond). 2026 Apr 22.
    A pipeline to characterize spinal cord pathology in neurological disorders combining magnetic resonance microscopy and histopathology.
    Charidimos Tsagkas, Maxime Donadieu, Roy Sun, Brandon Bujak, Kevin Hu, Camille Rood, Katherine Cameron, Stephen Dodd, Daniel S Reich, Govind Nair.
       BACKGROUND: The length, shape, and size of the spinal cord (SC) present unique challenges for MRI, including the need for high resolution to distinguish anatomical and pathological features along its span. Postmortem MRI offers an opportunity to map SC tissue abnormalities and investigate their histological correlates.
    METHODS: We developed a pipeline combining postmortem microscopic resolution MRI (MR microscopy; MRM) of whole formalin-fixed SC specimens with targeted histopathological analysis. A gadolinium-based tissue preparation protocol was optimized using SC tissue from common marmosets with experimental autoimmune encephalomyelitis. A custom tissue holder and container were designed to enable postmortem MRI of the entire human SC. Human SC samples from individuals with multiple sclerosis, amyotrophic lateral sclerosis, and intracranial hemorrhage were scanned at 75 μm isotropic resolution on a 9.4 T Bruker system after gadolinium preparation.
    RESULTS: MRM after gadolinium-based tissue preparation yields images with high signal- and contrast-to-noise ratio while minimizing acquisition times. MRI demonstrates fine anatomical detail and pathological features, including demyelination and neurodegeneration throughout the SC. A complementary custom-made cutting rack enables targeted histological sectioning of MRI-identified regions. This approach provides precise spatial correspondence between imaging and histological findings, demonstrating strong agreement across modalities.
    CONCLUSIONS: In summary, this pipeline facilitates comprehensive SC assessment by integrating MRM with histology. It enables accurate localization of both subtle and widespread SC pathology and enhances interpretation of MRI signals in the context of neurodegenerative and inflammatory diseases.
    DOI:  https://doi.org/10.1038/s43856-026-01577-8
  16. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May;27(3-4): 485-486
    How effective does a new drug for Amyotrophic Lateral Sclerosis need to be - the patient perspective: a letter in response to "Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND" published in vol. 26, pp. 249-258.
    Andrew Darke, Cali Orsulak.
      
    DOI:  https://doi.org/10.1080/21678421.2025.2589781
  17. Behav Brain Res. 2026 Apr 22. pii: S0166-4328(26)00218-4. [Epub ahead of print] 116242
    Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.
    Caizhen Shi, Kunpeng Jia, Yanjie Guo, Shenghao Qian, Bingbing Wang, Yue Qiu, Li Dan, Zhuokun Dang, Kun Xue, Feng Gao, Lin Zhao.
      Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress and cytoskeletal collapse under conditions of impaired reducing capacity. Neurodegenerative diseases (NDs), including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by oxidative stress, mitochondrial dysfunction, metabolic impairment, protein aggregation, and cytoskeletal instability-features that may provide a permissive intracellular context for disulfidptosis. However, its occurrence and pathological relevance in these disorders remain incompletely understood. In this review, we examine the potential involvement of disulfidptosis in neurodegenerative diseases from a disease-centered perspective. We emphasize that current evidence is largely indirect and based on mechanistic overlap rather than direct experimental validation in neural systems. Accordingly, we distinguish between direct evidence, indirect mechanistic support, and pathophysiological plausibility. We further discuss cell-type-specific susceptibility across neurons and glial cells, analyze its relationship with other cell death pathways, and consider potential therapeutic implications. Overall, disulfidptosis is best regarded as a context-dependent and emerging mechanism that may contribute to neuronal vulnerability under specific metabolic and redox constraints. Clarifying its disease relevance will be essential for determining its significance in neurodegeneration and its potential as a therapeutic target.
    Keywords:  cell death; disulfidptosis; mitochondria; neurodegenerative diseases; protein aggregation; redox imbalance
    DOI:  https://doi.org/10.1016/j.bbr.2026.116242
  18. Exploration (Beijing). 2026 Apr;6(2): 70114
    When Rare Is Not Small: Amyotrophic Lateral Sclerosis Initiatives and Therapy.
    Yang Liu, Xue Xia, Yingfang Chen, Haoying Yang, Xiaochen Chen, Lei Cai, Bingyang Shi.
      In the precision-medicine era, rare diseases must not be sidelined in translational infrastructure. The Mr. Cai Lei-led "Ice-Breaking Team" turns an amyotrophic lateral sclerosis patient community into a sustainable ecosystem, realigning philanthropy, data, and research and development to reshape rare-disease pipelines and guide precision therapies, offering a replicable blueprint for rare-disease strategies.
    DOI:  https://doi.org/10.1002/exp2.70114
  19. Proc Natl Acad Sci U S A. 2026 Apr 28. 123(17): e2536562123
    Monoclonal antibodies against nitrated nerve growth factor reveal an oxidation-dependent pathogenic hallmark in ALS.
    Valentina Varela, Santiago Garcimartín, Emiliano Trias, Ari Zeida, Monique Richter, Andrés de León, Ernesto Miquel, Peter H King, Brigitte Vulliez-Le Normand, Mariano Martinez, Pedro M Alzari, Silvina Bartesaghi, Rafael Radi, Luis Barbeito.
      Nerve growth factor (NGF) is a member of the neurotrophin family, essential for neuronal survival and phenotypic maintenance. However, in vitro, its function can be disrupted by oxidative posttranslational modifications such as tyrosine nitration. Nitrated NGF (NO2NGF) has been shown to have a gain-of-toxic, pro-apoptotic, activity in motoneuron cultures. Herein, we report the generation and characterization of monoclonal antibodies (mAbs) that specifically recognize NO2NGF to unravel its formation in vivo. Using hybridoma technology, we produced mAbs with high affinity and selectivity for NO2NGF, as demonstrated immunochemically and by surface plasmon resonance. The antibodies elicit neutralizing capacity to NO2NGF in neuronal cells. Nitrated Tyr52 within the NGF48-58 sequence was identified as the primary antigenic determinant by crystallographic analysis of antibody:peptide complexes at atomic resolution, peptide-based epitope mapping and molecular dynamics simulations, whereas local sequence NGF motifs around the nitrated tyrosine are important for protein specificity. The antibodies revealed NO2NGF accumulation in amyotrophic lateral sclerosis (ALS) rodent models and human subjects. Indeed, immunofluorescence showed selective accumulation of NO2NGF in spinal cord regions undergoing motor neuron degeneration, as well as in sciatic nerves and neuromuscular junctions. Our findings establish NGF nitration as an oxidative hallmark in ALS and demonstrate that monoclonal antibodies targeting this chemical modification are powerful tools for both mechanistic studies and biomarkers development. This work proposes a link between neurotrophin nitration and neurodegenerative disease progression and opens avenues for therapeutic exploration along the peroxynitrite-tyrosine nitration pathway.
    Keywords:  ALS; crystallography; monoclonal antibodies; nerve growth factor; tyrosine nitration
    DOI:  https://doi.org/10.1073/pnas.2536562123
  20. Cureus. 2026 Apr;18(4): e107259
    Synaptic Plasticity Fragility Underlies a Microglial Pruning Continuum in Major Depressive Disorder and Amyotrophic Lateral Sclerosis.
    Ngo Cheung.
      Background  Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are clinically distinct yet show intriguing comorbidity, often early in the disease course. We hypothesized a shared microglia-mediated synaptic pruning vulnerability, amplified differently by disorder-specific pathways, autophagy collapse in ALS versus RNA processing and immune dysregulation in MDD, thereby creating a biological continuum. Methods  Using large-scale genome-wide association study (GWAS) from the Psychiatric Genomics Consortium (PGC) (MDD, N=829,249) and Project MinE (ALS, effective N=87,381), we applied Multi-marker Analysis of GenoMic Annotation (MAGMA) for gene- and set-level associations, Gene Set Enrichment Analysis (GSEA)/Differential Gene Set Enrichment Analysis (DGSEA) for pathway enrichment and differential enrichment, S-PrediXcan transcriptome-wide association study (TWAS) across 14 GTEx tissues, and linkage disequilibrium score regression (LDSC) for partitioned heritability and cross-trait genetic correlation. Eight gene sets (housekeeping controls, monoaminergic, neurosteroid, glutamatergic, synaptic pruning, autophagy/protein quality, RNA processing, and immune/neuroinflammation) were tested for convergence and divergence. Results  Synaptic pruning emerged as the sole consistent cross-disorder signal, with robust enrichment in MDD (LDSC 1.32×, GSEA NES=1.415, p=0.0001) and nominal but consistent signals in ALS (GSEA NES=1.40, p=0.011; TWAS HLA-B). Autophagy dominated ALS (LDSC 2.20×, TWAS C9orf72 Z=13.43, GSEA NES=1.94) but was depleted in MDD. RNA processing and immune pathways were prominent in MDD (LDSC 1.48× and 1.89×, respectively), with only nominal signals in ALS. Overall genetic correlation was near zero (rg=-0.044, p=0.196). Conclusions  These findings support a microglial pruning continuum model: shared pruning liability as the foundation, with autophagy failure driving ALS neurodegeneration and RNA/immune dysregulation shaping MDD stress sensitivity. The low rg explains the modest overlap, while pathway specificity accounts for comorbidity and divergent progression. This framework offers testable predictions for polygenic risk score (PRS) stratification, complement modulators in ALS mood subsets, and microglial therapies in treatment-resistant MDD.
    Keywords:  als; depression; motoneuron diseases; neuronal plasticity and repair; plasticity
    DOI:  https://doi.org/10.7759/cureus.107259
  21. Gastroenterology. 2026 Apr 19. pii: S0016-5085(26)00357-4. [Epub ahead of print]
    Protein misfolding enteropathy predicts and prognosticates neurodegenerative disease years before symptom onset.
    Tatiana Langerová, Emma MacVicar, Rollo Press, Fiona L Read, Mattia Piana, Sarah Murdoch, Jayne Innes, Joan Wilson, Angus J M Watson, Fergal M Waldron, George Ramsay, Jenna M Gregory.
       BACKGROUND: Neurodegenerative disorders are characterized by progressive, irreversible neuronal loss that often advances silently for years before symptoms appear. Disease-modifying therapies are generally less effective once symptoms emerge, as substantial neuronal damage has already occurred. Consequently, there is an urgent need for accessible biomarkers that can predict disease well in advance and serve as reliable target-engagement measures in prevention trials.
    METHODS: We analysed archival gastrointestinal (GI) biopsies from 196 individuals with unexplained GI symptoms and 13-15 years of follow-up. Using sensitive histopathological staining, we assessed misfolded TDP-43, tau, and α-synuclein to test whether peripheral proteinopathies can serve as predictive biomarkers for neurodegeneration.
    RESULTS: Protein misfolding enteropathy was identified in 60% of cases. Individuals with GI proteinopathy were significantly more likely to develop non-Alzheimer's dementia or α-synucleinopathies, demonstrating >80% sensitivity; however, this performance should be balanced against a low specificity. The presence of two or more proteinopathy markers was associated with a dose-dependent reduction in survival, establishing GI proteinopathy as an independent, life-limiting prognostic factor. Importantly, these pathological changes were present 6.9 years before neurological symptoms emerged.
    CONCLUSION: Our findings reveal that neurodegeneration-associated proteinopathies are not confined to the central nervous system but can be detected in routine GI biopsies years before clinical onset. This discovery provides a practical and scalable biomarker platform that could transform early diagnosis, risk stratification, and target-engagement monitoring in clinical trials. Protein misfolding enteropathy represents a new frontier for disease interception in neurodegenerative disorders, enabling intervention at a stage when neuronal damage may still be preventable.
    Keywords:  Biomarker; Gastrointestinal tract; Neurodegeneration; Proteinopathy; TDP-43; Tau; Α-synuclein
    DOI:  https://doi.org/10.1053/j.gastro.2026.04.003
  22. Biomed Rep. 2026 Jun;24(6): 68
    Subtype-specific associations between serum lipid profiles and disease severity in patients with amyotrophic lateral sclerosis.
    Lu Cao, Gang Chen, Jing Zhou, Hai Huang, Aoling Xu, Ting Zhan, Yan Zhao, Hongtao Liu.
      Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder. Notably, the differences in lipid metabolism between bulbar- and limb-onset subtypes of ALS remain unclear, particularly in non-Western populations. The present study investigated serum lipid profiles in a Chinese cohort of patients with ALS to explore their associations with disease severity and clinical subtypes. A retrospective, cross-sectional study was conducted, involving 158 patients with ALS and 62 matched healthy controls. Serum lipid parameters, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), small dense LDL cholesterol (sdLDL-c), apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB) and the TG/HDL ratio, were compared between the groups. Correlation analyses and multivariable linear regression models incorporating phenotype x lipid interaction terms were conducted after adjusting for age, sex, body mass index and disease duration. Patients with ALS exhibited significantly higher TC, TG, LDL, sdLDL-c, ApoA1, ApoB and TG/HDL ratios than controls. Subtype-specific analyses revealed different associations; in bulbar-onset ALS, higher sdLDL-c and TG/HDL ratios were associated with better functional status, whereas higher HDL and ApoA1 levels were negatively correlated with functional status. By contrast, in limb-onset ALS, higher sdLDL-c and ApoB levels were associated with worse function. Interaction analyses confirmed significant phenotype modification for sdLDL-c, TG/HDL ratio, HDL and ApoA1. These results suggest that lipid-severity relationships in ALS vary by subtype, indicating metabolic heterogeneity across phenotypes and supporting the potential of specific lipid parameters as exploratory markers for disease monitoring.
    Keywords:  ALS; Chinese cohort; clinical subtypes; disease severity; serum lipid profiles
    DOI:  https://doi.org/10.3892/br.2026.2141
  23. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Apr 21. 1-13
    Speech and swallow outcome measures for ALS and perspectives on remote monitoring: an international survey of speech & language therapists.
    Lesley Doyle, Miriam Galvin, Avril Mc Tague, Dara Meldrum, David Murphy, Orla Hardiman, Deirdre Murray.
       OBJECTIVE: Dysarthria and dysphagia occur frequently in Amyotrophic Lateral Sclerosis (ALS). To manage these symptoms, speech & language therapists (SLTs) must identify relevant speech and swallow outcomes and select suitable outcome measurement instruments. Remote monitoring is an evolving mode of health status tracking. This survey aimed to establish SLT perspectives on ALS assessment regarding 1) the clinical meaningfulness of existing outcome measurement instruments 2) remote monitoring 3) usefulness of assessment devices for patient care and 4) bulbar function outcomes and measurement instruments useful for research studies.
    METHODS: An online English-language survey was distributed internationally through gatekeepers and social media.
    RESULTS: Sixty-six SLTs responded from 13 countries. Current outcome measurement instruments were regarded as clinically meaningful in ALS by 35% for speech and 41% for swallow. Only 12% had access to remote monitoring, but 77% would like to avail of it, with 58% perceiving its potential to enhance care. Eighty-two percent deemed remote monitoring using digital patient-reported outcome measures (PROMs) useful. Speech intelligibility measurement was selected as the most useful communication outcome for remote monitoring (92%) and research (94%). SLTs agreed that speech intelligibility test software (72%), smart device apps (70%) and tongue pressure measurement devices (54%) are useful assessment equipment.
    CONCLUSIONS: SLTs want better measurement instruments for speech and swallow in ALS. They regarded technologies including remote monitoring incorporating digital PROMs as useful. Outcomes reflecting communication and swallow functional success level were deemed most useful. These survey findings can inform the selection of digital speech and swallow outcomes for ALS.
    Keywords:  Amyotrophic lateral sclerosis; bulbar function; outcome measurement; remote monitoring; speech & language therapy
    DOI:  https://doi.org/10.1080/21678421.2026.2655735
  24. Neurodegener Dis. 2026 Apr 21. 1-25
    Beyond the Leak: Advanced MRI Assessment of the Blood-Brain Barrier in Neurodegeneration.
    Daniele Botta, Caterina Bernetti, Ioana Hutuca, Jose Federico Ojeda Esparza, Lukas Sveikata, Karl Olof Lovblad, Felix T Kurz.
      The blood-brain barrier (BBB) is a specialized multicellular interface that maintains the CNS's tightly regulated microenvironment. BBB disruption is increasingly recognized as a key feature of neurodegeneration, documented across disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and cerebral small vessel disease (cSVD). While the extent to which BBB breakdown is a cause or consequence of neuronal pathology remains unclear, its pronounced presence in disease states suggests a significant contributory role in progression. Advances in MRI have revolutionized our ability to visualize and quantify these alterations in vivo. This review provides a neuroradiological overview of advanced MRI approaches and their specific biomarkers, specifically Dynamic Contrast-Enhanced MRI (DCE) with Ktrans and Arterial Spin Labeling (ASL) with kw, detailing disease-specific BBB signatures in major neurodegenerative disorders. Current technological strides, including ultra-high-field MRI and AI-assisted post-processing, are pushing the sensitivity needed to detect subtle BBB changes. Ultimately, with technical refinement and standardization, MRI methods are transitioning from research tools into candidate neurovascular biomarkers with growing potential for early diagnosis, treatment monitoring, and longitudinal follow-up, pending multicenter standardization and normative validation.
    DOI:  https://doi.org/10.1159/000552173
  25. Neurology. 2026 May 12. 106(9): e214937
    Heterogeneity in the Analysis of the ALSFRS-R in ALS Clinical Trials and its Effect on the Validity and Precision of Trial Conclusions.
    Daphne N Weemering, Jordi W J van Unnik, Angela Genge, Leonard H van den Berg, Ruben P A van Eijk.
       BACKGROUND AND OBJECTIVES: Disability rating scales play a pivotal role in clinical trials, but there is a notable lack of guidance on how to analyze these scales. Using amyotrophic lateral sclerosis as a case study, our aim was to explore how disability rating scales have been analyzed in completed clinical trials and to assess how these different approaches influence both the risk of false-positive findings and the statistical power to detect true treatment effects.
    METHODS: We searched PubMed and Embase to systematically identify randomized, placebo-controlled clinical trials using the revised ALS functional rating scale (ALSFRS-R) as primary end point, with ≥20 randomly assigned patients and ≥12-weeks of follow-up. Data were extracted on the statistical analysis approaches and strategies for handling missing data. Variability in statistical methods was mapped to the various research questions that the trials aimed to address. A simulation study assessed how each statistical method influenced validity (false-positive rate) and precision (statistical power), using the Ceftriaxone trial data set to model a realistic trial scenario.
    RESULTS: Our analysis included 45 randomized clinical trials, comprising a total sample size of 7,338 patients, and identified 39 distinct statistical methods using a mixture of longitudinal and cross-sectional techniques. Most trials (55.6%) did not use all available (longitudinal) ALSFRS-R measurements, resulting in suboptimal utilization of patient data and reduced statistical precision. Applying the different statistical methods to the same trial data set resulted in large differences in the estimated treatment effect size, ranging from a negative 1.33 to a positive 2.33 SD difference. Among the methods used, 38.9% (95% CI 24.8%-55.1%) were at risk of increasing false-positive rates, potentially contributing to the erroneous advancement of ineffective treatments. Statistical power of valid strategies varied widely, ranging from 17.9% to 78.2%.
    DISCUSSION: Our results demonstrate considerable variability in statistical methods, with the choice of method able to influence the estimated treatment effects, potentially resulting in misleading conclusions and uncertainty about treatment effects. This limits the interpretability and comparability of clinical trials and influences clinical decision-making and drug development. Establishing statistical consensus recommendations could improve the utility of disability scales in clinical trials and accelerate progress toward effective therapies for neurodegenerative diseases.
    DOI:  https://doi.org/10.1212/WNL.0000000000214937
  26. Drug Discov Today. 2026 Apr 16. pii: S1359-6446(26)00078-4. [Epub ahead of print] 104673
    Medicinal chemistry strategies to breach the blood-brain barrier: structural design principles for brain-targeted therapeutics.
    Harikesh Kumar Gupta, Jatin Jangra, Vishwakarma Krishna Ramesh, Isha Mahindru, Rajnish Kumar.
      The blood-brain barrier (BBB) remains a critical limitation in central nervous system (CNS) drug development, restricting brain exposure to most therapeutics. Despite advances in macromolecular delivery, small molecules continue to predominate, necessitating the rational optimization of BBB permeability. This review integrates recent medicinal chemistry strategies focused on fine-tuning key physicochemical parameters, including lipophilicity, pKa, molecular weight, hydrogen bond donors, rotatable bonds and topological polar surface area, which govern passive diffusion and brain penetration. Structural modifications such as fluorination, bioisosteric replacement, intramolecular hydrogen bond masking and prodrug approaches are discussed alongside strategies to mitigate efflux and exploit carrier-mediated transport. The integration of in silico tools and experimental models provides a cohesive framework for designing next-generation CNS therapeutics with optimized permeability and efficacy profiles.
    Keywords:  CNS drug design; PAMPA-BBB assay; brain-to-plasma ratio; medicinal chemistry strategies; physicochemical parameters; structural modifications
    DOI:  https://doi.org/10.1016/j.drudis.2026.104673
  27. Ann Med. 2026 Dec;58(1): 2657638
    Role of the WNT signalling pathway in physiological and pathological blood-brain barrier.
    Feng Yang, Fang Wang, Yuancong Jiang, Da Qian, Lianping Chen.
       BACKGROUND: The blood-brain barrier (BBB) is essential for maintaining central nervous system (CNS) homeostasis and protecting neural tissue. The wingless-type MMTV integration site family (WNT) signalling pathway has emerged as a key regulator of BBB development, maintenance, and repair. Dysregulation of this pathway is implicated in BBB dysfunction associated with various neurological disorders.
    METHODS: We conducted a comprehensive review of recent literature integrating data from animal models, human induced pluripotent stem cell (iPSC)-derived BBB systems, and disease-specific mechanistic studies. The role of canonical and non-canonical WNT signalling in BBB formation, maturation, and pathological alteration was systematically analyzed.
    RESULTS: WNT7a/b ligands activate β-catenin-dependent signalling to drive cerebral angiogenesis and BBB differentiation, with G protein‑coupled receptor 124 (GPR124), Reversion‑inducing cysteine‑rich protein with Kazal motifs (RECK), and SRY‑related HMG‑box transcription factor 17 (Sox17) identified as critical co-regulators. In the mature BBB, WNT activity is suppressed epigenetically to maintain barrier stability. In diseases such as ischaemic stroke, Alzheimer's disease, multiple sclerosis, and glioblastoma, WNT signalling is disrupted, leading to BBB breakdown. Pharmacological activation of WNT/β-catenin signalling (e.g. lithium, Glycogen synthase kinase 3β (GSK-3β) inhibitors and engineered WNT ligands) restores BBB integrity in preclinical models. Additionally, modulation of WNT signalling can enhance drug delivery across the BBB, offering therapeutic advantages in brain tumours and neurodegenerative diseases.
    CONCLUSIONS: WNT signalling is a central molecular axis governing BBB integrity under both physiological and pathological conditions. Targeted modulation of this pathway represents a promising therapeutic strategy for restoring BBB function and improving CNS drug delivery. Further mechanistic and translational studies are warranted to advance clinical applications.
    Keywords:  CNS disorders; WNT signalling; blood-brain barrier; cerebral angiogenesis; endothelial cells; therapeutic targets
    DOI:  https://doi.org/10.1080/07853890.2026.2657638
  28. ACS Biomater Sci Eng. 2026 Apr 23.
    Chitosan-Based Nanoparticles for Nose-to-Brain Drug Delivery: A Real Path toward Effective CNS Therapy?
    Lorena R Riani, Gustavo F B Seno, Dominique M Silva, Cibele R Toledo, Mayara R B Paiva, Júlia S Santos, Rodrigo L Fabri, Frederico Pittella, Guilherme D Tavares.
      Treating central nervous system (CNS) disorders remains a major clinical challenge. The blood-brain barrier (BBB), systemic toxicity, and first-pass metabolism are key obstacles. These factors limit the effective drug delivery to the brain. Intranasal administration has emerged as a noninvasive strategy to bypass the BBB. This approach enables direct drug delivery to the brain through the olfactory and trigeminal nerve pathways, commonly referred to as nose-to-brain (N2B) delivery. In this context, chitosan (CS), a biocompatible and mucoadhesive polysaccharide with permeation-enhancing properties, has gained significant interest as a functional material for nanoparticle (NP) engineering. CS-based or CS-coated NP can prolong the residence time on the nasal mucosa and facilitate drug transport to the CNS. This review provides a comprehensive overview of recent advances in CS-based NP for N2B drug delivery across a range of CNS disorders, including neurodegenerative, neuropsychiatric, neoplastic, and infectious conditions. Particular attention is given to formulation strategies, mechanistic insights, and preclinical outcomes. Recent patent applications are surveyed to underscore the translational potential and commercial interest in this technology. Collectively, CS-based NPs effectively address major therapeutic barriers, establishing a transformative and innovative platform in CNS drug delivery.
    Keywords:  CNS disorders; chitosan; intranasal delivery; nanoparticles; nose-to-brain
    DOI:  https://doi.org/10.1021/acsbiomaterials.6c00137
  29. Tissue Cell. 2026 Apr 17. pii: S0040-8166(26)00232-6. [Epub ahead of print]102 103539
    Ultrastructural organization of the neurovascular unit: Nanoscale perspectives on blood-brain barrier architecture.
    Rabab S Hamad, Sameh Saber, Alshaimaa A Farrag, Hanan Eissa, Elsayed A Elmorsy, Attalla F El-Kott, Mohammed A AlShehri, Eman A Al-Shahari, Waleed Eltantawy, Mohamed A M Ali, Anis Ahmad Chaudhary, Ahmed Gaafar, Ahmed Y Kira.
      The blood-brain barrier (BBB) is commonly interpreted through molecular and transport-centered frameworks that emphasize junctional proteins, signaling pathways, and selective permeability. Increasing experimental evidence, however, indicates that barrier integrity cannot be fully explained by molecular composition alone. This review advances an architecture-centered framework in which BBB function emerges from hierarchical ultrastructural organization within the neurovascular unit (NVU), spanning nanoscale, cellular, multicellular, and tissue levels. By integrating data from ultrastructural electron microscopy, super-resolution imaging, and physically defined perturbation models, we demonstrate that BBB stability depends critically on spatial continuity, endothelial polarity, junctional geometry, perivascular coupling, and basement membrane integrity. Across diverse experimental and pathological contexts, BBB dysfunction frequently arises in the absence of junctional protein loss, endothelial death, or overt inflammation, instead reflecting progressive architectural disorganization. These findings support a model of structural causality, in which nanoscale perturbations initiate directional cascades of instability that propagate across organizational scales to produce tissue-level barrier failure. A key novelty of this review is the reinterpretation of nanomaterial-BBB interactions as controlled physical probes of architectural dependency rather than as delivery platforms or toxicological agents. By selectively perturbing membrane geometry, cytoskeletal anchoring, and junctional continuity, nanomaterials expose structural vulnerability thresholds that govern NVU stability independently of biochemical modulation. Beyond the BBB, the framework presented here generalizes to other endothelial and epithelial barriers, positioning the NVU as a paradigmatic structure-governed tissue interface. Emphasizing architecture as a primary determinant of barrier integrity provides a coherent foundation for multiscale, predictive investigation of barrier function and failure.
    Keywords:  Blood–brain barrier architecture; Junctional geometry; Multicellular coordination; Nanoscale structural perturbation; Neurovascular unit; Ultrastructural organization
    DOI:  https://doi.org/10.1016/j.tice.2026.103539
  30. Neuroprotection. 2026 Mar;4(1): 30-47
    Navigating the cholesterol maze: Key insights on use of statins in neurodegenerative disorders.
    Jun Han Kuan, Roshan S Raghavan, Dawn Li Wei Koh, Wing Yeng Tan, Igor Iezhitsa, Renu Agarwal.
      Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and multiple sclerosis (MS) involve progressive neuronal loss driven by dysregulated neurotransmission, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Cholesterol metabolism has emerged as a critical factor involved with both central and peripheral dysregulation contributing to pathology. This review synthesizes current evidence on cholesterol's role in neurodegeneration and evaluates the therapeutic potential of statins, which act via cholesterol-dependent and other pleiotropic mechanisms. A PubMed search covering 1985-2025 publications was conducted using terms related to neurodegenerative diseases, statins, cholesterol metabolism, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuroprotection. Studies were selected to highlight mechanistic insights into cholesterol regulation in the nervous system and clinical data on statin use. Neuronal loss in neurodegeneration is driven by processes including excitotoxicity, inflammation, and mitochondrial dysfunction. Excessive reactive oxygen species activate apoptotic pathways involving BAX, BAK, and p53. Dysregulated cholesterol metabolism is a significant contributor: In AD, the ApoE allele ε4 (ApoE4) links elevated cholesterol to amyloid-β (Aβ) accumulation and cognitive decline; in PD, cholesterol shows mixed effects, with some studies suggesting protection and others linking high levels to α-synuclein aggregation and mitochondrial impairment. In HD reduced cholesterol biosynthesis correlates with neuronal loss, while MS associates with elevated cholesterol and cognitive dysfunction. Statins, widely used cholesterol-lowering agents, reduce Aβ production, enhance its clearance, and improve synaptic function. Beyond lipid lowering, they exert anti-inflammatory, antioxidant, and anti-apoptotic effects. Clinical outcomes remain mixed, with benefits influenced by statin type, dose, treatment duration, disease stage, and patient genetics. Statins show multifaceted neuroprotective potential through cholesterol-dependent and independent pathways. While preclinical data are encouraging, clinical evidence is heterogeneous. Long-term, stratified trials are needed to clarify efficacy, and tailoring therapy to disease-specific mechanisms may offer a viable strategy for mitigating neurodegeneration and enhancing neuronal survival.
    Keywords:  Alzheimer's disease; Huntington's disease; Parkinson's disease; cholesterol/metabolism; hydroxymethylglutaryl‐CoA reductase inhibitors; multiple sclerosis; neurodegenerative diseases; neuroinflammation; neuroprotection; oxidative stress
    DOI:  https://doi.org/10.1002/nep3.70026
  31. Mol Biomed. 2026 Apr 24. pii: 57. [Epub ahead of print]7(1):
    Development and characterization of 3D spinal cord organoids to advance the study of amyotrophic lateral sclerosis.
    Matteo Bordoni, Eveljn Scarian, Letizia Messa, Maria Garofalo, Emanuela Jacchetti, Manuela Teresa Raimondi, Luca Diamanti, Stella Gagliardi, Stephana Carelli, Cristina Cereda, Orietta Pansarasa.
      
    DOI:  https://doi.org/10.1186/s43556-026-00453-0
  32. Drug Des Devel Ther. 2026 ;20 597087
    Peptide-Based Therapeutics for Alzheimer's Disease: Medicinal Chemistry, AI-Guided Computational Design, and Blood-Brain Barrier Delivery.
    Abdulaziz H Al Khzem, Mohamed S Gomaa.
      Alzheimer's disease (AD) represents a pressing challenge in modern medicine, with current therapeutics offering only symptomatic relief. Peptide-based therapeutics have emerged as promising candidates owing to their target specificity, favorable safety profiles, and ability to modulate protein-protein interactions inaccessible to small molecules. This narrative review evaluates medicinal chemistry and artificial intelligence (AI)-driven approaches that are reshaping peptide drug discovery for AD, spanning target selection, sequence design, synthesis optimization, and central nervous system (CNS) delivery. Peptides targeting key AD pathological mechanisms-including amyloid-β (Aβ) aggregation inhibition, tau hyperphosphorylation disruption, and neurotrophic signaling enhancement-are discussed alongside strategies such as cyclization, D-amino acid incorporation, PEGylation, and peptidomimetic design to improve metabolic stability and blood-brain barrier (BBB) penetration. We review automated fast-flow peptide synthesis with inline UV-vis monitoring as a platform for rapid, high-fidelity preparation of complex sequences suitable for translational development. Delivery platforms-including cell-penetrating peptides, intranasal formulations, and nanocarrier systems-which primarily increase systemic exposure or fundamentally alter CNS distribution mechanisms are presented. AI and machine-learning (ML) technologies, molecular simulations, and structure-prediction systems are examined as an integrated pipeline that supports end-to-end design, validation, and optimization, with emphasis on rigorous QSAR and docking/MD validation practices. Clinical translation is analyzed through peptide repurposing (e.g. GLP‑1 receptor agonists, intranasal insulin, oxytocin), dedicated peptide candidates, and evolving regulatory expectations. Finally, we outline concrete design checklists for CNS ready peptides, discuss key translational bottlenecks, and propose priorities for the next 5-10 years of peptide-based AD therapy development.
    Keywords:  Alzheimer’s disease; artificial intelligence; blood–brain barrier; clinical translation; drug discovery; peptide drugs; pharmaceutical medicinal chemistry
    DOI:  https://doi.org/10.2147/DDDT.S597087
  33. Front Nutr. 2026 ;13 1774416
    Luteolin as a dietary flavonoid for brain health: modulating neuroinflammation and cognitive decline in neurodegenerative disorders.
    Huanglei Jiang, Xiu'e Pang.
      Luteolin, a flavonoid naturally present in a variety of fruits, vegetables, and medicinal plants, has been recognized as a potentially effective neuroprotective nutraceutical because of its remarkable anti-inflammatory, antioxidant, and neurotrophic properties. Increasing evidence suggests that neuroinflammation and oxidative stress are major contributors to cognitive decline and neuronal degeneration in several prominent neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). Luteolin significantly inhibits microglial activation, reduces pro-inflammatory cytokine production, modulates the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and enhances Nrf2-mediated antioxidant mechanisms. Furthermore, it promotes synaptic plasticity through brain-derived neurotrophic factor (BDNF)-associated pathways and mitigates the aggregation of pathological proteins, including Aβ, tau, α-synuclein, and mutant huntingtin. Preclinical studies consistently demonstrate substantial improvements in cognitive function, motor performance, demyelination, and neuronal viability in models of AD, PD, MS, and HD. Preliminary clinical observations also indicate prospective advantages for cognitive function, regulation of inflammatory responses, and alleviation of symptoms, particularly concerning AD and MS. Notwithstanding these encouraging outcomes, obstacles persist due to luteolin's restricted bioavailability, ideal dosing parameters, and the translational discrepancies between experimental models and human pathophysiological conditions. In summary, luteolin emerges as a noteworthy candidate for nutraceutical-oriented approaches designed to alleviate neuroinflammation and cognitive deterioration in the context of neurodegenerative diseases.
    Keywords:  cognitive decline; luteolin; neurodegenerative diseases; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3389/fnut.2026.1774416
  34. Mol Neurobiol. 2026 Apr 21. pii: 575. [Epub ahead of print]63(1):
    Blood-Brain Barrier Permeability in Cases of Post-operative Delirium Is Associated with Central Nervous System Phosphatidylcholine Imbalances.
    Mijin Jung, Xiaobei Pan, Aoife Sweeney, Anthony P Passmore, Bernadette McGuinness, Daniel F McAuley, David Beverland, Amanda J Heslegrave, Jonathan Schott, Henrik Zetterberg, Emma L Cunningham, Brian D Green.
      Blood-brain barrier (BBB) permeability is reportedly increased in patients exhibiting postoperative delirium. Changes in either cerebrospinal fluid (CSF) or blood metabolites have also been reported in cases of delirium. This investigation examined whether BBB permeability influences metabolite concentrations on either side of the barrier, and whether this changes in cases of delirium. This study is a nested case-control cohort (n = 54) drawn from the entire cohort of n = 315 participants. Preoperative CSF and plasma from postoperative delirium and control participants matched for age and gender underwent metabolomic profiling. Concentrations of metabolites in plasma and in CSF were obtained, and where measurable, a CSF/plasma metabolite ratio (Qmetab) was calculated. CSF/plasma albumin ratio (Qalb), a recognized indicator of BBB permeability, was also calculated. The above parameters were compared between delirium and control groups. Finally, each Qmetab was correlated against Qalb for control or delirium cases. In cases where delirium would later occur there were significant elevations in the Qmetabs of amino acids (Gln, His, Met, Phe, Tyr and Val), and one phosphatidylcholine (PC). Many other PC Qmetabs significantly correlated with Qalb and this mainly occurred in individuals subsequently experiencing delirium. In persons prone to postoperative delirium, the equilibrium of certain species of PC across the BBB correlates with BBB permeability. It is unclear whether this occurs because of changes in PC metabolism or transit, but understanding this could improve our understanding of the mechanisms underlying delirium.
    Keywords:  Blood-brain barrier (BBB); CSF/serum albumin ratio (Qalb); Delirium; Phosphatidylcholine (PC)
    DOI:  https://doi.org/10.1007/s12035-026-05847-3
  35. Neurol Open Access. 2026 Jun;pii: e000082. [Epub ahead of print]2(2):
    Risk of Multiple Sclerosis Among Persons with Epstein Barr Virus-Positive Mononucleosis: A Population-Based Study.
    Jennifer L St Sauver, Susan Audrey Hall, Robert M Jacobson, B Mark Keegan, Chun Fan, Roderick A McPhee, Philip O Buck, John Diaz-Decaro.
       Background and Objective: Prior studies examining associations between Epstein Barr Virus (EBV)-positive infectious mononucleosis (IM) and risk of multiple sclerosis (MS) frequently lacked laboratory confirmation of EBV-positive IM or relied on billing codes to identify MS. We assessed whether laboratory-confirmed EBV-positive IM was associated with an increased risk of developing verified cases of MS.
    Methods: We conducted a population-based retrospective cohort study using medical records from the Rochester Epidemiology Project. We identified individuals with serologic evidence of EBV infection and an associated IM diagnosis (EBV-positive IM; exposed cohort) between 1998 and 2022. Age- (± 1 year) and sex-matched individuals without evidence of IM (3:1 match) comprised the unexposed cohort. Incident MS cases were verified through blinded expert chart review. Multivariate Cox proportional hazard models were used to assess associations between EBV-positive IM and risk of MS.
    Results: 4,721 persons had EBV-positive IM (exposed cohort: 55% female, 70% <20 years). The referent cohort included 14,163 persons without EBV-positive IM (55% female, 70% <20 years). During follow-up (median, 6 years for exposed; 8 years for referents), MS developed in 8 individuals with EBV-positive IM (0.17%) and 10 referents (0.07%). EBV-positive IM was associated with a >3-fold increased risk of MS (adjusted Hazard Ratio: 3.14, 95% Confidence Interval: 1.18-8.34).
    Discussion: EBV-positive IM was associated with a substantially higher risk of MS. Findings are consistent with prior studies and underscore the importance of preventive strategies targeting EBV to reduce the long-term burden of MS.
    Keywords:  [ 142 ] Viral infections; [ 41 ] Multiple sclerosis; [ 54 ] Cohort studies; [ 59 ] Risk factors in epidemiology
    DOI:  https://doi.org/10.1212/wn9.0000000000000082
  36. Neuroimage. 2026 Apr 17. pii: S1053-8119(26)00242-9. [Epub ahead of print] 121927
    Advancing Brain Age Estimation: Normative Deviation Mapping (NDM) for Sensitive Detection of Pathological Aging.
    Akihiko Shiino, Kenji Tanigaki, Maya Oki, Yoshiyuki Watanabe.
      Brain age is a valuable neuroimaging-based biomarker for assessing brain health, typically estimated using machine learning (ML) models. However, ML approaches suffer from inherent bias, requiring post-hoc correction, and may mask age-related biological variation, limiting their sensitivity to detect subtle biological aging. To overcome these limitations, we proposed a normative deviation mapping (NDM) model as an alternative to conventional ML. We analyzed MRI-derived volumes of 223 brain regions from 10,539 participants (aged 4-98 years). The NDM model assumes a normal distribution for age-specific volumes to calculate regional deviations, which are then aggregated across the brain to determine the final brain age. Compared to standard ML models (e.g., neural networks, extreme gradient boosting), the NDM model effectively eliminated regression bias. Consequently, the NDM model mitigated the underestimation of brain age in older adults, significantly enhancing the detection of pathological changes associated with neurodegenerative diseases, such as Alzheimer's disease. Furthermore, in healthy individuals, the NDM model showed a stronger correlation with cognitive function than chronological age. Our findings indicate that the use of ComBat-GAM for data harmonization could unintentionally mitigate the pathological associations of the brain age gap, suggesting a need for caution to preserve vital biological information. Overall, our model outperforms conventional ML in detecting pathological changes and reflecting biological brain age, while revealing the effects of amyloid accumulation and lifestyle habits on brain health, offering a more robust and biologically meaningful biomarker.
    Keywords:  brain age; brain function; machine learning; normative deviation mapping; voxel-based morphometry
    DOI:  https://doi.org/10.1016/j.neuroimage.2026.121927
  37. Free Radic Biol Med. 2026 Apr 16. pii: S0891-5849(26)00313-8. [Epub ahead of print]251 212-228
    Targeting pyroptosis in tauopathies: A redox-driven axis of neuroinflammation and neurodegeneration.
    E Alonso-López, I Silva-Llanes, E Díez-Tejedor, I Lastres-Becker.
      Tauopathies encompass a diverse group of neurodegenerative disorders characterized by abnormal TAU accumulation, synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Beyond its role as a pathological hallmark, increasing evidence indicates that TAU actively drives neurodegeneration by disrupting mitochondrial function, promoting oxidative stress, and triggering maladaptive innate immune responses. In this context, pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasome activation and GASDERMIN pore formation, has emerged as a critical mechanism linking TAU pathology to chronic neuroinflammation and neuronal damage. This review summarizes current advances on the molecular crosstalk between TAU pathology, redox imbalance, inflammasome signaling, and pyroptotic cell death across primary and secondary tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). We discuss how pathological TAU induces mitochondrial dysfunction and reactive oxygen species generation, providing key priming and activation signals for inflammasomes, particularly NLRP3, in microglia and other brain cells. Pyroptosis is highlighted as a downstream effector that amplifies neuroinflammation through the release of pro-inflammatory cytokines and danger-associated molecular patterns, thereby sustaining TAU propagation and neurodegeneration. Special attention is paid to the redox-sensitive transcription factor NRF2 as a central regulatory node capable of counteracting oxidative stress, inflammasome activation, and pyroptosis. Finally, we examine emerging therapeutic strategies targeting pyroptotic and redox pathways, discussing their translational potential and current limitations. Overall, this review positions pyroptosis-driven redox-immune dysregulation as a promising yet underexplored therapeutic target in TAU-driven neurodegenerative diseases.
    Keywords:  Inflammasome; NRF2; Neurodegeneration; Neuroinflammation; Oxidative stress; Pyroptosis; Redox signaling; TAU
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.029
  38. Neurobiol Dis. 2026 Apr 16. pii: S0969-9961(26)00144-0. [Epub ahead of print]224 107399
    Transneuronal cytokine delivery promotes functional recovery across spinal cord contusion severities via descending circuit plasticity.
    Marco Leibinger, Igor Moskaliov, Chinonso-John Ani, Dalia Halawani, Dietmar Fischer.
      Spinal cord injury (SCI) frequently leads to permanent motor and sensory deficits, with complete injuries causing total loss of function below the lesion and incomplete injuries preserving only partial connectivity. Intracortical delivery of an AAV2 vector encoding the designer cytokine hyper-interleukin-6 (AAV2-hIL-6) enhances recovery after complete SCI by transneuronally stimulating raphe nuclei. Here, we verified that AAV2-hIL-6 transneuronally activates subcortical neurons in the medulla and evaluated that this strategy enables recovery in clinically more relevant mouse models of mild, moderate, and severe contusion injury. Across all severities, AAV2-hIL-6 treatment significantly improved locomotor function compared to AAV2-GFP-treated controls. Although lesion size and neuronal loss correlated with contusion severity and were unaffected by the AAV2-hIL-6 treatment, it robustly increased the number and length of descending serotonergic axons in the lumbar cord. Selective ablation of serotonergic neurons abolished these gains, confirming their essential role in functional sensorimotor recovery. However, while AAV2-hIL-6 also reduced corticospinal tract (CST) axon retraction, it did not induce axon growth beyond the lesion, suggesting that CST regeneration was not required for recovery. Thus, intracortical AAV2-hIL-6 delivery drives circuit remodeling and functional restoration across contusion severities, highlighting its promise as a regenerative therapy for SCI with spared pathways.
    Keywords:  Axon regeneration; Contusion injury; Gene therapy; Hyper-interleukin 6; Raphe spinal tract; Spinal cord injury; Transneuronal delivery
    DOI:  https://doi.org/10.1016/j.nbd.2026.107399
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