bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–05–17
fifty papers selected by
Luca Bolliger, lxBio
  1. Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.
  2. Challenges in Brain Drug Delivery for Neurodegenerative Disorders and Recent Trends: A Review.
  3. Neurocritical progression in amyotrophic lateral sclerosis: pathological relevance and validation.
  4. Amyotrophic Lateral Sclerosis: A Review.
  5. Bridging the Funding Gap in Drug Development for Amyotrophic Lateral Sclerosis.
  6. Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.
  7. Comment on "profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis".
  8. Associations of cognitive and behavioural impairment in ALS with brain pathology: pTDP-43 versus microglial activation.
  9. Offset Conduction Velocity Reveals Prognostic Slowing of Motor Axons in Amyotrophic Lateral Sclerosis.
  10. The impact of long-term feeding with curcuminoids phospholipids enriched diet on disease progression of fALS.
  11. Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis.
  12. TDP-43: [GU]-ardian of the transcriptome.
  13. Sex-Stratified Association of Regional Dopamine Transporter Binding With Disease Progression in Amyotrophic Lateral Sclerosis.
  14. Axonal dying back of upper motor neurons in human ALS.
  15. Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.
  16. Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
  17. Alzheimer's Disease Co-Pathology and Cognitive Impairment in Amyotrophic Lateral Sclerosis.
  18. APOE ε4 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis.
  19. Decomposing heterogeneity in disease progression speeds and pathways.
  20. Mechanism of the N87D mutation in SOD1-atypical amyotrophic lateral sclerosis case report and literature review molecular mechanism of N87D mutation in SOD1.
  21. An interpretable, clinically grounded framework for digital speech biomarker development in neurodegenerative diseases.
  22. Innovative Nanoparticle-based Therapeutic Strategies: Overcoming Biological Barriers for Enhanced Efficacy.
  23. Carboplatin alleviates astrocytic TDP-43 neurotoxicity by inhibiting NF-κB activation.
  24. Cannabidiol and other non-psychotropic cannabinoids from Cannabis sativa as therapeutics for microglial-mediated neuroinflammation and neurodegeneration.
  25. TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD.
  26. A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.
  27. Clinical and electrophysiological features for differentiating MMN from hand-onset ALS.
  28. Targeting the NLRP3 inflammasome with antibody-based Therapeutics for chronic neurodegenerative diseases.
  29. Peripheral Neutrophil Activation and Extracellular Trap Formation in Amyotrophic Lateral Sclerosis.
  30. Efficacy and safety of pharmacological and biological therapies for amyotrophic lateral sclerosis: a network meta-analysis.
  31. Molecular and genetic landscape of amyotrophic lateral sclerosis in Latin America: a scoping review of pathogenic hypotheses and ancestral heterogeneity.
  32. Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.
  33. Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.
  34. Integrative Transcriptomics Identifies Ubiquitination-Related Genes BIRC2, COPS5, and TBK1 as Novel Biomarkers of T-Cell Dysregulation in Amyotrophic Lateral Sclerosis.
  35. Translational Perspectives on Anti-Inflammatory Interventions for Neurodegenerative Disorders: Evidence from Gut-Brain Axis.
  36. Beyond the surface: Exploring differing aspects of wishes to hasten death in patients with amyotrophic lateral sclerosis.
  37. A perfused, parallelized blood brain barrier-tumor platform for compound permeation and efficacy investigations.
  38. Astrocyte Functional Heterogeneity in Multiple Sclerosis.
  39. A novel nasal mucosal peptide-modified co-delivery system for ginsenoside Rg1, Rb1, and notoginseng saponin R1 in the amelioration of AD.
  40. Rituximab Beyond Oncology: Targeting B-Cell-Mediated Immunomodulatory Therapy in Neurodegenerative and Neuropsychiatric Disorders.
  41. S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis.
  42. Clinical Significance of Plasma Sphingosine-1-Phosphate Decline in Progression of Spinal and Bulbar Muscular Atrophy.
  43. Identifying targets at the blood-brain barrier for treating vascular cognitive impairment and dementia.
  44. Biosimilars: Antibody and nanobody-based therapeutic approaches towards protein misfolding diseases.
  45. Neuroengineering Frontiers: A Selective Review of Neural Interfaces, Brain-Machine Interactions, and Artificial Intelligence in Neurodegenerative Diseases.
  46. Neurovascular unit dysfunction in vascular cognitive impairment: Mechanisms, biomarkers, and translational strategies.
  47. Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.
  48. Nanozymes in Personalized Medicine: A Review of the Potential for Tailored Diagnostic and Therapeutic Applications.
  49. Advancing the Frontiers of Multiple Sclerosis Management: Emerging Immunotherapeutic Strategies.
  50. Artificial Intelligence Decodes Brain Elemental Signatures to Stratify Aging and Neurological Diseases.
  1. CNS Neurol Disord Drug Targets. 2026 May 08.
    Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.
    Jayasurya Ramesh, B Jayanthi, Vasanth Kumar Mohan, S Srinivasan, M K Vijayalakshmi, Magesh Mohan.
      Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.
    Keywords:  Blood–brain barrier (BBB); drug delivery systems; neurodegenerative diseases; neurovascular unit (NVU).; receptor-mediated transcytosis; targeted nanoparticles
    DOI:  https://doi.org/10.2174/0118715273444679260416064255
  2. CNS Neurol Disord Drug Targets. 2026 May 08.
    Challenges in Brain Drug Delivery for Neurodegenerative Disorders and Recent Trends: A Review.
    Ashif Anjukandan, Rajaganapathy Kaliyaperumal.
       INTRODUCTION: Age-related disorders known as neurodegenerative illnesses are defined by uncontrolled neuronal loss that gradually impairs brain function. The majority of age-related neurodegenerative disorders are caused by dementias, in particular. Nowadays, the neurodegenerative disorders are not limited to age and are reported in all age groups. The drug delivery to treat the neurodegenerative disorders is challenging due to the presence of the blood-brain barrier (BBB).
    METHOD: A critical literature review has been conducted across databases such as Scopus, Embase, Cochrane, and PubMed. Blood-brain barrier, neurodegenerative disorders, novel drug delivery system, and targeted drug therapy were the search terms.
    RESULTS: Neurodegenerative Diseases (NDD) impact the peripheral nervous system, nerve cells, muscles, and the nerve-muscle junction. This term broadly encompasses cognitive disorders, such as Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and vascular dementia. Additionally, other neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and spinocerebellar ataxias predominantly impair motor system function and nerves in the limbs. The existing therapeutic approaches to treat neurological diseases exhibit limited efficacy due to the BBB. This highly selective semipermeable membrane permits vital nutrients to enter the brain while blocking the potentially harmful toxins. It makes it very challenging to get medications into the brain. There are several effective approaches to deliver drugs to the brain (nanocarrier systems, intranasal administration, and focused ultrasound) to address the limitations of conventional treatments.
    CONCLUSION: This review discusses neurodegenerative disorders, brain anatomy/physiology, barriers to drug delivery, and strategies to overcome these limitations.
    Keywords:  Neurodegenerative; alzheimer's disease; blood-brain barrier; dementia; intranasal administration; nanocarrier
    DOI:  https://doi.org/10.2174/0118715273453002260416115852
  3. Open Life Sci. 2026 Jan;21(1): 20251323
    Neurocritical progression in amyotrophic lateral sclerosis: pathological relevance and validation.
    Jiayue Pan, Chengyi Zhang, Jingyao Li, Li Ma.
      Evidence from multiple clinical studies indicates that amyotrophic lateral sclerosis (ALS) frequently evolves into a condition requiring neurocritical care. In advanced stages or during acute complications, ALS can rapidly transition into a neurocritical state characterized by respiratory insufficiency, systemic dysfunction, and accelerated neurological decline. Although current management strategies for advanced-stage ALS are relatively well established, there remains a significant lack of targeted interventions aimed at preventing or attenuating neurocritical deterioration. This review systematically examines the pathophysiological mechanisms underlying neurocritical progression in ALS, including respiratory failure, metabolic imbalance, autonomic dysfunction, and multisystem involvement. We further evaluate emerging and potential therapeutic strategies designed to mitigate disease severity and stabilize critical neurological function. In addition, we analyze clinical and biological factors that increase susceptibility to neurocritical states and discuss evidence-based approaches to delay disease progression. By integrating clinical observations with mechanistic insights, this review aims to improve early recognition, optimize neurocritical management, and ultimately enhance outcomes for patients with ALS.
    Keywords:  advanced-stage state; amyotrophic lateral sclerosis; multisystem dysfunction; neurocritical care; pharmacological management; respiratory failure
    DOI:  https://doi.org/10.1515/biol-2025-1323
  4. JAMA. 2026 May 11.
    Amyotrophic Lateral Sclerosis: A Review.
    John Ravits, Dominic Ferrey, Betul Gundogdu, Wali Qayoumi, Chelsea Zale.
       Importance: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness due to degeneration of upper motor neurons in the brain and lower motor neurons in the brainstem and spinal cord. It affects approximately 25 000 individuals in the United States.
    Observations: Amyotrophic lateral sclerosis is characterized by progressive painless muscle weakness that typically begins in a focal region of the body, such as limb muscle weakness causing hand weakness or foot drop (65%), cranial muscle weakness causing speech or swallowing problems (20%-25%), or axial muscle weakness causing bent posture (5%-10%), and spreads to other body regions over time. The disease usually manifests with dysfunction indicative of both upper motor neurons (causing muscle stiffness and spasticity) and lower motor neurons (causing weakness, fasciculations, atrophy, and flaccidity). After onset, weakness spreads through the musculature and typically causes death due to respiratory muscle weakness. Among people with ALS, approximately 85% have sporadic ALS, which is not associated with known environmental or genetic factors, and 15% have familial ALS. Amyotrophic lateral sclerosis is diagnosed based on clinical features, which can be supported by results of electromyography. More than 60 genes have been associated with ALS, and most are autosomal dominant. Pathogenic variants in chromosome 9 open reading frame 72 (C9orf72) are found in 40% of all familial ALS cases, and pathogenic variants in superoxide dismutase 1 (SOD1) are found in 20% of patients with familial ALS. Patients with ALS survive a mean of 3 to 5 years after diagnosis, and there are currently no curative therapies. Clinical care primarily focuses on symptom management and quality of life. Three US Food and Drug Administration (FDA)-approved disease-modifying therapies are available in the United States. Riluzole and edaravone are oral medications that slow ALS progression by up to 2 to 4 months, and tofersen is an intrathecally administered gene therapy for patients with SOD1 gene variants. Specialized multidisciplinary teams, comprising neurologists, nurses, therapists, dietitians, and social workers, are associated with improved survival (4-7 months) and quality of life.
    Conclusions and Relevance: Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disorder of upper and lower motor neurons. No curative therapies exist. Two oral medications, riluzole and edaravone, are approved by the FDA and modestly decrease disease progression in sporadic ALS. Tofersen, an intrathecally administered gene-based therapy, is also FDA approved and slows disease progression in patients with SOD1 pathogenic gene variants.
    DOI:  https://doi.org/10.1001/jama.2026.6385
  5. Neurol Clin Pract. 2026 Jun;16(3): e200623
    Bridging the Funding Gap in Drug Development for Amyotrophic Lateral Sclerosis.
    Pineal Iyassu Bareamichael, Suma Babu, Trang Hoang, Mariana P Socal.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with few effective treatments and high clinical trial failure rates. Since 1995, only 3 drugs riluzole, edaravone, and tofersen have gained approval from the Food and Drug Administration, all offering modest benefits. Challenges in ALS drug development include poor translational preclinical models, underpowered early-phase trials, and the high cost of late-stage development. Despite federal initiatives such as the Accelerating Access to Critical Therapies for ALS Act and the ALL ALS Consortium, critical gaps remain in funding large multisite trials and sustaining research networks. Accelerating progress requires strengthening national registries, expanding adaptive trial platforms, integrating existing networks, and adopting innovative funding models such as milestone-based public-private partnerships and reinvestment of licensing revenues. A coordinated, sustainable research and funding ecosystem could transform ALS therapy development and serve as a model for advancing treatments for other rare neurodegenerative and neurogenetic disorders.
    DOI:  https://doi.org/10.1212/CPJ.0000000000200623
  6. Int Immunopharmacol. 2026 May 09. pii: S1567-5769(26)00627-2. [Epub ahead of print]182 116781
    Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.
    Gong Chen, Cong Zhao, Chun Wang, Guochun Chen, Jingming Shi, Huihui Chen.
      Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Glaucoma; Immunity; Microglia; Multiple sclerosis; Neurodegenerative diseases; T cells
    DOI:  https://doi.org/10.1016/j.intimp.2026.116781
  7. J Neurol Sci. 2026 Apr 15. pii: S0022-510X(26)00202-9. [Epub ahead of print]487 125920
    Comment on "profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis".
    Shubham, Abhishek Mathur.
      
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Cell-free mitochondrial DNA; Mitochondrial DNA; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.jns.2026.125920
  8. J Neurol. 2026 May 15. pii: 315. [Epub ahead of print]273(6):
    Associations of cognitive and behavioural impairment in ALS with brain pathology: pTDP-43 versus microglial activation.
    Hanneke M J Slaghekke, Rosanne Govaarts, Lucia Mesarosova, Angelika Mühlebner, Emma Beeldman, Marianne de Visser, Michael A van Es, Leonard H van den Berg, Anneke J van der Kooi, Yolande A L Pijnenburg, Eleonora Aronica, Joost Raaphorst.
       OBJECTIVE: Investigate associations between brain pathology (pTDP-43 inclusions and microglial activation) and cognitive and behavioural impairment in patients with amyotrophic lateral sclerosis (ALS).
    METHODS: Based on comprehensive neuropsychological examination and behavioural assessment, 21 ALS patients of whom post mortem brain tissue was obtained, were classified as having 1) no cognitive and/or behavioural impairment (pure motor ALS), 2) mild cognitive and/or behavioural impairment (ALSci/bi), and 3) ALS with behavioural variant frontotemporal dementia (ALS-bvFTD). Immunohistochemical staining of pTDP-43 and HLA-DR-defined microglial activation was semi-quantitatively assessed in grey and/or white matter of the prefrontal cortex, thalamus, hippocampus, and motor cortex.
    RESULTS: Fourteen patients had pure motor ALS, four patients had ALSci/bi, and three patients had ALS-bvFTD. pTDP-43 pathology in the grey matter of the prefrontal cortex and gyrus dentatus differed between groups, especially between pure motor ALS and ALS-bvFTD. For each extra-motor brain region, pTDP-43 severity was highest in patients with ALS-bvFTD and lowest in patients with pure motor ALS, with ALSci/bi in between. This pattern was not observed for microglial activation. Associations between white matter pTDP-43 severity and cognitive/behavioural impairment were less robust than those in grey matter.
    CONCLUSION: Severity of cognitive and/or behavioural impairment in ALS is related to severity of pTDP-43 pathology, in particular in the grey matter of extra-motor brain regions; we did not detect a clear association with microglial activation.
    Keywords:  Amyotrophic lateral sclerosis; behaviour; brain pathology; cognition; frontotemporal dementia; pTDP-43
    DOI:  https://doi.org/10.1007/s00415-026-13848-4
  9. Muscle Nerve. 2026 May 11.
    Offset Conduction Velocity Reveals Prognostic Slowing of Motor Axons in Amyotrophic Lateral Sclerosis.
    Toshio Shimizu, Hironobu Myojin, Kota Bokuda, Tomoya Kawazoe, Ryo Morishima, Hideki Kimura, Kazushi Takahashi, Yuki Nakayama.
       INTRODUCTION/AIMS: Slowing of motor nerve conduction is not classically regarded as a feature of amyotrophic lateral sclerosis (ALS). We introduce a novel electrophysiological parameter, offset motor conduction velocity (offset-MCV), to assess conduction in relatively slower motor axons and investigate its association with survival in ALS.
    METHODS: Motor nerve conduction studies of the median and tibial nerves were performed in 145 patients with ALS and 70 healthy controls. Onset and offset latencies of compound muscle action potentials were measured, and onset- and offset-MCVs were calculated. Patients were followed until death or tracheostomy, and associations between MCV parameters and survival were analyzed.
    RESULTS: Both onset- and offset-MCVs were significantly reduced in patients with ALS compared with controls for the median and tibial nerves (all p < 0.0001). Onset-MCVs were not associated with survival. In contrast, reduced offset-MCVs in both nerves were associated with short survival (log-rank test: median nerve, p = 0.009; tibial nerve, p = 0.021). Multivariate Cox regression analysis identified tibial nerve offset-MCV as an independent prognostic factor (p = 0.029).
    DISCUSSION: Pathological slowing of motor nerve conduction occurs in ALS and is associated with poor survival. Offset-MCV may reflect disease-related changes in slower α-motor axons and represents a potential prognostic biomarker in ALS.
    Keywords:  amyotrophic lateral sclerosis; median nerve; motor nerve conduction; survival prognosis; tibial nerve
    DOI:  https://doi.org/10.1002/mus.70273
  10. Neurochem Int. 2026 May 13. pii: S0197-0186(26)00074-4. [Epub ahead of print]197 106183
    The impact of long-term feeding with curcuminoids phospholipids enriched diet on disease progression of fALS.
    Sushmitha Somanahalli Purushotham, Rose Chesworth, Nisal Keembiyage, Gerald Münch, Erika Gyengesi, Yossi Buskila.
      Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease characterised by the progressive loss of motor functions affecting both upper and lower motor neurons. Although considered multifactorial with an unclear aetiology, it is believed that the interplay between genetic and environmental factors, with neuroinflammation playing a key role in disease progression, contributes to its development. There is currently no effective treatment for ALS. Curcumin has been recently highlighted for its potential therapeutic role in treating neurodegenerative diseases. Curcumin phospholipids, a highly bioavailable form of curcumin that allow the curcumin to be absorbed into the bloodstream more effectively than standard curcumin extracts, is considered as a natural cytokine-suppressive anti-inflammatory compound (CSAID) that is well-known for its therapeutic properties and is considered safe for humans and rodents at low to moderate concentrations. In this study, we investigated whether a long-term feeding regimen incorporating curcuminoids phospholipids-enriched diet early in disease progression could mitigate motor deficits and affect the lifespan of the SOD1 mouse model of familial ALS (fALS). Our results indicate sex-differences regarding the effect of curcumin supplementation on motor deficits and anxiety-like behaviour. While long-term feeding with curcuminoids phospholipids enriched diet had a complex effect on SOD1 female mice expressed as reduced anxiety like behaviour and motor deficits at the walking beam test, it had no effect on SOD1 male mice. Moreover, curcuminoids supplementation had a limited effect on disease onset and progression in SOD1 mice model for fALS.
    Keywords:  ALS; Excitability; Locomotion; Motoneuron disease; SOD1
    DOI:  https://doi.org/10.1016/j.neuint.2026.106183
  11. Clin Neurol Neurosurg. 2026 May 08. pii: S0303-8467(26)00158-7. [Epub ahead of print]267 109466
    Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis.
    Ahmad A Toubasi, Thuraya N Al-Sayegh.
       BACKGROUND: Previous studies have suggested that traumatic head injury (THI) is associated with amyotrophic lateral sclerosis (ALS). However, the evidence remains limited and inconsistent, partly due to small sample sizes.
    OBJECTIVES: In this meta-analysis, we aimed to investigate the association between THI and the risk of ALS.
    METHODS: We conducted a systematic review and meta-analysis of studies assessing the relationship between THI and ALS. The exposure of interest was THI, and the outcome of interest was ALS development. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used as effect measures.
    RESULTS: Eighteen studies comprising 578,815 participants were included. THI was associated with an increased risk of ALS (OR = 1.47; 95% CI: 1.23-1.76). The association was consistent across studies conducted in Europe (OR = 1.60; 95% CI: 1.19-2.15) and the Americas (OR = 1.27; 95% CI: 1.12-1.43). Subgroup analysis by sex showed a significant association among males (OR = 2.27; 95% CI: 1.41-3.66) but it was less significant among females (OR = 1.30; 95% CI: 0.78-2.17). Both single (OR = 1.48; 95% CI: 1.18-1.85) and multiple THIs (OR = 1.34; 95% CI: 1.15-1.56) were associated with ALS. Funnel and doi plots demonstrated asymmetry indicating significant publication bias.
    CONCLUSIONS: Our analysis demonstrated an association between THI and ALS, however the lack of dose-response relationship suggests it is less likely to be causative.
    Keywords:  Amyotrophic lateral sclerosis; Epidemiology; Traumatic head injury
    DOI:  https://doi.org/10.1016/j.clineuro.2026.109466
  12. Mol Neurodegener. 2026 May 14.
    TDP-43: [GU]-ardian of the transcriptome.
    Irika R Sinha, Abigail L Atkinson, Katherine E Irwin, Jonathan P Ling, Philip C Wong.
      TDP-43 is a ubiquitously expressed, primarily nuclear DNA/RNA-binding protein implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). In this review, we examine the structure and regulation of TDP-43, how these features influence its localization and functional activity, and how their disruption may contribute to disease. Among TDP-43's diverse functions, splicing repression of nonconserved RNA sequences termed cryptic exons has emerged as especially central to human disease. TDP-43 nuclear depletion and cytoplasmic aggregation are well-established pathological features in affected neurons and glia of neurodegenerative diseases, and accumulating evidence suggests that loss of TDP-43-mediated splicing repression occurs presymptomatically in disease. Advances in RNA-sequencing have enabled systematic identification of cryptic exon inclusion as a sensitive marker of TDP-43 dysfunction. Here, we synthesize current knowledge of TDP-43 biology and curate datasets from human tissues and experimental models, focusing on cryptic splicing to provide a resource for leveraging cryptic exon biology to better understand, detect, and target TDP-43 dysfunction.
    DOI:  https://doi.org/10.1186/s13024-026-00944-2
  13. Ann Clin Transl Neurol. 2026 May 14.
    Sex-Stratified Association of Regional Dopamine Transporter Binding With Disease Progression in Amyotrophic Lateral Sclerosis.
    Tomoya Kawazoe, Keizo Sugaya, Kentaro Hayashi, Keiko Hino, Yasuhiro Nakata, Kota Bokuda, Toshio Shimizu, Kazushi Takahashi.
       OBJECTIVE: To clarify the clinical relevance of dopamine transporter single-photon emission computed tomography (DAT-SPECT) abnormalities in amyotrophic lateral sclerosis (ALS), with a prespecified focus on sex-stratified associations with disease progression and short-term prognosis.
    METHODS: Fifty-eight consecutive patients with ALS were prospectively enrolled and underwent 123I-ioflupane DAT-SPECT, and DAT-SPECT data from 30 patients with essential tremor were analyzed as a reference group. We quantified the specific binding ratio (SBR) and the caudate-to-putamen binding ratio (BR-C/P) as age-adjusted Z-scores. Associations with functional decline (ΔALSFRS-R), respiratory function (forced vital capacity), neuropsychiatric measures, and a 6-month composite endpoint of death or ventilator support were examined using correlation and logistic regression analyses, with prespecified sex-stratified evaluation.
    RESULTS: A significant sex difference in BR-C/P Z-scores prompted sex-stratified analyses. SBR Z-scores were not associated with clinical or neuropsychiatric variables in either sex. In women, lower BR-C/P Z-scores correlated with faster functional decline and were independently associated with a higher risk of death or ventilator support within 6 months (odds ratio per 1-unit increase, 0.31; 95% confidence interval, 0.12-0.83). In men, BR-C/P Z-scores correlated with forced vital capacity and respiratory decline. Exploratory voxel-based morphometry suggested limbic and striatal gray matter correlates in women with lower BR-C/P Z-scores.
    INTERPRETATION: Regional dopaminergic imbalance captured by BR-C/P, rather than global SBR, demonstrated sex-stratified associations with disease progression in ALS. These findings support sex-specific interpretation of dopaminergic imaging biomarkers and suggest that BR-C/P may complement clinical measures for identifying higher-risk trajectories, particularly in women. Validation in larger, longitudinal cohorts is required.
    Keywords:  amyotrophic lateral sclerosis; disease progression; dopamine transporter; neuroimaging biomarkers; sex differences
    DOI:  https://doi.org/10.1002/acn3.70432
  14. Sci Rep. 2026 May 15.
    Axonal dying back of upper motor neurons in human ALS.
    Haley C Cropper, Fozia Mir, Jianguo Liu, Fabien Dachet, Vidushi R Srivastava, Mohammed Ramizuddin, Kylie Kopecky, Ebony Mocanu, Qin Li Jiang, Madhu Soni, Tibor Valyi-Nagy, Diana Mnatsakanova, Charles K Abrams, Fei Song, Jeffrey A Loeb.
      Patients with amyotrophic lateral sclerosis (ALS) typically present with arm, leg, or bulbar weakness. While genetics plays a clear role, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. In this clinicopathological case series, we examined the relationships between UMN/LMN disease in ten ALS patients. Detailed clinical assessments and motor cortex, brainstem, and spinal cord tissues were collected via rapid autopsy. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43, and RNA-sequencing was performed. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and both UMN/LMN involvement. LMN degeneration and microglial activation were highest at disease onset sites. UMN degeneration was present at all spinal cord levels through the medulla, regardless of onset site. Surprisingly, there was no evidence of UMN axonal degeneration above the brainstem. While extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. RNA-sequencing implicated inflammatory pathways at sites of disease onset. Our findings suggest that some ALS patients without FTD have a dying back of UMN axons rather than a primary upper neuronopathy of neurons.
    Keywords:  amyotrophic lateral sclerosis; corticospinal tract; lower motor neuron; neuroinflammation; upper motor neuron
    DOI:  https://doi.org/10.1038/s41598-026-52496-6
  15. Nutrients. 2026 Apr 28. pii: 1392. [Epub ahead of print]18(9):
    Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.
    Rafail C Christodoulou, Laura Lorentzen, Daniel Eller, Evros Vassiliou.
      Background: Neurodegenerative diseases (NDs) are mainly considered disorders marked by severe immunometabolic imbalance, characterized by ongoing neuroinflammation and glial activation. While mitochondrial dysfunction and oxidative stress are well-known features, the upstream metabolic factors linking these pathological processes remain poorly understood. Methods: In this review, we examined recent preclinical and clinical studies exploring the connections between lipid metabolism, glial immunometabolism, and regulated cell death pathways. Our focus was on how long-chain fatty acids (LCFAs) facilitate communication among mitochondria, reactive oxygen species (ROS), and ferroptosis in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Results: New evidence shifts LCFAs from merely being passive indicators of cellular damage to active, upstream regulators of the neuroimmune response. Existing research shows that excess LCFA intake can overload astrocytic mitochondrial oxidative phosphorylation, leading to abnormal lipid droplet buildup and reactive astrogliosis. This lipid-driven reactivity promotes microglial polarization toward a persistent pro-inflammatory state. Notably, high levels of specific LCFAs, especially arachidonic acid, increase ROS production and lipid peroxidation. This lipotoxic environment ultimately triggers ferroptosis, an iron-dependent form of cell death shared across multiple NDs. Conclusions: The harmful interaction among mitochondrial dysfunction, lipid peroxidation, and ferroptosis is driven by an imbalance in LCFA levels. Addressing current challenges, such as the complex effects of polyunsaturated fatty acid supplementation, requires advanced techniques like single-cell multi-omics and artificial intelligence. Understanding this intricate lipidomic-transcriptomic crosstalk is crucial for moving toward personalized neuroimmunometabolism and developing new treatments to prevent ferroptosis.
    Keywords:  astrogliosis; immunometabolism; lipid peroxidation; long-chain fatty acids; microglia; neurodegeneration; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3390/nu18091392
  16. BMC Med. 2026 May 14.
    Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
    Yoshitaka Tamaki, Shunya Kaneko, Makoto Urushitani.
       BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), recent evidence suggests that the earliest pathogenic event is the disruption of its physiological homodimeric structure. Under healthy conditions, TDP-43 forms dimers via its N-terminal domain, a configuration that is crucial for its nuclear solubility and cooperative RNA binding. In this review, we propose the "Molecular Zipper" hypothesis to describe the maintenance of TDP-43 structural homeostasis. In this framework, the N-terminal domain acts as a stabilizing "NTD-mediated anchor" that keeps the protein in a functional, "zipped" dimeric state, effectively sequestering its aggregation-prone C-terminal regions. Pathogenic triggers-including genetic mutations, aberrant post-translational modifications such as phosphorylation and acetylation, and environmental stressors-can "unzip" this structure, leading to the formation of pathogenic monomers. These pathogenic monomers show increased propensity for cytoplasmic mislocalization and recruit wild-type protein into aggregates through a prion-like seeded aggregation mechanism, culminating in nuclear functional loss and cytoplasmic gain-of-toxicity. We further evaluate the emerging diagnostic landscape, focusing on methods to monitor the dimer-to-monomer ratio.
    SHORT CONCLUSION: Integrating prior biochemical data on TDP-43 dimerization with structural modeling enables a more coherent account of the transition from the physiological dimer to pathological conformers. The Molecular Zipper framework offers a conceptual foundation for reconciling existing experimental findings and for guiding future studies on early structural changes in TDP-43 proteinopathy.
    Keywords:  Molecular Zipper hypothesis; NTD; RRM; TDP-43; dimerization
    DOI:  https://doi.org/10.1186/s12916-026-04935-4
  17. Ann Neurol. 2026 May 11.
    Alzheimer's Disease Co-Pathology and Cognitive Impairment in Amyotrophic Lateral Sclerosis.
    Elisabeth Kasper, Annaliis Lehto, Alexandra Jürs, Nina Nordmann, Oliver Peters, Julian Hellmann, Josef Priller, Eike Jakob Spruth, Gabor C Petzold, Ina Voigt, Patrick Weydt, Sarah Bernsen, Elisabeth Dinter, Björn Falkenburger, René Günther, Emrah Düzel, Wenzel Glanz, Matthis Synofzik, Lukas Beichert, Annika Spottke, Michael Wagner, Frederic Brosseron, Matthias C Schmid, Annett Halle, Jochen Herms, Anja Schneider, Stefan Teipel, Johannes Prudlo, Manuela Neumann, Andreas Hermann.
       OBJECTIVES: Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) share neuropathological features, including tau, amyloid, and TDP-43 pathology. This study investigated whether AD-related pathological changes are associated with cognitive impairment ALS.
    METHODS: Cerebrospinal fluid (CSF total-tau, phosphorylated-tau, beta-amyloid) and plasma biomarkers (TDP-43; neurofilament light chain [NfL]) were analyzed in 192 individuals with ALS or ALS with frontotemporal dementia (ALS-FTD) and 100 healthy controls. Cognitive performance was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Group comparisons and regression analyses examined associations between biomarker profiles and cognitive status. Autopsy data were available for a subset of participants.
    RESULTS: Compared with healthy controls, patients with ALS - particularly those with cognitive impairment (ALSci) or ALS-FTD - showed elevated AD-related biomarkers. Significant differences in beta-amyloid levels were observed between healthy controls (HCs) and patients with ALSci, but not between controls and cognitively unimpaired patients. CSF p-tau and total-tau levels were strongly associated with domain-specific cognitive performance. In contrast, plasma extracellular vesicle TDP-43 and NfL showed weak or no association with cognition. In vivo biomarkers alone reliably distinguished cognitive impairment only in ALSci and ALS-FTD. Postmortem analyses showed no strong association between ABC scores or overall TDP-43 burden and cognitive state; however, temporal and hippocampal TDP-43 burden was associated with cognitive dysfunction.
    INTERPRETATION: Our findings suggest that tau-related CSF biomarkers, particularly p-tau and total-tau, are associated with cognitive deficits in ALS, indicating that AD-related pathology might be associated to cognitive decline in ALS. However, postmortem data showed even stronger relation of TDP43 pathology to cognitive deficits in ALS. ANN NEUROL 2026 ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78227
  18. Acta Neuropathol. 2026 May 15. pii: 57. [Epub ahead of print]151(1):
    APOE ε4 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis.
    Yuya Hatano, Asa Nakahara, Mari Tada, Akiyoshi Kakita, Osamu Onodera, Tomohiko Ishihara.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, most sporadic cases exhibiting TAR DNA-binding protein 43 (TDP-43) pathology. The anatomical distribution of TDP-43 pathology varies among patients; however, factors contributing to this heterogeneity remain unclear. Apolipoprotein E (APOE) ε4 is known to influence the spread of pathological protein in several neurodegenerative diseases, raising the possibility that it also modulates the pathological distribution of TDP-43 inclusions in ALS. We investigated this hypothesis in a cohort of 145 autopsy-confirmed sporadic ALS cases. ALS-associated TDP-43 pathology was classified into two subtypes: type 1 - largely restricted to motor regions - and type 2 - characterized by widespread cortical involvement. APOE genotypes and rare variants in known ALS-associated genes were determined by exome sequencing. Amyloid-β and tau pathologies were assessed neuropathologically using established staging systems. Structural equation modeling (SEM) was applied to disentangle direct and indirect relationships among APOE ε4, temporal clinical parameters, Alzheimer's disease-related pathologies, and ALS TDP-43 subtype. Furthermore, we also performed an unbiased evaluation using random forest model. APOE ε4 carriers showed a significantly higher proportion of type 2 pathology than non-carriers. Bayesian SEM demonstrated that APOE ε4 was directly associated with the type 2, widespread TDP-43 subtype, independent of amyloid-β and tau pathology, while also reproducing the canonical cascade linking APOE ε4 to amyloid-β and tau. Rare variants in ALS-associated genes showed no clear effect on TDP-43 subtype. These findings indicate that APOE ε4 modifies the anatomical distribution of TDP-43 pathology in sporadic ALS through mechanisms independent of classical Alzheimer's disease pathology. Incorporation of APOE genotype into ALS stratification may be informative for biologically grounded subtype-specific therapeutic approaches.
    Keywords:  APOE; Amyloid-β; Amyotrophic lateral sclerosis; Structural equation modeling; TDP-43 pathology; Tau
    DOI:  https://doi.org/10.1007/s00401-026-03029-y
  19. NPJ Digit Med. 2026 May 12.
    Decomposing heterogeneity in disease progression speeds and pathways.
    Yuichiro Yada, Honda Naoki.
      Understanding why patients with the same diagnosis exhibit markedly different disease progression-some rapidly, others slowly, with distinct symptom patterns-remains a major challenge in medicine. Here, we developed a machine learning framework called DiSPAH (Disease-progression Speed and Pathway Analysis based on a Hidden Markov model) to estimate both the pathway and speed of disease progression in individual patients. DiSPAH models disease progression as continuous-time transitions among latent disease states with a patient-specific progression speed. We applied DiSPAH to longitudinal clinical scores from an amyotrophic lateral sclerosis (ALS) cohort and inferred each patient's trajectory of the latent disease states and progression speed. These dynamics were associated with baseline clinical features and enabled prediction of future course from first-visit data. Our results highlight that jointly modeling progression pathway and speed improves prediction of heterogeneous disease courses, offering a powerful tool for personalized care and research in ALS and other chronic conditions.
    DOI:  https://doi.org/10.1038/s41746-026-02665-8
  20. Neurogenetics. 2026 May 12. pii: 39. [Epub ahead of print]27(1):
    Mechanism of the N87D mutation in SOD1-atypical amyotrophic lateral sclerosis case report and literature review molecular mechanism of N87D mutation in SOD1.
    Chenghui Pi, Yang Liu, Zhihua Jia, Mingjie Zhang, Xiaolin Wang, He Zhao, Zhao Dong, Shengyuan Yu, Ruozhuo Liu.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unclear pathogenesis. This study aimed to investigate the possible molecular mechanisms of ALS by analyzing protein structure and dynamics in a rapidly progressing ALS patient carrying the N87D mutation. A patient with the N87D mutation experienced rapid disease progression and died within one year. We reviewed all known mutations at the 87th position of the superoxide dismutase (SOD1) gene and the clinical characteristics. To investigate the molecular basis of the severe phenotype, we performed protein structure modeling and molecular dynamics (MD) simulations, and compared wild type homodimers, mutant homodimers, and heterodimers in terms of energy, residue fluctuation, number of hydrogen bonds, radius of gyration (Rg), principal component analysis (PCA), free energy landscape (FEL), the contribution of dimer interface residues, solvent-accessible surface area, and metal ion coordination. Our analysis revealed that patients with mutations at the 87th position of the SOD1 gene typically exhibited rapid disease progression. Protein structure modeling and MD simulations demonstrated that the N87D mutation significantly increased the energy and RMSF of SOD1 heterodimers compared to homodimers. Furthermore, Rg, FEL and PCA analyses showed that the heterodimers had a broader and more unstable conformational energy distribution, along with a stronger tendency for aggregation. Additionally, the N87D mutation disrupted metal ion coordination, further destabilizing the heterodimer and promoting protein misfolding. These findings suggest a potential molecular mechanism underlying ALS and support a protein structure based approach for investigating the pathogenic mechanisms of disease causing mutations.
    Keywords:  Amyotrophic lateral sclerosis; Molecular dynamics simulations; N87D; Protein structure modeling; SOD1
    DOI:  https://doi.org/10.1007/s10048-026-00909-z
  21. Front Digit Health. 2026 ;8 1794169
    An interpretable, clinically grounded framework for digital speech biomarker development in neurodegenerative diseases.
    Panying Rong, Lindsey Heidrick.
       Introduction: Communication ability-a key determinant of quality of life-is frequently affected and progressively declines in neurodegenerative diseases. Effective management of progressive communication disorders requires a personalized approach to deliver timely interventions tailored to the evolving profiles of communicative impairment, thereby supporting functional communication throughout the disease course. To this end, reliable tools capable of detecting and quantifying both disease-specific patterns of communicative impairment and within-disease phenotypic variability are urgently needed. This study leverages Artificial Intelligence and advanced data analytics to develop an acoustic-based framework for automated extraction of interpretable, clinically grounded speech markers to enable objective assessment and phenotyping of progressive communication disorders.
    Methods: Three groups of participants, including 14 individuals with amyotrophic lateral sclerosis (ALS) and 15 individuals with Parkinson's disease (PD), alongside 10 neurologically healthy controls, performed a standardized oral passage reading task, yielding 739 speech samples. Fifty acoustic features were extracted using an automated analytic pipeline and subsequently clustered into six interpretable composite markers. The clinical utility of these markers was evaluated with the recorded speech samples by examining their (1) associations with standardized metrics of cognitive, motor speech, and overall communicative functions, (2) efficacy for detecting and differentiating disease-specific communicative impairment patterns in ALS and PD using supervised machine learning, and (3) utility for within-disease phenotyping and stratification using unsupervised clustering analysis.
    Results: The markers effectively (1) detected subtle subclinical changes across multiple domains prior to substantial declines in functional communication outcomes; (2) differentiated disease-specific patterns of communicative impairment (multiclass area under the curve > 0.90); and (3) identified subgroups with distinct speech profiles within each disease.
    Discussion: The findings support the potential of the proposed framework as a clinically translatable, objective tool to facilitate early detection, differential diagnosis, and phenotyping of progressive communication disorders, ultimately advancing personalized, measurement-based care in neurodegenerative diseases.
    Keywords:  digital speech marker; early detection; machine learning; neurodegenerative disease; personalized medicine; phenotyping; progressive communication disorder
    DOI:  https://doi.org/10.3389/fdgth.2026.1794169
  22. Curr Drug Targets. 2026 May 06.
    Innovative Nanoparticle-based Therapeutic Strategies: Overcoming Biological Barriers for Enhanced Efficacy.
    Sunny Rathee, Sakshi Soni, Debasis Sen, Sanjay K Jain.
      The Blood-Brain Barrier (BBB) poses a formidable challenge for drug delivery to the Central Nervous System (CNS) due to its selective permeability and robust defense mechanisms. This review provides a comprehensive examination of the anatomical structure, physiology, and physiological challenges of the BBB, along with innovative approaches for overcoming these barriers to enhance CNS drug delivery. The BBB is primarily composed of endothelial cells, pericytes, and astrocytic end-feet, reinforced by tight junctions that tightly regulate the passage of substances into the brain parenchyma. Various transport mechanisms, including carrier-mediated transport, receptor-mediated transport (e.g., via LDL and transferrin receptors), absorptive-mediated transport, and active efflux transport, govern the selective influx and efflux of molecules across the BBB to maintain CNS homeostasis. Biological approaches harness endogenous transport mechanisms to facilitate drug delivery across the BBB, while chemical approaches leverage nanotechnology to engineer nanoparticles capable of traversing the barrier. These include liposomes, solid-lipid nanoparticles, polymeric nanoparticles, and inorganic nanoparticles, each designed with specific parameters such as particle size, shape, and surface charge to optimize drug delivery. Drug loading strategies, such as covalent bonding and non-covalent adsorption, enhance the encapsulation and release of therapeutic agents from nanoparticles. Furthermore, the incorporation of ligands facilitates receptor targeting and protein corona formation, enhancing nanoparticle properties and improving BBB penetration. By synthesizing recent advancements in BBB permeation strategies, this review aims to provide insights into the development of effective therapies for neurological disorders, ultimately advancing the field of CNS drug delivery.
    Keywords:  Blood-brain barrier; endothelial cells; nanoparticles; neurotherapeutics; targeted drug delivery; tight junctions
    DOI:  https://doi.org/10.2174/0113894501387369251125091551
  23. Eur J Pharmacol. 2026 May 13. pii: S0014-2999(26)00450-4. [Epub ahead of print]1026 178968
    Carboplatin alleviates astrocytic TDP-43 neurotoxicity by inhibiting NF-κB activation.
    Jihye Song, Shinrye Lee, Jiyoung Lee, Yaeeun Gil, Taehyun Kim, Seung-Yoon Kim, Sun Joo Cha, Hyung-Jun Kim, Kiyoung Kim.
      Amyotrophic lateral sclerosis (ALS) is a rare and progressive motor neuron disease; however, its exact pathogenic mechanisms remain unclear. Currently, no effective treatments are available for this disease. Therefore, in this study, we investigated the anti-inflammatory effects of the anti-cancer agent, carboplatin, on neuronal cells and its potential therapeutic effects against ALS. Carboplatin inhibited NF-κB phosphorylation in the transactive response DNA-binding protein (TDP)-43-transfected astrocytes, reducing pro-inflammatory cytokine levels, without affecting the TDP-43 protein levels. In neuron-astrocyte co-culture models, carboplatin effectively alleviated TDP-43-induced toxicity by restoring mitochondrial integrity, specifically rescuing basal respiration, ATP production, and maximal respiratory capacity. In vivo, carboplatin rescued the locomotor deficits in glial-specific TDP-43-expressing Drosophila, without altering TDP-43 protein levels and subcellular localization. These findings suggest that TDP-43-induced astrocytic damage compromises mitochondrial functions in adjacent neurons, and that carboplatin-mediated restoration of TDP-43-mediated astrocyte damage is critical for neuronal survival and functions. Therefore, carboplatin, a chemotherapeutic agent, represents as a potential therapeutic candidate for TDP-43-associated proteinopathies.
    Keywords:  Amyotrophic lateral sclerosis; Astrocyte; Carboplatin; Inflammation; TDP-43
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178968
  24. J Cannabis Res. 2026 May 13.
    Cannabidiol and other non-psychotropic cannabinoids from Cannabis sativa as therapeutics for microglial-mediated neuroinflammation and neurodegeneration.
    Daniel K Fowler, Tylor M Savage, Duncan I Mackie.
      Non-psychotropic phytocannabinoids produced by Cannabis sativa, including cannabidiol, cannabigerol, cannabichromene and their varin and acidic analogs, are emerging as promising modulators of neuroinflammation, particularly through actions on microglia, the brain's resident immune cells. These compounds engage numerous receptors, ion channels, and intracellular signaling systems in microglia associated with neuroinflammation, and therefore are promising therapeutic candidates to treat chronic microglial inflammation-mediated neurodegenerative disorders. Despite substantial public and scientific interest, comprehensive evaluation of their mechanistic diversity, disease-relevant potential, and translational gaps across neurodegenerative disorders remains limited. Commonly, gaps also exist between cannabis breeders' and cultivators' knowledge of phytocannabinoid diversity and translational scientists' understanding of therapeutic potential. In this review, we first provide an in-depth overview of the main non-psychotropic phytocannabinoids, their biosynthesis, and the genetics that control their production in cannabis. We then summarize the known mechanisms of action for each cannabinoid in microglial-expressed molecular targets and signaling pathways relevant to neuroinflammation. Lastly, we review the effects of non-psychotropic phytocannabinoids in pre-clinical models and clinical trials of four neuroinflammation-associated neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Current evidence supports meaningful biological activity and complex cannabinoid-specific polypharmacology, yet substantial gaps persist, especially for cannabinoids other than cannabidiol; addressing these gaps in disease-relevant models will be essential for translating these compounds into future therapeutic strategies. Further, we anticipate the summarized information will foster collaboration between cannabis breeders/cultivators and applications scientists for therapeutic evaluation and development of emerging non-psychotropic phytocannabinoids.
    Keywords:  Alzheimer’s disease; Cannabichromene; Cannabidiol; Cannabigerol; Cannabinoid; Huntington’s disease; Inflammation; Microglia; Multiple sclerosis; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s42238-026-00445-5
  25. Neurochem Int. 2026 May 13. pii: S0197-0186(26)00071-9. [Epub ahead of print] 106180
    TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD.
    Florencia Vassallu, Milagros López, Florencia López Ambrosioni, Juan Casal, Laura Caltana, Lionel Muller Igaz.
      TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases have common underlying mechanisms. We have previously shown that transgenic (Tg) mice conditionally overexpressing a cytoplasmic form of human TDP-43 protein (TDP-43-ΔNLS) in forebrain neurons replicate key features of FTD/ALS, including altered cognitive, motor and social behaviors. These behavioral phenotypes and changes in plasticity-related gene expression can be detected as early as 1 month after Tg induction, before overt neurodegeneration occurs. To assess early ultrastructural features in this model, we performed Transmission Electron Microscopy (TEM) analysis in the cortex (Ctx) and hippocampus (Hp) of Tg animals and their non-Tg controls. TEM evaluation of Ctx and Hp revealed that synaptic density was significantly decreased and synapse length was increased in both regions of Tg animals. Synaptic cleft thickness was increased and post-synaptic density thickness was decreased only in the Ctx of Tg mice, revealing differential regional effects in synaptic morphology. We analyzed mitochondrial density and we found an increase in the Ctx and a decrease in the Hp of Tg animals, with preserved individual mitochondrial area. Lastly, transcriptomic and proteomic analysis from both transgenic TDP-43-ΔNLS mice and human proteinopathy showed widespread decreased expression of synaptic structure and function genes. The alterations in synaptic density and architecture reported here, combined with the mRNA/protein expression data, suggest that TDP-43-ΔNLS mice may exhibit abnormal synaptic transmission and that ultrastructural changes play a role in the early behavioral deficits observed in this model.
    Keywords:  Amyotrophic lateral sclerosis; Frontotemporal dementia; Mitochondria; Synapses; TDP-43 proteinopathy; Ultrastructural analysis
    DOI:  https://doi.org/10.1016/j.neuint.2026.106180
  26. Cell Death Dis. 2026 May 14.
    A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.
    Stefan M Pulst, Sharan Paul, Hieu Nguyen, Warunee Dansithong, Karla P Figueroa, Mandi Gandelman, Nancy M Bonini, Daniel R Scoles.
      RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.
    DOI:  https://doi.org/10.1038/s41419-026-08830-x
  27. J Chin Med Assoc. 2026 May 12.
    Clinical and electrophysiological features for differentiating MMN from hand-onset ALS.
    Shih-Yu Fang, Kang-Yang Jih, Yu-Chi Chao, Hou-Ping Sytwu, Yen-Cheng Shih, Yi-Chu Liao, Yi-Chung Lee.
       BACKGROUND: Multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS) can be difficult to differentiate, particularly at early disease stages in patients with hand-onset weakness and without upper motor neuron (UMN) signs. This study aimed to identify clinical and electrophysiological features that may facilitate early distinction between MMN and ALS.
    METHODS: We retrospectively analyzed the clinical, laboratory, and electrophysiological characteristics of patients diagnosed with MMN and ALS and receiving identical nerve conduction study protocol comprising extended motor stimulation.
    RESULTS: One hundred and twenty-five patients (74 men and 51 women) were included, consisting of eight patients with MMN and 117 patients with ALS, including 42 with hand-onset ALS. Patients with MMN had a significantly younger mean age at symptom onset than those with ALS (43.1 vs. 58.7 years, p = 0.004). ALS patients had more severe muscle weakness, more frequent muscle atrophy and fasciculation, UMN signs, and body weight loss. Compared with both the overall ALS and the hand-onset ALS groups, MMN patients showed significantly lower serum creatine kinase (CK) level and higher serum IgM levels. Elevated CK levels were observed in approximately one-third of patients with hand-onset ALS, whereas none of the MMN patients had elevated CK. Conduction block (CB) on nerve conduction studies was more common in MMN (87.5%) than in all ALS cases (19.7%, p < 0.001) or hand-onset ALS (31.0%, p = 0.005). MMN patients more frequently exhibited definite CBs involving multiple nerves (85.7%) compared with all ALS (17.4%, p = 0.002) and hand-onset ALS (7.7%, p = 0.001) patients.
    CONCLUSION: Our findings suggest that a combination of clinical features, serum CK and IgM levels, and electrophysiological evidence of CB provides valuable clues for distinguishing MMN from ALS.
    Keywords:  Amyotrophic lateral sclerosis; Conduction block; Lower motor neuron syndrome; Multifocal motor neuropathy; Nerve conduction studies
    DOI:  https://doi.org/10.1097/JCMA.0000000000001387
  28. Expert Opin Ther Targets. 2026 May 09.
    Targeting the NLRP3 inflammasome with antibody-based Therapeutics for chronic neurodegenerative diseases.
    Jagdeep K Sandhu, Jamshid Tanha, Mehdi Arbabi-Ghahroudi.
       INTRODUCTION: The NLRP3 inflammasome is a central regulator of innate immunity that becomes aberrantly activated by amyloid-β, hyperphosphorylated tau, and α-synuclein aggregates in chronic neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). Sustained activation drives neuroinflammation, synaptic dysfunction, and neuronal loss, making NLRP3 a compelling therapeutic target in chronic neurodegeneration.
    TOPICS COVERED: This review summarizes current insights into NLRP3 inflammasome biology in AD and PD, with emphasis on antibody-based interventions. Emerging delivery approaches, such as receptor-mediated transcytosis, nanoparticles, adeno-associated viral vectors, and magnetic resonance-guided focused ultrasound are also examined for their potential to enhance central nervous system (CNS) delivery of NLRP3-targeting antibodies.
    EXPERT OPINION: Antibody-based inhibitors of the NLRP3 inflammasome offer high specificity and favorable safety profile compared with small-molecular-weight inhibitors; however, limited blood-brain barrier (BBB) penetration remains a major challenge. Advances in antibody engineering, modular bi-/multi-specific designs, and targeted CNS delivery platforms may soon enable the development of first-in-class antibodies capable of directly modulating neuroinflammation. To realize this potential, the field should prioritize: (1) developing BBB-penetrant antibody constructs; (2) integrating delivery technologies with target biology; and (3) accelerating translation toward first-in-human studies. Successful implementation could transform therapeutic strategies for AD and PD and extend antibody-based interventions across a broader spectrum of neuroinflammatory disorders.
    Keywords:  ASC speck; Adeno-associated viral delivery; Alzheimer’s disease; Parkinson’s disease; blood-brain barrier; innate immune system; magnetic resonance-guided focused ultrasound; nanobody; nanoparticle; neuroinflammation; receptor-mediated transcytosis
    DOI:  https://doi.org/10.1080/14728222.2026.2671675
  29. Ann Clin Transl Neurol. 2026 May 14.
    Peripheral Neutrophil Activation and Extracellular Trap Formation in Amyotrophic Lateral Sclerosis.
    Lillia A Baird, Haley McQuown, Jihyun Park, Samuel J Teener, Ian F Webber-Davis, Andrew D Carter, Dae-Gyu Jang, Eva L Feldman, Stephen A Goutman, Benjamin J Murdock.
       OBJECTIVES: Peripheral neutrophil levels in amyotrophic lateral sclerosis (ALS) inversely correlate with survival, suggesting a role for neutrophils in disease progression. Here, we characterize markers of several neutrophil activation pathways and evaluate their associations with survival to identify potential mechanisms of disease.
    METHODS: Blood samples were obtained from participants at the University of Michigan ALS Clinic or from healthy controls. Ex vivo neutrophil extracellular trap (NET) formation was quantified via image analysis of primary neutrophils. Neutrophil function markers of general activation (calprotectin), migration (matrix-metalloproteinase 9 [MMP9]), and degranulation (neutrophil gelatinase-associated lipocalin [NGAL]) were then quantified in plasma via ELISA; NET formation (double-stranded DNA [dsDNA]) was assessed via fluorescence assay. These markers were then associated with ALS survival using Cox proportional hazard regression models, and analyses were stratified by sex.
    RESULTS: Spontaneous ex vivo NET formation (N = 20 controls, 66 ALS) was increased in ALS (1.0% vs. 9.7%; p = 0.017). In plasma (N = 233 controls, 178 ALS), calprotectin (294 vs. 372 ng/mL; p < 0.001), MMP9 (106 vs. 152 ng/mL; p < 0.001), and NGAL (61 vs. 66 ng/mL; p = 0.01) were elevated in ALS. Calprotectin, MMP9, and NGAL levels were not associated with ALS survival; however, dsDNA was associated with poorer ALS survival but only in females (HR = 1.77 [95% CI, 1.20-2.61]; p = 0.004).
    INTERPRETATION: Neutrophil function is altered in ALS, and NET formation is a potential mechanism by which neutrophils contribute to ALS, particularly in females.
    Keywords:  ALS; immune system; motor neuron disease; neutrophils
    DOI:  https://doi.org/10.1002/acn3.70431
  30. Front Neurol. 2026 ;17 1754716
    Efficacy and safety of pharmacological and biological therapies for amyotrophic lateral sclerosis: a network meta-analysis.
    Shixun Zhou, Xinpeng Li, Yurui Jiao, Juan Wu.
       Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder for which disease-modifying treatment options remain limited. This study aimed to systematically assess the efficacy and safety of pharmacological and biological therapies for ALS via a network meta-analysis (NMA).
    Methods: PubMed, EMBASE, Cochrane, and Web of Science were searched until February 25, 2025. Randomized controlled trials (RCTs) evaluating any pharmacological or biological intervention in ALS were eligible. Risk of bias was assessed using the Cochrane RoB 2 tool. A Bayesian NMA was performed in R (gemtc package). Effect estimates were expressed as mean differences (MDs) or risk ratios (RRs) with 95% credible intervals (CrIs). Interventions were ranked using the surface under the cumulative ranking curve (SUCRA). Publication bias was explored with funnel plots (Stata 18.0). Subgroup analyses were conducted for drug classes demonstrating significant efficacy and including at least three RCTs.
    Results: 109 trials involving 16,353 participants were included. The primary outcome was the ALS Functional Rating Scale-Revised (ALSFRS-R); secondary outcomes included forced vital capacity (FVC), mortality, and serious adverse events (SAEs). Compared with placebo, the combination of cell therapy and neuroprotective agents produced the greatest attenuation of ALSFRS-R decline (MD: 3.65, 95% CrI: 1.27-6.05) and was associated with the lowest SAE risk. Receptor agonists ranked highest for preservation of FVC, whereas alkaloids ranked first for mortality reduction; however, no intervention demonstrated a statistically significant survival benefit versus placebo. Within-class subgroup analyses further identified several specific agents, such as masitinib, talampanel, and EH301, as demonstrating relatively consistent efficacy, although substantial heterogeneity remained among enzyme inhibitors.
    Conclusion: Cell therapy combined with neuroprotective agents may slow functional decline in ALS. Receptor agonists may help preserve respiratory function. Survival benefits remain inconclusive, underscoring the continued importance of comprehensive supportive care.
    Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251000672, identifier CRD420251000672.
    Keywords:  Lou Gehrig’s disease; amyotrophic lateral sclerosis; biological therapies; motor neuron disease; pharmacological intervention; randomized controlled trial
    DOI:  https://doi.org/10.3389/fneur.2026.1754716
  31. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 09. 1-9
    Molecular and genetic landscape of amyotrophic lateral sclerosis in Latin America: a scoping review of pathogenic hypotheses and ancestral heterogeneity.
    Sergio V Flores, Patricia Lillo, Jorge Briceño-Moya, Ailin Pino-San Pedro.
      Background: The genetic architecture of amyotrophic lateral sclerosis (ALS) has been predominantly characterized in populations of European ancestry, while Latin American populations remain underrepresented despite their complex admixture. Objective: To map the molecular hypotheses explored in ALS research conducted in Latin American populations and identify key methodological and structural gaps. Methods: A scoping review was conducted following Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. Searches were performed in Web of Science, Scopus, PubMed/MEDLINE, SciELO, and LILACS. Studies investigating genetic or molecular aspects of ALS or the ALS-FTD spectrum in Latin American populations were included. Data were extracted using a standardized matrix and synthesized descriptively. Results: Nineteen studies met inclusion criteria. Most were small, single-center investigations employing targeted candidate-gene approaches, predominantly focused on C9orf72 expansions and SOD1 mutations. Reported C9orf72 frequencies varied substantially across countries, indicating population-specific genetic heterogeneity. Only one study incorporated explicit ancestry inference, and no genome-wide association studies or large multicenter ALS genomic cohorts were identified. Conclusions: ALS research in Latin America remains limited, fragmented, and largely candidate-gene driven, with minimal integration of ancestry-informed approaches. The absence of large-scale genomic studies, despite existing regional sequencing capacity, highlights the need for coordinated multicenter initiatives to enable equitable implementation of precision medicine.
    Keywords:  Amyotrophic lateral sclerosis; C9orf72; Latin America; frontotemporal dementia; genetic ancestry
    DOI:  https://doi.org/10.1080/21678421.2026.2668070
  32. Cent Nerv Syst Agents Med Chem. 2026 May 06.
    Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.
    Anjali Sharma, Vishnu Mittal, Devkant Sharma, Geeta Deswal, Amiya Das, Kumar Guarve, Ajmer Singh Grewal.
       INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.
    METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.
    RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.
    DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.
    CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.
    Keywords:  Natural products; bioactive compounds; neurodegenerative diseases; neuroprotection; oxidative stress; signaling pathways; therapeutic potential.
    DOI:  https://doi.org/10.2174/0118715249405308251210104405
  33. Nat Neurosci. 2026 May 14.
    Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.
    Ziyang Zhang, Lynn van Olst, Francesco Alessandrini, Matthew Wright, Alex J Edwards, Jake Boles, Anait Nalbandian, Anne V Forsyth, Nate Shepard, Thomas Watson, Evan Kaspi, Angeli Mittal, Joshua Kuruvilla, Natalie Piehl, Abhirami Ramakrishnan, Stanley Appel, Evangelos Kiskinis, David Gate.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron (MN) degeneration in the brain and spinal cord. Although neuroinflammation is increasingly recognized as a hallmark of ALS, the precise molecular programs linking immune responses to MN pathology remain poorly defined. Using an integrated approach that combines single-cell and bulk RNA sequencing with spatial proteogenomics, we characterized both shared and distinct immune dynamics in peripheral blood and spinal cord tissues from patients with sporadic ALS and those carrying C9orf72 repeat expansions. Our analysis revealed broad immune remodeling in C9orf72 ALS, ALS subtype-specific and progression-associated differences in monocyte activation and antigen-experienced CD8 effector memory T cells with clonal features consistent with antigen-driven responses. Spatial mapping revealed complement activation and lipid-programmed myeloid states converging at sites of MN loss and TDP-43 pathology. Together, these findings connect peripheral and central immune alterations to ALS heterogeneity and highlight stratified immunomodulation as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41593-026-02300-5
  34. J Inflamm Res. 2026 ;19 585872
    Integrative Transcriptomics Identifies Ubiquitination-Related Genes BIRC2, COPS5, and TBK1 as Novel Biomarkers of T-Cell Dysregulation in Amyotrophic Lateral Sclerosis.
    Ailing Jiang, Yanzhen Huang, Xianting Que, Chonglin Li, Ziqun Lin, Wen Huang.
       Purpose: Amyotrophic lateral sclerosis (ALS) is marked by immune dysregulation; however, the role of T cell-ubiquitination-related genes (TURGs) in its pathogenesis remains unclear. This study aimed to investigate the contribution of TURGs to T-cell dysfunction and ubiquitination imbalance in ALS.
    Patients and Methods: Differentially expressed genes were identified through analysis of bulk transcriptomes (GSE112680). CIBERSORT deconvolution and weighted gene co-expression network analysis were employed to define T-cell-associated modules. Integration with ubiquitination-related gene sets yielded T cell-ubiquitination-related differentially expressed genes (TURDEGs). Functional enrichment analysis and protein-protein interaction network construction, combined with multi-algorithm selection, facilitated the development of a risk-prediction model. Mechanistic insights were derived from Gene Set Enrichment Analysis, immune profiling, co-expression and regulatory network analyses, and drug-target prediction. Single-cell transcriptomic analysis provided insights into cellular-level pathogenic mechanisms in ALS. qPCR was used to validate core TURDEGs expression in peripheral blood samples from patients with ALS.
    Results: Thirty-nine TURDEGs were identified and exhibited significant enrichment in pathways related to ubiquitination, immune activation, autophagy, and NOD-like receptor signaling. BIRC2, COPS5, and TBK1 were identified as core genes. The resulting risk-prediction model demonstrated significant potential for clinical application. Immune infiltration analysis revealed positive correlations between core genes and CD4⁺ resting memory T cells, as well as negative correlations between COPS5, TBK1, and regulatory T cells. Adavosertib and MRS2211 were identified as potent modulators of TBK1 and BIRC2, respectively. Single-cell transcriptomics highlighted enhanced T cell-neutrophil interactions, suggesting a remodeling of the immune communication network in ALS. qPCR validation confirmed significantly increased expression of these genes in patients with ALS (p<0.05).
    Conclusion: TURDEGs-mediated T cell dysfunction and ubiquitination imbalance play critical roles in ALS pathogenesis, unveiling novel biomarkers and potential personalized therapeutic targets.
    Keywords:  amyotrophic lateral sclerosis; biomarkers; immune dysregulation; risk-prediction model; t cell ubiquitination-related genes
    DOI:  https://doi.org/10.2147/JIR.S585872
  35. Cent Nerv Syst Agents Med Chem. 2026 May 08.
    Translational Perspectives on Anti-Inflammatory Interventions for Neurodegenerative Disorders: Evidence from Gut-Brain Axis.
    Vasundhara Saxena, Vishwadeep Singh, Sanskriti.
      The Gut-Brain Axis (GBA) has a complex role in chronic neuroinflammation, which is increasingly connected to neurodegenerative diseases (NDDs) such as Multiple Sclerosis (MS), Parkinson's Disease (PD), and Alzheimer's Disease (AD). Through neuronal, endocrine, and immunological pathways, the GBA enables twoway communication between the gastrointestinal tract and the central nervous system. According to recent research, the pathophysiology of neuroinflammatory responses in NDDs may be significantly influenced by gut dysbiosis, increased intestinal permeability, and modified microbial metabolites, such as Short-Chain Fatty Acids (SCFAs) and polyphenols. This study summarizes preclinical and clinical data supporting several anti- inflammatory approaches targeting GBA. Probiotics and fecal microbiota transplantation are two examples of microbiota-based treatments that have demonstrated promise in reducing neuroinflammatory responses and enhancing cognitive performance. Mediterranean and polyphenol-rich diets are among the dietary therapies that show promise in modifying the composition of microorganisms, lowering pro-inflammatory signaling, and enhancing neuroprotection. Through microbiota regulation, pharmacological substances such as curcumin, resveratrol, and SCFA mimetics also have anti-neuroinflammatory benefits. However, a number of translational challenges still exist, including limitations in animal models, a lack of standardized therapies, and inter-individual microbiome heterogeneity. In order to provide precise, GBA-targeted therapies, future views place a strong emphasis on integrating multi-omics, artificial intelligence, and personalized medicine. This study highlights a new therapeutic approach to treating neurodegeneration by examining the translational potential of anti- inflammatory therapies targeting GBA. It also emphasizes the necessity of strong clinical studies to confirm these findings.
    Keywords:  Neurodegenerative disease; anti-inflammatory diets.; gut-brain axis; multiple sclerosis; neuroinflammation
    DOI:  https://doi.org/10.2174/0118715249430752260407050033
  36. Palliat Support Care. 2026 May 14. 24 e147
    Beyond the surface: Exploring differing aspects of wishes to hasten death in patients with amyotrophic lateral sclerosis.
    Tamara Thurn, Adriano Chiò, Miriam Galvin, Theocharis Stavroulakis, Johanna Anneser.
       OBJECTIVES: This study investigates differing aspects of wishes to hasten death (WTHD) distinguished by the extent to which WTHD were linked to patients' agency: desire for hastened death (DHD), defined as general wishes for death to come sooner, and hastening death intentions (HDI), defined as thoughts about ending one's life. In particular, this study aims to examine the differences between DHD and HDI in patients with amyotrophic lateral sclerosis (pALS) and identify predictive factors for both.
    METHODS: A cross-sectional nested study was conducted within a multi-center longitudinal study involving pALS from 5 European countries. Data collected included DHD (Schedule of Attitudes toward Hastened Death), HDI ("could you currently imagine ending your life?"), sociodemographic and clinical characteristics, psychological distress, quality of life, and social and spiritual-existential aspects.
    RESULTS: In our sample of 121 pALS, 12.4% (15/121) expressed DHD, and 28.1% (34/121) expressed HDI. Of the 38 patients reporting any WTHD, only 11 experienced both DHD and HDI simultaneously. 23 patients reported HDI without DHD, while 4 patients expressed DHD without HDI. Multivariable logistic regression identified loneliness (OR = 1.33, 95% CI 1.03-1.71, p = 0.028) and reduced meaning in life (OR = 0.89, 95% CI 0.84-0.95, p < 0.001) as independent predictors of DHD. For HDI, independent predictors were female gender (OR = 3.31, 95% CI 1.37-7.98, p = 0.008) and lower spirituality (OR = 0.92, 95% CI 0.88-0.95, p < 0.001).
    SIGNIFICANCE OF RESULTS: One in 3 pALS expressed WTHD. Our separate analysis of DHD and HDI supports the existence of distinct manifestations of WTHD and varying underlying factors. While DHD and HDI were associated with different predictors, our results point to the crucial role of spiritual-existential factors in the experience of WTHD, identifying these aspects as target points for intervention. This study highlights the importance of a nuanced understanding and communication regarding WTHD.
    Keywords:  Amyotrophic lateral sclerosis; end of life; motor neuron disease; wish to die; wish to hasten death
    DOI:  https://doi.org/10.1017/S1478951526102673
  37. Microsyst Nanoeng. 2026 May 12. pii: 175. [Epub ahead of print]12(1):
    A perfused, parallelized blood brain barrier-tumor platform for compound permeation and efficacy investigations.
    Wei Wei, Martin Stano, Bettina Kritzer, Javad Nazarian, Andreas Hierlemann, Mario M Modena.
      Few therapeutic options for treating neurological diseases are currently available due to the extremely selective nature of the blood-brain barrier (BBB), which strongly limits drug delivery from the systemic circulation into the central nervous system. The lack of effective treatment options is particularly dire for brain tumors, which ultimately result in very low survival rates. To address the challenge of evaluating drug permeation and efficacy within a physiologically relevant context, we developed a perfused, open-microfluidic platform that includes a human BBB model in co-culture with tumor spheroids. The platform was fabricated from inert plastics to enable quantitative small molecule testing, and it featured 32 testing units in a well-plate format. A pump-free, gravity-driven flow scheme was adopted to establish physiological shear-stress conditions and to enable simple parallelization on tilting stages for increased throughput. We tested the efficacy and permeation of four FDA-approved small-molecule chemotherapeutics - cisplatin, doxorubicin, homoharringtonine, and docetaxel on two patient-derived diffuse-midline-glioma models at sub-IC50 drug concentrations for the BBB. Our results demonstrate that the in vitro BBB significantly limited drug delivery to the tumor, thereby limiting drug efficacy. Furthermore, drug-induced BBB disruption occurred at sub-toxic doses, which led to increased drug permeation to the glioma models. Finally, cell-model-specific responses revealed distinct cytotoxicity behavior, demonstrating the importance of personalized therapy testing. Our scalable BBB-tumor platform provides a physiologically relevant in vitro model system to assess drug permeation, cytotoxicity, and tumor-BBB interactions and offers the potential to advance the discovery of new effective therapeutics against neurological diseases.
    DOI:  https://doi.org/10.1038/s41378-026-01268-3
  38. J Clin Neurol. 2026 May;22(3): 271-282
    Astrocyte Functional Heterogeneity in Multiple Sclerosis.
    Sehoon Hong, Kristen Gah-Hyeon Kim, Francisco J Quintana, Hong-Gyun Lee.
      Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by demyelination and axonal degeneration. Astrocytes have emerged as pivotal regulators of MS pathology, playing both pathogenic and regulatory roles. This review explores the mechanisms underlying astrocyte heterogeneity in MS, with a focus on how astrocyte functional states are influenced by extrinsic environmental factors such as inflammatory signals and dynamic interactions with immune cells and other glial populations. We discuss how the astrocyte heterogeneity established during development and further modulated by local environmental factors influences lesion formation, blood-brain barrier integrity, and tissue repair. We further outline protective and pathogenic astrocyte states together with the molecular mechanisms that govern neuroinflammatory responses. Finally, we highlight emerging therapeutic strategies for modulating astrocyte pathogenic responses. Collectively this work highlights astrocyte functional heterogeneity as a central feature of MS pathology and an emerging therapeutic opportunity for progressive MS.
    Keywords:  astrocyte; epigenetic memory; multiple sclerosis; neurodegenerative diseases; neuroinflammation; remyelination
    DOI:  https://doi.org/10.3988/jcn.2026.0100
  39. J Nanobiotechnology. 2026 May 12.
    A novel nasal mucosal peptide-modified co-delivery system for ginsenoside Rg1, Rb1, and notoginseng saponin R1 in the amelioration of AD.
    Yinjia Li, Changhui Hu, Chenjie Xia, Xitong Wang, Xuting Zhou, Rui Xu, Yunshu Li, Feng Mo, Binhao Zhao, Liu Xu, Chenqi Zhu, Zhipeng Chen.
      The drug delivery for Alzheimer's disease (AD) faces substantial obstacles owing to the presence of the blood-brain barrier (BBB). This circumstance highlights the nose-brain route as pivotal for enhancing drug distribution to the brain. As the efficiency of brain entry is constrained by the physiological barrier of the nasal cavity, the development of strategies to efficiently traverse this barrier is imperative for enhancing the effectiveness of AD treatment. In the present study, a cell-penetrating peptide (CPPs) named LK4, which originates from mastoparan-L (MPL), was employed. Its capacity to efficiently penetrate the physiological barrier of the nasal cavity was demonstrated. LK4 was modified into polydopamine (PDA) nanoparticles to construct nanoparticles containing ginsenoside Rg1, ginsenoside Rb1, and notoginseng saponin R1 (TGS), designated as LK4-TGS-PDA. Experiment results reveal that the LK4-TGS-PDA drug delivery system can enhance the uptake of olfactory neurons and promote epithelial transport. In an in vitro nasal mucosal barrier model, LK4 modification increased the apparent permeability coefficients of R1, Rg1, and Rb1 by 1.2-, 1.2-, and 12-fold, respectively, compared to unmodified nanoparticles. Following nasal administration, the brain concentrations of R1, Rg1, and Rb1 increased by 19-fold, 30-fold, and 15-fold, respectively, and the relative brain bioavailability reached 933.1%, 1375.0%, and 1144.4%, respectively. In the model of AD induced by amyloid-beta 1-42 (Aβ1-42), it was confirmed that LK4-TGS-PDA NPs can significantly improve cognitive dysfunction, with escape latency reduced by 30.3%, platform crossings increased by 5.4-fold, and target quadrant time extended by 2.4-fold, as well as reduce the effects of inflammation in the brain, with IL-1β, IL-6, and TNF-α decreased by 44.05%, 53.49%, and 84.40%, respectively. The present investigation outcomes reveal that the engineered LK4-TGS-PDA NPs demonstrates effectiveness and efficiency as a drug delivery approach for the nose-brain pathway, offering valuable insights and prospects for enhancing AD treatment.
    Keywords:  Alzheimer’s disease; Cell-penetrating peptides; Ginsenoside; Nose-to-brain drug delivery; Polydopamine
    DOI:  https://doi.org/10.1186/s12951-026-04532-w
  40. Immunopharmacol Immunotoxicol. 2026 May 11. 1-77
    Rituximab Beyond Oncology: Targeting B-Cell-Mediated Immunomodulatory Therapy in Neurodegenerative and Neuropsychiatric Disorders.
    Trina Saha, Tanya Vats, Sidharth Mehan.
      Neurological and neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune encephalitis (AE), represent a growing global health burden due to their multifaceted pathophysiology and limited treatment options. These disorders are characterized by neuroinflammation, oxidative stress, protein aggregation, and blood-brain barrier (BBB) disruption, which contribute to neuronal damage and progressive functional decline. Emerging evidence underscores the pivotal role of B cells in driving disease progression through antibody production, antigen presentation, and cytokine release. Rituximab, a chimeric monoclonal antibody targeting CD20 on B cells, has shown promise as a potential immunomodulatory therapy for these conditions. Rituximab mediates its therapeutic effects via mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. In MS, rituximab reduces pro-inflammatory cytokines, demyelination, and immune cell activity, thereby delaying disease progression. Preclinical studies suggest its neuroprotective potential in AD and PD by mitigating B-cell-mediated neuroinflammation and oxidative stress. Furthermore, rituximab demonstrates efficacy in AE, NMOSD, and MOGAD by depleting pathogenic B cells and reducing relapse rates. Despite its proven efficacy, rituximab poses risks such as hypogammaglobulinemia, infection, and infusion-related reactions, necessitating careful patient selection, continued monitoring, and optimization of dosing regimens. This review highlights rituximab's immunomodulatory mechanisms and its expanding role in neurodegenerative and neuropsychiatric disorders. While ongoing clinical trials explore its efficacy in ALS, depression, and schizophrenia, future research should focus on identifying biomarkers of treatment response, improving CNS penetration, and combining rituximab with other therapies to enhance safety and therapeutic outcomes. Rituximab's ability to target B-cell-driven pathology positions it as a promising agent in the evolving landscape of neuroimmunology.
    Keywords:  Autoimmune encephalitis; B cell depletion; Neurodegenerative therapy; Neuroinflammation; Neurological disorders; Rituximab
    DOI:  https://doi.org/10.1080/08923973.2026.2671714
  41. Mol Cell. 2026 May 12. pii: S1097-2765(26)00270-4. [Epub ahead of print]
    S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis.
    Wentao Xu, Huina Li, Wei Zhang, Ge Bai, Chengyong Shen, Kejing Zhang.
      TDP43 inclusion bodies are widely present in the majority of patients with familial and sporadic amyotrophic lateral sclerosis (ALS). The mechanisms regulating TDP43 solubility remain incompletely understood. Here, we report that TDP43 undergoes S-acylation primarily at the Cys244 residue by the S-acyltransferase zDHHC23. This S-acylation maintains the liquid-like properties of TDP43 by reducing the aberrant interaction with poly(ADP-ribose) polymerase 1 (PARP1) and PARylated proteins, thereby countering the pathological condensation of TDP43. S-acylation-deficient TDP43 inclusions sequester the translational machinery and inhibit cytoplasmic protein translation, ultimately resulting in neurotoxicity. Importantly, TDP43 S-acylation is decreased in the familial ALS-associated TDP43 mutants as well as in SOD1-G93A mice and C9orf72-ALS induced pluripotent stem cell (iPSC)-derived neurons, suggesting the widespread involvement of TDP43 S-acylation in ALS pathogenesis. Our findings reveal an undescribed modification of TDP43 and provide deeper insight into the regulation of TDP43 pathological condensation in ALS.
    Keywords:  S-acylation; TDP43; aggregation; amyotrophic lateral sclerosis; condensation
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.016
  42. J Clin Neurol. 2026 May;22(3): 327-337
    Clinical Significance of Plasma Sphingosine-1-Phosphate Decline in Progression of Spinal and Bulbar Muscular Atrophy.
    Young-Heun Jung, Hung Youl Seok, Minsung Kang, Young Woo Do, Junyoung O Park, Ju-Hyun Kim, Jin-Sung Park.
       BACKGROUND AND PURPOSE: Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked neuromuscular disorder characterized by slowly progressive motor decline. However, there is no specific fluid marker that reflects the severity or progression of the disease. Therefore, identifying measurable markers that reflect disease progression remains a major unmet need in SBMA management.
    METHODS: Plasma samples from 21 Korean patients with SBMA were collected at baseline and after 3 years. Untargeted and targeted metabolomics profiling was performed, and plasma sphingosine-1-phosphate (S1P) was the final candidate biomarker. S1P was then quantified using liquid chromatography-mass spectrometry. Associations between longitudinal S1P changes and clinical parameters, including the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), serum creatine kinase (CK), 6-minute walk test (6MWT), and forced vital capacity (FVC), were examined.
    RESULTS: Plasma S1P levels significantly declined in the fast progression group over 3 years, while remaining relatively stable in the slow progression group. Longitudinal changes in plasma S1P showed weak-to-moderate positive trends with clinical measurements, including ALSFRS-R, FVC, and 6MWT, and a negative trend with serum CK at follow-up.
    CONCLUSIONS: Plasma S1P represents a promising quantitative biomarker for monitoring SBMA progression. Validation in larger cohorts and mechanistic studies of S1P regulation are warranted to establish its role in clinical management.
    Keywords:  biomarker; disease progression; metabolomics; sphingosine-1-phosphate; spinal and bulbar muscular atrophy
    DOI:  https://doi.org/10.3988/jcn.2025.0556
  43. Expert Opin Ther Targets. 2026 May 12. 1-13
    Identifying targets at the blood-brain barrier for treating vascular cognitive impairment and dementia.
    Adnan Akif, Thi Thanh My Nguyen, Benjamin L Hao, Jianxiong Jiang, Xiang Li, Yibo Fan, Jiukuan Hao.
       INTRODUCTION: Vascular cognitive impairment and dementia (VCID) arise from chronic cerebrovascular dysfunction that compromises the blood-brain barrier (BBB), a critical interface maintaining neural homeostasis. The BBB's neurovascular unit (NVU) integrates endothelial cells, pericytes, astrocytes, and neurons, whose coordinated function preserves cerebral integrity. Persistent hypoperfusion, oxidative stress, and inflammation disrupt this system, triggering tight-junction degradation, impaired nutrient transport, and neuroinflammatory cascades that accelerate white matter damage and cognitive decline.
    AREAS COVERED: This review examines recent advances linking BBB dysfunction to VCID pathogenesis and summarizes pharmacological, cellular, and technological strategies to restore barrier function. Small molecules targeting oxidative and inflammatory signaling, cell-based therapies (mesenchymal and endothelial progenitors, iPSC-derived lineages), and advanced delivery platforms such as focused ultrasound and nanocarriers are evaluated for their potential to protect or repair the BBB.
    EXPERT OPINION: Effective VCID management will require precision medicine approaches integrating BBB biomarkers, vascular risk control, and targeted anti-inflammatory or regenerative therapies. Ongoing innovation in imaging, molecular diagnostics, and delivery systems offers a realistic path toward early intervention and prevention of cognitive decline by safeguarding neurovascular integrity.
    Keywords:  BBB permeability; chronic cerebral hypoperfusion; endothelial dysfunction; neuroinflammation; neurovascular unit; targeted drug delivery
    DOI:  https://doi.org/10.1080/14728222.2026.2671696
  44. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00101-4. [Epub ahead of print]151 157-195
    Biosimilars: Antibody and nanobody-based therapeutic approaches towards protein misfolding diseases.
    Subashchandrabose Chinnathambi, Nagaraj Rangappa.
      Neurodegenerative diseases, such as Alzheimer's disease, and Parkinson's disease, are characterized by progressive neuronal dysfunction and degeneration. These conditions often share pathological hallmarks such as protein misfolding, oxidative stress, neuroinflammation, and mitochondrial dysfunction. This review focuses on key pathological players like Tau and Amyloid-beta in Alzheimer's disease, highlighting their roles in microtubule destabilization, synaptic dysfunction, and neuronal death. The interplay between oxidative stress and these proteinopathies exacerbates neurodegeneration. Recent advances in therapeutic strategies are also explored, particularly the promise of biosimilars, cost-effective alternatives to biologics, targeting pathological hallmarks in neurodegenerative diseases. Biosimilars targeting Tau and Amyloid-beta in Alzheimer's disease, and alpha-synuclein in Parkinson's disease, hold the potential to improve treatment accessibility and reduce economic burdens. However, their development is still in its early stages. This review underscores the urgent need for innovative, affordable, and globally accessible therapeutic solutions to address the rising burden of neurodegenerative diseases.
    Keywords:  AD; Amyloid β; Biosimilars; Neurodegenerative diseases; Oxidative stress; Tau
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.014
  45. Appl Sci (Basel). 2025 Nov;pii: 11316. [Epub ahead of print]15(21):
    Neuroengineering Frontiers: A Selective Review of Neural Interfaces, Brain-Machine Interactions, and Artificial Intelligence in Neurodegenerative Diseases.
    Mutiyat Usman, Simachew Ashebir, Chioma Okey-Mbata, Yeoheung Yun, Seongtae Kim.
      Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), present a growing public health challenge globally. Recent advancements in neurotechnology and neuroengineering have significantly enhanced brain-computer interfaces, artificial intelligence, and organoid technologies, making them pivotal instruments for diagnosis, monitoring, disease modeling, treatment development, and rehabilitation of various diseases. Nonetheless, the majority of neural interface platforms focus on unidirectional control paradigms, neglecting the need for co-adaptive systems where both the human user and the interface continually learn and adapt. This selected review consolidates information from neuroscience, artificial intelligence, and organoid engineering to identify the conceptual underpinnings of co-adaptive and symbiotic human-machine interaction. We emphasize significant shortcomings in the advancement of long-term AI-facilitated co-adaptation, which permits individualized diagnostics and progression tracking in Alzheimer's disease and Parkinson's disease. We concentrate on incorporating deep learning for adaptive decoding, reinforcement learning for bidirectional feedback, and hybrid organoid-brain-computer interface platforms to mimic disease dynamics and expedite therapy discoveries. This study outlines the trends and limitations of the topics at hand, proposing a research framework for next-generation AI-enhanced neural interfaces targeting neurodegenerative diseases and neurological disorders that are both technologically sophisticated and clinically viable, while adhering to ethical standards.
    Keywords:  artificial intelligence; brain–computer interfaces; co-adaptation; human-AI symbiosis; neurodegenerative diseases; organoid models
    DOI:  https://doi.org/10.3390/app152111316
  46. Exp Neurol. 2026 May 07. pii: S0014-4886(26)00179-2. [Epub ahead of print]403 115815
    Neurovascular unit dysfunction in vascular cognitive impairment: Mechanisms, biomarkers, and translational strategies.
    Christina Hoyer-Kimura, Meredith Hay.
      Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous spectrum of cognitive disorders driven by cerebrovascular pathology and represents a major contributor to late-life cognitive decline. VCID is highly prevalent and frequently coexists with Alzheimer's disease pathology. Despite this, it remains poorly defined in clinical practice and lacks approved disease-modifying therapies. Therapeutic development has been hindered by biological heterogeneity, challenges in patient stratification, and a historical emphasis on neurodegenerative targets that inadequately address vascular mechanisms. Increasing evidence implicates dysfunction of the neurovascular unit-including small vessel disease, chronic hypoperfusion, blood-brain barrier disruption, and neuroinflammation-as a central driver of vascular-mediated cognitive impairment and a unifying therapeutic target across diverse VCID phenotypes. In this review, we synthesize current understanding of VCID pathobiology with a focus on neurovascular unit dysfunction and emerging mechanism-based strategies aimed at restoring vascular and neurovascular homeostasis. We further examine translational considerations for targeting neurovascular signaling pathways, including endothelial stabilization, modulation of vascular inflammation, and preservation of blood-brain barrier integrity. As an illustrative example, we discuss preclinical evidence supporting Mas receptor agonism, including the glycosylated angiotensin-(1-7) analogue PNA5, as a potential approach to address vascular-mediated cognitive impairment. Finally, we explore implications for biomarker selection, patient enrichment, and early clinical trial design. Together, this framework highlights neurovascular dysfunction as a tractable therapeutic target in VCID and underscores the need for mechanism-driven approaches to address a substantial unmet clinical need.
    Keywords:  Blood–brain-barrier; Mas-receptor; Neuroinflammation; Neurovascular unit; PNA5; Small vessel; VCID
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115815
  47. Protein Pept Lett. 2026 ;33(1): 258-274
    Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.
    Vidhan Chand Bala, Mukesh Kumar Singh, Amit Kumar, Sunil Kumar Tiwari, Asheesh Kumar Gupta, Rakesh Chawla, Sushil Kumar.
      Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; neurodegeneration; synucleinopathies; α- synuclein
    DOI:  https://doi.org/10.2174/0109298665429866260217115717
  48. Curr Pharm Biotechnol. 2026 May 09.
    Nanozymes in Personalized Medicine: A Review of the Potential for Tailored Diagnostic and Therapeutic Applications.
    Maryam Kainat, Irfan Ahmad, Afsana Huseynova Anvar, Sri Rahayu, Hafiz Abdullah Shakir, Muhammad Khan, Muhammad Irfan.
      Nanozymes are artificial nanoparticles similar to enzymes. They have received exceptional interest in personalized medicine. This is because of their superior characteristics such as stability, tunability, and multifunctionality. The purpose of the review is to explore the opportunities of nanozymes to transform global healthcare systems into individually tailored diagnostic and therapeutic tools. They can be point-of-care diagnostics, biosensing, delivery of targeted drugs, and provide specific-dose therapy. Nanozymes identify biomarkers in a very sensitive and specific manner. This enables the diagnosis at the early stages of a disease. The use of nanozymes also offers new therapeutic approaches. They are used in drug delivery systems and provide solutions for different ailments such as cancer, immune-related diseases, or neurodegenerative disorders. Although nanozymes find increased applications, several issues arise with their use. These are biocompatibility, potential toxicity, mass production, and regulatory issues. Such shortcomings confine their clinical translation. These issues are important to address to use nanozymes in personalized healthcare. This is possible through critical analysis and up-to-date material design. This review includes the latest developments, possible applications, and issues. It also mentions how nanozymes could have a promising role in next-generation medicine.
    Keywords:  Nanozymes; Point-of-care diagnostics; biocompatibility; biosensing; diagnostics; healthcare; nanobiotechnology.; personalized medicine; therapeutics
    DOI:  https://doi.org/10.2174/0113892010422141251203100000
  49. Curr Neurovasc Res. 2026 May 08.
    Advancing the Frontiers of Multiple Sclerosis Management: Emerging Immunotherapeutic Strategies.
    Injamamul Haque, Koushik Das, Zuber Khan, Mumtaz, Md Nasiruddin Khan, Divya Choudhary, Sidharth Mehan, Pankaj Kumar Maurya.
       INTRODUCTION: Multiple Sclerosis (MS) is a chronic neurodegenerative disease characterized by inflammation, demyelination, and neuronal loss in the CNS. Despite significant therapeutic advancements, MS remains incurable, especially the progressive forms like Primary Progressive MS (PPMS), due to a lack of understanding of the disease mechanisms and inadequate translational models.
    METHODS: This narrative review assesses literature on MS pathophysiology, phenotypes, diagnostic issues, and new immunotherapeutic strategies, analyzing preclinical and clinical evidence regarding biologics, neuroprotective agents, remyelination methods, advanced imaging, and biomarker development.
    RESULTS: Treatment regimens using anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, and ofatumumab have proven effective in reducing disease activity and slowing progression, especially in PPMS. Additionally, Bruton's tyrosine kinase inhibitors and agents that promote remyelination have the potential to address unmet medical needs. Enhanced imaging techniques, such as MRI and PET, and molecular biomarkers facilitate better disease monitoring and personalized treatment, enabling more tailored therapies that can improve patient outcomes in conditions like MS.
    DISCUSSION: Recent advances emphasize the important role of immune dysregulation, particularly involving B-cell mechanisms, in the progression of MS. Anti-CD20 monoclonal antibodies have demonstrated clinical benefits, effectively reducing disease activity and slowing progression, particularly in progressive MS cases. Nonetheless, challenges such as high costs, limited access, and reduced efficacy in later disease stages persist, especially in resource-constrained healthcare settings.
    CONCLUSION: Emerging immunotherapeutic, neuroprotective, and remyelination-based approaches may improve outcomes in patients with progressive MS. Further, to personalize the MS treatment, we need to combine advanced imaging, biomarker technologies, and real-world clinical data.
    Keywords:  Multiple sclerosis; myelin sheath; neuroprotective agents; rituximab; tyrosine kinase inhibitors.
    DOI:  https://doi.org/10.2174/0115672026452725260413095140
  50. Research (Wash D C). 2026 ;9 1283
    Artificial Intelligence Decodes Brain Elemental Signatures to Stratify Aging and Neurological Diseases.
    Augustin Tillement, Eszter Nemeth, Laurent David, Dilek Cenesiz, Ulrich Neumayer, Mathias Fousse, Yang Liu, Walter J Schulz-Schaeffer, Klaus Fassbender, Alexandre Detappe, François Lux, Sergiu Groppa, Olivier Tillement, Yann Decker.
      The elemental composition of brains changes progressively with age, yet these metallome alterations remain largely unexplored as diagnostic biomarkers in neurological disease. Here, we present a comprehensive analysis of 24 inorganic elements in paired cerebrospinal fluid and serum samples from 1,608 individuals spanning healthy aging through 14 neurological conditions, representing the largest systematically standardized cohort for neurological metallomics. Uniquely, our unselected, consecutively admitted clinical cohort captures the full heterogeneity of neurological presentations, overcoming the limitations of traditional case-control designs focused on isolated disease entities. Machine learning analysis reveals that aging is associated with distinct cerebrospinal fluid elemental signatures independent of peripheral blood changes, primarily reflecting blood-brain barrier permeability alterations that correlate with established albumin quotient measurements. We identify 2 predominant patterns of neurological elemental dysregulation: one mainly consistent with passive barrier-mediated leakage in inflammatory conditions, and another mainly indicative of disease-intrinsic perturbations of metal homeostasis in neurodegenerative disorders. Age-stratified analysis reveals that elemental signatures evolve differently across the lifespan for distinct pathological processes. The integration of elemental signatures with routine clinical parameters through ensemble learning approaches enhances diagnostic accuracy across all tested neurological categories, establishing metallomics as a complementary biomarker class that captures orthogonal pathophysiological information. These findings establish brain metallomics as an emerging field where artificial intelligence reveals complex multi-element interactions present in neurological aging, opening new avenues for precision medicine in age-related neurological disorders.
    DOI:  https://doi.org/10.34133/research.1283
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒17 at 9:15.