bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–04–05
fifty-four papers selected by
Luca Bolliger, lxBio
  1. The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.
  2. Neurovascular dysfunction in the development and progression of neuroinflammatory diseases.
  3. The Gut Microbiome in Amyotrophic Lateral Sclerosis: Emerging Mechanisms and Therapeutic Potential.
  4. Six months of experience at a specialized daytime care center for people with amyotrophic lateral sclerosis (ALS) in the Community of Madrid.
  5. Combination Disease-Modifying Therapy for Neurodegenerative Diseases Using Repurposed Drugs.
  6. Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.
  7. Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis.
  8. Increased CSF levels of soluble AXL at diagnosis correlate with poor prognosis in patients affected by amyotrophic lateral sclerosis.
  9. Impaired dynein function preserves spinal interneuron survival and positioning in an ALS-like mouse model.
  10. Cytoskeltal intermediate filaments in Tau pathology and neurodegeneration.
  11. Longitudinal Analysis of Superoxide Dismutase 1 Seeding Activity in Amyotrophic Lateral Sclerosis Cerebrospinal Fluid.
  12. Long non-coding RNAs in neurodegenerative diseases - Molecular mechanisms, liquid biopsy biomarkers, and therapeutic targets: A review.
  13. Impact of care by a multidisciplinary team on the assessment of cognitive aspects and decision-making at the end of life in a Spanish population with amyotrophic lateral sclerosis.
  14. Reappraisal of the Diagnostic Significance of Transcranial Magnetic Stimulation and Triple Stimulation in Amyotrophic Lateral Sclerosis.
  15. Molecular chaperones mediated proteostasis depletion: A cause of neurodegeneration?
  16. Exosome-like nanovesicles from acerola for CRISPR-Cas9 ribonucleoprotein delivery to the central nervous system.
  17. Long-interval intracortical inhibition is similar in people with and without amyotrophic lateral sclerosis.
  18. Cross-disease genetic and epigenetic architecture of the MOBP locus shows convergence in ALS-PSP.
  19. Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis.
  20. Targeting Blood-Brain Barrier Damage with Nanotechnology in the Fight Against Neurodegenerative Diseases.
  21. The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.
  22. AI-Driven Biomarker Discovery in Motor-Related Neurodegenerative Diseases.
  23. Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.
  24. Stable speech BCI performance during slow progression of ALS: A longitudinal ECoG study.
  25. Calcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS.
  26. Clinical parameters affecting the course of amyotrophic lateral sclerosis: a longitudinal analysis of the Greek registry for amyotrophic lateral sclerosis (ALS-GR).
  27. The role of blood-brain barrier integrity in the pathophysiology and progression of psychiatric disorders.
  28. Mucin-binding protein shuttles enable delivery of brain-targeted therapeutics.
  29. The economic burden of amyotrophic lateral sclerosis for patients and families: a survey on out-of-pocket expenses and income loss in France.
  30. Long-Term Exposure to Ambient Air Pollution and Incident Amyotrophic Lateral Sclerosis: A Prospective Cohort Analysis of the UK Biobank.
  31. Differential quadruple pattern: A new EEG signal classification framework.
  32. Criterion validity of equations as alternatives to reference standards for assessing body composition and energy expenditure in amyotrophic lateral sclerosis - a systematic literature review.
  33. Bioanalytical approaches applied to identify cytoskeletal proteins associated with neurodegenerative diseases.
  34. Neuroinflammation, Autophagy, and Neurodegeneration: Mechanisms and Therapeutic Insights.
  35. Advances in ocular motor and pupil biomarkers for neurological disorders.
  36. Cytoskeletal disintegration in cardiovascular disease-related neurodegeneration.
  37. COVID-19 and neurodegeneration: Perspectives on the impact of viruses on the brain.
  38. New insights in multiple sclerosis pathology.
  39. Animal models of multiple sclerosis: applications and future directions in disease research.
  40. Hereditary transthyretin amyloidosis mimicking ALS: First genetically proven case report from Saudi Arabia.
  41. The Bidirectional Regulatory Role of Neuroimmune Interaction in Neurodevelopment and Neurodegenerative Diseases.
  42. Clinical and biochemical characterization of amyotrophic lateral sclerosis in a CHCHD10 R15L family.
  43. The Role of the cGAS-STING Pathway in Central Nervous System Diseases.
  44. Neuroinflammation as a result of non-neurotropic herpesvirus infection.
  45. Programmable CAR immunotherapies for neurodegenerative proteinopathies.
  46. Examining pre-analytical factors for bioanalysis of protein therapeutics crossing the blood-brain barrier through receptor-mediated transcytosis.
  47. The Multifaceted Roles of GPR120 in Central Nervous System Disorders: Mechanistic Insights and Therapeutic Implications.
  48. Rethinking Neuroregenerative Microenvironments: Synergy Between Bioengineering and Organoids.
  49. NEAT1 as a Diagnostic Biomarker and Therapeutic Target for Alzheimer's Disease: A Comprehensive Review.
  50. A cell line-derived, immune-competent neurospheroid model to study neuroinflammation and human brain disorders.
  51. TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.
  52. Breaking barriers: Understanding and managing blood-spinal cord barrier dysfunction in spinal cord injury: A systematic review.
  53. Interactions between Innate Immune Memory and the Central Nervous System.
  54. Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.
  1. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00122-1. [Epub ahead of print]150 397-422
    The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.
    Chandrabose Selvaraj, Deepali Desai, Elayaperumal Sumitha.
      Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease are characterized by progressive neuronal dysfunction and loss. A growing body of evidence implicates cytoskeletal disruption as a central pathological mechanism in these conditions. Cytoskeletal proteins, including microtubules, actin filaments, tau, neurofilaments, and alpha-synuclein, not only provide structural integrity but also regulate axonal transport, synaptic connectivity, and neuroplasticity. Its dysfunction will lead to impaired intracellular trafficking, protein aggregation, and neuronal degeneration. This chapter explores clearly about the specific cytoskeletal abnormalities that are evident in major neurodegenerative disorders, highlighting the biological mechanisms such as tauopathy-induced microtubule instability in Alzheimer's, actin cytoskeleton dysregulation in Parkinson's, and neurofilament aggregation in ALS. Current therapeutic strategies aimed at the stabilizing cytoskeletal components, enhancing protein clearance, and restoring transport dynamics are examined, alongside the cutting-edge approaches including the gene therapy, CRISPR/Cas9 editing, and nanotechnology-based delivery systems. Challenges such as limited blood-brain barrier penetration, off-target toxicity, and patient heterogeneity are also discussed with the focus on need for precision medicine. Additionally, we have also explored the future directions that specifically focused on the biomarker development, combination therapies, and strategies to promote neuroregeneration and structural plasticity. Targeting cytoskeletal pathways holds significant promise not only for suppressing the disease progression but also for rebuilding the structural foundation of the nervous system, potentially reversing the neurodegenerative decline.
    Keywords:  Brain; Cytoskeletal proteins; Neurodegenerative diseases; Neuronal degeneration; Neuronal dysfunction
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.026
  2. Front Cell Neurosci. 2026 ;20 1741928
    Neurovascular dysfunction in the development and progression of neuroinflammatory diseases.
    Jamila Gowdy, Julie Ahn, Robert H Miller, Yusra Islam.
      The neurovascular unit (NVU) is critical for brain homeostasis through its roles in maintenance of an effective blood brain barrier (BBB) and regulation of cerebral blood flow. Perturbation of the NVU is a hallmark of the pathology of multiple neurodegenerative diseases resulting in loss of BBB integrity, neuroinflammation and neuronal dysfunction. The NVU is a complex structure composed of endothelial cells, pericytes, as well as central nervous system (CNS) glial and neuronal components. While the importance of the CNS vasculature in health and disease is well established, the mechanisms underlying vascular pathology and its contributions to neurodegenerative diseases are less well defined. Neuroinflammation and reactive gliosis occurs in the majority of neurodegenerative diseases and recent studies suggest that immune mediated disruption of the BBB contributes to the induction of reactive gliosis and neuronal dysfunction. Potential consequences of NVU disruption include immune-driven vascular inflammation and leukocyte infiltration in Multiple Sclerosis (MS), protease-mediated tight junction degradation in ischemic stroke (IS), α-synuclein-associated endothelial dysfunction in Parkinson's Disease (PD), amyloid-β- and tau-induced pericyte injury in Alzheimer's Disease (AD), and complement-mediated vascular damage in Amyotrophic Lateral Sclerosis (ALS). Here we review the nature of NVU perturbations in these common neurodegenerative diseases, with an emphasis on the contribution of immune modulation of BBB disruption in neuropathology and disease progression.
    Keywords:  B cells; blood–brain barrier; endothelial dysfunction; glial cells; multiple sclerosis; neurodegeneration; neuroinflammation; neurovascular unit
    DOI:  https://doi.org/10.3389/fncel.2026.1741928
  3. Mol Neurobiol. 2026 Apr 02. pii: 549. [Epub ahead of print]63(1):
    The Gut Microbiome in Amyotrophic Lateral Sclerosis: Emerging Mechanisms and Therapeutic Potential.
    Ghaleb Oriquat, Malathi H, Laxmidhar Maharana, Archana Dhyani, Shaker Al-Hasnaawei, Ashish Singh-Chauhan, Vimal Arora, Jatin Sharma, Reza Sadeghi-Samarjan.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons and a median survival of 2 to 3 years after symptom onset. Despite advances in genetics, particularly the identification of mutations in C9ORF72, SOD1, and TDP 43, substantial variability in disease onset and progression remains unexplained. Mounting evidence points to the gut microbiome as a potential modifier of ALS biology. Microbial communities within the intestine influence systemic and central immune responses, energy metabolism, and the bioavailability of nutrients and therapeutic agents. Animal studies reveal that dysbiosis contributes to intestinal barrier dysfunction, immune activation, and altered metabolite production, while supplementation with beneficial metabolites such as butyrate or nicotinamide can delay disease progression and extend survival. Human studies, though inconsistent in their findings, consistently identify microbial imbalances and loss of diversity in subsets of patients. The gut-brain axis provides a plausible framework for these effects, as microbial products can signal through endocrine, neural, and immune pathways to influence central nervous system function. Beyond motor decline, microbiota alterations may also contribute to non-motor symptoms such as depression, anxiety, and gastrointestinal dysfunction, further shaping quality of life. While methodological variability complicates interpretation, integration of microbiome research with host genomics and metabolomics offers a path toward precision medicine. Targeting microbial composition and function may ultimately represent a novel therapeutic approach capable of modifying both disease biology and patient outcomes in ALS.
    Keywords:  Amyotrophic lateral sclerosis; Gut microbiome; Gut-brain axis; Neuroinflammation; Precision medicine
    DOI:  https://doi.org/10.1007/s12035-026-05826-8
  4. Neurologia (Engl Ed). 2026 Mar 27. pii: S2173-5808(26)00057-X. [Epub ahead of print] 502006
    Six months of experience at a specialized daytime care center for people with amyotrophic lateral sclerosis (ALS) in the Community of Madrid.
    en representación del equipo CEADELA y grupo de investigación del Neuro-Cure del IdiPAZ
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to motor deterioration and a reduced quality of life. In the Community of Madrid, the ALS Network was established to improve patient care. In April 2024, the Specialized Day Care Centre for ALS (CEADELA) was inaugurated, complementing the care provided by the ALS Network. The aim of this study was to describe the experience of CEADELA during its first six months.
    MATERIALS AND METHODS: A retrospective descriptive study was conducted on a cohort of CEADELA patients between April and October 2024. Clinical, functional, and therapeutic data were analyzed, along with overall satisfaction levels.
    RESULTS: A total of 91 patients were included, with a mean age of 65.2 years (SD 11); of these, 59 (64.8%) were men. Most had spinal-onset ALS and were receiving treatment with riluzole. A significant increase was observed in the use of physiotherapy, speech therapy, and occupational therapy after referral to the centre. Functionality significantly declined over six months. The mortality rate was 12.1% (18.2% opted for assisted dying). Overall, 76 patients (83.5%) responded to the survey, with 100% reporting satisfaction or high satisfaction with the centre (80.2% very satisfied and 18.4% satisfied).
    CONCLUSIONS: CEADELA has improved access to specialized therapies with a high level of satisfaction, although disease progression remains a challenge. The need to continue developing integrated, evidence-based care models to optimize ALS management is highlighted.
    Keywords:  ALS; CEADELA; ELA; Motoneurona; Motor neuron; Neurodegenerativa; Neurodegenerative
    DOI:  https://doi.org/10.1016/j.nrleng.2026.502006
  5. Ann Neurol. 2026 Apr 02.
    Combination Disease-Modifying Therapy for Neurodegenerative Diseases Using Repurposed Drugs.
    Alexander Shtilbans, Anthony E Lang.
      We review the positive effects of several existing drugs from different classes, such as chemical chaperones, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), iron chelators, and cluster-Abelson tyrosine kinase inhibitors (c-Abl TKIs), in preclinical disease models and in available published human data following use of these drugs in individuals with common neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). A concept of combinatory neuroprotective therapy using a drug-repurposing approach is then discussed. Finally, we propose a strategy to design an ideal combination of drugs able to address multiple pathogenic processes involved in neurodegeneration to achieve clinically meaningful results. ANN NEUROL 2026 ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78190
  6. Curr Neuropharmacol. 2026 Mar 25.
    Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.
    Sumitra Patel, Radhika Sood, Shweta Shrivastava, Manish Kumar Jeengar.
      Neurodegenerative Disorders (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and other less prevalent conditions, represent a growing challenge in medical science due to their progressive nature and the absence of curative treatments. Cruciferous vegetables, such as those from the Brassicaceae family and other species in the Brassicales order, have been reported to offer potential benefits for treating and preventing NDDs. Their neuroprotective effects have been attributed to secondary metabolites, glucosinolates (GLs), and their hydrolytic products, isothiocyanates (ITCs). One of these ITCs is Erucin (ERU), chemically known as 4-isothiocyanatobutane, which is a specific type of ITC. ERU is the isothiocyanate derivative of erucic acid and is structurally related to sulforaphane (SFN), another well-known ITC. This review aims to synthesize current scientific knowledge on ERU's mechanisms of action in neurodegeneration, highlighting preclinical evidence supporting its neuroprotective effects in diseases such as AD and PD, and suggesting its potential as a treatment strategy for NDDs. Preliminary studies suggest that ERU may confer neuroprotection through antioxidative stress pathways, modulation of neuroinflammatory responses, and upregulation of neurotrophic factors. This article discusses ERU's chemical properties, pharmacokinetics, and observed impacts on neurodegenerative models, suggesting potential therapeutic pathways it may influence, thereby highlighting its promise as a future component of neuroprotective strategies against NDDs.
    Keywords:  Alzheimer's disease; Erucin; Parkinson's disease; cruciferous vegetables.; neurodegenerative diseases; neuroprotection
    DOI:  https://doi.org/10.2174/011570159X385491251208144807
  7. bioRxiv. 2026 Mar 25. pii: 2026.03.23.713695. [Epub ahead of print]
    Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis.
    Amr A Mahrous, Bradley S Heit, C J Heckman.
      Riluzole is the most commonly prescribed among the limited approved therapies for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motoneuron loss and paralysis. It is thought to act by suppressing motoneuron excitability and glutamate release, but its clinical benefits are modest and often diminish over time. We previously showed that homeostatic mechanisms in the SOD1 G93A (mSOD1) mouse model of ALS are hyperactive and prone to overcompensation. Here, we tested whether such dysregulated homeostasis antagonizes the effects of riluzole. Wild-type (WT) and presymptomatic mSOD1 mice received therapeutic doses of riluzole in drinking water for 10 days, with untreated littermates of both genotypes serving as controls. Motoneuron excitability and synaptic inputs were then examined using intracellular recordings from the isolated sacral spinal cord. The data showed that chronic riluzole treatment increased motoneuron excitability and polysynaptic inputs in mSOD1 mice but produced no detectable changes in WT motoneurons. These results suggest that hyperactive homeostatic mechanisms in ALS counteract the suppressive effects of riluzole. Notably, mSOD1 motoneurons exhibited larger membrane capacitance than WT, consistent with their increased cell size at this disease stage. Riluzole treatment reduced motoneuron membrane capacitance in mSOD1 mice to the range observed in WT animals, indicating normalization of cell size and potentially reduction in metabolic demand. Together, these findings help explain the limited clinical efficacy of riluzole while revealing a previously unrecognized neuroprotective mechanism of the drug in ALS.
    DOI:  https://doi.org/10.64898/2026.03.23.713695
  8. Brain Commun. 2026 ;8(2): fcag086
    Increased CSF levels of soluble AXL at diagnosis correlate with poor prognosis in patients affected by amyotrophic lateral sclerosis.
    Mauro G Spatafora, Jonas Dubin, Teuta Domi, Raffaella Lombardi, Paolo Cabras, Eleonora Dalla Bella, Monica Consonni, Angelo Quattrini, Manuela Verri, Giuseppe Lauria, Philip Van Damme, Koen Poesen, Nilo Riva, Marco Peviani.
      AXL, a receptor tyrosine kinase expressed in neurons and glial cells, involved in neuronal survival, myelination, and regulation of immune responses, can undergo shedding due to the activation of metalloproteases in neuroinflammatory conditions. Indeed, CSF and serum levels of soluble AXL (sAXL) have been correlated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). Based on these observations, we explored whether sAXL is implicated in amyotrophic lateral sclerosis (ALS). sAXL levels were measured in biofluids (CSF and serum) from two biorepositories, totalling 107 ALS patients, 76 healthy controls, 25 AD patients, 22 patients with multiple sclerosis and 51 patients with ALS disease mimicking disorders (i.e. patients that displayed symptoms resembling ALS, in whom eventually ALS was excluded after a thorough clinical examination). Gender and age were considered as covariate in the statistical analyses. Our results provide the first evidence of sAXL alterations in the CSF and serum of ALS patients at diagnosis and demonstrate a significant association between CSF sAXL levels and disease progression, as well as its prognostic value in ALS. While these observations require validation through multicentre studies, they suggest the involvement of the AXL pathway in ALS pathology and pave the way for leveraging CSF sAXL levels as a biomarker to aid ALS disease stratification.
    Keywords:  biomarker; disease progression; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1093/braincomms/fcag086
  9. PLoS One. 2026 ;21(4): e0346246
    Impaired dynein function preserves spinal interneuron survival and positioning in an ALS-like mouse model.
    Eleni Christoforidou, Jordan S Rowe, Fabio A Simoes, Raphaelle Cassel, Luc Dupuis, Peter Nigel Leigh, Majid Hafezparast.
      Impaired cytoplasmic dynein function has been implicated in amyotrophic lateral sclerosis (ALS) pathogenesis, yet the contributions of spinal interneurons to disease phenotypes remain unclear. We tested the hypothesis that hypomorphic dynein function in cholinergic neurons disrupts the development, survival, or positioning of inhibitory interneuron populations in the lumbar spinal cord. Using ChAT-Cre recombination, we generated four mouse genotypes with graded reductions in dynein activity in ChAT+ cells: Dync1h1+/+ (wildtype), Dync1h1-/+ (hemizygous wildtype), Dync1h1+/Loa (heterozygous Loa mutation), and Dync1h1-/Loa (hemizygous Loa). At 52 weeks of age, lumbar spinal cords (L3-L6) were harvested, cryosectioned, and immunostained for ChAT, GAD-67, Parvalbumin, and Calbindin. Cell counts were performed on confocal images from eight sections per mouse (N = 3 male mice/genotype), and radial distances from the central canal were normalised to gray matter width. Angular distributions were analysed via circular statistics. There were no significant genotype-dependent differences in the numbers of ChAT+, GAD-67+, Parvalbumin+, or Calbindin+ cells, nor in ChAT+ subpopulations (motor neurons versus interneurons) or double-positive interneuron subsets (e.g., ChAT+-GAD-67+, Parvalbumin+-GAD-67+, Parvalbumin+-Calbindin+). Radial positioning relative to the central canal was similarly preserved across all markers and genotypes. Circular-median tests revealed statistically significant shifts in mean angle for ChAT+, GAD-67+, and certain double-positive cells, but these amounted to only 5-10° displacements, translating to lateral shifts of ~10-20 µm, well within single laminar bands, and are unlikely to impact circuit connectivity. Despite substantial motor deficits and hallmark TDP-43 pathology previously seen in these models, impaired dynein function does not precipitate interneuron loss or gross migratory defects in the lumbar spinal cord. Instead, our findings suggest that the primary contributions of dynein to ALS-like phenotypes likely arise from functional disruptions in axonal transport, synaptic maintenance, and neuronal physiology rather than from structural alterations or loss of interneuron populations.
    DOI:  https://doi.org/10.1371/journal.pone.0346246
  10. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00124-5. [Epub ahead of print]150 351-376
    Cytoskeltal intermediate filaments in Tau pathology and neurodegeneration.
    Subashchandrabose Chinnathambi, Sneha Malik.
      Intermediate filaments are cytoskeletal proteins that are vital for proper cell structure formation and functioning. There are six types of these proteins. Type I includes acidic keratins, Type II includes basic and neutral keratins, both of which are present in epithelial cells. Type III includes vimentin, desmin, glial fibrillary acidic protein and peripherin, among which the last two are highly involved in neurodegenerative diseases. Type IV includes three types of neurofilament proteins, NF-L, NF-M and NF-H, where L signifies light, M signifies medium and H signifies heavy. The fourth protein in this category is α-internexin. All of these proteins are highly involved in neurodegenerative diseases, especially the neurofilament proteins. The type V intermediate filament proteins are lamins. The type VI intermediate filaments are nestins. Their involvement in a variety of neurodegenerative diseases has been observed, including Alzheimer's disease, Cerebral Ischemia, Multiple Sclerosis, Alexander Disease, Neuronal IF inclusion disease (NIFID) and Amyotrophic Lateral Sclerosis (ALS). Alzheimer's disease is a neurodegenerative disease in which two proteins are mainly involved, the Tau protein and the Amyloid-β protein. This review discusses the crosstalk of the intermediate filament proteins with the pathological proteins involved in the neurodegenerative diseases. For the case of the Alzheimer's disease, many of the intermediate filament proteins are involved in the disease pathology and are vital markers for the disease. One of the category of proteins involved is neurofilaments, among which NF-L is a marker for the disease. Keratin 9 and the glial fibrillary acidic protein (GFAP) are other intermediate filament proteins that are being explored as markers for the Alzheimer's disease.
    Keywords:  Alzheimer’s disease; Intermediate filaments; Keratin 9; Neurodegeneration; Neurofilaments; Tau; Vimentin
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.028
  11. medRxiv. 2026 Mar 25. pii: 2026.03.20.26348753. [Epub ahead of print]
    Longitudinal Analysis of Superoxide Dismutase 1 Seeding Activity in Amyotrophic Lateral Sclerosis Cerebrospinal Fluid.
    Mylene A Sebogo, Macie C Frans, Helan Paulose, Claire L Rodriguez, Ging-Yuek Hsiung, Neil R Cashman, Cindy V Ly, Moses J Leavens.
      Twenty percent of familial amyotrophic lateral sclerosis (fALS) cases are linked to mutations in the Superoxide Dismutase 1 ( SOD1) gene and accumulation of misfolded SOD1 aggregates. SOD1 misfolding from the broader ALS population without SOD1 mutations is less clear. Here, we report SOD1 seeding activity in antemortem cerebrospinal fluid (CSF) from ALS participants with and without SOD1 mutations during ALS progression. Antemortem CSF from controls, SOD1- ALS, and sporadic ALS (sALS) patients was subjected to SOD1 seed amplification real-time quaking induced conversion (RT-QuIC) assays. SOD1 -ALS CSF exhibited shorter lag phase and increased ThioflavinT (ThT) fluorescence amplitude compared to healthy controls and those with spinal muscular atrophy. CSF from sALS participants, who had no mutations in SOD1 or nine other ALS risk genes, also displayed SOD1 seeding activity, indicating wild-type SOD1 is aggregate-prone in the broader ALS population. Longitudinal CSF data indicated that SOD1 seeding activity correlates with ALS progression via the ALS Functional Rating Scale Revised (ALSFRS-R) slope decline and CSF neurofilament light. Our sALS CSF cohort primarily comprised of participants less than 2 years from symptom onset, suggesting that SOD1 seeding activity is an early biomarker that may enable inclusion in clinical trials. With the FDA-approval of tofersen (Qalsody), a SOD1-lowering antisense oligonucleotide, new SOD1 diagnostic, prognostic and pharmacodynamic biomarkers may enable SOD1-targeting strategies that could benefit the broader ALS population.
    DOI:  https://doi.org/10.64898/2026.03.20.26348753
  12. Biomol Biomed. 2026 Mar 31.
    Long non-coding RNAs in neurodegenerative diseases - Molecular mechanisms, liquid biopsy biomarkers, and therapeutic targets: A review.
    Yipeng Cheng, Mingyue Qiu, Zhijie Yu, Xu Tang, Jingjing Zhang.
      Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are age-related disorders characterized by progressive neuronal loss, cognitive decline, and limited options for disease-modifying treatments. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in neurodevelopment, neuronal homeostasis, and disease progression; however, their involvement in shared pathogenic pathways and clinical applications remains inadequately defined. This review consolidates recent experimental, transcriptomic, bioinformatic, and emerging clinical findings regarding the role of lncRNAs in NDDs. We examine how lncRNAs modulate common disease mechanisms, including protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, ferroptosis, synaptic failure, and aging-related neurodegenerative processes. These regulatory functions occur through various mechanisms, including epigenetic modifications, transcriptional regulation, post-transcriptional processes, and RNA-protein interactions, as well as novel mechanisms such as liquid-liquid phase separation (LLPS), peptide coding, and exosome-mediated intercellular communication. Current evidence supports the potential of lncRNAs as minimally invasive liquid biopsy biomarkers, detectable in blood, cerebrospinal fluid (CSF), and extracellular vesicles. Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms. Overall, lncRNAs have emerged as central molecular regulators and promising candidates for translation in NDDs. Nonetheless, challenges related to specificity, validation, delivery across the blood-brain barrier, and clinical standardization must be addressed before their routine application in precision neurology.
    DOI:  https://doi.org/10.17305/bb.2026.13978
  13. Neurologia (Engl Ed). 2026 Mar 26. pii: S2173-5808(26)00050-7. [Epub ahead of print] 501950
    Impact of care by a multidisciplinary team on the assessment of cognitive aspects and decision-making at the end of life in a Spanish population with amyotrophic lateral sclerosis.
    M I Chamorro-Muñoz, M N Afkir-Ortega, A Aguilar-Monge.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a disease with a fatal course, often associated with unassessed cognitive-behavioural disturbances, and very relevant end-of-life care decisions. The aim of this study is to verify whether multidisciplinary team care for ALS patients in our setting has modified the cognitive assessment and the end-of-life decision making, compared to a model of uncoordinated specialist care.
    METHODS: An observational, longitudinal, retrospective study was conducted on a cohort of patients with probable or definite ALS, in a referral hospital, between 01-01-2000 and 31-12-2022, differentiating whether they were treated before or after the implementation of a multidisciplinary model. We analysed the performance of cognitive assessment, the use of riluzole, gastrostomy, non-invasive ventilation and invasive ventilation, and the recording of patients' decisions regarding the care they wished to receive. Comparisons between variables were performed using the chi-square test or Fisher's exact test.
    RESULTS: We evaluated 47 patients seen by uncoordinated specialists and 146 with a multidisciplinary model. Patients cared for using the multidisciplinary model were more frequently cognitively assessed (55.48% vs 12.8%, p < 0.001), diagnosed with dementia (11.6% vs 2.3%, p < 0.048) and their advance directives were recorded (56.8% vs 23.4%, p < 0.001). We found no differences in the use of advanced interventions, except for invasive ventilation, which was only performed in the context of multidisciplinary care.
    CONCLUSIONS: The multidisciplinary model of care for ALS patients in our setting has improved cognitive assessment, promoted the registration of their advance directives, and thus helped to improve respect for their autonomous decisions and dignity.
    Keywords:  Amyotrophic lateral sclerosis; Demencia frontotemporal; End-of-life decision making; Equipo multidisciplinar; Esclerosis lateral amiotrófica; Frontotemporal spectrum disorder; Multidisciplinary care; Supervivencia; Survival; Toma de decisiones al final de la vida
    DOI:  https://doi.org/10.1016/j.nrleng.2026.501950
  14. Eur J Neurol. 2026 Apr;33(4): e70560
    Reappraisal of the Diagnostic Significance of Transcranial Magnetic Stimulation and Triple Stimulation in Amyotrophic Lateral Sclerosis.
    Birgit Andersen, Christian Krarup.
       OBJECTIVE: To reassess the importance of transcranial magnetic stimulation (TMS), including the triple stimulation technique (TST), to detect upper motor neuron (UMN) involvement in amyotrophic lateral sclerosis (ALS).
    METHODS: In this single-center prospective study, 144 consecutive patients suspected of having motor neuron disease were included over 5 years at the time of diagnosis. All patients were examined clinically and with EMG to assess UMN and lower motor neuron (LMN) involvement, and survival was ascertained 2 years after inclusion of the last patient. Our TMS protocol consisted of TST in both arms and conventional motor evoked potentials (MEP) in arms and legs to assess central motor conduction time (CMCT).
    RESULTS: The TST could be performed in 142 patients who showed central conduction failure in 63%, which was often markedly asymmetrical, and 50% had prolonged CMCT in the legs. Combining TST in the arms and conventional MEP in the legs showed central abnormalities in 77%. In 62 patients with only signs of LMN involvement at clinical and EMG assessment, the TST amplitude ratio was reduced in 45%, and combined TST to the arms and conventional MEP to the legs disclosed a central abnormality in 61%.
    CONCLUSION: The main clinical significance was the subclinical corticospinal involvement at TMS with TST in a large proportion of patients without clinical UMN involvement. TMS with TST is a sensitive, non-invasive electrophysiological method to detect corticospinal dysfunction in ALS.
    Keywords:  amyotrophic lateral sclerosis; corticospinal conduction failure; survival; transcranial magnetic stimulation; triple stimulation technique; upper motor neuron
    DOI:  https://doi.org/10.1111/ene.70560
  15. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00129-4. [Epub ahead of print]150 181-219
    Molecular chaperones mediated proteostasis depletion: A cause of neurodegeneration?
    Sumit Kinger, Akash Choudhary, Prashant Kumar, Yuvraj Anandrao Jagtap, Vivek Sharma, Rohan Dhiman, Amit Prasad, Rahul Verma, Subashchandrabose Chinnathambi, Amit Mishra.
      Protein homeostasis is a critical aspect of cellular homeostasis as proteins are one of the most diverse biomolecules, responsible for multiple molecular and cellular functions. Protein quality control machinery is essential for maintaining integrity of cellular proteome via regulating its synthesis, structure, function, and degradation. Molecular chaperones are central to the protein quality control apparatus of cells and assist in folding nascent polypeptides, maturation, sequestration, solubilisation, and degradation of proteins. The coordination and cooperation between multiple cellular chaperones and other quality control elements, such as ubiquitin-proteasome system and autophagy, form a network, critical for proteostasis. Disturbed proteostasis and protein aggregation are hallmark features of neurodegenerative diseases. Re-establishing cellular proteostasis and enhancing chaperones' levels and functions can alleviate protein aggregation and associated cytotoxicity. Here, we have explored the potential of abundant cellular chaperone Hsp90, large chaperone Hsp110, small chaperone Hsp27, and anti-oxidant and mitoprotective chaperone DJ-1 in the regulation of proteostasis, with implications for neurodegenerative diseases, Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. We have focused on roles and mechanisms of function of these chaperones in countering disturbed proteostasis in neurodegenerative disorders.
    Keywords:  Alzheimer’s; Amyotrophic lateral sclerosis; DJ-1; Hsp110; Hsp27; Hsp90; Huntington’s; Neurodegeneration; Parkinson’s; Proteostasis
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.033
  16. Mol Ther Nucleic Acids. 2026 Jun 16. 37(2): 102896
    Exosome-like nanovesicles from acerola for CRISPR-Cas9 ribonucleoprotein delivery to the central nervous system.
    Yui Nagamatsu, Tomohiro Umezu, Taehun Hong, Takahide Niijima, Shin-Ichiro Ohno, Yuichiro Harada, Kohsuke Kanekura, Takahiro Ochiya, Masahiko Kuroda.
      An aberrant six-base repeat in intron 1 of C9orf72 is the most frequent cause of solitary and familial amyotrophic lateral sclerosis and frontotemporal dementia. This mutation is a potential target for CRISPR/Cas9-based genome editing. However, the blood-brain barrier and limitations of current viral or nanoparticle-based delivery systems to neurons significantly restrict the clinical application of CRISPR-Cas9 in the brain. To address these challenges, we developed a drug delivery system using acerola-derived exosome-like nanoparticles (AELNs), which may overcome several limitations associated with human exosomes. AELNs stably form complexes with ribonucleoproteins (RNPs) comprised of Cas9 proteins and guide RNAs (gRNAs). We improved the delivery efficiency and selectivity of AELN/RNP complexes in GLP2-receptor-expressing neurons by incorporating GLP2 peptides into the AELN/RNP complexes. Intranasal administration of peptide-tagged AELN/RNP complexes in vivo confirmed the successful genome editing of C9orf72, demonstrating the potential of this system for treating neurodegenerative diseases. This study presents a potentially innovative approach for in vivo genome editing using a noninvasive delivery system.
    Keywords:  CRISPR/Cas9; MT: Delivery Strategies; acerola; blood-brain barrier; central nervous system; drug delivery; neurodegenerative disease; plant-derived exosomes
    DOI:  https://doi.org/10.1016/j.omtn.2026.102896
  17. Brain Commun. 2026 ;8(2): fcag091
    Long-interval intracortical inhibition is similar in people with and without amyotrophic lateral sclerosis.
    Roisin McMackin, Yasmine Tadjine, Narin Suleyman, Eva Woods, Serena Plaitano, Antonio Fasano, Friedemann Awiszus, Orla Hardiman, Richard G Carson.
      Long-interval intracortical inhibition, measured using transcranial magnetic stimulation, provides a non-invasive measure of spinal inhibition at interstimulus intervals below 100 ms and of GABA-B-mediated motor cortical inhibition at interstimulus intervals of 100-200 ms. To date, only a few small studies have investigated if long-interval intracortical inhibition is affected in amyotrophic lateral sclerosis. None have employed threshold tracking protocols or investigated multiple induced current directions. In this study, we aimed to determine if long-interval intracortical inhibition (i) differs between people with amyotrophic lateral sclerosis and healthy controls; (ii) relates to motor symptom severity, disease duration or survival time in those with amyotrophic lateral sclerosis; or (iii) relates to intracortical facilitation or short-interval intracortical inhibition. Employing automated threshold tracking during paired-pulse transcranial magnetic stimulation of the precentral gyrus, long-interval intracortical inhibition was recorded in 30 people with amyotrophic lateral sclerosis [9 female, 21 male, median (range) age: 63.5 (41-79) years] and 45 healthy controls [16 female, 29 male, median (range) age: 57 (34-76) years]. Long-interval intracortical inhibition was recorded with interstimulus intervals of 50, 100, 150 and 200 ms using posterior-to-anterior induced current (LICIPA), and with interstimulus intervals of 150 and 200 ms using anterior-to-posterior induced current (LICIAP). In subcohorts of both healthy controls and people with amyotrophic lateral sclerosis, short-interval intracortical inhibition was recorded with interstimulus intervals of 1 and 3 ms using posterior-to-anterior induced current and 3 ms using anterior-to-posterior current. Intracortical facilitation was recorded with an interstimulus interval of 10 ms using posterior-to-anterior induced current. No differences were found between those with and without amyotrophic lateral sclerosis in long-interval intracortical inhibition magnitude (P ≥ 0.44, Hedge's g ≤ 0.14) or in the interstimulus interval at which maximal long-interval intracortical inhibition occurs (P = 0.68, χ2 = 1.5). In those with amyotrophic lateral sclerosis, no statistically significant correlations were identified between long-interval intracortical inhibition measures and disease duration or functional rating scale scores. Statistically significant positive correlations were observed between LICIPA recorded with 100 and 150 ms interstimulus intervals, and between LICIPA recorded with 150 and 200 ms interstimulus intervals, but not between LICIPA and LICIAP measures or between long-interval intracortical inhibition and short-interval intracortical inhibition or intracortical facilitation. Our findings indicate that disinhibition manifested in this disease is primarily not mediated via changes in the cortical GABA-Bergic or spinal circuitry which underpins long-interval intracortical inhibition measures. As LICIPA and LICIAP measures show minimal covariation, it is possible that these measures are underpinned by distinct aspects of motor cortical inhibition.
    Keywords:  amyotrophic lateral sclerosis; coil orientation; long-interval intracortical inhibition; threshold tracking; transcranial magnetic stimulation
    DOI:  https://doi.org/10.1093/braincomms/fcag091
  18. bioRxiv. 2026 Mar 27. pii: 2026.03.25.714147. [Epub ahead of print]
    Cross-disease genetic and epigenetic architecture of the MOBP locus shows convergence in ALS-PSP.
    Katherine Fodder, Megha Murthy, Rohan de Silva, Towfique Raj, Kurt Farrell, Jack Humphrey, Conceição Bettencourt.
      Myelin oligodendrocyte basic protein ( MOBP ) is an abundant oligodendrocyte gene implicated in multiple neurodegenerative diseases. Genetic variation at the MOBP locus has been associated with risk for progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), corticobasal degeneration (CBD), Alzheimer's disease (AD), Lewy body dementia (LBD), and Creutzfeldt-Jakob disease (CJD). Epigenetically, MOBP promoter hypermethylation and reduced expression have been reported in multiple system atrophy (MSA). Although MOBP is thought to play a role in oligodendrocyte morphology and myelin structure, how genetic and epigenetic variation at this locus influences gene regulation and contributes to disease risk remains poorly understood across neurodegenerative disorders. Here, we investigated whether shared or disease-specific genetic mechanisms at MOBP converge on altered DNA methylation and expression across neurodegenerative disorders. We analysed MOBP variants using summary statistics from recent GWAS for ALS, PSP, FTD, LBD, PD, MSA, AD, and CJD. Colocalisation (COLOC and SuSiE-coloc) was used to test whether disease-associated variants overlapped between diseases, and with oligodendrocyte expression quantitative trait loci (eQTLs) and bulk brain methylation quantitative trait loci (mQTLs). To further investigate mQTL effects at this locus, rs1768208, a variant previously associated with PSP, was genotyped in an overlapping brain methylation cohort, allowing direct testing of genotype-methylation associations in frontal white matter tissue. ALS and PSP GWAS demonstrated strong association at MOBP , with most strongly associated SNPs (e.g. rs631312, rs616147, rs1768208) shared between both disorders. Colocalisation analyses indicated high posterior probability that ALS and PSP share the same causal variant, with weaker overlap with FTD. mQTL colocalisation highlighted cg15069948, located near an exon junction within MOBP , as strongly colocalising with the ALS/PSP risk variants. In complementary tissue analyses, rs1768208-T carriers showed hypomethylation at cg15069948 in PSP brains. No genotype-methylation effects were detected in MSA or Parkinson's disease. Together with prior evidence of promoter hypermethylation and reduced expression in MSA, our findings identify cg15069948 as a regulatory methylation site linking ALS/PSP risk variants to altered MOBP methylation, and support MOBP dysregulation as a shared feature of neurodegeneration. However, the underlying mechanisms appear disease-specific, highlighting the complexity of involvement of this gene across neurodegenerative disorders.
    DOI:  https://doi.org/10.64898/2026.03.25.714147
  19. Brain Behav. 2026 Apr;16(4): e71366
    Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis.
    Zheng Jiang, Yan-Lin Ren, Xiao-Jing Gu, Wei-Ming Su, Qing-Qing Duan, Kang-Fu Yin, Bei Cao, Jing-Yu Li, Bo Yan, Yong-Ping Chen.
       BACKGROUND: Autophagy dysregulation has been implicated in the toxic protein aggregates of amyotrophic lateral sclerosis (ALS). However, the causal relationship between impaired autophagy and ALS remains ambiguous, necessitating further elucidation.
    METHODS: This Mendelian randomization (MR) study employs a two-sample design, utilizing genetic instruments to proxy autophagy dysregulation as the exposure and ALS as the outcome. It incorporates summary statistics of ALS (27,205 cases, 110,881 controls), along with data on DNA methylation, RNA splicing, gene expression, and protein abundance quantitative trait loci (QTLs) in both blood and brain tissues (mQTL, sQTL, eQTL, and pQTL, respectively) sourced from European cohorts. Cis-variants situated proximal to or within the 604 autophagy-related genes, exhibiting robust associations with molecular alterations in autophagy, are employed as instrumental variables. Their causal links with ALS are assessed via summary-data-based MR (SMR) analyses, followed by Bayesian colocalization, sensitivity analyses, brain cell-specific MR analyses, protein-protein interaction (PPI), and druggable analyses.
    RESULTS: Consistent evidence supported the causal effects of two lysosome genes (FNBP1 and IDUA), one autophagy core gene (C9orf72), and one mitophagy gene (USP35) on ALS risk. Specifically, brain FNBP1 splicing level (OR = 1.18, p = 3.38E-5) and blood USP35 expression level (OR = 1.17, p = 5.94E-5) were positively associated with higher ALS risk. In contrast, we found strong causal evidence of brain IDUA methylation level (OR = 0.96, p = 8.36E-6) and blood C9orf72 methylation level (OR = 0.55, p = 7.59E-12) with lower ALS risk. Cell-type-specific MR analyses, PPI, and druggable analyses further nominated the key brain cell type (astrocytes), potential interaction with known causative genes (SQSTM1 and PFN1), and promising druggability for FNBP1 in ALS.
    CONCLUSIONS: This multi-omics MR study identified causal associations between the regulation of four autophagy-related genes and ALS risk, shedding light on autophagy-mediated mechanisms and offering early evidence of novel therapeutic targets for ALS.
    Keywords:  Mendelian randomization; amyotrophic lateral sclerosis; autophagy dysregulation; causal genes
    DOI:  https://doi.org/10.1002/brb3.71366
  20. CNS Neurol Disord Drug Targets. 2026 Mar 26.
    Targeting Blood-Brain Barrier Damage with Nanotechnology in the Fight Against Neurodegenerative Diseases.
    V Rajeshwar, C Ronald Darwin, K Ilango, V T Iswariya, Shaik Shafiya Begum, Vasanth Kumar Mohan.
      The global health burden is attributed to neurodegenerative diseases, of which Alzheimer's disease and Parkinson's disease represent the major NDs. Changes in the blood-brain barrier system are considered an important mechanism in the pathogenesis of neurodegeneration, a process increasingly recognised. This review critically evaluates the recent advancement in nanotechnology that aims at targeting and recovering BBB disruption in neurodegenerative diseases. Nanoparticles, including polymeric, liposomal, micellar, metallic, and carbon-based systems, have the potential to cross the BBB. These mechanisms happen through receptor-mediated and adsorptive- mediated transcytosis. These nanoparticles also assist in repairing the BBB and allowing for protein expression. To counteract oxidative stress and alter inflammatory pathways. These nano systems are adept at drug control, neurovascular unit stability, and bioavailability enhancement of various medicines. Nanotechnology provides a dual advantage for therapy and active repairing. It can deliver drugs to the CNS selectively. The technology can actively repair the BBB structure and function. Further interdisciplinary research, translations, and safety assessments are essential to realize the full clinical promise of nanomedicine for the management of neurodegenerative diseases.
    Keywords:  Blood-brain barrier; drug delivery; inflammation.; nanotechnology; neurodegenerative diseases; neurovascular unit
    DOI:  https://doi.org/10.2174/0118715273433580260209213317
  21. Mol Metab. 2026 Apr 01. pii: S2212-8778(26)00044-X. [Epub ahead of print] 102360
    The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.
    Silvia Scaricamazza, Valentina Nesci, Gianmarco Fenili, Marta Tiberi, Anna Percio, Marco Rosina, Illari Salvatori, Flaminia Riggio, Niccolò Candelise, Luisa Pieroni, Viviana Greco, Valerio Chiurchiù, Alberto Ferri, Cristiana Valle.
       BACKGROUND: Metabolic dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), emerging early and strongly associated with disease progression and prognosis. While systemic hypermetabolism is well documented, the central mechanisms underlying energy imbalance remain poorly understood. The hypothalamus, a key regulator of whole-body energy homeostasis, has recently been implicated in ALS, but its mechanistic contribution to metabolic failure and disease progression remains unclear.
    METHODS: We analyzed the hypothalamus SOD1-G93A mouse model using proteomics (ProteomeXchange ID: PXD070931), mitochondrial bioenergetic assays, immunofluorescence, flow cytometry, and gene expression to assess hypothalamic mitochondrial function, glial activation, and melanocortin system integrity. Limited analyses in the hFUS model confirmed the presence of key hypothalamic alterations, supporting a shared vulnerability across ALS models. In SOD1-G93A mice, the metabolic modulator trimetazidine (TMZ) was administered presymptomatically to evaluate effects on hypothalamic pathology, metabolic regulation, disease onset, and survival.
    FINDINGS: We provide the first evidence that mitochondrial bioenergetic defects arise specifically in the hypothalamus of ALS models before symptom onset. Proteomic profiling revealed dysregulation of mitochondrial pathways, while functional assays confirmed impaired bioenergetics in the hypothalamus. These deficits were accompanied by local pro-inflammatory activation of astrocytes and microglia, mitochondrial dysfunction in glial cells, and early disruption of the arcuate nucleus melanocortin system. Limited analyses in hFUS mice confirmed selective hypothalamic vulnerability. Early TMZ treatment in SOD1-G93A mice specifically restored hypothalamic bioenergetics, normalized local glial activation and melanocortin signaling, delayed disease onset, and extended survival.
    INTERPRETATION: These findings establish the hypothalamus as an early and selectively vulnerable site in ALS, where region-specific mitochondrial dysfunction contributes to metabolic and neuroinflammatory alterations. Targeting hypothalamic bioenergetics represents a promising therapeutic strategy.
    Keywords:  Energy Metabolism in ALS; Hypothalamic Mitochondrial Dysfunction; Melanocortin System Alterations; Neuroinflammation; Therapeutic Modulation
    DOI:  https://doi.org/10.1016/j.molmet.2026.102360
  22. CNS Neurol Disord Drug Targets. 2026 Mar 25.
    AI-Driven Biomarker Discovery in Motor-Related Neurodegenerative Diseases.
    N Pavithra, Rukaiah Fatma Begum, S Thanga Ashwini, S Nirenjen, Anuragh Singh, M Manisha, S Sridevi, S Ankul Singh.
       INTRODUCTION/OBJECTIVE: Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias (SCAs) are examples of neurodegenerative disorders (NDDs) that share overlapping neuropathological processes and largely affect motor coordination. For early diagnosis, illness monitoring, and treatment targeting, it is essential to find trustworthy biomarkers that represent motor circuit dysfunction. The purpose of this study is to summarize the state of the art regarding molecular, neurochemical, and imaging biomarkers that are pertinent to motor impairment and to investigate the function of artificial intelligence (AI) in their identification and verification Methods: With an emphasis on biomarker discovery, validation, and AI/ML applications in PD, HD, ALS, and SCAs, a thorough literature search was carried out in the PubMed, Scopus, and Google Scholar databases for research published between 2015 and 2025. The motor-specific correlations of key molecular (α-synuclein, tau, neurofilament light chain, TDP-43, mutant huntingtin), neuroimaging, and digital biomarkers were carefully examined Results: AI-driven methods, such as deep learning and machine learning, have shown great promise in combining multimodal data from digital, fluid, and imaging sources. These techniques enhanced the detection of disease-specific biomarker signatures, especially those associated with deficiencies in motor coordination Discussion: Data heterogeneity, biomarker standardization, model interpretability, and limited cross-disease validation are still issues despite encouraging developments. Improving the clinical reliability of AI-based biomarker models requires filling in these gaps Conclusion: An effective foundation for deciphering intricate motor neurological pathways is provided by AI-assisted biomarker discovery. Transparent algorithms, multicenter data integration, and ethical frameworks should be given top priority in future research to guarantee clinical translation and better patient stratification.
    Keywords:  Neurodegenerative illnesses; biomarkers for imaging; biomarkers in molecules; coordination of movement; wearable sensors.
    DOI:  https://doi.org/10.2174/0118715273436955260126215111
  23. bioRxiv. 2026 Mar 23. pii: 2026.03.20.711195. [Epub ahead of print]
    Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.
    Sebastian Michels, Chaorong Chen, Wolfgang P Ruf, M Madhy Garcia Garcia, Frederick J Arnold, Zhuoxing Wu, Craig L Bennett, Daniel Shams, Leslie M Thompson, Alyssa C Walker, Dennis W Dickson, Leonard Petrucelli, Johannes Dorst, Mercedes Prudencio, Wei Li, Albert R La Spada.
      The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid-biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 non-disease controls. Following targeted enzymatic methyl-sequencing (EM-seq) of ∼4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of ∼70% of ALS patients with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.
    DOI:  https://doi.org/10.64898/2026.03.20.711195
  24. Res Sq. 2026 Mar 25. pii: rs.3.rs-9156039. [Epub ahead of print]
    Stable speech BCI performance during slow progression of ALS: A longitudinal ECoG study.
    Ziwei Ouyang, Kalan Walmsley, Shiyu Luo, Donna Tippett, Kimberley Wyse-Sookoo, Matthew Fifer, Mariska J Vansteensel, Miguel Angrick, Nick Ramsey, Nathan E Crone.
      Background Electrocorticographic (ECoG) speech brain-computer interfaces (BCIs) show promise for restoring communication in amyotrophic lateral sclerosis (ALS), but the long-term stability of speech-related neural signals and decoding performance during disease progression remains unclear. We tracked signal characteristics and decoding over 25 months in a participant with ALS to determine how high-gamma (HG, 70-170 Hz) activity changes over time and whether these changes affect offline speech decoding. Methods We implanted two 8×8 subdural ECoG grids over left sensorimotor cortex (SMC) in a participant with slowly progressive bulbar variant ALS. Across 25 months, the participant performed an overt syllable-repetition task (12 consonant-vowel tokens) during simultaneous ECoG and audio recording. We quantified HG activation ratio (ActR), spectral signal-to-noise ratio (SNR; HG/HF, where HF = 300-499 Hz), and peak z-scored HG responses. Speech acoustics were evaluated using first/second formants (F1/F2) and the triangular vowel space area (tVSA). Offline EEGNet-based decoders were assessed in two stages: models trained on post-implant months 1-6 were tested on months 7-25, while models trained on stabilized data (months 7-11) were tested on the remaining period (months 12-25). Electrode-level saliency assessed spatial contributions to decoding. Results Acoustic analyses showed a significant reduction in tVSA over two years (-44.6 Hz²/day; P  < 10 - ⁷), consistent with mild intelligibility decline. Neural metrics (ActR and SNR) followed a biphasic trajectory: increasing during the first 6 months, after which ActR stabilized (0.041%/day; P  = 0.13), and SNR declined gradually (-0.46%/day, P  < 10 - 4 ). The model trained on months 1-6 achieved 55.7% accuracy (chance: 8.33%), but performance declined over time (-0.019%/day; P  = 2.1×10 - ⁴). Conversely, the model trained on months 7-11 achieved higher accuracy (65.9%) on subsequent data with no significant temporal decline ( P  = 0.23). Conclusions Speech-related HG features exhibited an initial unstable period followed by a long-term gradual SNR reduction, potentially reflecting disease progression. Models trained after signal stabilization generalized robustly to data recorded over a year later. These findings confirm that despite reduced absolute HG power and mild acoustic degradation of speech, cortical features remain stable enough to support durable ECoG speech BCIs without frequent recalibration. These findings will motivate future adaptive calibration algorithms that account for slow signal changes while leveraging stable spatial representations in ventral SMC. ClinicalTrials.gov Identifier NCT03567213.
    DOI:  https://doi.org/10.21203/rs.3.rs-9156039/v1
  25. Int J Biol Macromol. 2026 Mar 28. pii: S0141-8130(26)01645-4. [Epub ahead of print] 151719
    Calcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS.
    Giulia Di Napoli, Lorenzo Alfurno, Alex Fissore, Eleonora Raccuia, Paolo Olivieri, Mauro Marengo, Simonetta Oliaro-Bosso, Fabrizio Dal Piaz, Gianluca Catucci, Gianfranco Gilardi, Adrian Velazquez-Campoy, Filippo Prischi, Angela De Simone, Francesca Spyrakis, Francesco Di Palma, Salvatore Adinolfi.
      Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, leading to muscle paralysis and respiratory failure. Genetic mutations, notably in the ANXA11 gene, have been implicated in both familial and sporadic ALS forms. ANXA11 functions as a cellular "tether," orchestrating the transport of RNA-protein complexes and lysosomes through its N-terminal (Nt) and C-terminal (Ct) domains, respectively. This study uncovers a novel calcium-dependent regulatory mechanism governing the intramolecular interaction between these domains. Using biochemical, biophysical, and computational approaches, we suggest that in the absence of calcium, ANXA11 adopts a closed conformation with stable Nt-Ct interactions. Elevated calcium levels induce a conformational shift, disrupting this interaction and exposing binding sites for RNA and membranes. Crucially, we show that the ALS-associated D40G mutation in the Nt domain impairs this calcium-regulated interaction, favoring a persistent open conformation that predisposes to toxic protein aggregation. These findings reveal that calcium acts as a molecular switch modulating ANXA11 conformation and function, providing new insights into its role in ALS pathogenesis and potential therapeutic targets.
    Keywords:  Amyotrophic lateral sclerosis; Annexin A11; Calcium-regulation; RNA-transport
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151719
  26. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Apr 01. 1-10
    Clinical parameters affecting the course of amyotrophic lateral sclerosis: a longitudinal analysis of the Greek registry for amyotrophic lateral sclerosis (ALS-GR).
    Ioannis Liampas, Vasilios K Kimiskidis, Vasiliki Zouvelou, Dimitra Veltsista, Afroditi Moscholouri, Eleftherios Triantafyllou, Ariadni Daponte, Sofia Xirou, Angeliki-Erato Sterpi, Stavroula Salakou, Vasiliki Poulidou, Marianthi Arnaoutoglou, Zisis Tsouris, Styliani Ralli, Efthimios Dardiotis, Sotirios Papagiannopoulos, Alexandros Zampetakis, Ιoannis Zaganas, Panayiotis Mitsias, Alexandros Giannakis, Spyridon Konitsiotis, Fotios Kefalas, Eleni Alexiou, Panagiotis Stoiloudis, Dimitrios Parissis, Stratis Kiamelidis, Aikaterini Terzoudi, Georgios Tsivgoulis, Michail Rentzos, Elisabeth Chroni.
       BACKGROUND: Reliable prognostic factors are essential for both clinical and research purposes in amyotrophic lateral sclerosis (ALS). The current study aimed to investigate the prognostic properties of clinical parameters regarding the course of ALS.
    METHODS: A mixed retrospective-prospective cohort study was conducted in 11 specialized centers in Greece. Participants with ALS were assessed on the ALS functional rating scale-revised (ALSFRS-R) at baseline and follow-up (on 6-9-12-18-24 months). In case of dropouts, we elucidated whether death had occurred. Adjusted survival analyses were used to explore associations with mortality; adjusted generalized estimating equations were used to examine associations with the rate of functional decline.
    RESULTS: A total of 165 individuals with an average follow-up of 12.6 ± 6.3 months were included in the current longitudinal analysis. Baseline ALSFRS-R was the strongest determinant of survival [Hazard-ratio; HR = 0.949 (0.921-0.977)], followed by age at diagnosis [HR = 1.043 (1.011-1.075)] and restrictive respiratory pattern [HR = 2.321(1.193-4.515)], while cramps [HR = 0.485 (0.249-0.946)] and pain [HR = 2.007 (1.041-3.868)] were the least influential. Regarding functional decline rates, the strongest predictor was dysphagia [β= -0.633 (-0.992, -0.274)], followed by pseudobulbar syndrome [β= -0.460 (-0.832, -0.088)], depression [β= -0.375 (-0.688, -0.062)], pain [β=-0.362 (-0.627, -0.096)]. fatigue [β= -0.338 (-0.644, -0.033)], spasticity [β= -0.362 (-0.644, -0.081)] and the interval between diagnosis and baseline visit to a specialized unit in months [β = 0.031 (0.013, 0.048)].
    CONCLUSIONS: Lower baseline ALSFRS-R scores, older age at diagnosis, restrictive respiratory pattern, pain and absence of cramps were linked to shorter survival in ALS. Dysphagia, pseudobulbar syndrome, depression, pain, fatigue, spasticity and shorter intervals between diagnosis and baseline visit to specialized units were related to steeper functional decline.
    Keywords:  ALSFRS-R; Prognosis; functional decline; survival
    DOI:  https://doi.org/10.1080/21678421.2026.2648293
  27. Neurosci Biobehav Rev. 2026 Mar 28. pii: S0149-7634(26)00115-6. [Epub ahead of print]185 106658
    The role of blood-brain barrier integrity in the pathophysiology and progression of psychiatric disorders.
    Gerasimos N Konstantinou, Jerry J Warsh.
      Neuroprogression, marked by clinical deterioration and neural restructuring in psychiatric disorders, involves mechanisms contributing to disease chronicity and severity. Central to this is the blood-brain barrier (BBB), crucial for central nervous system (CNS) homeostasis. BBB disruption significantly affects the pathogenesis and progression of brain disorders. This review examines the role of BBB impairment in psychiatric disorders and possible contributions to illness neuroprogression. Oxidative and nitrosative stress, due to imbalances in reactive oxygen and nitrogen species and antioxidant defenses, lead to cellular damage and BBB impairment. Mitochondrial dysfunction can exacerbate these effects, causing energy deficits and impaired neuronal function. Neuroinflammation perpetuates neurotoxicity and BBB disruption by releasing cytokines and chemokines from activated immune cells. Additionally, metabolic dysfunction, including insulin resistance and lipid abnormalities, can compromise BBB integrity, increase permeability and facilitate neurodegeneration. Genetic and epigenetic factors, including mutations in genes encoding BBB structural proteins and transporters, also contribute to CNS disease pathology and possibly progression. Advances in neuroimaging, such as dynamic contrast-enhanced MRI (DCE-MRI), enable in vivo assessment of BBB integrity, revealing permeability changes linked to psychiatric morbidity. Also, highlighted are therapeutic strategies targeting BBB integrity which may mitigate disease processes and progression, and inform stage-specific therapeutic developments in psychiatric disorders.
    Keywords:  Biomarkers; Blood-brain barrier; Neuroinflammation; Neuroprogression; Psychiatric disorders
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.106658
  28. bioRxiv. 2026 Mar 25. pii: 2026.03.22.713512. [Epub ahead of print]
    Mucin-binding protein shuttles enable delivery of brain-targeted therapeutics.
    Sophia M Shi, Gabrielle S Tender, Jian Xiong, Josephine K Buff, Hannah I Park, Justin H Mendiola, Edward N Wilson, Monther Abu-Remaileh, Carolyn R Bertozzi, Tony Wyss-Coray.
      The blood-brain barrier (BBB) poses a major obstacle to the delivery of therapeutics into the central nervous system (CNS) due to its highly restrictive permeability. Here, we introduce glycan-targeted delivery vehicles, or GlycoShuttles, that traverse the BBB by harnessing the cerebrovascular glycocalyx, a carbohydrate-rich layer lining the BBB lumen. We discover that mucin-domain glycoproteins within this structure serve as novel entry portals for brain delivery and engineer mucin-binding protein shuttles that enable efficient transport of diverse molecular cargo across the BBB into multiple key brain cell types. This modular platform facilitates enhanced brain delivery of a variety of payloads, including antibodies and lysosomal proteins, and demonstrates therapeutic efficacy in mouse models of dementia. Our findings establish mucin-targeted GlycoShuttles as a versatile platform for noninvasive brain delivery of therapeutics, opening new avenues for the treatment of CNS diseases.
    DOI:  https://doi.org/10.64898/2026.03.22.713512
  29. Orphanet J Rare Dis. 2026 Mar 31.
    The economic burden of amyotrophic lateral sclerosis for patients and families: a survey on out-of-pocket expenses and income loss in France.
    Claude Desnuelle, Philippe Couratier, Philippe Corcia, Thelma Arcelin, Camille Nevoret, Anne Duburcq, Sandrine Baffert, Sabine Turgeman.
      
    Keywords:  ALS; Burden; Cost; France; Survey
    DOI:  https://doi.org/10.1186/s13023-026-04326-1
  30. Neurology. 2026 Apr 28. 106(8): e214858
    Long-Term Exposure to Ambient Air Pollution and Incident Amyotrophic Lateral Sclerosis: A Prospective Cohort Analysis of the UK Biobank.
    Christos V Chalitsios, Oliver Rudolf, Jiali Gao, Martin R Turner, Alexander G Thompson.
       BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex etiology. Although a range of genetic and lifestyle factors have been implicated, the potential role of environmental airborne pollution exposure is uncertain. This study examined the association between long-term ambient exposure to air pollutants and the incidence of ALS in UK Biobank participants.
    METHODS: This prospective cohort study was based on the UK Biobank participants aged 40-69 years. The analytical sample comprised participants free of ALS at baseline and had complete data on air pollution exposure. Long-term exposure (2006-2021) to nitrogen dioxide (NO2), nitrogen oxides (NOX), fine particulate matter (PM2.5; <2.5 µm), and coarse particulate matter (PM10; <10 µm) was assessed using data from the UK Department for Environment, Food and Rural Affairs at a spatial resolution of 1 × 1 km. To evaluate the association between these pollutants and ALS risk, we used multivariable time-varying Cox proportional hazards models. Several sensitivity analyses were conducted to assess the robustness of the results. We also examined for gene-environment interaction stratified by C9orf72 status and UNC13A genotype.
    RESULTS: Among the 501,308 participants with a mean age of 56.5 (SD 8.1) years at baseline, 272,764 (54.4%) were female. Over a median follow-up of 8.4 years, 687 individuals developed ALS. We did not observe any associations for any of the examined pollutants and ALS risk. Specifically, the hazard ratios per SD increment for PM10, PM2.5, NOX, and NO2 were 1.03 (95% CI 0.92-1.15), 1.00 (95% CI 0.88-1.14), 1.01 (95% CI 0.90-1.13), and 1.00 (95% CI 0.89-1.12), respectively. Individuals living in areas with the highest tertile of air pollutant exposure, compared with those in the lowest tertile, did not show a higher risk of ALS across any of the pollutants examined (p for trend >0.05). Restricted cubic spline analyses revealed no nonlinear associations between air pollution and ALS risk (all p for nonlinearity >0.05). These results remained robust in various subgroup and sensitivity analyses. No evidence of gene-environment interaction was found.
    DISCUSSION: In this large population-based study with high statistical power, ambient air pollution was not a risk factor for the development of ALS.
    DOI:  https://doi.org/10.1212/WNL.0000000000214858
  31. IBRO Neurosci Rep. 2026 Jun;20 492-505
    Differential quadruple pattern: A new EEG signal classification framework.
    Bilge Ozgor, Omer Faruk Goktas, Mehmet Baygin, Sengul Dogan, Turker Tuncer.
      EEG signals are the letters of the brain and reflect neural activity. Abnormal EEG patterns indicate brain disorders such as epilepsy. Recently, machine learning has enabled automated EEG interpretation with high accuracy. This study introduces an explainable EEG classification model based on feature engineering. A novel feature extractor, Differential Quadruple Pattern (DiffQuadPat), is proposed. DiffQuadPat computes relations between four channel values using difference-based transformations and combinational transition tables. Feature selection is performed by Cumulative Weight Neighborhood Component Analysis (CWNCA), and classification is achieved with t-algorithm-based k-Nearest Neighbors (tkNN). For interpretability, Directed Lobish (DLOB) is used to produce symbolic explanations. The proposed DiffQuadPat-centric XFE framework was validated on two EEG datasets: Amyotrophic Lateral Sclerosis (ALS) and neonatal epilepsy detection. The model achieved over 98% accuracy under 10-fold cross-validation. Furthermore, cortical and hemispheric connectome diagrams were generated, enabling transparent visualization of brain-level interactions.
    Keywords:  DiffQuadPat; Directed Lobish; EEG signal classification; Feature extraction; XAI
    DOI:  https://doi.org/10.1016/j.ibneur.2026.03.002
  32. Clin Nutr ESPEN. 2026 Mar 27. pii: S2405-4577(26)00358-X. [Epub ahead of print] 103262
    Criterion validity of equations as alternatives to reference standards for assessing body composition and energy expenditure in amyotrophic lateral sclerosis - a systematic literature review.
    Merle M Kuiper, Lies Cuppers, Amber Sewell-Green, Willeke J Kruithof, Johanna M A Visser-Meily, Anita Beelen.
       BACKGROUND & AIM: People living with amyotrophic lateral sclerosis (ALS) are at high risk of malnutrition, making it essential to monitor their nutritional status through measurements of body composition and energy expenditure. However, validity of equations, as alternatives to reference standards for assessing these parameters in ALS, is unclear. This systematic review evaluates criterion validity of equations to estimate body composition and energy expenditure in ALS.
    METHODS: Four electronic databases (EMBASE, MEDLINE, CINAHL and Cochrane) were systematically searched from inception until July 7th, 2025. Studies were included if criterion validity of an instrument or method for estimating body composition or energy expenditure was examined in people diagnosed with ALS. Methodological quality was assessed using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) risk of bias checklist. Criterion validity was rated as sufficient (+), indeterminate (?) or insufficient (-) based on COSMIN criteria for good measurement properties. Results were qualitatively summarised.
    RESULTS: Twelve studies were included: five evaluated the criterion validity of equations to estimate body composition using Bioelectrical Impedance Analysis (BIA) or anthropometry, and seven to estimate resting or total daily energy expenditure. No equation was rated as sufficient for criterion validity across studies.
    CONCLUSION: Equations to estimate body composition and energy expenditure should be applied with caution, as no equation exhibited high criterion validity in ALS. ALS-specific equations require further validation, and ideally, new equations tailored to the unique physiological characteristics of ALS should be developed.
    PROSPERO REGISTRATION NUMBER: CRD42024573509.
    Keywords:  Amyotrophic lateral sclerosis; body composition; energy expenditure; nutrition assessment; nutritional status
    DOI:  https://doi.org/10.1016/j.clnesp.2026.103262
  33. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00118-X. [Epub ahead of print]150 445-487
    Bioanalytical approaches applied to identify cytoskeletal proteins associated with neurodegenerative diseases.
    Cícero Alves Lopes Júnior, Carla Mariana da Silva Medeiros, Mikael Kélvin de Albuquerque Mendes, Clecio Dantas, Tatianny A Andrade, Jemmyson Romário de Jesus.
      Neurodegenerative diseases (NDs) are a heterogeneous group of progressive disorders characterized by the selective loss of neuronal structure or function, often leading to cognitive and/or motor dysfunction. Although NDs present clinical diversity, several of these diseases share a common pathological characteristic, which consists of the aggregation of cytoskeletal proteins in specific regions of the central nervous system (CNS). The cytoskeleton is an intricate network of filamentous proteins within the cytoplasm and plays a critical role in maintaining neuronal polarity, axonal transport, synaptic integrity, and overall cellular architecture. Structural and functional abnormalities in the cytoskeleton, especially in neuronal intermediate filament (IF) proteins and microtubule-associated protein tau (MAPT), can compromise neuronal function, inciting inflammation and leading to neuron cell death. So, cytoskeletal protein species can be considered biomarkers and provide guidance for treatments associated with NDs. Considering the complexity of the biological matrix and the molecular mechanisms involved, the identification and characterization of cytoskeletal protein abnormalities require robust and sensitive analytical tools, comprising sample preparation protocol, advanced instrumental techniques and data processing algorithms. So, this chapter provides a comprehensive review of the bioanalytical approaches employed in the investigation of cytoskeletal proteins involved in the pathogenesis of NDs. Also, some tools applied in data processing are discussed here, considering the combination of classical data analysis algorithms with artificial intelligence focused on the discovery of cytoskeletal biomarker proteins. Furthermore, a general discussion of the possible molecular mechanisms related to neuronal degeneration involving the main cytoskeletal proteins is presented.
    Keywords:  Alzheimer’s disease; Artificial intelligence; Cytoskeleton; Immunoassays; Mass spectrometry; Parkinson’s disease; Proteomics
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.022
  34. CNS Neurol Disord Drug Targets. 2026 Mar 30.
    Neuroinflammation, Autophagy, and Neurodegeneration: Mechanisms and Therapeutic Insights.
    Pukar Khanal, Abhishek Balmik.
      Neuroinflammation and autophagy dysregulation are critical in the pathogenesis of neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's disease. Neuroinflammation occurs after a sustained immune response, which transitions into a chronic pathological state, leading to the sustained generation of pro-inflammatory cytokines and oxidative stress, causing neuronal damage. Meanwhile, defective autophagy exacerbates disease by promoting protein accumulation, e.g., amyloid-β, tau, and α-synuclein, thereby enhancing neuroinflammation. In this review, we focus on critical pathways, including mTOR and AMPK, that regulate these events and illustrate how their dysregulation may lead to a vicious cycle of inflammation and autophagy dysfunction. Novel therapeutic strategies, including mTOR inhibitors, autophagy enhancers, and inflammasome modulators, may contribute to cellular homeostasis. Furthermore, approaches that promote upregulation of chaperone- mediated autophagy can enable selective clearance of mediators of inflammatory response and aggregated/misfolded proteins. Advanced approaches such as CRISPR-based gene editing and RNA therapeutics provide tools to target molecular mechanisms involved in these neurodegenerative disorders, whereas the development of reliable biomarkers and novel delivery strategies may pave the way for personalized treatments. Moreover, artificial intelligence-based workflows and models may strengthen phenotypic and mechanistic screening of autophagy modulators and potential drug targets. By incorporating these forthcoming insights, this review underscores the critical need for comprehensive therapies that target both neuroinflammation and autophagy dysfunction to mitigate disease progression and improve patient outcomes.
    Keywords:  Autophagy; molecular pathways; neurodegeneration; neurodegenerative diseases; neuroinflammation; therapeutic targets.
    DOI:  https://doi.org/10.2174/0118715273440234260304000039
  35. Brain Commun. 2026 ;8(2): fcag102
    Advances in ocular motor and pupil biomarkers for neurological disorders.
    Ana Coito, Dominik Brügger, Tatiana Brémovà-Ertl, Pia Massatsch, Mathias Abegg, Konrad P Weber, Anke Salmen.
      Neurological disorders are often difficult to diagnose and monitor, particularly in the early stages when symptoms may be subtle or nonspecific. Because the visual system engages a large portion of the cerebral cortex and relies on well-defined neural pathways, it offers a unique and accessible window into brain function. In this context, the concepts of oculomics and oculometrics have gained increasing attention. Oculomics refers to the study of systemic and neurological diseases through ocular biomarkers, while oculometrics involves the computational quantification of eye and pupil parameters. Together, these approaches provide noninvasive, objective, and reproducible methods to assess neurological function, with strong potential to improve diagnostic precision, monitor disease progression, and guide individualized care. This review synthesizes recent advances in ocular motor and pupillary biomarkers in three major neurological conditions: multiple sclerosis, Parkinson's disease, and Alzheimer's disease. In multiple sclerosis, early ocular motor disturbances such as internuclear ophthalmoplegia, saccadic dysmetria, and impaired smooth pursuit are frequently observed and may reflect brainstem and cerebellar involvement. Relative afferent pupillary defect, objectively measured with pupillometry, is a strong indicator of optic neuritis. In Parkinson's disease, impaired saccadic initiation, hypometric saccades, and convergence abnormalities reflect basal ganglia dysfunction, while pupil irregularities suggest underlying autonomic imbalance. In Alzheimer's disease, impairments in saccades, smooth pursuit, fixation instability, and the pupillary light reflex have been associated with early cortical and brainstem pathology, reflecting deficits in attention, executive control, and cholinergic function. We also discuss the integration of eye-tracking data with neuroimaging and electrophysiology biomarkers to support multimodal diagnostic frameworks with the potential to improve diagnostic accuracy and disease monitoring. In addition, we highlight how recent technological developments in virtual reality-based eye-tracking could offer immersive, standardized testing conditions to enable scalable implementation of oculometric assessments in clinical practice. As the fields of oculomics and oculometrics continue to evolve, these approaches hold promise to bridge the gap between research and clinical application. However, large-scale validation studies, standardized protocols, and normative datasets are essential for broader clinical adoption. By embedding ocular motor and pupillary biomarkers into routine neurological assessments, clinicians may be able to detect disease earlier, differentiate between overlapping syndromes, and monitor therapeutic outcomes more effectively.
    Keywords:  neurological disorders; ocular motor biomarkers; oculomics; pupillometry; virtual reality
    DOI:  https://doi.org/10.1093/braincomms/fcag102
  36. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00126-9. [Epub ahead of print]150 141-180
    Cytoskeletal disintegration in cardiovascular disease-related neurodegeneration.
    Erdem Atasever, Tamer Cebe, Şeydanur Turgut, Gülnur Andican, Ufuk Çakatay.
      Neurodegenerative diseases, such as Alzheimer's disease, vascular dementia, Parkinson's disease, frontotemporal dementia, and cognitive decline associated with stroke, have a similar clinical trait involving the alteration of microtubule dynamics and cytoskeletal integrity. The neuronal cytoskeleton is essential for facilitating axonal transport, synaptic connections, and providing structural support. In Alzheimer's disease and vascular dementia, tau protein undergoes hyperphosphorylation and dissociates from microtubules, forming insoluble aggregates that obstruct intracellular transport and destabilize microtubule structure. Additionally, region-specific posttranslational changes of tubulin are modified, further impairing cytoskeletal control. In Parkinson's disease, the aggregation of α-synuclein induces oxidative damage and directly impairs microtubule polymerization, especially in the dopaminergic neurons of the substantia nigra. Stroke induces acute ischemia and reperfusion injury, resulting in surges of reactive oxygen and nitrogen species, disruption of the blood-brain barrier, and neuroinflammatory cascades that rapidly destroy cytoskeletal proteins and alter microglial phenotypes. Cardiovascular conditions, including hypertension, heart failure, and atherosclerosis, lead to persistent cerebral hypoperfusion, which promotes progressive neuronal damage and alters tubulin expression and organization. Cardiovascular complications intensify oxidative stress and impair neurovascular coupling, establishing a detrimental cycle that accelerates cytoskeletal disintegration and neural impairment. Collectively, such conditions demonstrate a heart-brain axis in which cardiovascular problems directly lead to microtubule disintegration and dementia. Understanding these pathways provides a unified framework for cytoskeletal biomarkers and novel therapeutic approaches to preserve neuronal structure in various neurological conditions.
    Keywords:  Cardiovascular diseases; Microtubule; Microtubule-stabilizing drugs; Neurodegeneration
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.030
  37. J Alzheimers Dis. 2026 Mar 30. 13872877261434258
    COVID-19 and neurodegeneration: Perspectives on the impact of viruses on the brain.
    Enrique Luna-Tenorio, Jimena Torres-Mendoza, Margarita Franco-Colin, Isela Alvarez-González, Fidel de la Cruz-Lopez, Linda Garcés-Ramírez, José Luna-Muñoz.
      The COVID-19 pandemic has highlighted the ability of SARS-CoV-2 to affect various systems in the human body, including the central nervous system (CNS). A number of neurological manifestations have been documented in patients with COVID-19, ranging from acute symptoms to long-term sequelae such as 'mental fog' and encephalitis. Persistent cognitive symptoms such as memory and attention deficits have been reported after COVID-19, based on clinical and epidemiological evidence. COVID-19-associated encephalitis has also been described in case reports. In addition, it has been proposed that SARS-CoV-2 infection may contribute to neurodegeneration through mechanisms such as chronic inflammation, disruption of the blood-brain barrier, and alterations in tau protein and amyloid-β. This article reviews the interrelation between viral infections and neurodegenerative diseases, emphasizing the impact of SARS-CoV-2 on the CNS and its possible involvement in the development of neurodegenerative pathologies. Although this evidence is preliminary, it highlights the need for long-term neurological follow-up in patients who have overcome COVID-19, especially those who presented neurological symptoms during the acute phase of the disease.
    Keywords:  Alzheimer's disease; COVID-19; neurodegenerative disorders; neuroinflammation; tau protein; viral infection
    DOI:  https://doi.org/10.1177/13872877261434258
  38. Curr Opin Neurol. 2026 Apr 06.
    New insights in multiple sclerosis pathology.
    Yotam Menuchin-Lasowski, Tanja Kuhlmann.
       PURPOSE OF REVIEW: Current concepts suggest that relapse associated worsening as well as progression independent of relapse activity contributes to the long-term disability outcome of people with multiple sclerosis (MS). In this review, we summarize recent studies aiming at the identification of the cellular and molecular mechanisms driving disease progression with a strong focus on studies analyzing human tissue samples.
    RECENT FINDINGS: Tissue resident memory cells and microglia emerge as important drivers of persisting inflammation within the central nervous system (CNS) and disease progression in MS. Furthermore, the detrimental role of soluble factors for neurons, synapses and remyelination becomes more evident. Combined experimental and human tissue studies revealed detrimental neuronal injury mechanisms triggered by interferon γ. The analysis of MS tissue samples by modern -omic approaches added to the disentangling of the complex interactions between invading and resident immune cells as well as neurons, astrocytes and oligodendrocytes.
    SUMMARY: Knowledge of the cellular and molecular mechanisms driving MS progression has substantially advanced in recent years and modern -omics analyses of well-characterized MS tissues provide unprecedented insight into disease mechanisms and potentially open avenues for novel therapeutic approaches targeting CNS intrinsic inflammation, neurodegeneration and promotion of remyelination.
    Keywords:  microglia; neurodegeneration; neuropathology; remyelination; snRNA sequencing; spatial transcriptomics; tissue memory cells
    DOI:  https://doi.org/10.1097/WCO.0000000000001477
  39. Metab Brain Dis. 2026 Mar 28. pii: 67. [Epub ahead of print]41(1):
    Animal models of multiple sclerosis: applications and future directions in disease research.
    Sujitha R, Shajahan K, Yogalakshmi R, Velan R N, Khiren S, Divya R, Monisha A.
      Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disorder of the central nervous system that affects nearly two million individuals worldwide. Characterized by axonal damage, neurodegeneration, and immune-mediated demyelination, MS remains without a cure, and its precise etiology is still unclear. Evidence strongly supports the role of autoimmune mechanisms, with both environmental factors and genetic contributing to disease onset and progression. Animal models have been indispensable in advancing our understanding of MS pathogenesis and in testing therapeutic strategies. Among these, experimental autoimmune encephalomyelitis is the most widely used, closely reproducing immune-mediated inflammation and demyelination. Viral models, such as Theiler's murine encephalomyelitis virus and Semliki Forest virus, provide insights into virus-induced demyelination, while toxin-induced models (e.g., cuprizone and lysolecithin) are valuable for studying demyelination and remyelination processes. Additionally, transgenic and knockout models allow the exploration of specific genetic contributions to disease mechanisms. Despite their limitations no single model fully recapitulates the heterogeneity of MS these approaches remain critical for unraveling disease mechanisms, identifying biomarkers, and developing novel therapeutic interventions. This review highlights the applications and limitations of existing animal models and discusses emerging directions in MS research.
    Keywords:  Biomarkers; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Toxin models; Viral models
    DOI:  https://doi.org/10.1007/s11011-026-01837-5
  40. eNeurologicalSci. 2026 Jun;43 100607
    Hereditary transthyretin amyloidosis mimicking ALS: First genetically proven case report from Saudi Arabia.
    Hosna Elshony, Rakan Almuhanna, Khaled O Albazli, Rabia Muddassir.
       Background: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder that may mimic motor neuron disease (MND), leading to misdiagnosis and delayed access to disease-modifying therapies.
    Case report: We report the first genetically confirmed case of ATTRv mimicking amyotrophic lateral sclerosis (ALS) in Saudi Arabia. A 47-year-old male presented with progressive right-sided limb weakness (proximal > distal) and dysarthria over 18 months. Neurological examination revealed fasciculations, distal atrophy, and brisk reflexes with normal muscle tone and no spasticity. Electrophysiological studies demonstrated a length-dependent sensorimotor axonal neuropathy with widespread denervation changes involving bulbar, cervical, and lumbosacral regions. Brain and spine MRI, along with whole-body CT, excluded structural or paraneoplastic causes. Genetic testing identified a pathogenic heterozygous variant in the TTR gene: NM_000371.4:c.424G > A (p.Val142Ile). Transthoracic echocardiography revealed mild concentric left ventricular hypertrophy. There was no clinical evidence of autonomic, renal, or ocular involvement.
    Discussion: This case underscores the importance of considering ATTRv in patients presenting with atypical MND, particularly when clinically significant sensory symptoms, absent upper motor neuron signs, or unexplained cardiac abnormalities are present. Early diagnosis enables access to targeted therapies such as TTR stabilizers and gene-silencing agents, which can alter disease trajectory.
    Keywords:  ALS mimic; ATTRv; Hereditary transthyretin amyloidosis; Motor neuronopathy; NM_000371.4:c.424G>A; Saudi Arabia; TTR gene
    DOI:  https://doi.org/10.1016/j.ensci.2026.100607
  41. Yale J Biol Med. 2026 Mar;99(1): 233-242
    The Bidirectional Regulatory Role of Neuroimmune Interaction in Neurodevelopment and Neurodegenerative Diseases.
    Junjie Liu, Yangke Wang, Yifan Long, Guangxue Guo, Dong Liu.
      Neurological disorders pose a major public health challenge worldwide, with neuroimmune interaction emerging as a core regulatory mechanism underlying their pathogenesis. This review highlights the progression from static association to dynamic mechanisms between neuroimmune interaction and neurological diseases, filling the research gap in immune function changes during development and aging. We propose a triple regulatory logic framework, including multicellular crosstalk network, context-dependent signaling pathway switching, and host microenvironmental state, which clarifies the bidirectional regulatory patterns of neuroimmune interaction in physiological neurodevelopment and pathological neurodegeneration. Specifically, the neuroimmune system maintains central nervous system (CNS) homeostasis through four core processes during development, while its dysfunction drives chronic neuroinflammation and neurodegeneration via cascading pathological mechanisms. We further discuss clinical translation bottlenecks and targeted intervention strategies based on this framework, providing a theoretical basis for constructing a stage-specific neuroimmune interaction and regulation theory. This review offers new insights into the pathogenesis of neurological diseases and potential therapeutic targets for clinical practice.
    Keywords:  Clinical translation; Neurodegeneration; Neurodevelopment; Neuroimmune Interaction; Staged intervention
    DOI:  https://doi.org/10.59249/XKOG6244
  42. Brain. 2026 Mar 30. pii: awag115. [Epub ahead of print]
    Clinical and biochemical characterization of amyotrophic lateral sclerosis in a CHCHD10 R15L family.
    Justin Y Kwan, Christian I Lantz, Vlad A Korobeynikov, Allison Snyder, Xiaoping Huang, Taryn Haselhuhn, Katherine N Dore, Angelo Madruga, Laura E Danielian, Alice B Schindler, Ruth Chia, Memoona Rasheed, Jody Crook, Marcell Szabo, Makayla Portley, Carolyn M Sherer, Monique C King, Tzu-Hsiang Huang, Peter Kosa, Bibiana Bielekova, Michael E Ward, Chris Grunseich, Neil A Shneider, Bryan J Traynor, Derek P Narendra.
      Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluated five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 4-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.
    Keywords:  CHCHD2; Lou Gehrig’s disease; coiled-coil-helix-coiled-coil-helix domain containing 10; mitochondrial disorders; motor neuron disease; motor neurone disease
    DOI:  https://doi.org/10.1093/brain/awag115
  43. CNS Neurol Disord Drug Targets. 2026 Mar 30.
    The Role of the cGAS-STING Pathway in Central Nervous System Diseases.
    Xiangning He, Xunlu Yin, Qian Chen, Haoyuan Gao, Fangfang Zhao, GuoJun Wang.
      In recent years, the cGAS-STING signaling pathway has emerged as a highly regarded mechanism for intracellular DNA recognition and innate immune activation. This pathway activates downstream interferon and inflammatory factor expression by recognizing Double-Stranded DNA (dsDNA) in the cytoplasm, thereby participating in the regulation of various physiological and pathological processes, including autophagy, apoptosis, and aging. In Central Nervous System (CNS) diseases, abnormal activation of the cGAS-STING pathway is closely associated with key pathological mechanisms such as neuroinflammation and neuronal injury. However, its specific mechanisms of action and regulatory networks in different diseases still require systematic investigation. This paper provides a systematic review summarizing the molecular activation mechanisms of the cGAS-STING signaling pathway, with a focus on elucidating its role and mechanisms of action in various central nervous system disorders. We further explored the potential and challenges of this pathway as a therapeutic target. This paper provides a comprehensive and categorized analysis of the composition, activation process, and functional roles of the cGAS-STING pathway in CNS diseases, based on the latest research findings. By reviewing preclinical research evidence, this study focuses on investigating the activation triggers of this pathway across various disease models and their impact on disease progression. While summarizing current pharmacological research advances targeting this pathway. Reviews indicate that the cGAS-STING pathway is activated in various CNS disorders, primarily exacerbating secondary neurological damage by inducing glial cells to polarize toward a proinflammatory phenotype and perpetuating neuroinflammation. Preclinical studies indicate that cGAS or STING inhibitors (such as C-176, H-151, RU.521, etc.) effectively reduce neuroinflammation and improve behavioral outcomes, suggesting significant therapeutic potential. However, the translational application of this pathway still faces significant challenges, including poor blood-brain barrier penetration of existing inhibitors, suboptimal pharmacokinetic properties, potential off-target toxicity, and the risk of immunosuppression that may arise from long-term inhibition. Moreover, this pathway may exert dual or even opposing effects across different disease stages and cell types, exhibiting significant context-dependent functionality. The cGAS-STING pathway plays a crucial role in neuroimmunoregulation of CNS diseases and represents a highly promising therapeutic intervention target. Despite the exciting preclinical evidence, its translation into clinical applications remains constrained by numerous challenges, including drug delivery, selectivity, safety, and potential interference with physiological immune function. Future research should focus on elucidating the precise regulatory network of this pathway in specific pathological contexts and developing novel modulators with high blood-brain barrier permeability, high selectivity, and favorable safety profiles. Concurrently, conduct systematic efficacy and safety validation in models more closely resembling human diseases to advance the ultimate realization of targeted therapeutic strategies for this pathway. Activation of the cGAS-STING signalling pathway and its role in central nervous system diseases. (ICH: Intracerebral hemorrhage; TBI: Traumatic brain injury).
    Keywords:  CNS diseases; STING; autoimmunity.; cGAS; cGAS-STING pathway; neuroinflammation
    DOI:  https://doi.org/10.2174/0118715273428657260309045542
  44. Immunol Cell Biol. 2026 Mar 31.
    Neuroinflammation as a result of non-neurotropic herpesvirus infection.
    Christian Münz.
      The non-neurotropic Epstein Barr virus (EBV) has been suggested to initiate the prodromal phase of multiple sclerosis (MS), often years before the first clinical symptoms. This review discusses mechanisms by which EBV might cause neuroinflammatory B-cell migration to the central nervous system (CNS), as observed during primary CNS lymphomas and MS. Furthermore, mechanisms of molecular mimicry and autoreactive B-cell expansion by EBV will also be summarized. Finally, approaches to target EBV-mediated neuroinflammation for therapeutic interventions in people with MS (pwMS) will be explored. The recently provided information on EBV's association with MS gives exciting insights into the initiation of this autoimmune disease. Successful therapeutic interventions on the basis of this knowledge might provide evidence that EBV contributes also to the clinical phase of this autoimmune disease.
    Keywords:  Epstein Barr virus (EBV); atypical memory B cells (ABCs); molecular mimicry; multiple sclerosis (MS); systemic lupus erythematosus (SLE)
    DOI:  https://doi.org/10.1111/imcb.70108
  45. Trends Pharmacol Sci. 2026 Apr 01. pii: S0165-6147(26)00042-8. [Epub ahead of print]
    Programmable CAR immunotherapies for neurodegenerative proteinopathies.
    Giulia Pesce, Marc Estivill-Alonso, Salvador Ventura.
      Abnormal protein aggregation and a dysregulated neuroimmune environment are defining features of many neurodegenerative disorders. In Alzheimer's disease, systemic monoclonal antibodies against amyloid-β provide proof of principle that immunotherapy can modify disease trajectory. However, clinical benefit is limited by low brain exposure, short-lived activity, the need for repeated dosing, and inflammation-linked toxicity. Building on transformative clinical success in oncology, chimeric antigen receptor (CAR) immunotherapies offer a complementary approach to address these limitations, combining the molecular precision of antibody-derived binders with the versatility and persistence of engineered immune cells. These technologies are being explored for central nervous system (CNS) proteinopathies, where they can couple the selective recognition of pathogenic proteoforms to immune programs that are compatible with the CNS's low tolerance for collateral inflammation. Here, we review CAR strategies for aggregate-selective targeting and explore how to incorporate tunable controls and safety mechanisms. Finally, we examine how distinct CAR-engineered effector cell types may modulate key processes in neurodegeneration, from aggregate clearance to immune rebalancing. Together, these advances define CAR design principles for durable, programmable, and targeted immunomodulation in neurodegenerative disease.
    Keywords:  CAR design; cell-based therapies; chimeric antigen receptors; disease-modifying therapies; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1016/j.tips.2026.02.009
  46. Bioanalysis. 2026 Apr 02. 1-9
    Examining pre-analytical factors for bioanalysis of protein therapeutics crossing the blood-brain barrier through receptor-mediated transcytosis.
    Wenyu Li, Jun Chen, Isha Taneja, Wilson Edwards, Wenying Jian, Brian Geist.
       BACKGROUND: The blood-brain barrier (BBB) poses challenges for delivering large-molecule therapeutics to the brain. While engineered cross-BBB delivering platforms such as antibodies utilizing receptor-mediated transcytosis (RMT) aim to improve drug delivery, accurate quantization of antibody exposure in the brain is critical. This study investigates pre-analytical factors impacting the analysis of BBB-shuttling antibodies in mice and seeks to bring attention to steps that can be optimized to enhance efficiency and throughput.
    RESEARCH DESIGN AND METHODS: We evaluated factors such as perfusion, capillary depletion, and freeze-thaw in a humanized mouse model treated with antibodies, with or without a BBB shuttle. Hemoglobin and albumin were investigated as markers for blood contamination.
    RESULTS: Blood contamination was effectively reduced when cardiac puncture was performed, and perfusion further minimized the contamination. Albumin is a more representative blood contamination marker than hemoglobin for antibody bioanalysis in brain tissue. Capillary depletion did not significantly affect PK analysis under-tested conditions, and no considerable differences were found between frozen and fresh samples.
    CONCLUSIONS: Careful investigation of these pre-analytical procedures should be conducted to understand their impact. This will facilitate the development of an optimized and efficient workflow for discovery screening.
    Keywords:  BBB-shuttling; Blood-brain barrier; bioanalytical; brain tissue processing; capillary depletion; pharmacokinetics; pre-analytical factors; receptor-medicated transcytosis
    DOI:  https://doi.org/10.1080/17576180.2026.2653856
  47. Mol Neurobiol. 2026 Mar 31. pii: 540. [Epub ahead of print]63(1):
    The Multifaceted Roles of GPR120 in Central Nervous System Disorders: Mechanistic Insights and Therapeutic Implications.
    Liangxue Zhang, Honglin Jia, Chengyu Pan, Zucai Xu, Shuang Liu.
      G protein-coupled receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), is a receptor for ω-3 polyunsaturated fatty acids (ω-3 PUFAs), mainly including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). It is widely expressed in the central nervous system on microglia, astrocytes, and neurons, where it regulates neuroinflammation and homeostasis. This review summarizes the mechanism insights and therapeutic potential of GPR120 in neurological and psychiatric disorders. Mechanistic studies indicated that GPR120 activation predominantly engages a β-arrestin2-dependent signaling pathway, which inhibits the TAK1/TAB1 complex, suppresses NF-κB and NLRP3 inflammasome pathways, and thus alleviates neuroinflammation. GPR120 signaling also regulates mitophagy and mitigates endoplasmic reticulum stress, promoting neuronal survival and function. In disease models, GPR120 activation is consistently neuroprotective, reducing seizure severity in epilepsy by inhibiting the NLRP3/caspase-1/IL-1β axis, decreasing pathological deposits in Alzheimer's disease by enhancing Aβ clearance, improving post-ischemic outcomes in stroke via anti-apoptotic and anti-inflammatory mechanisms, and improving behavior in depression models by suppressing microglial M1 polarization and restoring synaptic plasticity. Preclinical studies support the efficacy of selective GPR120 agonists (such as TUG-891, CpdA). However, clinical translation faces major challenges: differences in receptor pharmacology between humans and mice (about 82% sequence homology), weak endogenous ligands, high plasma protein binding (> 99%), and the absence of neurologically focused clinical trials. Future research should focus on addressing species differences, optimizing brain-targeted delivery strategies, and advancing translational studies from preclinical to clinical settings to evaluate the practical application value of GPR120 in central nervous system disorders.
    Keywords:  Cerebrovascular disease; Epilepsy; GPR120; NLRP3 inflammasome; Neuroinflammation; Therapeutic target
    DOI:  https://doi.org/10.1007/s12035-026-05776-1
  48. Adv Healthc Mater. 2026 Apr 02. e71115
    Rethinking Neuroregenerative Microenvironments: Synergy Between Bioengineering and Organoids.
    He Zhu, Kai Guo, Juan Feng, Youwu Guo, Zhonglei Wang, Chenfeng Li, Zongzong Lu, Yiliu Zou, Wei Yuan, Xiongfei Zheng, Xin He.
      Neurological injuries and neurodegenerative disorders, including spinal cord injury, traumatic brain injury, stroke, and Parkinson's disease remain largely incurable. In the central nervous system (CNS), a self-reinforcing cascade of neuroinflammation, oxidative stress, blood-brain barrier breakdown, and glial fibrotic scarring restricts long-distance axonal regrowth and graft survival. The peripheral nervous system (PNS) exhibits greater intrinsic regenerative potential, yet critical-length defects remain challenging and have driven the development of clinically relevant conduit designs. This review provides an overview of the microenvironment following CNS injury and summarizes the key design requirements for engineered repair matrices, while highlighting lessons from advanced peripheral nerve guidance conduits. Injectable extracellular matrix (ECM)-mimetic and smart hydrogels can conformally fill CNS cavities, modulate immune and redox cascades, restore vascular function, and provide permissive niches for neural stem/progenitor and endothelial cells. CNS-compatible bioinks and 3D bioprinting enable the fabrication of neurovascular architectures and multicellular constructs with controlled mechanics, topology, and circuit geometry. Advances in nerve guidance conduits inform translation of PNS principles to the brain and spinal cord. Organoid-based strategies, including vascularized organoids, biomaterial-supported grafts, and organoid-neuroelectronic interfaces, suggest routes toward modular biohybrid constructs. Integrating pathology-informed biomaterials, biofabrication, and organoid engineering offers a roadmap for neural circuit reconstruction.
    Keywords:  3D bioprinting; neural organoids; neuroregenerative microenvironment; neurovascular unit; vascularized constructs
    DOI:  https://doi.org/10.1002/adhm.71115
  49. CNS Neurol Disord Drug Targets. 2026 Mar 26.
    NEAT1 as a Diagnostic Biomarker and Therapeutic Target for Alzheimer's Disease: A Comprehensive Review.
    Mohammad Yasin Zamanian, Olga F Belaia, Zhanna R Gardanova.
      Alzheimer's disease (AD) is marked by progressive cognitive decline and memory loss. Emerging evidence underscores the role of long non-coding RNAs (lncRNAs), particularly nuclearenriched abundant transcript 1 (NEAT1), in AD pathogenesis. NEAT1, a pivotal lncRNA that regulates diverse cellular processes, shows dysregulated expression in AD and impairs neuronal survival. This review explores NEAT1's molecular mechanisms, biomarker potential, and therapeutic relevance. NEAT1 contributes to AD pathology by acting as a competitive endogenous RNA (ceRNA) that sequesters protective microRNAs, including miR-124 and miR-107, thereby dysregulating downstream targets. It facilitates PINK1 degradation and potentially drives mitochondrial dysfunction and neuronal injury. Elevated NEAT1 levels are associated with amyloid-beta accumulation, tau hyperphosphorylation, and NF-κB-mediated neuroinflammation. Preclinical studies suggest that modulating NEAT1 expression can alleviate AD‑like pathology, making NEAT1 a promising target for intervention. Increased plasma NEAT1 in patients indicates its value as a non-invasive early diagnostic biomarker. NEAT1 regulates multiple AD-related pathways, including IGF1R, TRAF2, BACE1, CREB/BDNF, and Nrf2/NQO1, and interacts with lncRNAs linked to metabolic and neurodegenerative diseases, such as XIST and KCNQ1OT1. By influencing amyloid processing, synaptic function, mitochondrial health, and inflammatory responses, NEAT1 emerges as a central regulator in AD. Targeting NEAT1 offers dual benefits: advancing precision diagnostics and enabling multi-pathway therapeutic approaches. This review underscores NEAT1's significance as both a biomarker and therapeutic target, providing insights for future strategies to mitigate the burden of AD.
    Keywords:  Alzheimer's disease; BACE1.; MicroRNA; NEAT1; lncRNA
    DOI:  https://doi.org/10.2174/0118715273431267260210124040
  50. Front Immunol. 2026 ;17 1792896
    A cell line-derived, immune-competent neurospheroid model to study neuroinflammation and human brain disorders.
    Alexandro Angelo Bufi, Andrea Papait, Serafina Farigu, Elsa Vertua, Patrizia Bonassi Signoroni, Elisa Scalvini, Elisabetta Giuzzi, Alice Paini, Paola Chiodelli, Antonietta Rosa Silini, Peter Ponsaerts, Ornella Parolini.
       Introduction: Three-dimensional (3D) human brain models have become indispensable tools to investigate neuroimmune interactions and inflammatory processes in the human central nervous system in vitro. Nevertheless, existing models, including brain organoids and other iPSC-derived systems, are often constrained by lengthy differentiation protocols, considerable cost, and substantial batch-to-batch variability, restricting their applicability in translational neuroimmunology.
    Methods: We developed a scalable and reproducible 3D human neurospheroid model (tri-hNSPHs) composed of neuronal, astrocytic, and microglial human cell lines, specifically designed to study neuropathogenic mechanisms. Tri-NSPHs were exposed to a defined pro-inflammatory cytokine cocktail (IL-1β, TNFα, and IFNγ) to quantify the secretion of multiple inflammatory mediators. The inflammation was also counteracted using distinct anti-inflammatory pharmacological compounds and cellular adaptations to hypoxic stress were modeled.
    Results: Tri-hNSPHs rapidly self-assemble while maintaining key neuro-glial interactions and enabling precise analysis of immune responses not attainable with conventional two-dimensional cultures. The stimuli we provided triggered robust and quantifiable inflammatory activation, demonstrating the versatility of the model and its suitability for dissecting neuroinflammatory pathways. Pharmacological modulation effectively attenuated these responses, further validating the platform for mechanistic and therapeutic studies. In addition to modeling neuroinflammation, tri-hNSPHs reliably recapitulated cell reactions to hypoxic stress, a pathological condition tightly intertwined to neuroimmune activation in numerous neurological disorders.
    Discussion: Together, these findings establish tri-hNSPHs as a scalable, experimentally robust, and translationally relevant 3D neuroimmune model for investigating inflammation-driven brain pathology and evaluating anti-inflammatory strategies in a controlled and reproducible in vitro setting. This platform holds significant promise for advancing neuroimmune research and preclinical screening of immunomodulatory therapies.
    Keywords:  3D model; cell lines; drug screening; hypoxia; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1792896
  51. Front Mol Neurosci. 2026 ;19 1671909
    TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.
    Seham Almalki, Mohamed Salama, Matthew J Taylor, Zubair Ahmed, Richard I Tuxworth.
      Mislocalization and aggregation of the DNA/RNA binding protein, TDP-43, is seen in most cases of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Accumulating DNA damage in neurons is also a common feature of ALS-FTD. TDP-43 has several characterized roles in the regulation of the DNA damage response (DDR). This review systematically explored the relationship between TDP-43, DNA damage and the DNA damage response in various models of ALS-FTD, facilitating comparison of findings between studies using similar models. Twelve peer-reviewed papers, covering eight TDP-43 mutations out of nearly 40, were reviewed and five experimental models included: cell lines, patient-derived iPS cells, organoids, and rodent models, plus post-mortem cortex and spinal cord tissue from ALS-FTD patients. Across the studies and models, depletion of TDP-43 or ALS-linked mutations consistently increased genomic instability. Q331K-expressing cells showed a 2-3-fold reduction in DNA repair activity and a 4-6-fold increase in DDR activation, while TDP-43-depleted cells showed a 20-fold rise in double strand breaks. TDP-43 normally binds to damaged chromatin, participates in early DDR signaling and scaffolds core DNA damage repair factors, including Ku70, XRCC4 and DNA ligase 4. This systematic review and narrative synthesis sheds light on mechanisms that explain how TDP-43 dysfunction impairs genome maintenance. When TDP-43 is mislocalized, mutated or aggregated, these interactions are disrupted, resulting in impaired DNA repair. DNA damage is also caused by increasing R-loops, dysregulation of mismatch repair gene transcription, and sequestering of repair proteins into cytoplasmic inclusions. Upstream DNA damage can further drive TDP-43 mislocalisation, creating a feed-forward loop. Given the ubiquity of TDP-43 pathology across neurodegenerative diseases, targeting the DDR mechanisms affected by TDP-43 may offer new therapeutic opportunities.
    Keywords:  ALS; ALS-FTD; DDR; DNA damage; DNA repair; FTD; TDP-43
    DOI:  https://doi.org/10.3389/fnmol.2026.1671909
  52. J Clin Orthop Trauma. 2026 May;76 103401
    Breaking barriers: Understanding and managing blood-spinal cord barrier dysfunction in spinal cord injury: A systematic review.
    Eslam Abourisha, Tanmay Jitendra Talavia, Gaurav Jha, Sanjeevi Bharadwaj, Alexander Curran, Sriram Harish Srinivasan.
       Background: Spinal cord injury (SCI) has life-changing consequences, not just from the initial trauma, but also from a series of damaging processes that unfold afterwards, such as oxidative stress, inflammation, and nerve cell loss. At the heart of these events is the breakdown of the blood-spinal cord barrier (BSCB). When BSCB fails, harmful substances start flooding in, leading to progressive tissue damage.
    Methods: In this review, we explore findings from 38 studies - including animal models and patient research - to shed light on how and why the BSCB fails after SCI, as well as what can be done to diagnose and treat this problem. The systematic review was registered with PROSPERO (ID No- 1173511).
    Results: New diagnostic tools, like specialized MRI scans and blood or spinal fluid biomarkers, are helping doctors track changes in the BSCB. The causes of barrier breakdown are complex, involving oxidative stress, iron buildup, enzyme activity, genetic regulation, and immune responses, all of which make the injury worse over time. Promising treatments include a wide range from medicines and biological therapies to physical approaches like targeted exercise or nerve stimulation-all showing benefits in laboratory studies, though we still need more real-world evidence.
    Conclusions: Protecting BSCB represents a promising but underutilized treatment strategy for spinal cord injury. BSCB dysfunction is diffuse, persistent, and biologically reversible across acute-subacute stages, providing a rationale for stage-specific therapeutic targeting. Based on the latest research, we offer a practical pathway for doctors to detect and manage BSCB damage - matching the type of treatment to the stages of SCI recovery. Greater consistency in research, early clinical trials, and better use of new biomarkers will help move these therapies from the lab to everyday patient care. Ultimately, preserving the BSCB after injury is not just about protecting tissue - it's about giving people a better chance at recovery and a return to their lives.
    Keywords:  Blood-spinal cord barrier; Inflammation; Magnetic resonance imaging; Oxidative stress; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.jcot.2026.103401
  53. Neuroimmunomodulation. 2026 Mar 30. 1-34
    Interactions between Innate Immune Memory and the Central Nervous System.
    Rafaela Rodrigues Valerio, Andressa Bernardi, Adriana Bonomo, Rudimar Luiz Frozza.
       BACKGROUND: Traditionally, immunology has assumed the dogma that immunological memory is exclusive to cells of the adaptive immune system. However, over the past decade, this paradigm has been challenged by compelling evidence showing that innate immune cells can mount adaptive characteristics, leading to long-term changes in their function. After exposure to infections or sterile inflammation, innate immune cells can exhibit either an enhanced or suppressed inflammatory response upon secondary challenge. This de facto immune memory has been termed trained immunity or immune tolerance, respectively.
    SUMMARY: This review outlines both classical and newly described features of innate immune cells, highlighting the concepts of trained immunity and innate tolerance, along with their underlying molecular mechanisms. We also discuss the implications of innate immune memory in microglia and explore the potential therapeutic approaches for manipulating innate immunity in the context of neurodegenerative disorders.
    KEY MESSAGES: While trained immunity plays a crucial role in protecting the host against infections, its dysregulation can lead to chronic inflammation, autoimmune diseases, and potentially contribute to the development of neurodegenerative disorders. On the other hand, tolerance can reduce the inflammatory response and promote tissue regeneration but can also result in increased susceptibility to secondary infections. The long lifespan of microglia, coupled with their ability to learn and adapt their response to previously encountered pathogens or stimuli, underscores the potential long-term implications of their innate immune memory for the development of neuropathology.
    DOI:  https://doi.org/10.1159/000551784
  54. bioRxiv. 2026 Mar 27. pii: 2026.03.24.712448. [Epub ahead of print]
    Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.
    Joyce Yang, Mitsunori Nomura, Jonathan X Meng, Thelma Y Garcia, Timothy R Matsuura, Daniel P Kelly, Ken Nakamura, John C Newman.
      Glucose is the brain's primary fuel, but the brain can also use alternative energy substrates, especially during development or starvation. Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimer's disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific Bdh1 knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival-even under normal nutritional conditions. Mechanistically, phenotypes of Bdh1 knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimer's disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimer's.
    DOI:  https://doi.org/10.64898/2026.03.24.712448
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