bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–03–08
47 papers selected by
Luca Bolliger, lxBio
  1. Respiratory Onset Amyotrophic Lateral Sclerosis in a Patient With C9orf72 Expansion.
  2. Exploring the use of narrative-based approaches in individuals with amyotrophic lateral sclerosis: A narrative review.
  3. [Mechanism of action and clinical trial results of a new drug for amyotrophic lateral sclerosis (ALS), Mecobalamin (Rozebalamin®) for intramuscular injection, 25 mg].
  4. Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model.
  5. Granules Gone Rogue: Nuclear and Cytoplasmic Ribonucleoprotein Structures in Amyotrophic Lateral Sclerosis-Fused in Sarcoma (ALS-FUS) Pathology.
  6. NeuroViOme: a viral orfeome collection for studies of neurodegenerative disease.
  7. Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.
  8. Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice.
  9. Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.
  10. Neuroinflammation and Oxidative Stress in SOD1 Animal Models of ALS: A Meta-analysis Study of Their Effects on Disease Onset and Progression.
  11. Patient and caregiver attitudes to cognitive and behavioral testing in Amyotrophic Lateral Sclerosis.
  12. Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis.
  13. Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.
  14. Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.
  15. Integrating Serum Neurofilament Light Chain Into Amyotrophic Lateral Sclerosis Diagnostic Criteria.
  16. Copper Homeostasis and Cuproptosis in Neurological Disorders.
  17. Subjective sleep quality in amyotrophic lateral sclerosis: a systematic review and meta-analysis.
  18. Exploring the Lived Experiences of Individuals with Amyotrophic Lateral Sclerosis (ALS): A Qualitative Study and Conceptual Model of Signs, Symptoms, and Functional Impacts.
  19. Calprotectin as an immune-dysregulation biomarker in amyotrophic lateral sclerosis: Insights for diagnosis and therapy.
  20. The spatial architecture of neuroimmune interactions in epilepsy.
  21. Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis.
  22. "What about me? I'm supposed to be … superhuman?": exploring staff perspectives on how to deliver high quality psychological care for people living with amyotrophic lateral sclerosis.
  23. Targeting epigenetic remodeling of the blood-brain barrier: current knowledge for drug therapy.
  24. Trained immunity in neuroinflammation: emerging evidence, clinical perspectives, and future directions.
  25. Glioinflammation: disease-associated microglia and astrocytes in psychiatric disorders, neurodegeneration, and senescence.
  26. Immunosenescence and inflammaging in Parkinson's disease: mechanisms and therapeutic prospects.
  27. The therapeutic potential of cytisine and its derivatives in disorders of the central nervous system.
  28. Loss of Splicing Homeostasis as a Hallmark of Aging.
  29. Innovative socio-sanitary rehabilitation models in central nervous system disorders: a systematic review.
  30. Farnesol, the farnesol pathway, and the immune-gut-brain axis.
  31. Context-dependent effects of adaptive immunity on IFN-α-mediated neurotoxicity in Aicardi-Goutières syndrome.
  32. The Amyotrophic Lateral Sclerosis House Call Program: A Single-Center Experience in the United States.
  33. Impairment of brain short association fibers across clinical stages in amyotrophic lateral sclerosis: a new biomarker mirroring disease progression.
  34. TREM2 in neurodegeneration and diseases.
  35. Exploring Intimacy in Amyotrophic Lateral Sclerosis: A Pilot Study of Educational Support in a Multidisciplinary Clinic.
  36. From scaffold to effector: reframing GFAP in neurodegeneration.
  37. TDP-43 phosphorylation: Exploring kinases, phosphatases, and therapeutic potential in neurodegeneration.
  38. Voltage-gating and neuronal signalling in neurodegeneration: From neuropathology to therapeutic opportunities in motor neuron disease.
  39. The spinal lymphatic system: an emerging pathway bridging fluid homeostasis, immunity, and disease.
  40. TREM2 and microglial immunity in Alzheimer's disease: mechanisms, genetics, and therapeutic opportunities.
  41. Central nervous system-penetrant anti-C1q therapy reduces neuroinflammation and preserves neurological function in a model of progressive multiple sclerosis.
  42. Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders.
  43. Advanced 3D Platforms for Modeling CNS Neuroinflammation: Cell Integration, Techniques, and Challenges.
  44. Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
  45. Drug Polymer Nanoparticles: An Advancement in Biomedical Solutions and Targeted Drug Delivery.
  46. PAR-1 in Alzheimer's Disease: Pathophysiological Insights and Mechanistic Perspectives.
  47. Consumption of coffee and tea and the risk of developing neurodegenerative diseases: a cohort study in the UK biobank.
  1. J Clin Neuromuscul Dis. 2026 Mar 01. 27(3): 96-98
    Respiratory Onset Amyotrophic Lateral Sclerosis in a Patient With C9orf72 Expansion.
    Reece M Hass, Sandra Reiter-Campeau, Ruple S Laughlin, Teerin Liewluck.
       ABSTRACT: Respiratory-onset amyotrophic lateral sclerosis (ALS) is uncommon, accounting for less than 5% of all patients with ALS. Familial ALS is also uncommon, with the most common variant being related to a C9orf72 hexanucleotide repeat expansion. Respiratory-onset ALS in familial ALS is rare, with few cases discussed in the literature related to ERBB4, SOD1, and FUS variants. Here we present a case of respiratory-onset ALS related to a C9orf72 repeat expansion, expanding the spectrum of associated phenotypes associated with C9orf72 expansions and highlighting the importance of genetic testing in patients living with ALS.
    Keywords:  C9orf72; amyotrophic lateral sclerosis; familial ALS; motor neuron disease; respiratory-onset ALS
    DOI:  https://doi.org/10.1097/CND.0000000000000556
  2. Palliat Support Care. 2026 Mar 05. 24 e81
    Exploring the use of narrative-based approaches in individuals with amyotrophic lateral sclerosis: A narrative review.
    Kristie Calix Kannaley.
       OBJECTIVES: Narrative-based approaches have been utilized in medicine to better understand the illness experiences of individuals living with chronic conditions. In particular, people with amyotrophic lateral sclerosis (pALS) may benefit from use of narrative-based approaches, given the potential impact of progressive decline on identity of self. This review explores the use of narrative-based approaches in studies involving pALS to provide further insight to the experiences and psychosocial needs of this population.
    METHODS: A search was conducted utilizing EMBASE, CINAHL, PsycInfo, and Google Scholar with several terms related to amyotrophic lateral sclerosis (ALS) and narrative-based approaches. Studies were included if they were written in English, incorporated methods that promoted the production of narratives, and reported data that could be clearly isolated to pALS.
    RESULTS: The search revealed a total of 154 articles for title and abstract screening. Fifty-two articles were selected for full-text review. Thirty-two articles met the criteria for data extraction. Four descriptive categories emerged upon examination of the narrative-based approaches implemented across the studies: psychosocial intervention, illness experience, intervention targeting specific needs, and secondary analysis of data. Some of the common themes identified across studies included: loss of physical and communicative function, adaptation to life changes, shifts in identity, and tension with the healthcare system.
    SIGNIFICANCE OF RESULTS: Despite the communication challenges that often coincide with disease progression, narrative-based approaches can be utilized in pALS. These approaches should be implemented to gain insight on the disease experiences of pALS, providing opportunity for patient-centered interventions to address the psychosocial needs of this population.
    Keywords:  Amyotrophic lateral sclerosis; Lou Gehrig’s disease; motor neuron disease; narrative medicine; narrative-based intervention
    DOI:  https://doi.org/10.1017/S1478951526101965
  3. Nihon Yakurigaku Zasshi. 2026 ;161(2): 115-122
    [Mechanism of action and clinical trial results of a new drug for amyotrophic lateral sclerosis (ALS), Mecobalamin (Rozebalamin®) for intramuscular injection, 25 mg].
    Tetsuhiro Niidome, Takayuki Ishida.
      Amyotrophic lateral sclerosis (ALS) is a progressive, intractable neurodegenerative disease characterized by generalized muscle atrophy and weakness, dysarthria, dysphagia, and respiratory muscle paralysis. Respiratory dysfunction due to muscle weakness is the primary cause of death; without mechanical ventilation, death typically occurs within 2 to 5 years after onset. Mecobalamin, an active form of vitamin B12, is thought to suppress homocysteine-induced neuronal cell death in ALS by acting as a coenzyme for methionine synthase, which catalyzes the conversion of homocysteine to methionine. Since the 1990s, research on neurodegenerative diseases supported by Japan's Ministry of Health, Labour and Welfare has suggested that high-dose mecobalamin may confer clinical benefits in ALS. This led to the initiation of clinical development. A Phase II/III double-blind, placebo-controlled comparative trial was conducted, but did not meet its primary endpoint. Based on these trial findings, an investigator-initiated Phase III placebo-controlled, double-blind comparative trial was conducted primarily at Tokushima University Hospital, targeting patients who developed ALS within one year before starting the trial. The trial demonstrated the efficacy of high-dose mecobalamin in slowing the decline in the Revised ALS Functional Rating Scale total score, which was the primary endpoint. Safety was also confirmed. Based on these results, mecobalamin received regulatory approval in September 2024 for the indication "slowing the progression of functional impairment in ALS." It is expected to offer a new treatment option for patients with ALS.
    DOI:  https://doi.org/10.1254/fpj.25066
  4. Mol Brain. 2026 Mar 03.
    Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model.
    Ryosuke Hirota, Karen L Lankford, Masahito Nakazaki, Masayuki Toyoshima, Jeffery D Kocsis.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with no established disease-modifying therapy. Mesenchymal stem/stromal cells (MSCs) have been reported to exert neuroprotective effects in models of injury and disease, acting primarily through release of small extracellular vesicles (sEVs). MSC-derived sEVs (MSC-sEVs) have therefore attracted attention as a potential cell-free therapeutic approach for treating neurological conditions such as ALS. Because MSC-sEVs can cross both the nasal epithelial barrier and blood-brain barrier to reach the central nervous system (CNS), intranasal administration represents an attractive approach for repeated delivery of MSC-sEVs for long-term administration. In this study, we administered bone marrow-derived MSC-sEVs or vehicle intranasally to a SOD1(G93A) transgenic mouse model of ALS; the large majority of the sEVs had surface markers for exosomes. Dosing was for three consecutive days per week beginning one day after onset of neurological symptoms and continuing until a moribund state. Neurological score and body weight were recorded daily. Although total survival time and post-onset survival duration were not significantly prolonged by MSC-sEV treatment, MSC-sEV treatment significantly delayed progression from a mild symptom phase (NeuroScore 1) to more severe symptoms (NeuroScore 2) compared with vehicle-treated controls and showed a trend toward slower weight loss. These findings indicate that intranasal administration of MSC-sEVs can delay functional deterioration and prolong the mild impairment stage in an ALS mouse model. If translatable to human patients, such preservation of neurological function could represent a clinically meaningful outcome.
    Keywords:  Amyotrophic lateral sclerosis; Exosome; Intranasal administration; Mesenchymal stromal cell; Small extracellular vesicles
    DOI:  https://doi.org/10.1186/s13041-026-01288-0
  5. Mol Neurobiol. 2026 Mar 02. pii: 479. [Epub ahead of print]63(1):
    Granules Gone Rogue: Nuclear and Cytoplasmic Ribonucleoprotein Structures in Amyotrophic Lateral Sclerosis-Fused in Sarcoma (ALS-FUS) Pathology.
    Vanshika Ahuja, Bandana Sahu, Shiffali Khurana, Kritika Kumari, Nirmal Kumar Ganguly, Mandaville Gourie-Devi, Sagar Verma, Somasish G Dastidar, Vibha Taneja.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of motor neurons. Among its genetic subtypes, mutations in the fused in sarcoma (FUS) gene represent an aggressive form, often associated with early onset and rapid progression. FUS is a ubiquitously expressed DNA/RNA-binding nuclear protein involved in maintaining DNA damage repair and RNA metabolism. It also plays a crucial role in the formation of ribonucleoprotein (RNP) granules such as cytoplasmic stress granules and nuclear paraspeckles under stress. In ALS, pathogenic FUS mutations frequently disrupt the subcellular distribution of FUS, leading to cytoplasmic mislocalization and aggregation. Mutant FUS further disrupts granular dynamics by its aberrant incorporation into stress granules and altering their biophysical properties. The loss of nuclear FUS function leads to elevated levels of the long non-coding RNA NEAT1 and enhanced paraspeckle assembly with disrupted structural integrity. The impaired nucleocytoplasmic granular dynamics compromise the cellular resilience, thereby increasing motor neuron vulnerability. The interaction of FUS with other ALS-associated proteins causes pathological alterations in the cellular milieu, suggesting a common underlying disease mechanism. This comprehensive review emphasizes the FUS-mediated RNP granule regulation under physiological and pathological conditions. Further, clinically approved and emerging therapeutic strategies aimed at attenuating FUS pathology and RNP granule dynamics have been described.
    Keywords:  Amyotrophic lateral sclerosis; Fused in sarcoma; Paraspeckles; Ribonucleoprotein granules; Stress granules; Therapeutics
    DOI:  https://doi.org/10.1007/s12035-026-05736-9
  6. J Neurovirol. 2026 Mar 02. pii: 11. [Epub ahead of print]32(2):
    NeuroViOme: a viral orfeome collection for studies of neurodegenerative disease.
    Benjamin Weller, Chung-Wen Lin, Simin Rothballer, Michael A Calderwood, Pascal Falter-Braun, Claudia Falter.
      Neurodegenerative diseases such as Alzheimer's and Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS) pose a global health challenge due to their progressive course and lack of curative therapies. These conditions lead to severe neurological decline, significantly impacting patient independence and quality of life, and ultimately result in lethal outcome. Emerging evidence suggests that viral infections contribute to the onset and progression of these neurological diseases, Leblanc and Vorberg (PLoS Pathog 18:e1010670, 2022), either by directly inducing neurological symptoms or by triggering immune responses resulting in neuropathology. Nevertheless, systematic studies of the direct interplay between viral and host proteins in neurodegeneration remain scarce. A key aspect of viral pathogenesis is direct interaction between viral and host proteins (protein-protein interactions, PPIs), which are essential for viral replication and can disrupt or redirect host cell function Kim et al. (Nat Biotechnol, 2022); Zhou et al. (Res Sq, 2022), potentially contributing to the development of diseases traditionally considered non-communicable. Understanding these molecular mechanisms is crucial for advancing diagnostic and therapeutic strategies in neurodegenerative conditions, particularly ALS and MS. To enable systematic studies of these interactions, we introduce NeuroViOme as ORFeome resource encompassing nearly all protein-coding sequences from nine viruses selected based on their prevalence, neurotropism, and mechanistic or epidemiological links to neurodegenerative processes. NeuroViOme includes ORFs from Enteroviruses (EV-A71, EV-D68, CVB3, Echovirus E30), Herpesviruses (HSV-1, EBV, HHV3/Varicella Zoster), the endogenous retrovirus HERV-K, and Polyomavirus JCPyV. To our knowledge, this represents the most comprehensive viral ORF set assembled for neurodegeneration research to date. The collection builds the foundation for interactome mapping and functional genomics analyses and provides a valuable basis for systematic studies of viral perturbations of host pathways.
    Keywords:  Amyotrophic lateral sclerosis; Neurodegenerative diseases; Neurotrophic virus; ORFeome; Viral pathogenesis
    DOI:  https://doi.org/10.1007/s13365-025-01303-5
  7. Front Aging Neurosci. 2026 ;18 1711422
    Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.
    Noureddine Ben Khalaf.
      The maintenance of protein homeostasis is essential for neuronal survival and function; however, it progressively declines with age, predisposing the brain to neurodegenerative diseases. Molecular chaperones Hsp70 and Hsp90 are key guardians of proteostasis, pivotally regulating protein folding, refolding, and degradation under both physiological and stress conditions. This review integrates an overview of the structural features, isoforms, and mechanistic interactions of Hsp70 and Hsp90. It highlights how their dysfunction contributes to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. We first examine the architecture and ATP-driven chaperone cycles of Hsp70 and Hsp90, their co-chaperone networks, and the feedback regulation by the Heat Shock Factor-1 pathway. We then discuss evidence linking age-related declines in chaperone expression and HSF-1 activity to proteostasis collapse and neuronal vulnerability. The review particularly examines how Hsp70 and Hsp90 differentially influence pathogenic protein aggregation (e.g., tau, α-synuclein, TDP-43, and mutant huntingtin) and how this balance is altered in the aging brain. Regarding therapeutic approaches, we summarize current strategies targeting these chaperones, including small-molecule modulators of Hsp70 and Hsp90, co-chaperone inhibitors, and recombinant chaperone therapy, which has shown to restore proteostasis and cognitive function in experimental models. These emerging interventions underscore the dual nature of Hsp70/Hsp90 systems, acting as both protectors and potential contributors to neurodegeneration, depending on their regulation and interaction context. By linking molecular chaperone biology to aging and translational therapeutics, this review establishes a framework for developing precision approaches that enhance proteostasis capacity, delay age-associated neurodegeneration, and promote healthy brain aging.
    Keywords:  alpha-synuclein; heat shock proteins; molecular chaperone; neurodegenerative diseases; proteostasis; tau
    DOI:  https://doi.org/10.3389/fnagi.2026.1711422
  8. Sci Rep. 2026 Mar 04.
    Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice.
    Alannah J Mortimer, Chiara F Sander, Amisha R Parmar, Ailsa J Williams, Mimoun Azzouz, Guillaume M Hautbergue, Pamela J Shaw, Laura Ferraiuolo, Richard J Mead.
      Gene therapies are promising for diseases previously considered incurable. Adeno-associated virus serotype 9 (AAV9) demonstrates remarkable tropism for motor neurons (MNs) and represents an exciting candidate to target genetic causes of motor neuron diseases like amyotrophic lateral sclerosis (ALS). However, systemic delivery risks immunogenicity and off-target effects, therefore localised delivery to the CNS is advantageous. We assessed MN transduction in wild-type post-natal mice using AAV9-controlled, cytomegalovirus-promoter driven, enhanced GFP expression. Intra-cisterna magna (ICM) and intra-cerebroventricular (ICV) methods were compared. Four weeks post-delivery, GFP positivity in MN and astrocytes were quantified via immunohistochemical approaches and viral genome copy number determined by qPCR. All delivery methods achieved high MN transduction in lumbar spinal cord (> 68%). Unilateral ICV delivery provided the highest and most consistent levels (89 ± 3%), and minimal peripheral viral copies. ICV delivery resulted in higher astrocytic transduction, most notably in the cortex. Brainstem MN transduction was high with all methods (> 55%). We failed to find evidence of neuronal transduction in motor cortex. Viral genome copies trended higher in spinal cord and brainstem with ICV approaches, however further work is required to understand how bilateral repeated dose delivery leads to more profound increases. Whilst several routes of administration into cerebrospinal fluid exist, direct comparisons for targeting MNs in vivo remain limited. Overall, all methods of CNS-directed delivery result in high levels of motor neuron transduction in the lumbar spinal cord and brainstem, but not in motor cortex. Unilateral ICV appears to provide the best balance between consistent, high levels of transduction and low off-target effects. However, ICM might be the better option if seeking to avoid astrocytic transduction.
    Keywords:  AAV9; Gene therapy; ICM; ICV; Motor neuron
    DOI:  https://doi.org/10.1038/s41598-026-38039-z
  9. Neural Regen Res. 2026 Feb 28.
    Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.
    Faizan Ali Shah Rizvi, Yusuf Jimoh, Mohammed Z Allouh, Dalia Rahmon, G Rasul Chaudhry.
       ABSTRACT: Neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, retinal degenerative diseases, Alzheimer's disease, and Parkinson's disease, continue to pose a significant clinical challenge due to the progressive loss of neural tissue structure and function. Stem cell-based therapies are gaining attention for the treatment of neurodegenerative diseases. Mesenchymal stem cells, particularly those derived from perinatal tissues, exhibit remarkable plasticity, along with immunomodulatory, neurotrophic, and regenerative capabilities. Mesenchymal stem cells primarily influence their environment through paracrine signaling and can also differentiate into neural lineages, aiding in neuronal repair. Tissue-specific progenitor cells, such as neural stem cells and retinal progenitor cells, offer greater therapeutic precision. This review examines advancements in mesenchymal stem cell-based therapies for neurodegenerative diseases, discusses relevant clinical trials, and highlights the challenges, while proposing that personalized regenerative treatments utilizing lineage-restricted progenitors may improve patient outcomes in these complex disorders.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; cell therapy; mesenchymal stem cells; multiple sclerosis; neurodegenerative diseases; neuroregeneration
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01147
  10. Mol Neurobiol. 2026 Mar 01. pii: 477. [Epub ahead of print]63(1):
    Neuroinflammation and Oxidative Stress in SOD1 Animal Models of ALS: A Meta-analysis Study of Their Effects on Disease Onset and Progression.
    Maria Ciuro, Maria Sangiorgio, Giampiero Leanza, Rosario Gulino.
      Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder characterized by progressive motor neuron degeneration. Among the key mechanisms implicated in ALS pathogenesis, neuroinflammation and oxidative stress have emerged as prominent contributors to disease progression. This systematic review with meta-analysis involved 344 preclinical studies conducted on SOD1 animal models of ALS, to quantitatively evaluate the effects of treatments targeting neuroinflammation and oxidative stress on functional outcomes such as disease onset, survival, motor neuron degeneration, and locomotion. Data extraction and validation were performed using a combination of a large language model and human review. Results show that while most interventions led to reduced astrogliosis, M1 microgliosis, and oxidative stress, and increased M2 microgliosis, these effects were more strongly associated with improved survival and motor outcomes than with delayed disease onset. The analysis also revealed that treatment timing significantly influences outcomes, with interventions initiated during the late pre-onset window showing the highest efficacy. Furthermore, sex differences were noted, with male mice displaying better outcomes in progression metrics but worse in the age at onset. Overall, this meta-analysis indicates that inflammation and oxidative stress are important contributors to ALS progression in SOD1 animal models, identifies potentially critical therapeutic windows, and supports the consideration of sex-balanced and stage-specific treatment strategies at the preclinical level.
    Keywords:  Amyotrophic lateral sclerosis; Disease progression; Meta-analysis; Neuroinflammation; Oxidative stress; SOD1 animal models
    DOI:  https://doi.org/10.1007/s12035-026-05773-4
  11. Neurodegener Dis Manag. 2026 Feb 28. 1-10
    Patient and caregiver attitudes to cognitive and behavioral testing in Amyotrophic Lateral Sclerosis.
    Leslie Ing, Alys Wyn Griffiths, Emily Mayberry, Yasmin Ali, Daniel Blackburn, Christopher McDermott.
       BACKGROUND: Cognitive and behavioral changes affect up to 50% of people with Amyotrophic Lateral Sclerosis (ALS) and are associated with worse outcomes, yet remain under-recognized in clinical care. Understanding patient and caregiver perspectives is important for engagement with cognitive screening.
    METHODS: Semi-structured interviews were conducted with 10 patients with ALS and 9 caregivers, analyzed using reflexive thematic analysis. Participants were recruited via a multidisciplinary ALS clinic and the Motor Neurone Disease Association UK.
    RESULTS: Engagement with testing was shaped by emotional readiness, personal values, relational dynamics, practical barriers, and perceived value. Views ranged from seeing testing as an opportunity for preparedness and autonomy, to concerns it could undermine identity or add distress. Caregivers often valued testing to support planning but faced challenges balancing advocacy with respect for patient autonomy. Limited awareness of cognitive symptoms in ALS and unclear communication from clinicians reduced perceived relevance. Testing was most meaningful when tailored to personal priorities, introduced sensitively, and linked to actionable outcomes.
    CONCLUSION: Cognitive screening in ALS requires a flexible, patient-centered approach that considers emotional readiness, relational contexts, and clear communication. Tailoring discussions and delivery to patient and caregiver needs may enhance acceptance and integration of cognitive assessment into holistic ALS care.
    Keywords:  Amyotrophic lateral sclerosis (ALS); cognitive impairment; cognitive screening; patient and caregiver attitudes; person-centered care; qualitative research
    DOI:  https://doi.org/10.1080/17582024.2026.2637424
  12. BMC Med. 2026 Mar 06.
    Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis.
    Elham Alhathli, Johnathan Cooper-Knock, Zain-Ul-Abideen Girach, Thomas H Julian, Claudia Bauer, Hannah O Timmons, Billie D Ward, Heather Walker, Mimoun Azzouz, Mohamed A Elrayess, Fatima Al-Khelaifi, Noha A Yousri, Aytac Gul, Alan Kelsall, Tobias Moll, Calum Harvey, Sarah Gornall, Kari Wong, Scott P Allen, Andrew Strange, Pamela J Shaw.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with limited therapeutic options. The circulating metabolome comprises small molecules present in plasma/serum which are the intermediates and end-products of cellular metabolism, and is linked to ALS pathogenesis.
    METHODS: We conducted hypothesis-free two-sample Mendelian randomisation (MR) analysis of the concentration of 575 plasma/serum metabolites, to determine which are causally linked to risk of ALS. Significant metabolites were validated in an independent GWAS of plasma/serum metabolite concentrations and evaluated for sex-specific effects. Correlations between directly measured patient biofluid metabolite concentrations and ALS risk/severity were examined in 94 ALS patients and 40 controls. We experimentally assessed metabolic function in a murine neurons and human astrocytes carrying an ALS-associated G4C2-repeat expansion within C9orf72.
    RESULTS: MR causally associated five metabolites with ALS risk after multiple-testing correction. Higher serum concentration of glycoprotein acetyls (P = 9.7e - 9, β = 0.21) and the peptide DSGEGDFXAEGGGVR (P = 8.0e - 6, β = 0.22) was associated with increased ALS risk, whereas higher plasma concentration of phenylalanylserine, isobutyrylcarnitine, and acetylcarnitine was protective (P < 5e - 5, β = - 0.29 to - 0.72). DSGEGDFXAEGGGVR has been linked to glucose metabolism but we have used genetic fine-mapping to link DSGEGDFXAEGGGVR, neuronal glucose uptake through GLUT3, and ALS risk. Direct measurement of metabolite concentrations in patient biofluids revealed elevated acetylcarnitine levels in patients with ALS, which were associated with delayed symptom onset (Cox regression, P = 0.02, HR = 0.4). Similarly, lactate is elevated in ALS patient CSF (ANOVA, P = 1.3e - 3) and in patients with longer survival time (Cox regression, P = 0.03, HR = 0.3). Plasma fructose is elevated in ALS patients with shorter survival time (Cox regression, P = 0.02, HR = 1.1). In vitro, neurons and astrocytes carrying an ALS-associated G4C2-repeat expansion within C9orf72 demonstrated reduced metabolic flexibility.
    CONCLUSIONS: We provide evidence that impaired energy substrate availability contributes to ALS risk and severity. CNS cell types differ in their use of energy substrates and therefore we postulate the relative importance of different cell types for different stages of disease. Our findings support further investigation of metabolic interventions to treat or prevent ALS.
    Keywords:  Acetylcarnitine; Amyotrophic lateral sclerosis; Carnitine shuttle; Cerebrospinal fluid; Energy metabolism; GLUT3; Mendelian randomisation; Metabolomics; Neuronal vulnerability
    DOI:  https://doi.org/10.1186/s12916-026-04727-w
  13. J Neurochem. 2026 Mar;170(3): e70395
    Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.
    Yesim Kaya, Kevser Kübra Kırboğa.
      Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.
    Keywords:  3D disease modeling; brain organoids; induced pluripotent stem cells; neurodegenerative diseases
    DOI:  https://doi.org/10.1111/jnc.70395
  14. Front Neurosci. 2026 ;20 1764964
    Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.
    Yanxu Zheng, Wenke Zhou, Haozhe Chang, Kuihong Zheng.
      Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have become major global causes of disability and mortality. Their complex pathogenic mechanisms remain incompletely understood, and effective disease-modifying therapies are still lacking. Traditional animal models and two-dimensional (2D) cell culture systems exhibit notable limitations in structural complexity, human relevance, and translational validity, making it difficult to faithfully recapitulate human-specific neuropathology. In recent years, brain organoid technology derived from induced pluripotent stem cells (iPSCs) has advanced rapidly, enabling the self-organization of diverse neuronal and glial cell types within a three-dimensional (3D) architecture that partially mimics human brain development and disease-related pathological events. When integrated with CRISPR-Cas9-based genome editing and multi-omics profiling, organoids support causal mechanism studies, target validation, and individualized drug-response prediction, highlighting their growing value in early-stage drug discovery. Despite current challenges-including insufficient maturation, lack of vascularization and immune components, and batch variability-the continuous progress in bioengineering, microfluidic systems, and artificial intelligence (AI)-driven multimodal data analysis is steadily expanding the translational potential of organoids as human-relevant preclinical models. Overall, brain organoids provide an essential foundation for constructing physiologically relevant and predictive research platforms for neurodegenerative diseases, offering new opportunities for therapeutic development and precision medicine.
    Keywords:  CRISPR-Cas9 genome editing; brain organoids; drug discovery; induced pluripotent stem cells (iPSCs); neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnins.2026.1764964
  15. Muscle Nerve. 2026 Mar 07.
    Integrating Serum Neurofilament Light Chain Into Amyotrophic Lateral Sclerosis Diagnostic Criteria.
    Sean E Smith, Timothy M Miller, Andrew Atkinson, Alan Pestronk, Robert C Bucelli.
       INTRODUCTION/AIMS: Serum neurofilament light chain (NfL) is a promising diagnostic biomarker for differentiating amyotrophic lateral sclerosis (ALS) from clinical mimics. This study assessed the utility of integrating serum NfL into current diagnostic criteria to enhance diagnostic certainty in patients with a provisional ALS diagnosis who were confirmed as having ALS at follow-up.
    METHODS: We conducted a single-center, retrospective study of consecutive patients with a provisional ALS diagnosis at their initial visit at the WashU Medicine ALS Center. All underwent electrodiagnostic testing and serum NfL measurement via SIMOA using an HD-X analyzer (Quanterix). Elevated serum NfL was defined with a cutoff of 38 pg/mL.
    RESULTS: The study included 43 patients with a provisional ALS diagnosis (29 men [67.4%]; median age, 63 years [range, 36-80 years]). At follow-up, 27/43 (62.8%) patients progressed to definite ALS. Serum NfL was elevated in 34/43 (79.1%) of the total cohort and 24/27 (88.9%) of those who progressed to definite ALS. Integrating serum NfL with Gold Coast Criteria (GCC) was associated with a tenfold increase in the odds of identifying patients likely to progress to definite ALS (OR 10 [1.39, 71.87], p = 0.02).
    DISCUSSION: Our results suggest that serum NfL is a robust complement to current ALS diagnostic criteria and shows potential to improve early identification and diagnostic certainty of patients likely to progress to definite ALS. Integrating serum NfL with GCC provided the strongest predictive model. These findings warrant larger multicenter, prospective studies to confirm results.
    Keywords:  amyotrophic lateral sclerosis; biomarker; diagnostic criteria; disease progression; neurofilament
    DOI:  https://doi.org/10.1002/mus.70212
  16. Drug Des Devel Ther. 2026 ;20 580005
    Copper Homeostasis and Cuproptosis in Neurological Disorders.
    Wu Liu, Yan Xue, Chenyin Cao, Liting Yang, Lijun Zhang.
      Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development.
    Keywords:  copper chelators; copper homeostasis; cuproptosis; neurological diseases
    DOI:  https://doi.org/10.2147/DDDT.S580005
  17. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Mar 05. 1-12
    Subjective sleep quality in amyotrophic lateral sclerosis: a systematic review and meta-analysis.
    Juyeon Oh, Seong-Il Oh.
       OBJECTIVE: Sleep disturbances are common and clinically significant non-motor symptoms in amyotrophic lateral sclerosis (ALS), arising from motor, respiratory, and psychological factors. This study aimed to synthesize available evidence on subjective sleep quality in ALS, estimate the prevalence of poor sleep quality, examine associated factors, and compare patients with healthy controls.
    METHODS: : PubMed, EMBASE, Cochrane Central, and CINAHL were searched for studies published between January 2000 and August 2025 that assessed subjective sleep quality in ALS using validated patient-reported outcome measures, such as Pittsburgh Sleep Quality Index (PSQI). Pooled analyses were performed using random-effects models. Meta-regression was applied to explore associations with demographic and clinical variables.
    RESULTS: : A total of 23 studies comprising 1899 ALS patients were included, of which 20 were eligible for meta-analysis. All included studies assessed subjective sleep quality using the PSQI, and the pooled mean PSQI score was 6.94, exceeding the clinical cutoff for poor sleep quality. The pooled prevalence of poor sleepers was 56.7%. Nine studies including healthy controls showed significantly higher PSQI scores in ALS patients compared with controls (mean difference 2.69). Several factors, including functional status, depression, anxiety, fatigue, daytime sleepiness, constipation, and cognitive impairment, were associated with poorer sleep, however, meta-regression did not identify significant associations with age, sex, disease duration, or ALSFRS-R.
    CONCLUSIONS: : Sleep disturbances are highly prevalent and clinically significant in ALS. These findings highlight the need for systematic screening and proactive management across all stages of the disease. Future research should evaluate a wider range of interventions to improve sleep quality and patient outcomes.
    Keywords:  Amyotrophic lateral sclerosis; Pittsburgh Sleep Quality Index; meta-analysis; non-motor symptoms; sleep quality
    DOI:  https://doi.org/10.1080/21678421.2026.2614597
  18. Neurol Ther. 2026 Mar 03.
    Exploring the Lived Experiences of Individuals with Amyotrophic Lateral Sclerosis (ALS): A Qualitative Study and Conceptual Model of Signs, Symptoms, and Functional Impacts.
    William B Nowell, Nadine McGale, Oren Levy, Sarah Wilding, Phoebe Heinrich, Nick C Patel, Jinsy A Andrews, Diana Rofail.
       INTRODUCTION: This study aimed to explore the experience of living with amyotrophic lateral sclerosis (ALS) and to develop a conceptual model for this rare disease.
    METHODS: Concept elicitation interviews were conducted (January-September 2024) with people living with ALS (PLwALS; n = 31), caregivers (n = 20), and clinicians (n = 10). Qualitative data were analyzed separately to develop a conceptualization of the experience of living with ALS. Concept saturation was assessed every 5-6 interviews, and a conceptual model was developed.
    RESULTS: The mean age of PLwALS was 42.4 years (standard deviation [SD] 11.5), 81% were female, 84% were white, and 23% had SOD1-ALS. The mean time since diagnosis was 4.6 years (SD 4.2); mean normed Rasch Overall ALS Disability Scale score was 76 (SD 17.16). Signs, symptoms, and functions reported during PLwALS interviews included neuromuscular, bulbar, speech, neurocognitive (e.g., memory issues), and a range of physical functioning issues (e.g., motor coordination). PLwALS also reported impacts on a range of activities and psychosocial interactions (e.g., eating, depressed mood, and relationships), alongside management strategies they employed. Interviews with caregivers and clinicians supported findings from the PLwALS interviews. Caregivers also identified signs such as drooling/excess salivation, and impacts related to ALS management (e.g., need for writing aids). Clinicians additionally considered loss of speech and neurocognitive signs (e.g., behavior/personality change) as ALS clinical manifestations. Concept saturation was reached, and a consolidated, comprehensive conceptual model was developed.
    CONCLUSION: This research provides a holistic understanding of the experience of living with ALS and is the first conceptual model based on in-depth concept elicitation interviews. The findings highlight the range of signs, symptoms, and impacts that PLwALS experience, emphasizing its serious humanistic impact and high unmet need, and will help to guide patient-centric evaluation of clinical outcome assessments in future ALS studies.
    Keywords:  ALS; Conceptual model; Patient-centered outcomes research
    DOI:  https://doi.org/10.1007/s40120-026-00895-2
  19. Rev Neurol (Paris). 2026 Mar 05. pii: S0035-3787(26)00451-0. [Epub ahead of print]
    Calprotectin as an immune-dysregulation biomarker in amyotrophic lateral sclerosis: Insights for diagnosis and therapy.
    A Mendon, S Jain, N Mishra, S Bagwe Parab.
      Motor neuron degeneration is a defining feature of amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder. Early diagnosis remains challenging due to the absence of reliable and validated biomarkers. Calprotectin, a well-established inflammatory marker in various neuroinflammatory conditions, has paradoxically been found at reduced levels in the blood of ALS patients in a limited number of studies, raising the hypothesis of immune dysregulation rather than classical neuroinflammation. However, these findings are primarily derived from small patient cohorts and have yet to be independently replicated. This review critically assesses the emerging role of calprotectin in ALS by comparing it with other candidate biomarkers, including vascular endothelial growth factor (VEGF), apolipoprotein A1 (ApoA1), interleukin-8 (IL-8), interleukin-7 (IL-7), and interleukin-10 (IL-10). While calprotectin may reflect a distinct immunological profile, its standalone diagnostic value remains unclear. Nonetheless, its integration into a multi-analyte biomarker panel could enhance diagnostic precision and biological insight. The review also explores underlying immunological mechanisms, including receptor interactions (RAGE, TLR4, CD33), cellular mediators (microglia, lymphocytes, monocytes), and therapeutic implications. Future research should prioritize mechanistic investigation of calprotectin modulation in ALS, longitudinal validation in larger cohorts, and integration within multimodal biomarker frameworks. A better understanding of disease-specific immune alterations may contribute to earlier diagnosis, stratified patient monitoring, and targeted therapeutic development.
    Keywords:  Biomarkers; Calprotectin; Immune dysregulation; Inflammation
    DOI:  https://doi.org/10.1016/j.neurol.2026.02.148
  20. Front Immunol. 2026 ;17 1742927
    The spatial architecture of neuroimmune interactions in epilepsy.
    Dianwu Chu, Wuhao Zhang, Xing Zhou, Hang Yin, Jian Yin.
      Epilepsy is increasingly recognized as a disorder not only of neuronal dysfunction but also of immune dysregulation within the central nervous system (CNS). Accumulating evidence points to a critical role for the immune microenvironment in shaping epileptogenesis-the process that underlies the development and progression of epilepsy. In this Review, we examine the spatial dynamics of neuroimmune interactions, highlighting how local inflammatory niches emerge and evolve across brain compartments such as the parenchyma and perivascular space. We describe how the spatial organization and activation of resident glial cells, alongside the infiltration of peripheral immune cells facilitated by blood-brain barrier (BBB) disruption, contribute to region-specific patterns of neuroinflammation. Critically, we emphasize that understanding "where" these neuroimmune interactions occur-their precise spatial organization within distinct cellular microenvironments-is as fundamental as identifying "what" immune cells are involved or "how" they function. Particular focus is given to the localized actions of immune mediators, including regulatory T cells and pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, and their influence on neuronal excitability. We also discuss the spatiotemporal heterogeneity of immune signatures across different epilepsy syndromes, drawing from both experimental models and clinical observations. Finally, we explore emerging therapeutic strategies that target spatially defined immune responses and consider the potential of spatial biomarkers and advanced tissue-mapping technologies to refine disease classification and guide precision therapies. By positioning the spatial immune landscape as a central feature of epileptogenesis, we propose a framework for developing effective, potentially curative interventions for epilepsy.
    Keywords:  astrocyte; epilepsy; immune microenvironment; microglia; neuroinflammation; spatial transcriptomics
    DOI:  https://doi.org/10.3389/fimmu.2026.1742927
  21. Brain. 2026 Feb 28. pii: awag083. [Epub ahead of print]
    Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis.
    Nayana Gaur, Christin Angerer, Zeynep I Gunes, Mihai Ancau, Mengzhe Wang, Henrick Riemenschneider, Charlene-Annett Hurler, Simon Mungwa, Patrick Lüningschrör, Anxhela Zhiti, Robert Steinbach, Michael Briese, Mugdha Srivastava, Mario Plaas, Andreas Hermann, Michael Sendtner, Sarah Jäkel, Dieter Edbauer, Jochen Herms, Sabine Liebscher, Julian Grosskreutz, Monika S Brill.
      Chitinases are hydrolytic enzymes responsible for degrading chitin and have been evolutionarily conserved across various species. Although their signaling pathways are not fully understood, the chitinases are considered active immunomodulators across several cell types. Specific isoforms, including Chitotriosidase-1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1), and human-specific Chitinase-3-like protein 2 (CHI3L2), have emerged as markers of inflammation across the neurodegenerative spectrum, including amyotrophic lateral sclerosis (ALS). ALS is a fatal neuromuscular condition, and therapeutic development has been severely hindered by phenotypic heterogeneity and an incomplete understanding of etiology. Although several overlapping disease mechanisms can contribute to neuronal death, inflammation can exacerbate pathology. Prior studies have reported that CHIT1, CHI3L1, and CHI3L2 levels are elevated in the cerebrospinal fluid (CSF) of ALS patients and associated with disease aggressiveness. Nevertheless, several open questions critical to our understanding of the chitinases' role in ALS disease burden remain: namely, 1) which cell types in the central nervous system (CNS) are chitinase sources under physiological conditions, 2) which of these display chitinase upregulation in ALS, and 3) what is the diagnostic utility of the chitinases relative to established biomarkers. Here, we utilize pre-clinical models and post-mortem human tissue to demonstrate at both the transcriptomic and protein level that neurons are a primary source of chitinases; furthermore, neuronal chitinase expression is conserved across species. Under physiological conditions, CHI3L1 is more abundant and widely expressed across various cell types, whereas CHIT1 is predominantly expressed in neurons. Additionally, utilizing symptomatic mice from three familial ALS models, we demonstrate isoform-specific expression profiles, with astroglial and microglial upregulation of CHI3L1, and neuronal and microglial upregulation of CHIT1. Differing expression dynamics and diagnostic utility were also noted in our clinical cohort: CSF CHIT1 and CHI3L2 levels had more discriminatory power when distinguishing between ALS vs. non-ALS controls, while CHI3L1 was more closely associated with inflammation and aging across the neurodegenerative spectrum. Although the chitinases did not diagnostically outperform the neurofilament proteins as biomarkers, we propose that appreciating their expression patterns can aid in optimizing biomarker-guided trial design. Taken together, we demonstrate that chitinase upregulation in ALS is evident in various CNS cell types and that its neuronal expression may provide new insights into its role in disease activity.
    Keywords:  CHI3L1; CHI3L2; CHIT1; amyotrophic lateral sclerosis; chitinase; neuron
    DOI:  https://doi.org/10.1093/brain/awag083
  22. Neurodegener Dis Manag. 2026 Mar 06. 1-12
    "What about me? I'm supposed to be … superhuman?": exploring staff perspectives on how to deliver high quality psychological care for people living with amyotrophic lateral sclerosis.
    Sarah Creer, Alys Wyn Griffiths, Esther Hobson, Sian Davies, Charlotte Massey, Louis Stokes, Bryony Waters-Harvey, Rosie Bamber, Sal Hastings, Jen Bedford, Rebecca L Gould, Christopher McDermott, Emily Mayberry.
       OBJECTIVES: To explore healthcare professionals' experiences of providing informal psychological care in Amyotrophic Lateral Sclerosis (ALS) services.
    METHODS: A qualitative focus group and interview study with 28 UK-based, ALS healthcare professionals. Data was analyzed using reflexive thematic analysis.
    RESULTS: Healthcare professionals reported psychological distress in their roles arising from the intrinsic nature of ALS, alongside system factors and their needs as staff members. Participants identified critical needs for themselves to improve psychological care including: psychological skills training, clear role definition, understanding of specialist psychology and structured staff support. Participants identified patient needs as: support for informal carers, access to specialist psychology, clear and inclusive referral pathways, and having person-centered, tiered approaches to care delivery.
    CONCLUSIONS: The psychological impact of ALS extends beyond patients and families to healthcare professionals, creating systemic challenges in care delivery. Effective psychological care in ALS requires a comprehensive approach that addresses not only the needs of individual patients but also staff and systemic issues. A distress loop exists where inadequate psychological services affect both staff wellbeing and care quality for patients and their families. Without addressing patient, staff, and service-level issues, people living with ALS and healthcare professionals will continue to experience preventable psychological distress.
    Keywords:  Motor neuron disease; amyotrophic lateral sclerosis; healthcare professionals; moral distress; psychological care; service delivery
    DOI:  https://doi.org/10.1080/17582024.2026.2637420
  23. Epigenomics. 2026 Mar 02. 1-18
    Targeting epigenetic remodeling of the blood-brain barrier: current knowledge for drug therapy.
    Maya Akhoury, Nicole Vegara, Svetlana M Stamatovic, Richard F Keep, Anuska V Andjelkovic.
      The blood - brain barrier (BBB) is a dynamic regulator of brain homeostasis, and its dysfunction is a hallmark of many neurological and psychiatric disorders. Yet, in most conditions, the causal relationship between BBB injury and disease progression remains unclear, as shared systemic risk factors, such as inflammation, infection, oxidative stress, and genetic predisposition, produce highly variable patterns of barrier disruption. Epigenetic mechanisms, including DNA and RNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs, have emerged as key regulators of BBB integrity. Their dysregulation contributes to pathological BBB remodeling in disorders such as cerebrovascular and neurodegenerative diseases, promoting a decline in barrier function (structural and biochemical) and accelerating disease progression. Owing to their reversible nature, epigenetic modifications represent promising therapeutic targets, and their disease-stage-specific patterns offer potential as biomarkers for BBB injury and recovery. This review summarizes current knowledge on how epigenetic processes drive BBB dysfunction and highlights emerging epigenetic signatures with diagnostic and therapeutic relevance across neurological and psychiatric diseases.
    Keywords:  Alzheimer’s disease; DNA methylation; RNA methylation; blood-brain barrier; histone modification; stroke
    DOI:  https://doi.org/10.1080/17501911.2026.2637419
  24. Neuroscience. 2026 Mar 03. pii: S0306-4522(26)00156-9. [Epub ahead of print]
    Trained immunity in neuroinflammation: emerging evidence, clinical perspectives, and future directions.
    Enis Guso, Alessia Lupoli, Emanuele Olivieri, Alessia Bottoni, Maira Gironi, Davide M Missarelli, Ahmed T Toosy, Elena Rossi, Roberto Furlan.
      Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and systemic implications of trained immunity are widely discussed, evidence in central nervous system (CNS) diseases remains fragmented and largely confined to individual pathological conditions. As a result, a comprehensive framework integrating these findings and identifying shared mechanisms across neurological disorders is still lacking. In this review, we explore the concept of trained immunity with a focus on neuroinflammatory and neurodegenerative diseases, synthetizing evidence from multiple CNS pathologies, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebrovascular disorders. We first critically examine preclinical and experimental studies addressing innate immune memory in the CNS and subsequently integrate these findings with emerging clinical evidence, aiming to identify convergent mechanisms and disease-relevant immune memory signatures. Finally, we discuss potential therapeutic targets identified in preclinical settings and outline key unresolved issues, including the nature of triggering stimuli, thresholds, and temporal dynamics shaping innate immune memory in the CNS. By highlighting current limitations and defining critical questions for future research, this review presents a unifying perspective on trained immunity in neurological diseases and underscores the translational potential to modulate neuroinflammation and to influence disease progression.
    Keywords:  Cell metabolism; Epigenetic remodelling; Innate immune memory; Ischemic stroke; Neurodegeneration; Neuroimmunology; Neuroinflammation; Trained immunity
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.02.047
  25. Front Cell Neurosci. 2025 ;19 1669272
    Glioinflammation: disease-associated microglia and astrocytes in psychiatric disorders, neurodegeneration, and senescence.
    Kumiko Uemura, Shunya Hiro, Suthinee Attachaipanich, Ruixue Du, Nur Intan Saidaah Mohamed Yusof, Miyu Kinoshita, Momoka Hikosaka, Gen Ohtsuki.
      In this review, we synthesize recent conceptual and experimental advances in neuroscience, highlighting selected studies that delineate the roles of reactive microglia and astrocytes in the contexts of developmental inflammatory stress, neurodegenerative diseases, and cellular senescence. Since the characterization of disease-associated glial phenotypes in 2017, building on earlier pioneering discoveries, we focus here on disease-associated microglia (DAM) and disease-associated astrocyte (DAA) to reassess their contributions to glio-inflammation. It is now recognized that the stress-induced glial states are far from uniform; however, the ontogeny, molecular determinants, and functional consequences of this heterogeneity remain incompletely understood, particularly in psychiatric disorders, Alzheimer's disease, and amyotrophic lateral sclerosis. Accordingly, we compare the glial heterogeneity and its underlying mechanisms across translational mouse models and human neuropathology, considering their evolutionary and physiological contexts. While this review does not aim to be exhaustive, we propose an integrative framework that redefines glial stress responses through the combined lenses of inflammation, transcriptomics, mitochondrial dynamics, lipid metabolism, epigenomic regulation, and cellular senescence. Finally, we outline emerging frontiers for AI-enabled multi-omic physiological and pathological approaches, emphasizing their potential to illuminate glial state transitions and accelerate therapeutic discovery in the near future.
    Keywords:  astrocyte; epigenetics; glial heterogeneity; microglia; mitochondria; neurodegenerative disease; psychiatric disorder; senescence
    DOI:  https://doi.org/10.3389/fncel.2025.1669272
  26. Front Immunol. 2026 ;17 1749278
    Immunosenescence and inflammaging in Parkinson's disease: mechanisms and therapeutic prospects.
    Ruyu Yan, Hongfang Feng, Jie Zhang.
      Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, with growing evidence underscoring the critical role of immunosenescence-the age-related dysregulation of the immune system-in its pathogenesis. This review delineates the intricate interplay between systemic immunosenescence, chronic neuroinflammation, and neurodegeneration in PD. We explore how age-related remodeling of the peripheral immune system, termed "inflammaging," promotes a pro-inflammatory milieu that compromises blood-brain barrier integrity and drives microglial activation within the central nervous system. A central focus is the senescence-associated secretory phenotype, a cocktail of pro-inflammatory factors released by senescent glial cells, which perpetuates a self-sustaining cycle of neuroinflammation, facilitates the propagation of pathological α-synuclein, and ultimately accelerates neuronal loss. The review further examines the disruption of vital neuroimmune communication pathways, including aberrant neuron-glia and gut-brain axis signaling, which are corrupted in the aging brain. We evaluate the translational promise of emerging therapeutic strategies designed to target this immunosenescence-neuroinflammation axis. These include senolytic agents to clear senescent cells, adoptive regulatory T-cell therapy, cytokine-targeted immunomodulation, and immune rejuvenation approaches. Finally, we discuss significant translational challenges and outline future research directions, emphasizing the need for advanced model systems, biomarker development, and AI-driven personalized medicine to successfully develop disease-modifying immunotherapies that disrupt the vicious cycle of immunosenescence and neurodegeneration in PD.
    Keywords:  Parkinson’s disease; immunosenescence; neuroinflammation; senescence-associated secretory phenotype; therapeutic strategies
    DOI:  https://doi.org/10.3389/fimmu.2026.1749278
  27. Biochem Pharmacol. 2026 Feb 26. pii: S0006-2952(26)00184-X. [Epub ahead of print] 117853
    The therapeutic potential of cytisine and its derivatives in disorders of the central nervous system.
    Ming Cheng, Danchen Zhu, Shuyu Chen, Jinjing Jia, Jinbiao Xu, Xiansi Zeng.
      Cytisine is a quinolizidine alkaloid that is widely used in smoking cessation, exerting its neurological and other biological actions primarily through binding to the nicotinic acetylcholine receptor (nAChR). Cytisine binds to the nAChR (herein represented by α4β2) and exhibits distinct receptor recognition characteristics that provide a basis for the structural optimization of its derivatives in terms of affinity and selectivity. An increasing number of studies indicate that cytisine and its derivatives exhibit a variety of neuroprotective and functional benefits in disorders of the central nervous system (CNS), including Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, depression, and ischemic stroke. In this review, the binding interactions between cytisine and nAChR are discussed extensively. Then the neuroprotective roles of cytisine and its derivatives in CNS diseases are summarized, and cellular and molecular mechanisms are further highlighted. This review aims to provide a basis for further research and to promote the possible clinical application of cytisine and its derivatives. Taken together, cytisine and its derivatives may provide promising drug candidates to treat a range of CNS diseases.
    Keywords:  Cytisine; Depression; Epilepsy; Ischemic stroke; Neurodegenerative diseases; Smoking cessation; nAChR
    DOI:  https://doi.org/10.1016/j.bcp.2026.117853
  28. Mol Cell Biol. 2026 Mar 02. 1-19
    Loss of Splicing Homeostasis as a Hallmark of Aging.
    Stefano Donega, Myriam Gorospe, Lorna W Harries, Luigi Ferrucci.
      Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity weakens, contributing to decline in RNA homeostasis and disrupting essential cellular functions, including mitochondrial oxidative phosphorylation, genome stability, and immune regulation, and in turn accelerating tissue and organ dysfunction. Evidence from senescent cells, aged tissues, and model organisms shows that altered levels of splicing factors and increased RNA polymerase II elongation rates impair co-transcriptional splicing and promote mis-spliced isoforms that reinforce senescence and drive pathology. Dysfunction of RNA-binding proteins further contributes to aberrant splicing, linking splicing defects to age-related diseases such as atherosclerosis, osteoarthritis, sarcopenia, and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic strategies to correct splicing defects, such as antisense oligonucleotides, RNA interference, CRISPR-Cas systems, ADAR-mediated editing, and RNA aptamers, can restore a homeostatic balance of mRNA isoforms. However, major challenges remain, including distinguishing adaptive physiological from pathological splicing 'noise' and achieving targeted delivery to tissues. Despite these obstacles, RNA splicing dysregulation represents a promising avenue to extend health span by reestablishing homeostatic RNA programs, and reinforces the idea that "transcriptomic instability" is a hallmark of aging.
    Keywords:  Splicing; adaptive gene expression programs; aging; proteomic diversity; senescence
    DOI:  https://doi.org/10.1080/10985549.2026.2627235
  29. Front Public Health. 2026 ;14 1742821
    Innovative socio-sanitary rehabilitation models in central nervous system disorders: a systematic review.
    G Morlino, M Chimienti, O Zerellari, R Shkreli, D Ndreca, K Stefanidhi, S Gjergji, F Leonforte, V Nicosia, A Mistretta, E Buonomo, G Liotta, L Palombi.
       Introduction: Because neurological disorders profoundly affect patients' lives, care models are increasingly oriented toward an integrated clinical and socio-sanitary approach. This being said, the actual context of this integration and the literature itself presents notable gaps and inconsistencies. The aim of this study was to review the existing literature to provide an overview of the current implementation of these services, while identifying gaps and potential areas for improvement.
    Methodology: We conducted a systematic review following the PRISMA guidelines including only peer-reviewed articles retrieved from PubMed, Scopus, and Web of Science that focused on neurological conditions and socio-sanitary services. For each peer-reviewed study, we identified specific characteristics to review them.
    Results: Sixty-four studies were included, with stroke as the most frequently studied condition, followed by Alzheimer's disease, multiple sclerosis, Parkinson's disease, and spinal cord injury. Most of the services were embedded within public health systems with a prevalence of home or territorial-setting.
    Conclusion: The review identifies promising evidence of positive impacts associated with socio-sanitary services, particularly in relation to functional outcomes, patient satisfaction and support for community living. At the same time there are important gaps in their implementation, integration, and the methodological consistency of existing studies. Across multiple settings, continuity of care appears fragmented, and case management functions are inconsistently implemented or, in some cases, entirely absent. Together, these findings suggest that while socio-sanitary models can offer meaningful benefits, persistent gaps in coordination and follow-up represent key structural barriers to achieving effective and sustainable integration.
    Keywords:  central nervous system; integrated care; neurorehabiliation; rehabiliatation; socio-sanitary
    DOI:  https://doi.org/10.3389/fpubh.2026.1742821
  30. Front Pharmacol. 2026 ;17 1718322
    Farnesol, the farnesol pathway, and the immune-gut-brain axis.
    Megan Gates, Sean M Schumacher, William J Doyle, Natalie Sofaly, Jean-Baptiste Roullet, Javier Ochoa-Repáraz.
      Experimental models and clinical evidence suggest that the gut and the central nervous system (CNS) interact in a multifactorial, bidirectional manner. A third player, the immune system, has recently been identified in these interactions, with research linking the gut microbiome to inflammatory conditions, including those affecting the CNS. The molecular signals involved in communication between the gut, brain, and immune system have been extensively studied. However, no unique signaling pathway has been identified for each component of the immune-gut-brain (IGB) axis to date. In this review, we argue that isoprenoids, and specifically farnesol, are key signaling molecules that link the gut and its microbiota, the immune system, and the CNS. The pharmacological properties of farnesol, an intermediate in the broadly conserved mevalonate pathway, are diverse and encompass quorum sensing and microbial biofilm inhibition, neuroinflammatory protection, and modulation of intracellular calcium (Ca2+) signaling pathways. Many of these signaling pathways are implicated in neuron-to-neuron communication and in the responses of immunocompetent cells to immunogenic stimuli. We will first address the biological relevance of the immune-gut-brain axis and the gut microbiome in regulating health and disease. Next, we will review the molecular and cellular mechanisms by which farnesol regulates both the gut microbiota and the host's innate and adaptive immune systems. Finally, we will provide a perspective on the immunoregulatory mechanisms underlying farnesol's protective properties in models of neuroinflammatory diseases. In summary, we propose a review of the most salient studies that establish farnesol as a significant modulator of the immune-gut-brain axis.
    Keywords:  farnesol; immune-gut-brain axis; isoprenoids; neuroinflammation; quorum-sensing
    DOI:  https://doi.org/10.3389/fphar.2026.1718322
  31. Neurobiol Dis. 2026 Mar 03. pii: S0969-9961(26)00087-2. [Epub ahead of print] 107343
    Context-dependent effects of adaptive immunity on IFN-α-mediated neurotoxicity in Aicardi-Goutières syndrome.
    Martina Pesenti, Heli Soni, Manuela Estphan, Barney Viengkhou, Markus J Hofer.
      Aicardi-Goutières syndrome (AGS) is a severe neuroinflammatory disorder characterized by chronic overexpression of interferon-alpha (IFN-α) in the central nervous system (CNS), leading to progressive encephalopathy, developmental regression, and high mortality. Recent work has identified the brain microvasculature, particularly the blood-brain barrier (BBB) endothelial cells, as a central mediator of IFN-α-induced neurotoxicity. This microangiopathy is accompanied by the infiltration of B and T lymphocytes into the brain parenchyma, but their contribution to disease progression remains unclear. Here, we investigated the role of adaptive immune cells in AGS pathogenesis using a transgenic mouse model that overexpresses IFN-α in the brain, but lacks mature B and T cells. Loss of adaptive immune cells partially ameliorated IFN-α-driven neurotoxicity, improving neurological disease and reducing histopathological damage, without altering interferon or interferon-stimulated gene expression. These findings indicate that adaptive immunity is not essential but modulates specific aspects of disease. Together, our results support a model in which IFN-α primarily targets CNS-resident cells, such as endothelial cells, astrocytes, and microglia, while adaptive immune responses act as a secondary enhancer of pathology. This work provides new mechanistic insight into AGS and highlights therapeutic opportunities aimed at modulating IFN-α signalling or glial-driven neuroinflammation to slow disease progression.
    Keywords:  Adaptive immunity; Aicardi-Goutières syndrome (AGS); Blood-brain barrier; Interferon-α neuroinflammation; Neurotoxicity
    DOI:  https://doi.org/10.1016/j.nbd.2026.107343
  32. Neurol Res Int. 2026 ;2026 6629960
    The Amyotrophic Lateral Sclerosis House Call Program: A Single-Center Experience in the United States.
    Erica Scirocco, Jennifer Scalia, Benedetta Ugolini, Gabriella Casagrande, Doreen Ho, Jennifer L Hagar, Kristen Kingsley, Ron Hoffman, Christopher Cooley, Merit E Cudkowicz, Sabrina Paganoni, James D Berry.
       Background: Accessing multidisciplinary care poses challenges for people living with amyotrophic lateral sclerosis (ALS) due to mobility issues. As ALS care rarely requires hospital-based technology, most care is available through home visits. The Daniella Lipper ALS House Call Program (HCP) at Massachusetts General Hospital (MGH), launched in 2017 in collaboration with Compassionate Care ALS, has pioneered home-based ALS care in Eastern Massachusetts.
    Methods: A retrospective chart review of ALS and primary lateral sclerosis (PLS) patients enrolled in the HCP at MGH was conducted. Data on demographics, visit details, and procedures performed during home visits were collected from electronic health records for patients seen from January 2024 to December 2024.
    Results: In 2024, the ALS HCP conducted 959 visits for 142 patients (average age: 68 years, range: 36-93; 47.9% female). Of these patients, 137 (96.5%) were diagnosed with ALS and 5 (3.5%) with PLS. Notably, 61 patients (43%) received care exclusively at home. Key interventions included 44 gastrostomy tube exchanges and 59 respiratory assessments, both of which significantly reduced hospital visits. The average distance traveled by the care team was 30.32 miles per visit.
    Conclusions: The Daniella Lipper ALS HCP at MGH brings ALS expertise into the patient's home, minimizing travel burdens and ensuring continuity of care. The program illustrates the feasibility and impact of home-based ALS care, suggesting potential for broader implementation across the nation. Development will focus on expanding services, such as tracheostomy changes in the homes, and on creating sustainable models for similar initiatives.
    Keywords:  amyotrophic lateral sclerosis; healthcare access; house calls; multidisciplinary care; neuropalliative care
    DOI:  https://doi.org/10.1155/nri/6629960
  33. BMC Med. 2026 Mar 06.
    Impairment of brain short association fibers across clinical stages in amyotrophic lateral sclerosis: a new biomarker mirroring disease progression.
    Nao-Xin Huang, Zi-Wei Cai, Shao-Peng Zhuang, Hong-Yu Lin, Sheng Chen, Zhang-Yu Zou, Ye Wu, Hua-Jun Chen.
       BACKGROUND: A quantitative biomarker for clinical staging is essential for amyotrophic lateral sclerosis (ALS) stratification. This study evaluated microstructural impairment in brain short association fibers (SAFs) across ALS stages via neurite orientation dispersion and density imaging (NODDI) and assessed correlations with disease severity.
    METHODS: Diffusion-weighted imaging data were collected from 87 ALS patients (categorized into four groups King's stages) and 37 healthy controls. Whole-brain SAF mapping was performed via a spherical deconvolution-driven probabilistic tractography approach. Diffusion tensor imaging (DTI) and NODDI parameters (neurite density index, NDI; orientation dispersion index, ODI; isotropic volume fraction, ISO) were estimated for each SAF.
    RESULTS: Seven SAFs connecting the left postcentral-precentral gyrus, left precentral-precentral gyrus, right postcentral-precentral gyrus, right paracentral-posterior cingulate gyrus, left paracentral-posterior cingulate gyrus, left precentral-superior parietal gyrus, and left precentral-superior frontal gyrus exhibited significant NDI differences across the five groups. Additionally, one fiber connecting the left medial orbitofrontal-rostral anterior cingulate gyrus demonstrated an ISO difference [false discovery rate (FDR)-corrected p < 0.05]. Progressive trends of NDI reduction and ISO increase were observed at higher ALS stages. No intergroup differences were found in the ODI or DTI parameters. The NDI values of these seven SAFs were positively correlated with disease severity scores (FDR-corrected p < 0.05). Combining NDI and ISO revealed moderate classification potential for ALS (area under the curve = 0.780).
    CONCLUSIONS: Neurite injury in SAFs involving primary motor and extramotor areas worsened alongside clinical staging and motor disability in ALS. NODDI provides quantitative SAF-related biomarkers for assessing ALS disease severity.
    Keywords:  Amyotrophic lateral sclerosis; Clinical stages; Microstructural impairment; Neurite orientation dispersion and density imaging; Short association fiber
    DOI:  https://doi.org/10.1186/s12916-026-04770-7
  34. Mol Psychiatry. 2026 Mar 06.
    TREM2 in neurodegeneration and diseases.
    Altaf A Abdulkhaliq, Glowi Alasiri, Bonglee Kim, Johra Khan, Amir Ajoolabady, Shimaa Mohammad Yousof, Jun Ren, Jaakko Tuomilehto, Anwar Borai, Bahauddeen M Alrfaei, Domenico Pratico.
      Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface transmembrane receptor from the TREM receptor family, predominantly expressed on the microglia in the central nervous system (CNS). TREM2-initiated signaling plays a crucial role in regulating neuroinflammation and neurodegeneration, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), through the activation of downstream signaling pathways and transcriptional regulation of relevant genes. In this review, we aim to provide a concise review of the role and mechanistic implications of TREM2 in neurodegeneration and neuroinflammation, with a specific focus on AD and PD. We will discuss the most recent preclinical studies to highlight current advancements in the field. This review is intended to support both basic researchers and clinicians by enhancing their understanding of microglial function in the pathophysiology of AD and PD, as well as its role in neuroinflammation and neurodegeneration. Ultimately, we hope this contribution will pave the way for new discoveries and the development of potential therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41380-026-03505-7
  35. J Clin Neuromuscul Dis. 2026 Mar 01. 27(3): 82-88
    Exploring Intimacy in Amyotrophic Lateral Sclerosis: A Pilot Study of Educational Support in a Multidisciplinary Clinic.
    Cassie Kuhn, Mark Bromberg, Amber Margolis, Heather Hayes.
       OBJECTIVE: This pilot study explored the feasibility and perceived usefulness of an educational intervention on intimacy delivered within a multidisciplinary ALS clinic.
    METHODS: Individuals with ALS and their partners (if applicable) received the publicly available "Sexuality, Intimacy & Chronic Illness" fact sheet during routine clinic visits. A follow-up survey was conducted 4-6 weeks later to assess whether the information was informative, sufficient, and helpful. Demographic and clinical data were collected, and open-ended responses were analyzed descriptively.
    RESULTS: Forty-two individuals received the fact sheet; 6 individuals and their partners (N = 12) completed follow-up surveys. Most respondents (83%) reported that ALS had impacted their intimate relationships, and 75% had discussed these changes with their partner. Half found the fact sheet informative, and 58% felt the information was sufficient. Open-ended responses revealed diverse needs, including interest in tailored content (eg, erectile dysfunction) and a desire for providers to ask permission before discussing intimacy. Caregivers described shifting roles and emotional strain, indicating that written materials alone may not fully address intimacy-related challenges.
    CONCLUSIONS: Integrating discussions of intimacy into ALS care is feasible and appreciated by some patients and partners. Although written educational materials may offer a useful starting point, a more personalized, consent-based approach-potentially modeled on frameworks like Ex-PLISSIT-may better address the relational needs of individuals with ALS and their caregivers. These findings support incorporating intimacy into holistic ALS care and developing guidelines to facilitate such discussions in multidisciplinary settings.
    Keywords:  amyotrophic lateral sclerosis; caregivers; education; intimacy
    DOI:  https://doi.org/10.1097/CND.0000000000000546
  36. J Adv Res. 2026 Mar 01. pii: S2090-1232(26)00185-2. [Epub ahead of print]
    From scaffold to effector: reframing GFAP in neurodegeneration.
    Yong-Heng Lu, Xiu-Ping Zhu, Song Li, Feng-Ning Zhang, Chuan-Bin Cai, Mao Tian, Yu-Hang Zhu, Ling-Hui Zeng, Jun Tan, Chang-Yin Yu, Jiang Chen.
       BACKGROUND: Neurodegenerative disorders impose a growing global burden, yet disease-modifying therapies remain limited. Glial fibrillary acidic protein (GFAP) has shifted from a passive astrocytic marker to an active effector that shapes neurodegenerative pathology.
    AIM: of Review: This review synthesizes mechanistic and translational evidence that defines GFAP as a proteoform-governed hub and highlights its value for biomarker-guided precision intervention. Key Scientific Concepts of Review: An extensive literature search across major databases was conducted using predefined keywords and strict inclusion criteria, covering mechanistic, pathological, and clinical studies. Evidence supports a GFAP proteoform code in which alternative splicing generates functionally distinct isoforms, and PTMs encode context-dependent assembly dynamics and signaling outputs. We summarize how GFAP proteoforms integrate cytoskeletal remodeling with inflammatory transcriptional programs (notably STAT3 and NF-κB), proteostasis stress, and mitochondrial dysfunction, thereby coupling astrocyte state transitions to neuronal vulnerability and synaptic impairment. Disease trajectories are context-specific: GFAP dysfunction drives primary toxicity in Alexander disease (AxD); in Alzheimer's disease (AD), isoform-specific mechanisms intersect with amyloidogenic machinery and track early preclinical astrocyte activation; and in frontotemporal dementia (FTD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), GFAP reflects inflammatory-metabolic coupling during progression. Translationally, ultrasensitive plasma assays reveal GFAP elevation years to decades before symptom onset, complementing NfL and amyloid/tau within AT(N)-oriented diagnostic frameworks. Therapeutically, we evaluate precision strategies beyond global suppression, including ASO-based modulation, targeting STAT3/NF-κB-driven reactive programs, and restoring proteostasis via chaperone/autophagy pathways. Future progress hinges on isoform-/PTM-specific probes, conformational sensors, and spatial proteomic atlases validated in prospective longitudinal cohorts. In conclusion, GFAP represents both a mechanistic driver and a scalable biomarker, offering a translationally actionable axis to advance precision medicine in neurodegeneration.
    Keywords:  Astrocyte reactivity; GFAP; Plasma biomarkers; Proteoforms; Therapeutic targeting
    DOI:  https://doi.org/10.1016/j.jare.2026.02.051
  37. J Alzheimers Dis. 2026 Mar 04. 13872877261424284
    TDP-43 phosphorylation: Exploring kinases, phosphatases, and therapeutic potential in neurodegeneration.
    Liti Zhang, Yichen Huang, Wei Huang, Qianqian Huang, Yizhou Lin, Jianlan Gu.
      TAR DNA-binding protein 43 (TDP-43) is a multifunctional DNA/RNA-binding protein whose abnormal phosphorylation and aggregation are central to the pathogenesis of several neurodegenerative diseases. TDP-43 proteinopathy, characterized by hyperphosphorylation and cytoplasmic accumulation, is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and is frequently observed in Alzheimer's disease. The phosphorylation state of TDP-43 is dynamically regulated by a network of protein kinases-including CK1, GSK3β, CDC7, and PKA-and counterbalanced by phosphatases such as PP2A and PP1; however, the precise molecular mechanisms governing this equilibrium in disease remain incompletely understood. Notably, phosphorylated TDP-43 acquires prion-like properties, enabling self-templated aggregation and cell-to-cell propagation, which amplifies pathology and drives disease progression. These insights have catalyzed the development of therapeutic strategies aimed at modulating TDP-43 phosphorylation, with kinase inhibitors and phosphatase enhancers emerging as promising candidates for targeting TDP-43 proteinopathies. This review integrates current knowledge on the regulatory networks controlling TDP-43 phosphorylation, examines its role in prion-like spread, and evaluates emerging therapeutic approaches aimed at mitigating TDP-43-mediated neurodegeneration.
    Keywords:  Alzheimer's disease; TDP-43; neurodegenerative disease; phosphatase; phosphorylation; protein kinase
    DOI:  https://doi.org/10.1177/13872877261424284
  38. Neurobiol Dis. 2026 Feb 27. pii: S0969-9961(26)00080-X. [Epub ahead of print] 107336
    Voltage-gating and neuronal signalling in neurodegeneration: From neuropathology to therapeutic opportunities in motor neuron disease.
    Charan Kotapati, Le Thuy Van Tran, Fernanda C Cardoso.
      Voltage-gated ion channels (VGICs) are central to motor neuron excitability, governing the initiation and propagation of action potentials and synaptic transmission. Disruption of their finely tuned gating properties contributes to pathology-associated hyperexcitability, a hallmark of several neurodegenerative conditions, including motor neuron disease (MND). In this review, we examine the physiological roles of voltage-gated sodium, calcium and potassium channels in motor neurons, and evaluate how mutations, altered expression, aberrant biophysics, and maladaptive signalling impair the voltage signalling processes that drive and underlie neuronal dysfunction and degeneration. We synthesise evidence linking ion channel dysfunction to altered excitability, excitotoxicity, impaired neurotransmission, motor system instability and progressive motor neuron loss in MND. We discuss current therapies that offer modest benefit and may act directly or indirectly on neuronal excitability but with limited target specificity. Motivated by the the urgent need for effective treatments for MND, we discuss emerging strategies that leverage highly selective VGIC modulators, particularly gating-modifier peptides inhibitors, to counteract hyperexcitability in MND. We further highlight that understanding how voltage-sensing and channel gating are altered in MND offers new avenues for selective targeted intervention. Together, the evidence supports VGICs as critical yet poorly explored therapeutic targets for halting motor neurodegeneration.
    Keywords:  Amyotrophic lateral sclerosis; Drug target; Hyperexcitability; Motor neuron disease; Neuropathogenesis; Voltage-gated ion channel
    DOI:  https://doi.org/10.1016/j.nbd.2026.107336
  39. Bone Res. 2026 Mar 05. pii: 28. [Epub ahead of print]14(1):
    The spinal lymphatic system: an emerging pathway bridging fluid homeostasis, immunity, and disease.
    Yubao Hou, Jianwei Wu, Shuo Yang, Hongwei Wang, Xianghe Wang, Zian Lu, Zhenhao Chen, Jing Feng, Hongli Wang.
      The lymphatic system, traditionally regarded as a unidirectional conduit for interstitial fluid and immune cell transport, has recently been redefined through the discovery of lymphatic networks along the spinal axis. These spinal lymphatic vessels, encompassing the spinal cord, vertebral bones, and intervertebral discs, challenge long-standing anatomical dogmas and introduce new perspectives on the interplay between the central nervous system (CNS) and the vertebral column. This review systematically summarizes the distribution and dual functions of the spinal lymphatic system in regulating cerebrospinal fluid drainage, maintaining tissue homeostasis, and mediating immune responses. Furthermore, we highlight emerging evidence linking spinal lymphatic dysfunction to spinal pathologies, neurological disorders, and vertebral degeneration. Based on these findings, we propose that the spinal lymphatic system constitutes a previously underappreciated pathway integrating spinal cord and vertebral physiology, with potential implications for both disease progression and therapeutic intervention. While research on the cranial lymphatic system has rapidly advanced, the spinal lymphatic system remains comparatively underexplored. We hope this review will catalyze further investigation into spinal lymphatic biology and inform the development of novel therapeutic strategies targeting spinal and neurological diseases.
    DOI:  https://doi.org/10.1038/s41413-026-00508-6
  40. Front Immunol. 2026 ;17 1739875
    TREM2 and microglial immunity in Alzheimer's disease: mechanisms, genetics, and therapeutic opportunities.
    Tianqing Wang, Xinru Liu, Xifeng Wang, Fuzhou Hua, Lei Yan.
      Alzheimer's disease (AD) is increasingly recognized as a disorder of innate immune dysregulation within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2), a microglial immunoreceptor, has emerged as a pivotal genetic risk factor for late-onset AD, underscoring the critical role of neuroimmune interactions in disease pathogenesis. This review synthesizes recent advances concerning TREM2's modulation of core microglial functions, including phagocytosis, inflammatory signaling, cellular metabolism, and survival, processes that are essential for responding to amyloid-β plaques and neuronal damage. We highlight the TREM2-APOE pathway as a central mechanism driving the disease-associated microglia (DAM) phenotype and examine how loss-of-function mutations such as R47H disrupt immune surveillance, aggravate amyloid pathology, and promote neuroinflammation. Additionally, we explore the diagnostic and therapeutic potential of soluble TREM2 (sTREM2) and TREM2-targeted immunotherapies, which enhance plaque encapsulation and cognitive outcomes in preclinical models. By integrating genetic, molecular, and clinical evidence, this review establishes TREM2 as a keystone regulator linking amyloidosis, tauopathy, and neuroinflammation, highlighting its promise as a target for disease-modifying therapies.
    Keywords:  Alzheimer’s disease; TREM2; immunotherapy; microglia; neuroimmunology
    DOI:  https://doi.org/10.3389/fimmu.2026.1739875
  41. Brain Behav Immun. 2026 Mar 03. pii: S0889-1591(26)00274-6. [Epub ahead of print] 106526
    Central nervous system-penetrant anti-C1q therapy reduces neuroinflammation and preserves neurological function in a model of progressive multiple sclerosis.
    Michael Linzey, Steven C Pike, Nour-Maria Bouzid, Aine Scholand, Cinthia Gonzalez Cruz, Andrew Philips, Laura DeCristofano, Hiep Tran, Francesca Gilli.
      Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) characterized by both neuroinflammation and neurodegeneration. While significant progress has been made in the treatment of relapsing-remitting MS, with more than 20 FDA-approved therapies available as of mid-2025, effective therapeutic options for progressive forms of the disease (PMS) remain limited and largely inadequate. Among the mechanisms implicated in PMS pathogenesis is the dysregulation of the complement system, a key component of the innate immune response that also plays essential roles in CNS development and homeostasis. Hyperactivation of the classical complement cascade through C1q has been linked to chronic inflammation, synaptic pruning, and neurodegeneration. In MS, one potential trigger for sustained C1q activation is intrathecal immunoglobulin synthesis (IIgS), a hallmark of the disease that correlates with severity and progression. Persistent IIgS may provide continuous antigen-antibody complexes capable of engaging C1q, thereby perpetuating complement-mediated injury within the CNS. To investigate this mechanistic link, we used Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established murine model of PMS that features chronic demyelination, neurodegeneration, neuroinflammation, and robust IIgS. We tested the therapeutic potential of CNS-targeted C1q inhibition using two approaches: direct intraventricular administration of a murine anti-C1q monoclonal antibody and intraperitoneal delivery of a CNS-penetrant anti-C1q nanobody. Our results demonstrate that, regardless of the administration route, C1q blockade significantly reduces neuroinflammation, demyelination, preserves axons, and improves clinical scores. These findings support the concept that classical complement activation downstream of IIgS plays a central role in driving progressive CNS damage. By interrupting the pathological feedback loop between intrathecally produced antibodies and complement activation, C1q antagonism may represent a novel and promising therapeutic avenue for PMS. Importantly, the favorable biodistribution, brain penetration, efficacy, and less invasive route of administration of the nanobody highlight its potential as a clinically translatable treatment strategy for MS.
    Keywords:  C1q; Complement system; Intrathecal immunoglobulin synthesis; Multiple sclerosis; Nanobody therapy; Neurodegeneration; Neuroinflammation; Progressive multiple sclerosis
    DOI:  https://doi.org/10.1016/j.bbi.2026.106526
  42. Front Pharmacol. 2026 ;17 1748360
    Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders.
    Marcos Roberto de Oliveira.
      Dimethyl fumarate (DMF; C6H8O4) is an ester of fumaric acid widely used in clinical practice for the treatment of relapsing forms of multiple sclerosis and plaque psoriasis. Beyond its established immunomodulatory actions, DMF is increasingly recognized as a small molecule capable of reshaping cellular redox homeostasis and mitochondrial physiology. Mitochondria are double-membrane organelles that integrate energy metabolism, calcium buffering, and apoptosis regulation, while also generating reactive oxygen species that function as signaling mediators. Given their central role in neuronal survival and function, mitochondrial integrity is a critical determinant of neuroprotection. The aim of this review is to discuss the mechanistic aspects by which DMF influences mitochondrial physiology in central nervous system (CNS) cells, based on evidence from experimental models and patient-derived samples. Data consistently show that DMF activates the Nrf2 pathway, leading to increased expression of antioxidant enzymes (e.g., NQO-1, HO-1) and induction of mitochondrial biogenesis markers (e.g., PGC-1α, NRF1, TFAM). In neurons and oligodendrocytes, DMF enhances respiratory function and limits apoptosis by modulating BCL-2 family proteins and suppressing cytochrome c release. Disease-relevant studies further demonstrate frataxin upregulation in Friedreich's ataxia and reduction of mitochondrial reactive oxygen species in C9orf72-related models. Conversely, in microglia, T cells, and vascular cells, DMF may impair mitochondrial respiration or increase apoptosis, particularly under inflammatory stress, suggesting a context-dependent effect. In conclusion, DMF exerts multifaceted and cell type-specific actions on mitochondria. Understanding these mechanisms may guide optimized therapeutic strategies and the identification of biomarkers for precision use in neurological disorders.
    Keywords:  dimethyl fumarate; mitochondria; mitochondrial biogenesis; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.3389/fphar.2026.1748360
  43. Adv Healthc Mater. 2026 Mar 05. e04508
    Advanced 3D Platforms for Modeling CNS Neuroinflammation: Cell Integration, Techniques, and Challenges.
    Emmanuelle D Aiyegbusi, Julia Di Stefano, Dearbhaile Dooley.
      Neuroinflammation is a multicellular immune response within the central nervous system (CNS) triggered by injury, infection, or disease, and it drives long-term changes in neurons and glia. Understanding this mechanism is important for advancing research into neurodegenerative diseases and trauma-induced CNS damage. Three-dimensional (3D) cell culture models offer enhanced structural and functional capabilities compared to traditional 2D models, yet their implementation remains challenging. Key limitations include cell survival, faithful recapitulation of CNS cellular diversity, simulation of immune responses, and issues of scalability and long-term culture. This review explores state-of-the-art methods for incorporating neurons, astrocytes, microglia, oligodendrocytes, and other CNS-relevant cell types into 3D models to study neuroinflammation. Additionally, it examines emerging trends in bioengineering, co-culture strategies, and dynamic systems that improve model scalability and longevity. By critically evaluating both established and innovative protocols, we aim to provide guidance for researchers in selecting effective methodologies and to accelerate the development of physiologically relevant in vitro models for neuroinflammation research.
    Keywords:  3D models; bioengineering; immune cells; neuroinflammation
    DOI:  https://doi.org/10.1002/adhm.202504508
  44. Eur J Neurosci. 2026 Mar;63(5): e70449
    Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
    Nermeen Z Abuelezz, Fayza Eid Nasr, Amira Emad Abd El Aziz, Mariam K Ahmed, Nesrine S El Sayed.
      Mitochondrial dysfunction is a pivotal feature in the pathogenesis of various neurological and neurodegenerative disorders. The brain, with its high metabolic demands, is particularly vulnerable to impaired mitochondrial function, leading to oxidative stress, disturbed calcium homeostasis, and hyperactivated microglial responses. Mitochondrial disturbances majorly contribute to neuronal damage, synaptic dysfunction, and cognitive decline, making mitochondria a crucial target for therapeutic intervention in brain disorders. In this context, mitochondrial-derived vesicles (MDVs) are increasingly emerging as a novel aspect of mitochondrial biology with significant implications for brain health and disease. Prior to mitophagy, MDVs are released from stressed mitochondria, incorporating either healthy or damaged mitochondrial components as an earlier defense mechanism to maintain mitochondrial integrity and homeostasis. Furthermore, MDVs contribute to intercellular communication and extracellular neuroinflammation signaling, potentially influencing the progression of neurological disorders. This review provides a thorough overview of MDVs' subpopulations, highlighting the most recently reported MDVs roles across multiple neurological disorders and exploring their potential in diagnostic and therapeutic settings. Additionally, we further analyze the current limitations that hinder broader clinical applications of MDVs and present future perspectives and key recommendations to overcome these obstacles, aiming to enhance their effectiveness in diagnosis, therapy, and brain-targeted drug delivery.
    Keywords:  mitochondrial communication; mitochondrial dysfunction; mitophagy; neurodegenerative disorders; vesicles
    DOI:  https://doi.org/10.1111/ejn.70449
  45. Drug Des Devel Ther. 2026 ;20 562785
    Drug Polymer Nanoparticles: An Advancement in Biomedical Solutions and Targeted Drug Delivery.
    Pranita Rananaware, Mahesh Narayan, Varsha Brahmkhatri.
      Polymer nanoparticles (PNPs) are compact particulate systems typically ranging from 10 to 1000 nm in size and have emerged as versatile platforms in modern biomedical research. Their growing importance stems from a unique combination of physicochemical properties, including tunable size, surface functionality, high drug loading capacity, and favourable biocompatibility. These features enable PNPs to act as efficient matrix carriers capable of encapsulating, protecting, and co-delivering a wide variety of therapeutic agents, including small molecules, proteins, and nucleic acids, within a single targeted delivery system. One of the key advantages of PNPs lies in their ability to improve both pharmacokinetic and pharmacodynamic profiles of drugs. By controlling drug release, enhancing solubility of poorly water soluble compounds, and reducing premature degradation or clearance, PNP-based systems can increase therapeutic efficacy while minimizing systemic toxicity. Targeting ligands can be incorporated on the nanoparticle surface to promote site-specific drug delivery, further improving treatment outcomes. A range of preparation techniques has been developed for the fabrication of advanced PNPs. These methods are generally classified according to the underlying particle formation mechanism, including polymerization-based approaches that generate nanoparticles directly and techniques that utilize preformed polymers. Advances in nanotechnology and polymer chemistry have enabled precise control over nanoparticle composition, morphology, and surface characteristics, leading to the development of sophisticated colloidal drug delivery systems. The integration of diverse nanomaterials into PNP formulations has further expanded their functional scope, significantly influencing the pharmacological and biopharmaceutical behavior of encapsulated drugs. Owing to their biocompatibility and design flexibility, PNPs have found broad applications in the treatment of cancer, neurodegenerative diseases, central nervous system disorders, and other complex medical conditions. This review elaborates on these aspects, highlighting the potential of PNPs as adaptable and powerful tools in next-generation therapeutic strategies.
    Keywords:  disease cure; drug delivery; liposomes; polymer nanoparticles; targeted therapy
    DOI:  https://doi.org/10.2147/DDDT.S562785
  46. Curr Med Sci. 2026 Mar 05.
    PAR-1 in Alzheimer's Disease: Pathophysiological Insights and Mechanistic Perspectives.
    Neha, Snehashis Mandal, Vipual Sharma, Jessica Dhindsa, Khadga Raj Aran.
      The G protein-coupled receptor (GPCR) known as protease-activated receptor-1 (PAR-1) is triggered by thrombin and plays a multifaceted role in the onset and progression of Alzheimer's disease (AD). AD is an irreversible neurodegenerative disease characterized by amyloid-β (Aβ) accumulation, neuroinflammation, tau hyperphosphorylation, and synaptic dysfunction. Thrombin activates PAR-1, which plays multiple roles in the brain. It exacerbates neuroinflammation and Aβ pathology but also protects synaptic plasticity. In a preclinical model, PAR-1 inhibition rescues cognitive deficits and decreases Aβ accumulation, suggesting therapeutic potential. However, PAR-1 activation promotes Tau hyperphosphorylation and neurofibrillary tangle formation, contributing to synaptic loss and cognitive decline. PAR-1 increases the permeability of the blood‒brain barrier (BBB), facilitating the entry of toxic substances into the brain and increasing neurodegeneration. Although strong preclinical evidence exists, no clinical trials have yet directly targeted PAR-1 in AD. This review summarizes current understanding of the PAR-1 mechanism in AD and highlights its roles in Aβ deposition, neuroinflammation, and tau pathology. It also discusses the challenges and opportunities for translating PAR-1 modulation into clinical therapies, including repurposing existing PAR-1 inhibitors. By addressing the dual role of PAR-1 function, researchers may develop novel multitarget strategies to combat the multifactorial pathophysiology of AD.
    Keywords:   Amyloid-beta; Neuroinflammation; Tau pathology; Alzheimer's Disease; Astrocytes; Blood-brain barrier; Neurodegeneration; Protease-activated receptor-1 (PAR-1); Synaptic plasticity
    DOI:  https://doi.org/10.1007/s11596-026-00175-y
  47. Nutr J. 2026 Mar 03.
    Consumption of coffee and tea and the risk of developing neurodegenerative diseases: a cohort study in the UK biobank.
    Yixiang Lin, Yisen Shi, Lina Chen, Zhuoli Chen, Huilin Zhong, Yuxuan Zhong, Ruitian Zeng, Xinyan Chen, Fabin Lin, Guoen Cai.
       BACKGROUND: Coffee and tea are among the most consumed drinks worldwide. Increasing evidence indicates an association between coffee or tea intake and neurodegenerative diseases. However, most studies have focused on the association of coffee or tea alone; studies on the interactive associations between coffee and tea and neurodegenerative diseases are few. Therefore, this study aimed to explore the individual or interactive associations between coffee and tea intake and neurodegenerative diseases and their various subtypes.
    METHODS: This study included 134,425 participants without neurodegenerative diseases at baseline in UK Biobank. A total of 6483 participants developed neurodegenerative diseases during a median follow-up time of 13.5 years. The median daily coffee intake was two cups, and the median daily tea intake was three cups. A restricted cubic spline was used to explore the nonlinear associations between coffee or tea intake and neurodegenerative diseases. The individual or interactive associations between coffee and tea intake and neurodegenerative diseases were assessed using the Cox proportional-hazards model.
    RESULTS: An individual association was noted between coffee or tea intake and neurodegenerative diseases. A significant J-shaped association was found between coffee intake and all-cause neurodegenerative diseases (Pnonlinear = 0.004) and vascular neurodegenerative diseases (Pnonlinear = 0.023), with increased risk at higher consumption. Moreover, a nonlinear association was observed between tea intake and all-cause neurodegenerative diseases (Pnonlinear = 0.004), vascular neurodegenerative diseases (Pnonlinear = 0.031), other neurodegenerative diseases (Pnonlinear = 0.002), and vascular dementia (VD) (Pnonlinear = 0.026). Furthermore, a significant interactive association was noted between coffee and tea intake among all-cause neurodegenerative diseases (Pinteraction = 0.004); Further, this interaction was also observed in Alzheimer's disease (AD) (Pinteraction = 0.006).
    CONCLUSIONS: Excessive coffee consumption was significantly associated with an increased risk of all-cause neurodegenerative diseases and vascular neurodegenerative diseases. The results also showed that tea intake was associated with a reduced risk of all-cause neurodegenerative disease, vascular neurodegenerative disease, other neurodegenerative diseases, and VD. Moreover, coffee and tea had an interactive relationship with all-cause neurodegenerative diseases and AD, with specific combinations significantly associated with reduced risk of disease onset.
    Keywords:  Coffee; Neurodegenerative disease; Tea
    DOI:  https://doi.org/10.1186/s12937-026-01291-0
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒08 at 8:25.