@article {pmid41963935,
year = {2026},
author = {Zhang, B and Shang, D},
title = {Commentary on "Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells".},
journal = {Molecular cancer},
volume = {25},
number = {1},
pages = {},
pmid = {41963935},
issn = {1476-4598},
support = {2025AHGXZK40703//Anhui Provincial Department of Education Natural Science Research Youth Project/ ; 2025byjbgs064//Bengbu Medical University "Jie Bang Gua Shuai" Research Project/ ; 82374248//National Natural Science Foundation of China/ ; },
abstract = {We recently carefully read the article titled “Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells” published by Chu-An Wang et al. in Molecular Cancer. While this study provides valuable insights into tumor-immune crosstalk, we raise two points for clarification to enhance its precision. First, the manuscript classifies T2N0M0 samples as stage II pancreatic ductal adenocarcinoma (PDAC), which conflicts with the eighth edition of the AJCC Cancer Staging Manual that designates T2N0M0 as stage IB. Second, the authors used pancreatic stellate cells (PSCs) as a surrogate for fibroblasts to model stromal effects, but accumulating evidence indicates that PSCs and fibroblasts are not equivalent. To address this, we integrated single-cell, spatial, and bulk transcriptomic data from multiple cohorts. Our analyses revealed substantial differences between fibroblasts and stellate cells in abundance (fibroblasts enriched in primary pancreatic cancer tumor tissues), prognostic relevance (high fibroblasts associated with poorer survival, high stellate cells with better prognosis), spatial distribution (fibroblasts localized around malignant tumor cells), and intercellular communication (fibroblasts as stronger signal senders to malignant tumor cells). These findings confirm that PSCs cannot accurately represent fibroblasts in PDAC. We emphasize that clarifying these points will not undermine the study’s significance but will strengthen its rigor and comparability. Wang et al.’s work remains a valuable contribution to understanding PDAC progression, and we anticipate these clarifications will further advance stromal-immune crosstalk research in PDAC.},
}

@article {pmid42149299,
year = {2026},
author = {Morimoto, S and Takahashi, S and Okano, H},
title = {Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42149299},
issn = {1867-108X},
support = {JP21H05278, JP22K15736, JP25H00007//Japan Society for the Promotion of Science/ ; JP26K10434//Japan Society for the Promotion of Science/ ; JP26H02431//Japan Society for the Promotion of Science/ ; JP23bm1123046, JP23kk0305024, JP25ek0109811//Japan Agency for Medical Research and Development/ ; JP21wm0425009, JP22bm0804003, JP22ek0109616, JP23bm1423002, JP25wm0625519//Japan Agency for Medical Research and Development/ ; UBE Academic Foundation//UBE Academic Foundation/ ; the Kato Memorial Trust for Nambyo Research//the Kato Memorial Trust for Nambyo Research/ ; 2024A04//Japan Intractable Diseases Research Foundation/ ; Inamori Foundation//Inamori Foundation/ ; Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology//Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology/ ; Ono Medical Research Foundation//Ono Medical Research Foundation/ ; Nakatomi Foundation//Nakatomi Foundation/ ; },
abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.},
}

@article {pmid42148083,
year = {2026},
author = {Li, L and Wang, S and Duan, L and Zhang, L and Yan, H and Chen, X and Tao, L and Gao, Y},
title = {Ferroptosis-immune crosstalk in CNS diseases: mechanisms and translational insights.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1807104},
pmid = {42148083},
issn = {1664-3224},
mesh = {*Ferroptosis/immunology ; Humans ; Animals ; *Central Nervous System Diseases/immunology/metabolism/etiology/pathology ; Iron/metabolism ; },
abstract = {Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, which plays a pivotal role in regulating the inflammatory-immune microenvironment of central nervous system (CNS) diseases. Mounting evidence indicates that dysregulated iron metabolism and an imbalance in antioxidant defenses can induce ferroptosis in neurons and glial cells while simultaneously remodeling immune cell function, thereby establishing a bidirectional feedback loop that amplifies neuroinflammation and tissue damage. In neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), pro-inflammatory cytokines such as TNF-α and IL-1β released by activated microglia upregulate neuronal iron transporters (e.g., DMT1 and TfR1), promoting iron accumulation and ferroptotic cell death. In turn, damage-associated molecular patterns released from ferroptotic cells further potentiate immune activation, forming a self-amplifying cycle. In contrast, within the glioma microenvironment, CD8[+] T cell-derived IFN-γ suppresses SLC7A11 expression in tumor cells, leading to glutathione depletion and glutathione peroxidase 4 inactivation, thereby triggering ferroptosis and modulating anti-tumor immunity. Although targeting ferroptosis or neuroimmune pathways has shown therapeutic promise in mitigating neurological deficits and enhancing anti-tumor responses, the underlying mechanisms governing ferroptosis-immune crosstalk remain inadequately characterized. Herein, this review systematically summarizes the key biological characteristics of ferroptosis and immune responses, with particular emphasis on their interplay across major CNS disorders (i.e., AD, PD, ALS, multiple sclerosis, stroke, and glioma). Furthermore, we discuss emerging therapeutic strategies encompassing small molecules, immunomodulatory approaches, and nanotechnology-based interventions, highlighting the ferroptosis-immune axis as a promising therapeutic target for CNS diseases.},
}

*Ferroptosis/immunology
Humans
Animals
*Central Nervous System Diseases/immunology/metabolism/etiology/pathology
Iron/metabolism

@article {pmid42135750,
year = {2026},
author = {Tamaki, Y and Kaneko, S and Urushitani, M},
title = {Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04935-4},
pmid = {42135750},
issn = {1741-7015},
support = {24K18702//Japan Society for the Promotion of Science/ ; 23K24211//Japan Society for the Promotion of Science/ ; 25wm0625522h0001//Japan Agency for Medical Research and Development/ ; },
abstract = {BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), recent evidence suggests that the earliest pathogenic event is the disruption of its physiological homodimeric structure. Under healthy conditions, TDP-43 forms dimers via its N-terminal domain, a configuration that is crucial for its nuclear solubility and cooperative RNA binding. In this review, we propose the "Molecular Zipper" hypothesis to describe the maintenance of TDP-43 structural homeostasis. In this framework, the N-terminal domain acts as a stabilizing "NTD-mediated anchor" that keeps the protein in a functional, "zipped" dimeric state, effectively sequestering its aggregation-prone C-terminal regions. Pathogenic triggers-including genetic mutations, aberrant post-translational modifications such as phosphorylation and acetylation, and environmental stressors-can "unzip" this structure, leading to the formation of pathogenic monomers. These pathogenic monomers show increased propensity for cytoplasmic mislocalization and recruit wild-type protein into aggregates through a prion-like seeded aggregation mechanism, culminating in nuclear functional loss and cytoplasmic gain-of-toxicity. We further evaluate the emerging diagnostic landscape, focusing on methods to monitor the dimer-to-monomer ratio.

SHORT CONCLUSION: Integrating prior biochemical data on TDP-43 dimerization with structural modeling enables a more coherent account of the transition from the physiological dimer to pathological conformers. The Molecular Zipper framework offers a conceptual foundation for reconciling existing experimental findings and for guiding future studies on early structural changes in TDP-43 proteinopathy.},
}

@article {pmid42135847,
year = {2026},
author = {Sinha, IR and Atkinson, AL and Irwin, KE and Ling, JP and Wong, PC},
title = {TDP-43: [GU]-ardian of the transcriptome.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00944-2},
pmid = {42135847},
issn = {1750-1326},
abstract = {TDP-43 is a ubiquitously expressed, primarily nuclear DNA/RNA-binding protein implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). In this review, we examine the structure and regulation of TDP-43, how these features influence its localization and functional activity, and how their disruption may contribute to disease. Among TDP-43's diverse functions, splicing repression of nonconserved RNA sequences termed cryptic exons has emerged as especially central to human disease. TDP-43 nuclear depletion and cytoplasmic aggregation are well-established pathological features in affected neurons and glia of neurodegenerative diseases, and accumulating evidence suggests that loss of TDP-43-mediated splicing repression occurs presymptomatically in disease. Advances in RNA-sequencing have enabled systematic identification of cryptic exon inclusion as a sensitive marker of TDP-43 dysfunction. Here, we synthesize current knowledge of TDP-43 biology and curate datasets from human tissues and experimental models, focusing on cryptic splicing to provide a resource for leveraging cryptic exon biology to better understand, detect, and target TDP-43 dysfunction.},
}

@article {pmid42136825,
year = {2026},
author = {Pan, J and Zhang, C and Li, J and Ma, L},
title = {Neurocritical progression in amyotrophic lateral sclerosis: pathological relevance and validation.},
journal = {Open life sciences},
volume = {21},
number = {1},
pages = {20251323},
pmid = {42136825},
issn = {2391-5412},
abstract = {Evidence from multiple clinical studies indicates that amyotrophic lateral sclerosis (ALS) frequently evolves into a condition requiring neurocritical care. In advanced stages or during acute complications, ALS can rapidly transition into a neurocritical state characterized by respiratory insufficiency, systemic dysfunction, and accelerated neurological decline. Although current management strategies for advanced-stage ALS are relatively well established, there remains a significant lack of targeted interventions aimed at preventing or attenuating neurocritical deterioration. This review systematically examines the pathophysiological mechanisms underlying neurocritical progression in ALS, including respiratory failure, metabolic imbalance, autonomic dysfunction, and multisystem involvement. We further evaluate emerging and potential therapeutic strategies designed to mitigate disease severity and stabilize critical neurological function. In addition, we analyze clinical and biological factors that increase susceptibility to neurocritical states and discuss evidence-based approaches to delay disease progression. By integrating clinical observations with mechanistic insights, this review aims to improve early recognition, optimize neurocritical management, and ultimately enhance outcomes for patients with ALS.},
}

@article {pmid42141236,
year = {2026},
author = {Maxwell, K and Leung, S and Ozakinci, G},
title = {The psychological impact of using 3D printing and imaging technology for patient education: a scoping review.},
journal = {3D printing in medicine},
volume = {12},
number = {1},
pages = {},
pmid = {42141236},
issn = {2365-6271},
abstract = {BACKGROUND: The way in which patient education is delivered during clinical consultations can have an impact on cognitive and emotional outcomes in patients. 3D printing and imaging can be used in patient education to improve understanding of the information and satisfaction with care. This scoping review sought to explore the psychological impact of using 3D models in patient education.

METHODS: Searches were conducted in PsycINFO, PsycARTICLES, PubMed, Medline and CINAHL. Levac et al.'s enhanced version of Arksey & O'Malley's methodological framework for conducting scoping reviews, and the PRISMA-ScR, were used to guide the screening and identification of relevant studies. Studies were included if they investigated the effect of using 3D models in patient education and explored psychological outcomes. Both quantitative and qualitative research were included.

RESULTS: Eleven studies were included in the review, including 2 qualitative studies. 3D models were most often used in educational consultations preceding a surgical procedure (n = 9). Psychological outcomes assessed were anxiety, quality of life, distress relief, and decisional conflict. The results were mixed, showing that using 3D models can have a positive as well as negative effect on psychological outcomes such as fear and disempowerment.

CONCLUSIONS: Using 3D models in patient education has the potential to improve patient anxiety and other psychological outcomes. However, more research is required to identify which patients and types of consultations 3D models are most useful for. For example, appointments involving important decision-making may benefit from the inclusion of 3D models. It is also essential to consider the communicative approach of the healthcare professional in the delivery of patient education with 3D models, as this factor is key to the outcomes of shared decision-making.},
}

@article {pmid42142504,
year = {2026},
author = {Abd-Eldayem, AM and Mohammed, RA},
title = {Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.},
journal = {Current opinion in pharmacology},
volume = {88},
number = {},
pages = {102632},
doi = {10.1016/j.coph.2026.102632},
pmid = {42142504},
issn = {1471-4973},
abstract = {Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, Riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer's disease (AD), Huntington's disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of Riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in Riluzole pharmacology and outlines key considerations for future mechanistic and translational research.},
}

@article {pmid41965692,
year = {2026},
author = {Vergano, M and Craxì, L and Zamperetti, N and Latronico, N},
title = {Sliding doors at the bedside: conditional outcomes and moral judgments in end-of-life care.},
journal = {Critical care (London, England)},
volume = {30},
number = {1},
pages = {},
pmid = {41965692},
issn = {1466-609X},
abstract = {BACKGROUND: Intensive care medicine has increasingly embraced shared decision-making and advance care planning as core components of good clinical practice. Nonetheless, clinical reasoning is sometimes implicitly framed as a linear, biologically driven process. In contexts of prognostic uncertainty, this framing risks obscuring a structural feature of decision-making: the constitutive role of value-based judgments in shaping prognosis and outcomes.

MAIN BODY: This paper introduces the concept of conditional outcomes to clarify a structural feature of certain clinical situations, in which survival or death does not follow from biology alone but is co-determined within the range of biologically possible trajectories by value-based choices made by patients, families, and clinicians regarding whether and how to intervene. Using the case of Mrs. Elizabeth, a woman with advanced amyotrophic lateral sclerosis, we show how an identical clinical state may be framed as either terminal or amenable to escalation, not because it is assessed differently, but because values and goals are interpreted and enacted differently. Even when shared decision-making is practiced, the way value judgments shape prognostic determinations often remains implicit. Making these assumptions explicit complements shared decision-making and advance care planning, clarifying how clinical outcomes are logically dependent on prior value-based commitments that shape judgments about benefit, burden, and the goals of care.

CONCLUSIONS: Making the conditional structure of outcomes explicit clarifies that value-based judgments are not ancillary to prognosis but structurally shape prognostic determinations and subsequent outcomes. Recognizing the conditional nature of prognostication strengthens clinical reasoning by integrating biological knowledge with ethical commitments in end-of-life care.},
}

@article {pmid42123994,
year = {2026},
author = {Christodoulou, RC and Lorentzen, L and Eller, D and Vassiliou, E},
title = {Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.},
journal = {Nutrients},
volume = {18},
number = {9},
pages = {},
pmid = {42123994},
issn = {2072-6643},
mesh = {*Ferroptosis ; Humans ; *Mitochondria/metabolism ; *Lipid Peroxidation ; *Neurodegenerative Diseases/metabolism ; *Fatty Acids/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; Lipid Metabolism ; },
abstract = {Background: Neurodegenerative diseases (NDs) are mainly considered disorders marked by severe immunometabolic imbalance, characterized by ongoing neuroinflammation and glial activation. While mitochondrial dysfunction and oxidative stress are well-known features, the upstream metabolic factors linking these pathological processes remain poorly understood. Methods: In this review, we examined recent preclinical and clinical studies exploring the connections between lipid metabolism, glial immunometabolism, and regulated cell death pathways. Our focus was on how long-chain fatty acids (LCFAs) facilitate communication among mitochondria, reactive oxygen species (ROS), and ferroptosis in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Results: New evidence shifts LCFAs from merely being passive indicators of cellular damage to active, upstream regulators of the neuroimmune response. Existing research shows that excess LCFA intake can overload astrocytic mitochondrial oxidative phosphorylation, leading to abnormal lipid droplet buildup and reactive astrogliosis. This lipid-driven reactivity promotes microglial polarization toward a persistent pro-inflammatory state. Notably, high levels of specific LCFAs, especially arachidonic acid, increase ROS production and lipid peroxidation. This lipotoxic environment ultimately triggers ferroptosis, an iron-dependent form of cell death shared across multiple NDs. Conclusions: The harmful interaction among mitochondrial dysfunction, lipid peroxidation, and ferroptosis is driven by an imbalance in LCFA levels. Addressing current challenges, such as the complex effects of polyunsaturated fatty acid supplementation, requires advanced techniques like single-cell multi-omics and artificial intelligence. Understanding this intricate lipidomic-transcriptomic crosstalk is crucial for moving toward personalized neuroimmunometabolism and developing new treatments to prevent ferroptosis.},
}

*Ferroptosis
Humans
*Mitochondria/metabolism
*Lipid Peroxidation
*Neurodegenerative Diseases/metabolism
*Fatty Acids/metabolism
Animals
*Neuroinflammatory Diseases/metabolism
Reactive Oxygen Species/metabolism
Oxidative Stress
Lipid Metabolism

@article {pmid42135109,
year = {2026},
author = {Yin, X and Zhang, H and Zhang, R and Xue, J and Hou, Y},
title = {Epigenetic noise in the aging brain: tuning neuronal vulnerability to neurodegeneration.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.04.006},
pmid = {42135109},
issn = {1878-108X},
abstract = {Aging is the predominant risk factor for neurodegenerative diseases, yet the mechanisms linking biological aging to selective neuronal degeneration remain incompletely understood. Accumulating evidence indicates that aging progressively disrupts epigenetic regulation, manifested as increased epigenetic noise in DNA methylation, histone modifications, and chromatin accessibility, which undermines transcriptional precision and the stability of neuronal identity. Recent advances in single-cell and spatial epigenomics further suggest that these age-associated epigenetic alterations are not merely correlative but can actively shape neuronal vulnerability across brain regions and cell types. In this review, we synthesize emerging evidence showing how epigenetic noise contributes to selective neurodegeneration across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and discuss emerging strategies aimed at stabilizing the aging neuronal epigenome.},
}

@article {pmid42116599,
year = {2026},
author = {Saha, T and Vats, T and Mehan, S},
title = {Rituximab Beyond Oncology: Targeting B-Cell-Mediated Immunomodulatory Therapy in Neurodegenerative and Neuropsychiatric Disorders.},
journal = {Immunopharmacology and immunotoxicology},
volume = {},
number = {},
pages = {1-77},
doi = {10.1080/08923973.2026.2671714},
pmid = {42116599},
issn = {1532-2513},
abstract = {Neurological and neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune encephalitis (AE), represent a growing global health burden due to their multifaceted pathophysiology and limited treatment options. These disorders are characterized by neuroinflammation, oxidative stress, protein aggregation, and blood-brain barrier (BBB) disruption, which contribute to neuronal damage and progressive functional decline. Emerging evidence underscores the pivotal role of B cells in driving disease progression through antibody production, antigen presentation, and cytokine release. Rituximab, a chimeric monoclonal antibody targeting CD20 on B cells, has shown promise as a potential immunomodulatory therapy for these conditions. Rituximab mediates its therapeutic effects via mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. In MS, rituximab reduces pro-inflammatory cytokines, demyelination, and immune cell activity, thereby delaying disease progression. Preclinical studies suggest its neuroprotective potential in AD and PD by mitigating B-cell-mediated neuroinflammation and oxidative stress. Furthermore, rituximab demonstrates efficacy in AE, NMOSD, and MOGAD by depleting pathogenic B cells and reducing relapse rates. Despite its proven efficacy, rituximab poses risks such as hypogammaglobulinemia, infection, and infusion-related reactions, necessitating careful patient selection, continued monitoring, and optimization of dosing regimens. This review highlights rituximab's immunomodulatory mechanisms and its expanding role in neurodegenerative and neuropsychiatric disorders. While ongoing clinical trials explore its efficacy in ALS, depression, and schizophrenia, future research should focus on identifying biomarkers of treatment response, improving CNS penetration, and combining rituximab with other therapies to enhance safety and therapeutic outcomes. Rituximab's ability to target B-cell-driven pathology positions it as a promising agent in the evolving landscape of neuroimmunology.},
}

@article {pmid42118400,
year = {2026},
author = {Pi, C and Liu, Y and Jia, Z and Zhang, M and Wang, X and Zhao, H and Dong, Z and Yu, S and Liu, R},
title = {Mechanism of the N87D mutation in SOD1-atypical amyotrophic lateral sclerosis case report and literature review molecular mechanism of N87D mutation in SOD1.},
journal = {Neurogenetics},
volume = {27},
number = {1},
pages = {},
pmid = {42118400},
issn = {1364-6753},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Superoxide Dismutase-1/genetics/chemistry ; Molecular Dynamics Simulation ; *Mutation ; Protein Conformation ; Male ; Female ; Middle Aged ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unclear pathogenesis. This study aimed to investigate the possible molecular mechanisms of ALS by analyzing protein structure and dynamics in a rapidly progressing ALS patient carrying the N87D mutation. A patient with the N87D mutation experienced rapid disease progression and died within one year. We reviewed all known mutations at the 87th position of the superoxide dismutase (SOD1) gene and the clinical characteristics. To investigate the molecular basis of the severe phenotype, we performed protein structure modeling and molecular dynamics (MD) simulations, and compared wild type homodimers, mutant homodimers, and heterodimers in terms of energy, residue fluctuation, number of hydrogen bonds, radius of gyration (Rg), principal component analysis (PCA), free energy landscape (FEL), the contribution of dimer interface residues, solvent-accessible surface area, and metal ion coordination. Our analysis revealed that patients with mutations at the 87th position of the SOD1 gene typically exhibited rapid disease progression. Protein structure modeling and MD simulations demonstrated that the N87D mutation significantly increased the energy and RMSF of SOD1 heterodimers compared to homodimers. Furthermore, Rg, FEL and PCA analyses showed that the heterodimers had a broader and more unstable conformational energy distribution, along with a stronger tendency for aggregation. Additionally, the N87D mutation disrupted metal ion coordination, further destabilizing the heterodimer and promoting protein misfolding. These findings suggest a potential molecular mechanism underlying ALS and support a protein structure based approach for investigating the pathogenic mechanisms of disease causing mutations.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Superoxide Dismutase-1/genetics/chemistry
Molecular Dynamics Simulation
*Mutation
Protein Conformation
Male
Female
Middle Aged

@article {pmid42114427,
year = {2026},
author = {Ritu, JR and Uddin, MH and Ferrari, MCO and Chivers, DP},
title = {Ecotoxicological implications of environmental neurotoxin β-N-methylamino-L-alanine (BMAA) in fishes: An emerging concern.},
journal = {Ecotoxicology and environmental safety},
volume = {318},
number = {},
pages = {120252},
doi = {10.1016/j.ecoenv.2026.120252},
pmid = {42114427},
issn = {1090-2414},
abstract = {Harmful algal blooms (HABs), intensified by climate change, eutrophication, and altered hydrological regimes, are expanding globally, releasing cyanotoxins that threaten aquatic ecosystems and human health. β-N-methylamino-L-alanine (BMAA), a non-protein amino acid with neurotoxic potential, has been recognized as a global emerging concern. Following exposure, BMAA is present in both free and protein-bound forms, forming an endogenous toxin reservoir that exacerbates potential neurotoxicity in aquatic organisms and humans. Its presence in aquatic food webs not only elevates ecological risks for wildlife but also raises potential human health concerns, particularly its potential association with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and the ALS/Parkinsonism-dementia complex. This review aims to explore current knowledge of the ecotoxicological impacts of BMAA in fishes, focusing on developmental, behavioural and cognitive perturbations, along with their mechanistic underpinnings. BMAA exposure induces developmental abnormalities, including convulsions, spinal axis malformations, pericardial edema, and altered heart rate, as well as neurodevelopmental impairments, such as reduced motor neuron length and altered neuromuscular colocalization in fishes. Additionally, BMAA exposure affects a wide array of behaviours in fishes, including motor coordination, locomotion, feeding, startle responses, anxiety-like behaviours, and cognitive performance, primarily through excitotoxicity, oxidative stress, apoptosis, metabolic disruption, neuroendocrine modulation, and dysregulated neurotransmitter signalling. Future research should focus on more environmentally relevant exposure scenarios, elucidating BMAA toxicokinetics, and investigating cyanotoxin co-exposure toxicity in fishes. Advancing integrative phenotypic endpoints and knowledge of molecular mechanisms of BMAA toxicity in aquatic organisms is essential for effective ecological risk assessments and for developing regulatory standards to safeguard aquatic ecosystems and human health.},
}

@article {pmid42116584,
year = {2026},
author = {Bala, VC and Singh, MK and Kumar, A and Tiwari, SK and Gupta, AK and Chawla, R and Kumar, S},
title = {Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.},
journal = {Protein and peptide letters},
volume = {33},
number = {1},
pages = {258-274},
doi = {10.2174/0109298665429866260217115717},
pmid = {42116584},
issn = {1875-5305},
mesh = {Humans ; *alpha-Synuclein/metabolism/genetics/antagonists & inhibitors ; *Synucleinopathies/metabolism/therapy/drug therapy/pathology ; *Parkinson Disease/metabolism/therapy/drug therapy/pathology ; Autophagy/drug effects ; Animals ; Oxidative Stress ; },
abstract = {Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.},
}

Humans
*alpha-Synuclein/metabolism/genetics/antagonists & inhibitors
*Synucleinopathies/metabolism/therapy/drug therapy/pathology
*Parkinson Disease/metabolism/therapy/drug therapy/pathology
Autophagy/drug effects
Animals
Oxidative Stress

@article {pmid42114078,
year = {2026},
author = {Bareamichael, PI and Babu, S and Hoang, T and Socal, MP},
title = {Bridging the Funding Gap in Drug Development for Amyotrophic Lateral Sclerosis.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {3},
pages = {e200623},
pmid = {42114078},
issn = {2163-0933},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Drug Development/economics ; United States ; Clinical Trials as Topic/economics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with few effective treatments and high clinical trial failure rates. Since 1995, only 3 drugs riluzole, edaravone, and tofersen have gained approval from the Food and Drug Administration, all offering modest benefits. Challenges in ALS drug development include poor translational preclinical models, underpowered early-phase trials, and the high cost of late-stage development. Despite federal initiatives such as the Accelerating Access to Critical Therapies for ALS Act and the ALL ALS Consortium, critical gaps remain in funding large multisite trials and sustaining research networks. Accelerating progress requires strengthening national registries, expanding adaptive trial platforms, integrating existing networks, and adopting innovative funding models such as milestone-based public-private partnerships and reinvestment of licensing revenues. A coordinated, sustainable research and funding ecosystem could transform ALS therapy development and serve as a model for advancing treatments for other rare neurodegenerative and neurogenetic disorders.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/economics
Humans
*Drug Development/economics
United States
Clinical Trials as Topic/economics

@article {pmid42107892,
year = {2026},
author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H},
title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.},
journal = {International immunopharmacology},
volume = {182},
number = {},
pages = {116781},
doi = {10.1016/j.intimp.2026.116781},
pmid = {42107892},
issn = {1878-1705},
abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.},
}

@article {pmid42111077,
year = {2026},
author = {Zhou, S and Li, X and Jiao, Y and Wu, J},
title = {Efficacy and safety of pharmacological and biological therapies for amyotrophic lateral sclerosis: a network meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1754716},
pmid = {42111077},
issn = {1664-2295},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder for which disease-modifying treatment options remain limited. This study aimed to systematically assess the efficacy and safety of pharmacological and biological therapies for ALS via a network meta-analysis (NMA).

METHODS: PubMed, EMBASE, Cochrane, and Web of Science were searched until February 25, 2025. Randomized controlled trials (RCTs) evaluating any pharmacological or biological intervention in ALS were eligible. Risk of bias was assessed using the Cochrane RoB 2 tool. A Bayesian NMA was performed in R (gemtc package). Effect estimates were expressed as mean differences (MDs) or risk ratios (RRs) with 95% credible intervals (CrIs). Interventions were ranked using the surface under the cumulative ranking curve (SUCRA). Publication bias was explored with funnel plots (Stata 18.0). Subgroup analyses were conducted for drug classes demonstrating significant efficacy and including at least three RCTs.

RESULTS: 109 trials involving 16,353 participants were included. The primary outcome was the ALS Functional Rating Scale-Revised (ALSFRS-R); secondary outcomes included forced vital capacity (FVC), mortality, and serious adverse events (SAEs). Compared with placebo, the combination of cell therapy and neuroprotective agents produced the greatest attenuation of ALSFRS-R decline (MD: 3.65, 95% CrI: 1.27-6.05) and was associated with the lowest SAE risk. Receptor agonists ranked highest for preservation of FVC, whereas alkaloids ranked first for mortality reduction; however, no intervention demonstrated a statistically significant survival benefit versus placebo. Within-class subgroup analyses further identified several specific agents, such as masitinib, talampanel, and EH301, as demonstrating relatively consistent efficacy, although substantial heterogeneity remained among enzyme inhibitors.

CONCLUSION: Cell therapy combined with neuroprotective agents may slow functional decline in ALS. Receptor agonists may help preserve respiratory function. Survival benefits remain inconclusive, underscoring the continued importance of comprehensive supportive care.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251000672, identifier CRD420251000672.},
}

@article {pmid42113315,
year = {2026},
author = {Mishra, R and Upadhyay, A},
title = {Exosomes in Amyloid Propagation-Roles in Neurodegeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42113315},
issn = {1559-1182},
mesh = {*Exosomes/metabolism ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Amyloid/metabolism ; },
abstract = {Extracellular vesicle (EVs)-mediated cell-to-cell communication is crucial for cell growth, signaling, and metabolism. Exosomes are a subtype of EVs originating from endosomal cellular machinery and have a relatively smaller size (30-150 nM). They carry nucleic acids, proteins, miRNA, lipids, metabolites, and growth factors, making them an exciting research tool for understanding the pathophysiology of complex human diseases. Different brain cells also communicate with themselves by the release of exosomes which helps in overall brain growth and in cell signaling. Recent studies have highlighted the importance of exosomes in neurodegenerative diseases (NDDs) of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion, and Huntington's disease (HD). Exosomes are involved in the spread of amyloid-like protein aggregates formed in these diseases, but a comprehensive understanding of this spread mechanism is limited. In this article, we have analyzed the roles of exosomes in the spread of amyloid protein aggregates in the NDDs. Furthermore, we have discussed possible measures to address several gaps in our current understanding of cross talks between exosomes and protein aggregates in neurodegenerative disorders (NDDs). We have also discussed the therapeutic opportunities to delay or prevent pathogenic amyloid aggregate spread by exploiting exosomal transport. Overall, the review will contribute to develop a better understanding vesicular transport of amyloids and will help contend their propagation in different NDDs.},
}

*Exosomes/metabolism
Humans
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Amyloid/metabolism

@article {pmid42103041,
year = {2026},
author = {López-Blanch, R and Oriol-Caballo, M and Estrela, JM and Obrador, E},
title = {Multimodal strategies for diagnosis, stratification, and therapeutic monitoring in ALS.},
journal = {Neuroscience and biobehavioral reviews},
volume = {187},
number = {},
pages = {106727},
doi = {10.1016/j.neubiorev.2026.106727},
pmid = {42103041},
issn = {1873-7528},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of motor neurons (MN) that is currently diagnosed through a prolonged process of exclusion, often delaying intervention. This review provides an overview of fluid, imaging, electrophysiological, and genetic biomarkers, explicitly linking each modality to early detection, patient stratification, disease monitoring, therapeutic development, and clinical trial design. Fluid biomarkers (i.e., neurofilament light chain, phosphorylated neurofilament heavy chain, inflammatory cytokines, microRNAs, and proteins in blood or cerebrospinal fluid) reflect neuronal injury and/or disease activity, enabling early identification of pres-ymptomatic individuals and longitudinal tracking of neurodegeneration. Imaging biomarkers, such as structural and diffusion MRI of the motor cortex, corticospinal tracts, and spinal cord, as well as PET imaging neuroinflammation or metabolism, provide objective measures of MN degeneration and extra-motor involvement. Electrophysiological biomarkers, including high-density electromyography, motor unit number, transcranial magnetic stimulation, and electrical impedance myography, quantitatively assess upper and lower MN loss and functional reserve. Genetic biomarkers, encompassing variants in genes such as C9orf72, SOD1, FUS, and TARDBP, enable presymptomatic screening and molecular stratification. In this context, transposable elements have emerged as an additional layer linking genomic variation and RNA dysregulation. We highlight the importance of multimodal and stage-specific biomarker integration to improve diagnostic accuracy and illuminate distinct disease phases. This approach supports stratification by progression rate or molecular subtype, enrichment of clinical trial cohorts, and the development of surrogate endpoints. We conclude by discussing current challenges, including disease heterogeneity and assay standardization, and outline future directions toward biomarker-driven precision medicine in ALS.},
}

@article {pmid42105306,
year = {2026},
author = {Flores, SV and Lillo, P and Briceño-Moya, J and Pedro, AP},
title = {Molecular and genetic landscape of amyotrophic lateral sclerosis in Latin America: a scoping review of pathogenic hypotheses and ancestral heterogeneity.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2026.2668070},
pmid = {42105306},
issn = {2167-9223},
abstract = {Background: The genetic architecture of amyotrophic lateral sclerosis (ALS) has been predominantly characterized in populations of European ancestry, while Latin American populations remain underrepresented despite their complex admixture. Objective: To map the molecular hypotheses explored in ALS research conducted in Latin American populations and identify key methodological and structural gaps. Methods: A scoping review was conducted following Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. Searches were performed in Web of Science, Scopus, PubMed/MEDLINE, SciELO, and LILACS. Studies investigating genetic or molecular aspects of ALS or the ALS-FTD spectrum in Latin American populations were included. Data were extracted using a standardized matrix and synthesized descriptively. Results: Nineteen studies met inclusion criteria. Most were small, single-center investigations employing targeted candidate-gene approaches, predominantly focused on C9orf72 expansions and SOD1 mutations. Reported C9orf72 frequencies varied substantially across countries, indicating population-specific genetic heterogeneity. Only one study incorporated explicit ancestry inference, and no genome-wide association studies or large multicenter ALS genomic cohorts were identified. Conclusions: ALS research in Latin America remains limited, fragmented, and largely candidate-gene driven, with minimal integration of ancestry-informed approaches. The absence of large-scale genomic studies, despite existing regional sequencing capacity, highlights the need for coordinated multicenter initiatives to enable equitable implementation of precision medicine.},
}

@article {pmid42102977,
year = {2026},
author = {Zhang, J and Wang, C and Li, Y and Xiao, Z and Cai, Z and Qian, Y and Shi, L and Zhang, Q},
title = {Lipid Dysregulation as a Central Contributor of Neurodegenerative Diseases: Emerging Therapeutic Targets and Strategies.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103159},
doi = {10.1016/j.arr.2026.103159},
pmid = {42102977},
issn = {1872-9649},
abstract = {Lipid homeostasis is essential for preserving the structural integrity and functional capacity of the brain. A diverse array of lipids, including cholesterol, phospholipids, and sphingolipids, has been identified as playing pivotal roles. Dysregulation of lipid metabolism is increasingly recognized as a central pathological mechanism in neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Cerebrotendinous Xanthomatosis, though much of the existing evidence comes from associative studies, and causal relationships still need to be further validated through interventional studies. Here we systematically review the metabolic pathways and regulatory networks of major brain lipids, with a focus on delineating disease-specific alterations and summarizing emerging therapeutic strategies targeting lipid metabolism. These strategies encompass the modulation of cholesterol homeostasis, sphingolipid metabolism, phospholipid signaling, and fatty acid oxidation, alongside approaches that enhance lipid clearance and neural repair. Preclinical advances and ongoing clinical trials underscore the translational potential of lipid-targeted interventions. In conclusion, we emphasize the potential of lipid metabolism as a promising avenue for developing novel treatments, offering insights to guide future research and therapeutic innovation in neurodegeneration.},
}

@article {pmid41864411,
year = {2026},
author = {Davias, A and Tang, IW and Hansen, J and Knekt, P and Rantakokko, P and Weisskopf, MG},
title = {Associations between pre-disease biomarkers of persistent organic pollutants and amyotrophic lateral sclerosis risk in four European cohorts.},
journal = {Environmental research},
volume = {299},
number = {},
pages = {124337},
doi = {10.1016/j.envres.2026.124337},
pmid = {41864411},
issn = {1096-0953},
support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 TS000315/TS/ATSDR CDC HHS/United States ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/chemically induced/blood ; Male ; Female ; Biomarkers/blood ; Middle Aged ; Denmark/epidemiology ; *Persistent Organic Pollutants/blood/toxicity ; Cohort Studies ; Prospective Studies ; Aged ; Adult ; Finland/epidemiology ; Pesticides/blood ; },
abstract = {OBJECTIVES: Previous retrospective studies suggested that occupational exposures to persistent organic pollutants (POPs) may be associated with amyotrophic lateral sclerosis (ALS), but prospective studies with biomarker exposure assessment are scarce. This study aimed to prospectively investigate the relationship between POP exposures and ALS risk in the Danish Diet, Cancer and Health study (EPIC) cohort and to conduct a meta-analysis including results from the prior study of 3 small prospective Finnish cohorts in addition to the Danish EPIC cohort.

METHODS: We identified 166 incident ALS cases between 1993 and 1997 using the Danish National Patient Register and randomly selected 334 controls by individual matching on birth-year and sex. Levels of 13 polychlorinated biphenyls, 9 organochlorine pesticides and 3 polybrominated diphenyl ethers were assessed from baseline plasma samples. We employed conditional logistic regression models using exposure quartiles, and generalized additive models (GAMs), adjusting for confounders. We conducted a meta-analysis combining 3 Finnish prospective cohorts with the Danish data using a random-effects model.

RESULTS: The Danish results suggested generally inverse trends between several POPs and the predicted ALS risk; especially for chlordane-related compounds (co-pollutant quartile model, p-value<0.01). GAMs supported these trends, although most were not statistically significant. However, hexachlorobenzene was positively associated with ALS risk in co-pollutant GAM (p-value = 0.02). Additionally, the GAMs suggested higher ALS odds at the highest levels of exposure of some POPs, but the data at these levels was sparse. Meta-analysis results were mostly consistent with the Danish findings.

CONCLUSION: Our study suggested elevated ALS risk among those exposed to hexachlorobenzene when adjusting for co-pollutants. Higher level of some POPs suggested a positive association with ALS occurrence, but the data was scarce at these levels.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/chemically induced/blood
Male
Female
Biomarkers/blood
Middle Aged
Denmark/epidemiology
*Persistent Organic Pollutants/blood/toxicity
Cohort Studies
Prospective Studies
Aged
Adult
Finland/epidemiology
Pesticides/blood

@article {pmid42097486,
year = {2026},
author = {Deloncle, R},
title = {Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.},
journal = {Experimental neurology},
volume = {403},
number = {},
pages = {115812},
doi = {10.1016/j.expneurol.2026.115812},
pmid = {42097486},
issn = {1090-2430},
abstract = {Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.},
}

@article {pmid42099104,
year = {2026},
author = {Oriquat, G and Jasim, IK and Gajjar, TB and Hanumanthayya, M and Abdulhameed Ahmad, I and Singh, G and Maharana, L and Bainsal, N},
title = {SUMOylation in Neural Health and Disease: From Cellular Homeostasis to Neurodegeneration.},
journal = {DNA and cell biology},
volume = {},
number = {},
pages = {10445498261444640},
doi = {10.1177/10445498261444640},
pmid = {42099104},
issn = {1557-7430},
abstract = {Neurodegenerative diseases (NDDs) represent a growing global health burden, particularly in aging populations. These disorders primarily affect neurons and are characterized by progressive neuronal dysfunction and loss within specific regions of the central nervous system. Major NDDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and stroke. Although each disorder exhibits distinct genetic backgrounds and pathological protein aggregates, they share common pathogenic mechanisms, including chronic neuroinflammation, impaired autophagy and mitophagy, disrupted proteostasis, telomere instability, and epigenetic alterations. A hallmark feature across NDDs is the accumulation of misfolded proteins, leading to synaptic dysfunction and neuronal degeneration. Small ubiquitin-like modifiers (SUMOs) are a family of ∼100 amino acid proteins, including SUMO1 and the closely related SUMO2/3 isoforms. SUMOylation is a dynamic posttranslational modification that regulates protein function through the covalent attachment or removal of SUMO moieties. This reversible process is mediated by SUMO-specific E1 activating, E2 conjugating, and E3 ligating enzymes and is counterbalanced by SUMO/Sentrin-specific proteases. The SUMOylation status of target proteins depends on the tightly controlled balance between conjugation and deconjugation systems. Acting as a molecular switch, SUMOylation modulates diverse cellular processes such as DNA damage repair, RNA metabolism, transcriptional regulation, and protein quality control, all of which are essential for maintaining cellular homeostasis. Accumulating evidence links dysregulated SUMOylation to the pathogenesis of multiple neurological disorders, including polyglutamine and synucleinopathies. SUMOylation influences neuroinflammation, oxidative stress, protein aggregation, neuroangiogenesis, ischemic injury, and demyelination. This review highlights recent advances in understanding the role of SUMOylation in NDDs and explores its potential as a promising therapeutic target.},
}

@article {pmid42101470,
year = {2026},
author = {Panchal, D and Solanki, D and Solanki, R and Yadav, AK and Bhatia, D and Yadav, P},
title = {Biomaterials and Nanoparticle-Based Therapeutics in Neurodegenerative Diseases: Bridging the Gap Between Innovation and Translation.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00245},
pmid = {42101470},
issn = {1948-7193},
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis, represent a growing global health crisis characterized by irreversible neuronal loss, protein aggregation, chronic neuroinflammation, and mitochondrial dysfunction. Central to their therapeutic intractability is the blood-brain barrier (BBB), a highly selective neurovascular interface that excludes nearly 98% of conventional pharmacological agents from the central nervous system (CNS). Nanoparticle- and biomaterial-based delivery platforms have emerged as promising strategies to overcome these barriers, encompassing liposomes, polymeric nanoparticles, engineered exosomes, inorganic nanoparticles, and hydrogel scaffolds capable of enabling targeted CNS drug delivery. This Review systematically evaluates the landscape of nanomaterial-based neurotherapeutics across disease-specific pathological contexts, critically analyzing translational failure mechanisms including limited parenchymal brain exposure, receptor saturation during transcytosis, protein corona-mediated immune clearance, and nanoscale toxicity in postmitotic neural tissue. Preclinical-to-clinical translational gaps arising from interspecies BBB transporter heterogeneity and pharmacokinetic divergence are examined alongside manufacturing and regulatory barriers impeding Good Manufacturing Practice (GMP)-scale production. Emerging convergence strategies─including AI-integrated design, hybrid physiologically based pharmacokinetic modeling, theranostic nanoplatforms, and wearable bioresponsive delivery systems─are evaluated for their capacity to address these limitations. The review concludes by proposing a framework for developing clinically viable, disease-modifying CNS nanomedicines.},
}

@article {pmid42091757,
year = {2026},
author = {Puthusseri, SP and Ravivarma, S and Johny, M and Vengellur, A},
title = {Hypoxia-inducible factor-1α: Dual roles in maintaining neuronal homeostasis and neuronal degeneration via regulation of oxidative stress, mitochondrial dynamics, and bioenergetics.},
journal = {Journal of physiology and biochemistry},
volume = {82},
number = {1},
pages = {},
pmid = {42091757},
issn = {1877-8755},
mesh = {*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; Humans ; *Oxidative Stress ; Energy Metabolism ; Animals ; *Neurons/metabolism/pathology ; *Mitochondrial Dynamics ; *Mitochondria/metabolism/pathology ; Homeostasis ; *Nerve Degeneration/metabolism/pathology ; },
abstract = {Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor with an inherently paradoxical biology: under mild-to-moderate hypoxic stress, it functions as a pro-survival regulator, yet under severe or prolonged hypoxia, the same signalling axis promotes apoptotic and autophagic cell death. This duality carries particular significance in neurons, where HIF-1α serves as a critical nexus among neuronal survival, metabolic adaptation, and mitochondrial integrity, and where the consequences of its dysregulation are most profound given their exceptional metabolic demands and limited regenerative capacity. This review examines the molecular determinants governing this protective-to-detrimental switch, integrating key interconnected dimensions: the context-dependent regulation of oxidative stress, the control of mitochondrial bioenergetics, dynamics, mitophagy, and axonal transport; the dual role of HIF-1α in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia; and the therapeutic implications of precision-targeted HIF-1α modulation. Across all these contexts, a consistent pattern emerges: early or acute HIF-1α activation is broadly neuroprotective, while chronic or severe hypoxic stress converts the same pathway into a driver of neurodegeneration. Understanding the determinants of this switch, including hypoxia duration, severity, and cell-type specificity, provides a framework for designing temporally precise therapeutic interventions for hypoxia-related neurological disorders.},
}

*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics
Humans
*Oxidative Stress
Energy Metabolism
Animals
*Neurons/metabolism/pathology
*Mitochondrial Dynamics
*Mitochondria/metabolism/pathology
Homeostasis
*Nerve Degeneration/metabolism/pathology

@article {pmid42092970,
year = {2026},
author = {Liu, H and Hu, C and Liu, H and Gong, Z and Jiang, S and Xie, J and Li, Y and Liu, C and Wang, Y and Zou, C and Yang, G},
title = {Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03815-1},
pmid = {42092970},
issn = {1742-2094},
support = {2023JJ40952//the Natural Science Foundation of Hunan Province/ ; 2024JJ6618//the Natural Science Foundation of Hunan Province/ ; 82204733//Foundation for Innovative Research Groups of the National Natural Science Foundation of China/ ; 20254677//Health Research Project of Hunan Provincial Health/ ; 82474009//the National Natural Science Foundation of China/ ; },
abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on canonical cGAS-STING signaling in the central nervous system (CNS) and discuss non-canonical branches only when directly relevant to neurodegeneration. We summarize structural and activation-termination mechanisms and synthesize cell-type-biased outputs across microglia, astrocytes, neurons, and oligodendroglial lineage cells. We then integrate Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by mapping shared DNA-stress triggers to multicellular amplification loops and by grading causal evidence from genetic perturbation, pharmacological pathway interference, and correlative human datasets. Finally, we classify inhibitor modalities and emerging enabling technologies while emphasizing translational constraints, including blood-brain barrier (BBB) delivery, long-term safety, human STING-allele diversity, and pharmacodynamic biomarkers. Collectively, we propose an evidence-calibrated framework for judging when cGAS-STING is most plausibly positioned as a causal node, a permissive amplifier, or a secondary correlate in neurodegenerative disease, and where therapeutic translation should proceed cautiously.},
}

@article {pmid42093907,
year = {2026},
author = {Talukder, A and Kelly, M and Gray, D and Sarma, H},
title = {Addressing the double burden of malnutrition in Bangladesh: Evidence from National Policy Documents and gaps in policy integration.},
journal = {Global epidemiology},
volume = {11},
number = {},
pages = {100258},
pmid = {42093907},
issn = {2590-1133},
abstract = {Bangladesh faces a growing double burden of malnutrition (DBM), where persistent undernutrition coexists alongside rapidly rising overweight and obesity. Despite numerous national policies addressing malnutrition, the extent to which these policies explicitly recognize and integrate DBM remains unclear. Objective: This study critically analyzes major national nutrition, food security, health, and agriculture policies in Bangladesh to assess DBM integration and identify gaps requiring urgent policy attention. Methods: We conducted a narrative policy analysis of five purposively selected national policy documents on nutrition implemented between 2015 and 2030. Policies were evaluated using a structured analytical framework informed by Hawkes et al.'s double-duty actions framework, the Essential Nutrition Actions framework of the World Health Organization, and the policy principles of the Global Nutrition Report. The analysis examined three dimensions: (i) recognition and framing of DBM, (ii) intervention design and content, and (iii) implementation systems. Data were extracted using a pre-specified template, verified by a second reviewer, and compared against framework components to identify gaps. Recommendations were then classified into immediate, medium-term, and long-term priorities based on feasibility and urgency. Results: All five policies demonstrated comprehensive undernutrition programming, with measurable targets. However, overnutrition has received minimal attention in all the policies. Only the National Nutrition Policy (2015) explicitly acknowledged DBM, but this fell short of an integrated operational framework. The remaining four policies continued to treat malnutrition as synonymous with undernutrition, leaving overnutrition largely invisible as a policy concern. No policy has provided integrated service delivery models, household-level DBM strategies, life-course surveillance systems, or food environment regulations. Seven critical gap categories were identified: service delivery, monitoring and evaluation, human resources, dietary guidelines, food environment regulation, equity and targeting, and multi-sectoral coordination. Conclusions: Bangladesh's nutrition policies remain structurally misaligned with its evolving DBM burden. Urgent policy actions are needed to explicitly recognize DBM as a distinct policy problem, establish integrated operational frameworks, develop household-level strategies, strengthen food environment regulations, and build multisectoral governance capacity. Phased recommendations spanning immediate, medium-term, and long-term timeframes are proposed to guide systematic DBM policy integration and support progress toward Sustainable Development Goal targets.},
}

@article {pmid42096854,
year = {2026},
author = {De Avila-Arias, M and Fang, L and Hoyos-Hoyos, V and Harris Ricardo, J and Cadena-Cruz, C and Villarreal-Camacho, JL and Fortich Mesa, N},
title = {Candida-bacteria interactions in peri-implantitis: A narrative review of evidence, mechanisms, and clinical implications.},
journal = {Archives of oral biology},
volume = {188},
number = {},
pages = {106603},
doi = {10.1016/j.archoralbio.2026.106603},
pmid = {42096854},
issn = {1879-1506},
abstract = {OBJECTIVE: To critically synthesize clinical, molecular, and mechanistic evidence on the contribution of the oral mycobiome, particularly Candida albicans, to peri-implantitis, and to evaluate how fungal-bacterial interactions influence biofilm pathogenicity, host responses, and potential therapeutic implications.

DESIGN: Narrative review of peer-reviewed studies including clinical and epidemiological investigations, molecular analyses (quantitative polymerase chain reaction [qPCR] and next-generation sequencing [NGS] targeting the internal transcribed spacer [ITS] region for fungal profiling and the 16S ribosomal RNA [16S rRNA] gene for bacterial profiling), in vitro and in vivo interkingdom biofilm models, and immunological mechanistic studies. Evidence was evaluated qualitatively, with emphasis on detection methods, study design, and translational relevance.

RESULTS: Molecular studies detect Candida spp. in a notable fraction of peri-implantitis sites, with higher detection by qPCR/NGS than by culture. Co-occurrence of C. albicans with periodontopathogens (e.g., Porphyromonas gingivalis, Fusobacterium nucleatum) is frequently reported. Mechanistic studies show that C. albicans forms hyphal scaffolds, consumes oxygen to create microanaerobic niches, mediates bacterial adhesion via Als adhesins, and participates in metabolic exchange and cooperative proteolysis. These processes enhance biofilm resilience, promote inflammatory signalling pathways (nuclear factor kappa B [NF-κB] and mitogen-activated protein kinase [MAPK]), activate the NLRP3 inflammasome, and increase antimicrobial tolerance. No randomized controlled trials of antifungal or interkingdom-directed therapies are currently available.

CONCLUSIONS: Evidence supports an interkingdom, polymicrobial model of peri-implantitis in which fungi contribute to biofilm stability and inflammation. However, heterogeneity in definitions, sampling, and detection methods limits causal inference. Longitudinal and interventional studies are required before mycobiome-directed therapies can be recommended.},
}

@article {pmid42025804,
year = {2026},
author = {Woodard, GE},
title = {C3 and C5 complement cascade activation in brain injury and disease: Molecular mechanisms, pathological roles, and therapeutic implications.},
journal = {Neurochemistry international},
volume = {196},
number = {},
pages = {106161},
doi = {10.1016/j.neuint.2026.106161},
pmid = {42025804},
issn = {1872-9754},
mesh = {Humans ; Animals ; *Complement Activation/physiology/drug effects ; *Complement C3/metabolism/immunology ; *Complement C5/metabolism/immunology ; *Brain Injuries/metabolism/immunology/pathology/drug therapy ; Brain/metabolism/pathology ; Neurodegenerative Diseases/metabolism ; },
abstract = {The complement system represents a crucial component of innate immunity with increasingly recognized roles in central nervous system pathology and homeostasis. Complement components C3 and C5 serve as central molecular hubs in the complement cascade, orchestrating inflammatory responses, synaptic pruning, and neuronal injury across diverse neurological conditions. This comprehensive review examines the molecular mechanisms underlying C3 and C5 activation in the brain, their pathological contributions to acute brain injuries including traumatic brain injury and ischemic stroke, and their complex involvement in chronic neurodegenerative diseases such as Alzheimer disease, multiple sclerosis, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Emerging evidence demonstrates that complement activation in the central nervous system extends beyond traditional immune functions to encompass critical roles in neurodevelopment, synaptic plasticity, and neural circuit refinement. The dual nature of complement function in the brain, exhibiting both neuroprotective and neurodegenerative properties depending on context and activation levels, presents unique therapeutic challenges and opportunities. This review synthesizes current understanding of complement-mediated neuroinflammation, discusses validated and emerging therapeutic strategies targeting C3 and C5, evaluates complement biomarkers for disease diagnosis and monitoring, and identifies critical knowledge gaps requiring future investigation. Understanding the nuanced roles of C3 and C5 in neurological disease provides essential foundations for developing targeted immunomodulatory therapies that preserve beneficial complement functions while mitigating pathological activation.},
}

Humans
Animals
*Complement Activation/physiology/drug effects
*Complement C3/metabolism/immunology
*Complement C5/metabolism/immunology
*Brain Injuries/metabolism/immunology/pathology/drug therapy
Brain/metabolism/pathology
Neurodegenerative Diseases/metabolism

@article {pmid42086408,
year = {2026},
author = {Ibrahim, M and Hossain, MS and Ooi, L and Hasan, MM and Ahsan, S and Salem, AK and Piazza, GA and Feng, X and Ahsan, F},
title = {Targeting the NAD[+]-PARP1-XRCC1 axis in ALS.},
journal = {Trends in molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42086408},
issn = {1471-499X},
support = {R01 HL144590/HL/NHLBI NIH HHS/United States ; R43 HL169134/HL/NHLBI NIH HHS/United States ; },
abstract = {Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, and progressive NAD[+] depletion contribute to motor neuron degeneration. The NAD[+]-PARP1-XRCC1 axis sits at the intersection of genome maintenance and metabolic control, linking DNA damage signaling to cellular bioenergetics. When dysregulated, this pathway may drive persistent PARP1 activation, failed repair, and energetic collapse. In this review, we integrate mechanistic and translational evidence supporting this axis as a therapeutic target in ALS. We propose a staged translational framework that prioritizes repurposable low-trapping PARP1 inhibitors combined with NAD[+] support, followed by central nervous system-directed RNA-lipid nanoparticle delivery of repair factors, with poly(ADP-ribose) and NAD[+] metabolites as pharmacodynamic biomarkers.},
}

@article {pmid42088060,
year = {2026},
author = {Hou, DL and Ho, J and Guan, T and Dong, XX and Zeng, L and Sanders, LH and Wu, YC and Tan, EK and Zhou, ZD},
title = {E3 ubiquitin ligases in neurodegenerative diseases.},
journal = {Military Medical Research},
volume = {13},
number = {1},
pages = {100032},
pmid = {42088060},
issn = {2054-9369},
mesh = {Humans ; *Ubiquitin-Protein Ligases/therapeutic use ; *Neurodegenerative Diseases/physiopathology ; },
abstract = {Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, trans-active response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.},
}

Humans
*Ubiquitin-Protein Ligases/therapeutic use
*Neurodegenerative Diseases/physiopathology

@article {pmid42074613,
year = {2026},
author = {Quak, ZX and Wang, F and Tay, SKH and Koh, PL and Yap, ES and Ng, KWP},
title = {Thrombosis in Neuromuscular Medicine: Current Evidence, Unmet Needs, and Future Directions.},
journal = {Journal of clinical medicine},
volume = {15},
number = {8},
pages = {},
pmid = {42074613},
issn = {2077-0383},
abstract = {Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is an important but under-recognised complication in neuromuscular diseases. In adults, emerging epidemiological data suggests increased VTE occurrence in conditions such as Amyotrophic Lateral Sclerosis, myotonic dystrophy, myasthenia gravis, inflammatory neuropathies, inflammatory myopathies, and POEMS syndrome. This heightened risk reflects not only disease-related immobility but also disorder-specific biological mechanisms, including inflammation, endothelial dysfunction and cardiomyopathy-related stasis. Therapies such as corticosteroids, IVIG-related hyperviscosity, long-term central venous access, perioperative immobility, critical illness, and complex orthopaedic procedures have prothrombotic effects. Despite this multifactorial risk profile, disease-specific guidance for thromboprophylaxis is lacking, and current practice relies heavily on extrapolation from general medical and surgical recommendations rather than data derived from neuromuscular cohorts. In children and adolescents, the VTE burden is less well-characterised, but events have been reported in Duchenne and Becker muscular dystrophy, congenital myopathies, and spinal muscular atrophy particularly with advanced motor impairment, severe cardiomyopathy, ventilatory insufficiency, and prolonged hospitalisation. Beyond venous events, selected neuromuscular disorders also exhibit increased arterial thrombosis risk. Myotonic dystrophy and dystrophinopathies are associated with cardiomyopathy and arrhythmia that predispose to systemic embolism and stroke, while inflammatory myopathies may demonstrate arterial events related to vasculitic or endothelial processes, although overall evidence remains limited. This review summarises available empirical and epidemiological evidence on venous and arterial thrombosis across adult and paediatric neuromuscular disorders, outlines disease-specific mechanistic pathways, examines treatment-related contributors, and highlights key evidence gaps that must be addressed to guide rational and targeted prophylaxis strategies in this complex, heterogeneous population.},
}

@article {pmid42076023,
year = {2026},
author = {Rodkin, S and Gasanov, M and Tushev, A and Belousova, E and Gordeeva, Y and Nwosu, C and Tolmacheva, A},
title = {The Dual Role of Connexins in Stroke, Neurotrauma, Neurodegenerative and Psychiatric Disorders: A Global Systematic Review.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {8},
pages = {},
pmid = {42076023},
issn = {1420-3049},
support = {25-75-10137//Russian Science Foundation/ ; },
mesh = {Humans ; *Connexins/metabolism/genetics ; *Mental Disorders/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism ; *Stroke/metabolism ; Gap Junctions/metabolism ; *Brain Injuries, Traumatic/metabolism ; Spinal Cord Injuries/metabolism ; },
abstract = {Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood-brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries-including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury-as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis-Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial-neuronal communication and cognitive-emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood-brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx-particularly Cx43-occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation.},
}

Humans
*Connexins/metabolism/genetics
*Mental Disorders/metabolism
Animals
*Neurodegenerative Diseases/metabolism
*Stroke/metabolism
Gap Junctions/metabolism
*Brain Injuries, Traumatic/metabolism
Spinal Cord Injuries/metabolism

@article {pmid42085565,
year = {2026},
author = {Singh, K and Ahmad, I and Jain, D and Mim, TJ and Noman, AA and Shihab, MPR and Kondaveeti, SB and Gupta, JK and Wal, P},
title = {Novel Cellular Signalling Axes in Neurodegenerative Diseases: From NLRP3 Inflammasome to Wnt/β-Catenin and Hippo-YAP Pathways.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70880},
doi = {10.1002/jbt.70880},
pmid = {42085565},
issn = {1099-0461},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Wnt Signaling Pathway ; Animals ; Hippo Signaling Pathway ; *beta Catenin/metabolism ; YAP-Signaling Proteins ; *Adaptor Proteins, Signal Transducing/metabolism ; *Protein Serine-Threonine Kinases/metabolism ; *Transcription Factors/metabolism ; Signal Transduction ; },
abstract = {Neurodegenerative diseases (NDs), including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), are characterised by impaired cellular homeostasis and progressive neuronal loss. Emerging evidence highlights the critical role of cellular signalling pathways in the progression and pathogenesis of these disorders. With a focus on the NLRP3 inflammasome, Wnt/β-catenin, and Hippo-YAP cascades, this review focuses on new signalling pathways linked to neurodegenerative disorders. Among them, the NLRP3 inflammasome is a crucial mediator of neuroinflammation, causing neuronal damage and persistent immune activation. In contrast, these pathways regulate neurogenesis, synaptic plasticity, and cell survival, offering potential neuroprotective functions. Dysregulation of these pathways disrupts cellular integrity, exacerbates disease progression, and represents a convergence point for therapeutic intervention. In NDs, knowing how these pathways interact offers fresh perspectives on disease processes and finds new targets for the creation of disease-modifying treatments.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Inflammasomes/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Wnt Signaling Pathway
Animals
Hippo Signaling Pathway
*beta Catenin/metabolism
YAP-Signaling Proteins
*Adaptor Proteins, Signal Transducing/metabolism
*Protein Serine-Threonine Kinases/metabolism
*Transcription Factors/metabolism
Signal Transduction

@article {pmid42086102,
year = {2026},
author = {Chen, M and Huang, X and Li, Y and Hu, L and Lu, R and Li, L},
title = {Microplastics as an emerging environmental pollutant potentially leading to neurodegenerative diseases.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.04.033},
pmid = {42086102},
issn = {1873-7544},
abstract = {Microplastics (MPs), defined as plastic fragments less than 5 mm in diameter, are ubiquitous in the environment. As an emerging environmental pollutant, MPs can infiltrate the human body through multiple pathways, including inhalation, ingestion, dermal contact and bloodborne transmission.Correspondingly, MPs, which can penetrate the blood-brain barrier and enter the central nervous system (CNS), have been linked to the development of neurodegenerative diseases (NDs).In this review, we provide a comprehensive analysis of the environmental distribution of MPs, the pathways of entry into the human body, and the distribution within the CNS. Furthermore, we explore intrinsic factors influencing the neurotoxicity of MPs and elucidate the mechanisms underlying MPs-induced NDs, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Beyond mechanistic insights, we offer a novel perspective by exploring the potential adaptation of emerging environmental MPs detection and removal technologies for CNS applications. Ultimately, elucidating these mechanisms positions the reduction of MPs accumulation as a critical intervention point, highlighting the adaptation of environmental technologies as a promising strategy for the prevention and management of NDs.},
}

@article {pmid42071322,
year = {2026},
author = {Buttifant, E and Allogmanny, S and Probst, Y},
title = {Investigating Disordered Eating Behaviours Among Individuals Living With Neurodegenerative Disease: A Scoping Review.},
journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association},
volume = {39},
number = {3},
pages = {e70250},
pmid = {42071322},
issn = {1365-277X},
mesh = {Humans ; *Feeding and Eating Disorders/etiology/epidemiology/complications ; *Neurodegenerative Diseases/complications/psychology ; *Feeding Behavior/psychology ; Hyperphagia ; Female ; Male ; Alzheimer Disease/complications ; },
abstract = {AIM: Neurodegenerative diseases and disordered eating have become rapidly expanding areas of research. However, research addressing the relationship between the two is lacking.

METHODS: A scoping review guided by the Joanna Briggs Institute methodological framework was completed to synthesise the evidence related to disordered eating behaviours among individuals living with neurodegenerative disease. A systematic search strategy was applied across four scientific databases. A narrative descriptive analysis was conducted to identify key patterns in the studies categorised by the type of eating behaviour. The types of tools used within studies were explored.

RESULTS: Thirty-six evidence sources were included in this review. Overeating-related issues such as hyperphagia were identified (n = 5, 25%) for dementia and Alzheimer's disease-related studies. Appetite-related changes were prevalent across amyotrophic lateral sclerosis (n = 1, 100%) and dementia and Alzheimer's disease-related studies (n = 6, 30%). Food addiction and binge eating were reported in all Parkinson's disease studies (n = 9, 100%), and in one case report for dementia. Eating disorders such as anorexia, bulimia and binge eating disorder were identified in all multiple sclerosis-related studies (n = 6, 100%). Validated and unvalidated tools (53%, n = 19) were used to identify eating behaviours.

CONCLUSIONS: This review revealed reports of disordered eating behaviours among various neurodegenerative disease types. Additional research is required to understand the aetiology and mechanisms behind disordered eating behaviours in these populations. Standardised tools to assess eating behaviours for people living with a neurodegenerative disease are needed. Eating behaviours should be screened upon neurodegenerative disease diagnosis and monitored as part of routine care.},
}

Humans
*Feeding and Eating Disorders/etiology/epidemiology/complications
*Neurodegenerative Diseases/complications/psychology
*Feeding Behavior/psychology
Hyperphagia
Female
Male
Alzheimer Disease/complications

@article {pmid42073997,
year = {2026},
author = {Rafique, A and Junaid, A and Bakovic, M},
title = {Impact of Oxidative Stress-Driven Ferroptosis in Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
pmid = {42073997},
issn = {1422-0067},
support = {APP465536/CAPMC/CIHR/Canada ; },
mesh = {*Ferroptosis ; Humans ; *Oxidative Stress ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Lipid Peroxidation ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Ferroptosis is an iron-dependent cell death driven by lipid peroxidation and failure of cellular antioxidant defenses. It is triggered by oxidative stress and can be aggravated by aging, inflammation, and dysregulation of iron homeostasis. In the central nervous system, iron dyshomeostasis, mitochondrial dysfunction, and membrane lipid remodeling can amplify oxidative injury and increase susceptibility to ferroptotic damage, particularly in vulnerable neurons. There is growing evidence that ferroptosis-related processes are linked to Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. This review addresses novel approaches to track ferroptosis in vivo, such as imaging and biomarker techniques, and important molecular mechanisms linking iron metabolism, reactive oxygen species, and PUFA-driven lipid peroxidation to neuronal damage. We also explore upstream transcriptional control via NRF2, iron chelation and iron-handling modulation, inhibition of lipid peroxidation, and reinforcement of the System Xc-GSH-GPX4 and CoQ10-linked defense pathways. Subsequently, we highlight translational issues that need attention to further progress ferroptosis-targeted therapies for neurodegenerative disease.},
}

*Ferroptosis
Humans
*Oxidative Stress
Animals
*Neurodegenerative Diseases/metabolism/pathology
Lipid Peroxidation
Iron/metabolism
Reactive Oxygen Species/metabolism

@article {pmid42074010,
year = {2026},
author = {Goloborshcheva, VV and Kostikova, YS and Kucheryanu, VG and Morozov, SG and Kokhan, VS},
title = {Insights into the Impact of Low-Dose Ionizing Radiation on Neurodegenerative Disease Progression in In Vivo Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
pmid = {42074010},
issn = {1422-0067},
support = {FGFU-2025-0004//Russian state contract/ ; },
mesh = {Animals ; Humans ; *Radiation, Ionizing ; *Neurodegenerative Diseases/radiotherapy/pathology/metabolism ; Disease Models, Animal ; Disease Progression ; Autophagy/radiation effects ; DNA Repair/radiation effects ; },
abstract = {The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored.},
}

Animals
Humans
*Radiation, Ionizing
*Neurodegenerative Diseases/radiotherapy/pathology/metabolism
Disease Models, Animal
Disease Progression
Autophagy/radiation effects
DNA Repair/radiation effects

@article {pmid42074537,
year = {2026},
author = {Yesbek Kaymaz, A and Bora-Akoğlu, G and Erdem Yurter, H and Grunseich, C},
title = {Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.},
journal = {Genes},
volume = {17},
number = {4},
pages = {},
pmid = {42074537},
issn = {2073-4425},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Genetic Therapy/methods ; *Muscular Atrophy, Spinal/therapy/genetics ; Gene Editing/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Genetic Vectors/genetics ; },
abstract = {Advances in technology have provided a better understanding of the genetic basis of neurodegenerative disorders and their underlying molecular pathophysiology. However, treating these disorders with conventional strategies is a major challenge. The approval of gene targeted therapy for spinal muscular atrophy (SMA) has laid the foundation for developing highly personalized therapies for other neurodegenerative disorders. As intensive research and efforts to advance gene targeted therapies continue, this review provides an overview of viral and non-viral vectors and delivery methods, as well as treatment strategies, including gene addition, replacement, editing, silencing, and splice modulation. Gene targeted approaches and clinical trials for SMA and amyotrophic lateral sclerosis (ALS) have demonstrated success, and additional studies are in progress. The design of efficient clinical trials which facilitate successful translation into clinical practice is of critical importance. Key considerations include the selection of appropriate disease models, understanding the natural history of the disease, and establishing well-defined outcome measures to assess prognosis of the disease and therapeutic efficacy. Finally, the precision of CRISPR-based gene editing offers the potential for one-time corrective therapies for monogenic disorders like SMA and SOD1-ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/genetics
*Genetic Therapy/methods
*Muscular Atrophy, Spinal/therapy/genetics
Gene Editing/methods
Animals
*Neurodegenerative Diseases/therapy/genetics
Genetic Vectors/genetics

@article {pmid41730342,
year = {2026},
author = {Thomas, T and Jones, L and Dawson, S and Houghton, C and Hunter, A and O'Connell, N and Biesty, L},
title = {Existing research guidelines for inclusive trials methodology. Working toward the integration of qualitative research, equity, diversity, and inclusion and trials methodology: a focused mapping review.},
journal = {Journal of clinical epidemiology},
volume = {193},
number = {},
pages = {112202},
doi = {10.1016/j.jclinepi.2026.112202},
pmid = {41730342},
issn = {1878-5921},
mesh = {Humans ; Qualitative Research ; *Research Design/standards ; *Guidelines as Topic ; *Clinical Trials as Topic/methods/standards ; *Patient Selection ; Cultural Diversity ; Diversity, Equity, Inclusion ; },
abstract = {BACKGROUND: Equity, diversity, and inclusion (EDI) are increasingly emphasized in clinical research, yet practical guidance for applying inclusion principles across all clinical trial stages remain limited. Qualitative research can help address this gap by exploring participant experiences and identifying barriers to inclusive trial conduct. The aim of this review is to map guidelines and recommendations in relation to inclusive trials methodology and to identify areas across these resources that can be potentially informed by qualitative research. This review presents Phases 1 and 2 of the QuAlitative reSearch Supporting IncluSive Trials (Q-ASSIST) study.

METHODS: In Phase 1, we conducted a focused mapping review and synthesis (FMRS) of publicly available guidelines related to Phase 3 and later clinical trials involving human participants. Eligible guidelines included those offering recommendations to enhance inclusive trial design and conduct. Each guideline was mapped to a priori data extraction framework informed by the Standard Protocol Items: Recommendations for Interventional Trials and Consolidated Standards of Reporting Trials 2025 guidelines. We then performed a narrative synthesis to examine the EDI focus of the selected guidelines and structured the findings according to the PRO-EDI Framework. In Phase 2, we juxtaposed the trial stages identified through our FMRS with O'Cathain et al's framework of qualitative research in trials.

RESULTS: We identified 15 guidelines through FMRS. Through conceptual mapping to Standard Protocol Items: Recommendations for Interventional Trials and Consolidated Standards of Reporting Trials headings, we developed a 12-stage trial lifecycle framework (the Q-ASSIST trial stages model) to organize inclusion guidance. Most guidelines emphasized early stages of trials, with later stages less frequently addressed. Mapping to the PRO-EDI framework showed strong attention to race/ethnicity, gender, socioeconomic status, and disability, but limited focus on sexual identity, education, or intersectionality. Juxtaposition with O'Cathain et al's framework highlighted similar gaps in how qualitative research has been used, especially in later trial stages.

CONCLUSION: Current inclusion guidance is concentrated in the early stages of trial design, with limited attention to later trial stages. Qualitative research offers a valuable way to address these gaps by capturing participant perspectives and supporting inclusive practices across the trial lifecycle. This review provides a foundation for developing practical tools to guide more inclusive trials, with the next phase involving coproduction of guiding principles with interest holders.},
}

Humans
Qualitative Research
*Research Design/standards
*Guidelines as Topic
*Clinical Trials as Topic/methods/standards
*Patient Selection
Cultural Diversity
Diversity, Equity, Inclusion

@article {pmid41855303,
year = {2026},
author = {Drouin, E and Pereon, Y},
title = {Historical and Clinical Analysis of a Case of Progressive Muscular Atrophy (1853-1871).},
journal = {European neurology},
volume = {},
number = {},
pages = {1-8},
doi = {10.1159/000550658},
pmid = {41855303},
issn = {1421-9913},
abstract = {BACKGROUND: Progressive muscular atrophy (PMA) emerged in the mid-19th century as a distinct clinical entity within the evolving field of French neurology, notably through the work of François Amilcar Aran, Duchenne de Boulogne, and later Jean-Martin Charcot. During this period, uncertainties persisted regarding its nosological status, pathophysiology, and relationship to amyotrophic lateral sclerosis (ALS). Longitudinal clinical observations from this era remain rare but are essential for understanding both the natural history of motor neuron diseases and the historical construction of neurological knowledge.

SUMMARY: This article presents a historical and clinical analysis of a unique case of PMA observed for over nearly 2 decades (1853-1871) in Parisian hospitals. The case concerns Auguste-Joseph Bellinghen, whose condition was first documented in an unpublished handwritten manuscript in 1853 and later published with photographic illustrations in 1871. Through a comparative analysis of these two observations, the study traces the slow, asymmetrical, and irreversible progression of muscular atrophy, marked by early fasciculations, the absence of sensory disturbances, and eventual severe motor disability. The case is examined within its institutional, nosological, and therapeutic contexts, highlighting hospital circulation, the role of medical interns, and the empirical treatments of the time, including electrotherapy and thermal baths. Reinterpreted in light of contemporary neurology, this historical observation likely corresponds to a spinal-onset motor neuron disease closely related to ALS. Beyond its clinical significance, the case illustrates the transition from descriptive clinical medicine to anatomoclinical correlation and contributes to the historiography of neurology by illuminating how individual patient trajectories shaped medical knowledge in the 19th century.

KEY MESSAGES: (1) Long-term historical clinical observations provide valuable insights into the natural history of PMA and motor neuron diseases. (2) The Bellinghen case illustrates the evolution of neurological semiology, particularly the early recognition of fasciculations and asymmetrical muscle wasting. (3) This case highlights the transition from Aran's initial clinical description of PMA to Charcot's anatomopathological framework linking PMA to ALS. (4) Historical medical archives offer not only scientific data but also a window into the social consequences of chronic neurological disease in the 19th century. (5) Integrating historical and clinical analysis enriches contemporary understanding of motor neuron disease nosology and medical memory.},
}

@article {pmid42070160,
year = {2026},
author = {Abdel Mageed, SS and Sayed, GA and Mahdy, A and El-Dakroury, WA and Abdulkader, AO and Moustafa, HAM and Mansour, RM and Mohammed, OA and Elballal, MS and Elesawy, AE and Doghish, AS},
title = {miRNAs in Amyotrophic Lateral Sclerosis: Tiny Molecules, Tremendous Impact.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42070160},
issn = {1559-1182},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis/metabolism ; Humans ; *MicroRNAs/genetics/metabolism ; Animals ; Biomarkers/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by progressive motor neuron degeneration, with diverse clinical manifestations and complex genetic and environmental triggers. The variability in disease progression underscores the necessity for tailored diagnostic and therapeutic approaches. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers and therapeutic targets in ALS. Dysregulation of specific miRNAs has been linked to mechanisms of ALS, including neuromuscular dysfunction, neuroinflammation, and neuronal survival/apoptosis. The potential of miRNA-based therapies, such as mimics and inhibitors, offers a more integrated approach by modulating entire disease networks, rather than targeting isolated pathways. However, challenges persist, particularly in delivering these therapies efficiently across the blood-brain barrier and minimizing off-target effects. Current delivery strategies involving nanoparticles, viral vectors, and exosome-based approaches require optimization for clinical use. This review synthesizes the latest research on miRNA-mediated mechanisms in ALS, evaluating their diagnostic, prognostic, and therapeutic potential, while highlighting the current limitations in clinical validation. It underscores the importance of standardized methodologies, multi-omics integration, and rigorous validation to facilitate the clinical translation of miRNA-based strategies. Standardized protocols and multicenter validation in large cohorts are essential to confirm the diagnostic accuracy of miRNAs, paving the way for their clinical application in ALS precision medicine.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis/metabolism
Humans
*MicroRNAs/genetics/metabolism
Animals
Biomarkers/metabolism

@article {pmid42070757,
year = {2026},
author = {Liu, JY and Liu, SY and Ran, LX and Qiao, WH and Zhang, F and Zhang, KS and Liang, XX and Liu, MY and Yu, ZH and Wei, MJ and Zhong, X},
title = {Organelle-orchestrated cGAS-STING signaling and its role in neurodegeneration.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108216},
doi = {10.1016/j.phrs.2026.108216},
pmid = {42070757},
issn = {1096-1186},
abstract = {The cGAS-STING signaling pathway serves as a central signalling axis of the innate immune system, and its aberrant activation plays a pivotal role in inflammatory responses. Recent studies have demonstrated that its regulation depends not only on individual organelles but also on a coordinated interorganelle network. This review systematically analyze how mitochondria, centrosomes, the endoplasmic reticulum (ER), membrane contact sites (MCSs), the Golgi apparatus, endosomes, and lysosomes collectively orchestrate cGAS-STING signaling. Mitochondria initiate signaling by releasing mitochondrial DNA; centrosomes serve as platforms for double-stranded DNA accumulation to potentiate cGAS activation; the ER anchors STING in a calcium homeostasis-dependent manner; mitochondrial-associated ER membranes (MAMs) integrate calcium and lipid signaling as regulatory checkpoints governing STING trafficking to the Golgi apparatus; the Golgi amplifies downstream signaling through site-specific post-translational modifications of STING; finally, the endosome-lysosome system, together with ER-lysosome MCSs, acts as a coordinated hub for STING sorting, lysosomal degradation and signal termination. Consequently, disruption of organelle homeostasis leads to persistent STING activation. In neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease, organelle dysfunction resulting from calcium overload, impaired organelle clearance, proteolytic cleavage of tethering proteins or multi-source attacks drives aberrant STING signaling. Sustained STING activity exacerbates pathological cascades such as protein misfolding, chronic neuroinflammation, and progressive neuronal loss. Therefore, therapeutic strategies targeting key regulatory nodes of the STING pathway, from upstream organelle repair to direct pharmacological inhibition, offer significant potential to mitigate disease-associated pathological progression and constitute a promising foundation for precision therapeutics in neurodegenerative disorders.},
}

@article {pmid42055490,
year = {2026},
author = {Banerjee, C and Singh, RK and Mehan, S},
title = {Raloxifene Beyond Osteoporosis: Unlocking Neurorestoration Through Remyelination, Inflammatory Regulation, and Neuroimmune Modulation in CNS Pathologies.},
journal = {International immunopharmacology},
volume = {181},
number = {},
pages = {116668},
doi = {10.1016/j.intimp.2026.116668},
pmid = {42055490},
issn = {1878-1705},
abstract = {Raloxifene, a selective estrogen receptor modulator (SERM), has emerged as a promising candidate for repurposing in neurodegenerative and neuropsychiatric disorders. Traditionally approved for osteoporosis and breast cancer prevention, its tissue-selective estrogen receptor modulation underpins its potential therapeutic applications. This review critically examines the pharmacological, preclinical, and clinical evidence supporting raloxifene's neuroprotective and neuropsychiatric effects, as well as its mechanisms of action, safety profile, and clinical limitations. Raloxifene exerts neuroprotective effects by targeting estrogen receptors, including ERα, ERβ, and GPER, modulating genomic and non-genomic pathways. These pathways regulate oxidative stress, mitochondrial stability, neuroinflammation, and apoptosis-core features of neurological disorders such as Alzheimer's (AD), Parkinson's (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Preclinical studies demonstrate raloxifene's ability to reduce amyloid-β aggregation in AD, protect dopaminergic neurons in PD, mitigate demyelination in MS, and decrease protein aggregation in ALS. Additionally, raloxifene exhibits positive effects on memory, attention, and negative symptoms in schizophrenia, alongside antidepressant and anxiolytic properties. Although promising, raloxifene's clinical translation faces challenges. Existing trials are limited by small sample sizes, heterogeneous designs, and a lack of long-term data. Most studies focus on postmenopausal women, leaving gaps regarding effects in men, premenopausal women, and younger populations. Furthermore, discrepancies between preclinical and clinical dosing complicate its therapeutic optimization. Future research should explore sex-specific effects, optimize CNS-targeted dosing strategies, and employ biomarkers for neuroprotection and inflammation. Long-term trials are essential to evaluate its disease-modifying potential. Raloxifene represents a promising repurposing candidate for CNS disorders, however, its therapeutic role remains to be established through robust clinical validation.},
}

@article {pmid42057546,
year = {2026},
author = {Jha, NK and Chauhan, P and Abomughaid, MM and Avinash, D and Almutary, AG and Lakhanpal, S and Singh, A and Sulaimani, GM and Al-Kuraishy, HM and Mohammed, HA and Misra, J and Thakur, K and Kumar, D},
title = {mTOR Signalling in Neurodegenerative Disorders: Unveiling Key Factors, Mechanistic Insights, and Possible Therapeutic Interventions.},
journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology},
volume = {60},
number = {2},
pages = {136-174},
doi = {10.33594/000000858},
pmid = {42057546},
issn = {1421-9778},
mesh = {*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; Humans ; *Signal Transduction/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; AMP-Activated Protein Kinases/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy ; Autophagy ; },
abstract = {Neurodegenerative diseases (NDDs) are defined by the gradual degeneration of neuronal cells, wherein the accumulation of misfolded proteins can lead to memory impairments, motor dysfunctions, and other deteriorations. Despite the widespread impact, there are currently no viable pharmaceuticals to treat these disorders. The mTOR protein is a crucial regulator of cell survival, growth, autophagy, and apoptosis. Targeted modulation of mTOR signaling holds promise for mitigating neurodegeneration in Alzheimer's, Huntington's, ALS, and Parkinson's disease. Understanding its interactions with pathways such as PI3K/Akt, AMPK, and SIRT1 is essential for developing effective therapeutics.},
}

*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors
Humans
*Signal Transduction/drug effects
*Neurodegenerative Diseases/metabolism/pathology/drug therapy
Animals
Phosphatidylinositol 3-Kinases/metabolism
Proto-Oncogene Proteins c-akt/metabolism
AMP-Activated Protein Kinases/metabolism
Alzheimer Disease/metabolism/pathology/drug therapy
Autophagy

@article {pmid42059992,
year = {2026},
author = {Ghiyamihoor, F and Asemi Rad, A and Hassanifar, P and Kaur, R and Patel, JH and Kim, I and Marzban, A and Mehdizadeh, M and Levin, DB and Ghavami, S and Toncheva, A and Benali, S and Dubois, P and Balci, F and Habibi, HR and Manto, M and Marzban, H},
title = {Micro- and Nanoplastics in the Human Brain: Mechanistic Plausibility, Translational Challenges, and Links to Neurological Disease Trends.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42059992},
issn = {1559-1182},
mesh = {Humans ; *Brain/pathology/metabolism/drug effects ; *Nervous System Diseases/metabolism/pathology ; *Translational Research, Biomedical/trends ; *Microplastics/adverse effects/toxicity ; Animals ; Blood-Brain Barrier/metabolism ; },
abstract = {The exponential growth in plastic production since the mid-twentieth century has led to the pervasive presence of micro- and nanoplastics (MNPs) across ecosystems and human exposure pathways, coinciding with a rising global burden of neurological disorders. Increasing evidence demonstrates that MNPs are not confined to peripheral tissues but can accumulate even in the human brain, raising concerns about their potential contribution to neurological disease. This structured review synthesizes global trends in plastic production, environmental MNP burden, and human exposure, together with emerging data on brain accumulation, entry pathways, neurotoxic mechanisms, and key translational challenges. We present evidence showing that MNPs may cross brain barriers via multiple routes, including the blood-brain barrier, blood-cerebrospinal fluid barrier, olfactory, and circumventricular pathways, particularly under conditions of barrier vulnerability. Experimental studies reveal that once in neural tissue, MNPs may disrupt synaptic function, mitochondrial homeostasis, autophagy, and redox balance, while activating neuroinflammatory and gut-brain axis-mediated pathways. These mechanisms intersect with disease-relevant processes implicated in multiple neurological disorders whose global prevalence and societal burden have sharply increased over recent decades, including stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, mood disorders, and neurodevelopmental conditions. Despite growing mechanistic plausibility, translational and human epidemiological evidence remains limited by methodological heterogeneity, a lack of standardized detection methods, and the absence of longitudinal clinical data/studies. We highlight critical analytical and translational gaps, public health implications, and priorities for longitudinal, biomarker‑driven studies needed to rigorously test whether MNPs may contribute to population‑level risk of neurological disease.},
}

Humans
*Brain/pathology/metabolism/drug effects
*Nervous System Diseases/metabolism/pathology
*Translational Research, Biomedical/trends
*Microplastics/adverse effects/toxicity
Animals
Blood-Brain Barrier/metabolism

@article {pmid41866924,
year = {2026},
author = {Seyam, M and Morelli, KH and Waheed, W and van den Berg, LH and Tandan, R},
title = {Predicting Disease Progression and Survival in Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {73},
number = {6},
pages = {961-965},
doi = {10.1002/mus.70198},
pmid = {41866924},
issn = {1097-4598},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; *Disease Progression ; Predictive Value of Tests ; },
abstract = {Amyotrophic lateral sclerosis (ALS) progresses relentlessly and is characterized by a median survival of 2-5 years from symptom onset with death from respiratory failure. ALS is a complex, multi-system neurodegenerative disorder with significant phenotypic heterogeneity and markedly variable disease progression. This variability presents challenges in determining the optimal timing for therapeutic interventions, complicates clinical trial design due to lack of effective stratification methods, and makes it difficult to reliably measure the longitudinal impact of specific interventions. Accurately capturing disease progression in ALS can be challenging. We propose that early respiratory phenotyping offers a promising approach to facilitate patient stratification, improve assessments of disease progression, and predict survival.},
}

Humans
*Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology
*Disease Progression
Predictive Value of Tests

@article {pmid42051550,
year = {2026},
author = {Chakraborty, DK and Roy, T and Ngo, ST and Al-Chalabi, A and Al Khleifat, A},
title = {Gut microbiota and ALS: cause, consequence or correlation? - a systematic review.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1774417},
pmid = {42051550},
issn = {1662-4548},
abstract = {BACKGROUND: Gut microbiome disturbances have been proposed as contributors to amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder characterised by motor neuron loss, extra-motor symptoms, and rapid progression. Mechanistic links between dysbiosis, epithelial and blood-brain barrier dysfunction, metabolic imbalance, and immune activation have been suggested, but causality remains unresolved. We conducted a systematic review to evaluate the evidence supporting microbiome involvement in ALS pathogenesis.

METHODS: We searched PubMed, Medline, Embase, Scopus, Semantic Scholar, and Google Scholar (Nov 23, 2025) for human and ALS-relevant animal studies assessing bacterial microbiota, gut or blood-brain barrier integrity, microbial metabolites, or immune pathways. No language or date restrictions were applied. Studies were screened according to predefined criteria, and quality was assessed using QUADAS-2. Owing to the heterogeneity of study designs and sequencing approaches, findings were synthesised narratively.

FINDINGS: 61 of 2,397 studies met inclusion criteria. Across human cohorts, ALS was consistently associated with reduced microbial diversity, shifts in key taxa, and disruption of microbial pathways regulating short-chain fatty acids, nicotinamide metabolism, and inflammatory signalling. Several mechanistic animal studies demonstrated that microbiota manipulation, through antibiotics, faecal microbiota transfer, or supplementation with protective taxa, modulated motor function, microglial activation, gut permeability, and survival, indicating that dysbiosis can influence disease trajectories. Conversely, longitudinal human data showed that dysbiosis often emerged alongside worsening physical function, gastrointestinal dysmotility, weight loss, and changes in dietary intake, suggesting secondary effects of disease progression. Integrative multi-omics studies linked microbial alterations with systemic cytokine profiles, metabolic stress pathways, and CNS immune phenotypes, reinforcing a bidirectional gut-brain axis. However, the predominance of cross-sectional designs and small sample sizes substantially limits causal inference.

INTERPRETATION: Current evidence supports a model in which gut dysbiosis interacts with ALS via barrier failure, metabolic disruption, and immune dysregulation, but does not establish dysbiosis as a primary cause of disease. Preclinical findings highlight microbiome-derived mechanisms with disease-modifying potential, yet human data largely indicate association rather than initiation. Clarifying temporal relationships will require longitudinal, multi-modal studies, integration with pre-symptomatic cohorts, and controlled interventional trials. Microbiome-targeted therapies remain a promising but unproven avenue for ALS.},
}

@article {pmid42051853,
year = {2026},
author = {Eissazade, N and Nazemi, L and Haghi Ashtiani, B and Moradi-Lakeh, M},
title = {Neutrophil-to-lymphocyte ratio in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag132},
pmid = {42051853},
issn = {2632-1297},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited diagnostic and prognostic biomarkers. The neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, has been proposed as a potential indicator. This systematic review and meta-analysis assesses the diagnostic and prognostic value of NLR in ALS. We searched PubMed, Scopus, Embase and Web of Science through June 2025 for peer-reviewed studies evaluating NLR in adults with ALS diagnosed by established criteria. Eligible studies reported validated measurements of NLR and diagnostic or prognostic outcomes. Two reviewers independently extracted data and assessed quality. Random-effects meta-analyses were performed, with heterogeneity, publication bias, evidence certainty and sources of heterogeneity evaluated using meta-regression. Sixteen studies from 12 countries including 357 044 participants met inclusion criteria, comprising 8710 ALS patients (mean age 60.3 years; 59.1% male) and 348 334 controls (mean age 57.8 years; 47.6% male). Meta-analysis of 11 studies showed a pooled mean NLR of 2.74 in ALS patients [95% CI (2.42, 3.10); I [2] = 95.4%], while three control studies yielded a pooled mean NLR of 1.94 [95% CI (1.55, 2.43); I [2] = 94.7%]. Comparison of three studies demonstrated a 35% higher NLR in ALS patients than controls [95% CI (1.03, 1.76); I [2] = 88.3%], with low certainty according to GRADE due to observational design and substantial heterogeneity. Elevated NLR was consistently associated with worse clinical outcomes, including faster disease progression, lower ALSFRS-r scores, reduced forced vital capacity, shorter survival and increased mortality. Pooled univariate analyses from four studies showed that higher NLR predicted mortality [HR = 1.16; 95% CI (1.04, 1.29); I [2] = 93.8%]. Multivariable-adjusted analyses from six studies confirmed NLR as an independent predictor of poorer survival (HR = 1.13; 95% CI (1.06, 1.21); I [2] = 86.5%), with heterogeneity modestly reduced after adjustment for age and sample size. Certainty of evidence for prognostic outcomes was rated low to moderate. Associations between higher NLR and age at onset, sex and classical ALS phenotype were inconsistent. NLR correlated with inflammatory markers and gut microbiota features, supporting a potential mechanistic link between systemic inflammation and ALS disease progression. Elevated NLR is associated with ALS diagnosis and poorer prognosis, including faster disease progression and reduced survival. Despite heterogeneity and potential bias, NLR appears to be a readily accessible biomarker for disease monitoring and risk stratification in ALS, warranting validation in large, longitudinal studies.},
}

@article {pmid42052844,
year = {2026},
author = {Chen, W and Wang, J and Li, Q and Zhang, L and Wu, X and Luo, S and Xie, Y and Guo, P},
title = {Keap1-Nrf2 Signaling Pathway-Mediated Antioxidant Defense in Neurodegenerative Diseases: Mechanisms and Traditional Chinese Medicine Therapeutic Strategies.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {4},
pages = {45233},
doi = {10.31083/FBL45233},
pmid = {42052844},
issn = {2768-6698},
support = {81660671//National Natural Science Foundation of China/ ; 202101AZ070001-172//Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Chinese Medicine/ ; 202105AG070014//Yunnan Provincial Key Laboratory of Formula Granules/ ; zyzdxk-2023192//High-level Discipline Construction Project of Dai Medicine, National Administration of Traditional Chinese Medicine/ ; 2024SS24045//Yunnan Key Laboratory for Dai and Yi Medicines/ ; },
mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Signal Transduction/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Medicine, Chinese Traditional/methods ; *Antioxidants/metabolism/therapeutic use ; Oxidative Stress/drug effects ; Animals ; Drugs, Chinese Herbal/therapeutic use ; },
abstract = {Neurodegenerative diseases (NDs) are incurable, progressively disabling disorders marked by sustained neuronal degeneration and loss. Their molecular basis involves intricate regulatory networks, while current therapeutic strategies remain inadequate. Oxidative stress (OS) constitutes a major driver in the initiation and progression of age-related pathologies. Kelch-like enoyl-CoA hydratase-associated protein-1 (Keap1)-Nuclear factor Erythroid 2-related factor 2 (Nrf2) signaling pathway, an essential antioxidant system, exerts protective effects by limiting OS-mediated cellular injury. Extensive evidence demonstrates a close association between Nrf2 signaling and the pathological processes of NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Traditional Chinese medicine, characterized by multi-target and multi-pathway regulatory actions of its bioactive constituents, offers distinctive therapeutic potential for NDs. This review provides an integrated analysis of current advances of Nrf2 involvement in NDs and evaluates therapeutic strategies based on traditional Chinese medicine and its active components, with the aim of guiding future clinical translation.},
}

Humans
*NF-E2-Related Factor 2/metabolism
*Signal Transduction/drug effects
*Kelch-Like ECH-Associated Protein 1/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy
*Medicine, Chinese Traditional/methods
*Antioxidants/metabolism/therapeutic use
Oxidative Stress/drug effects
Animals
Drugs, Chinese Herbal/therapeutic use

@article {pmid42054746,
year = {2026},
author = {Biscetti, L and Gambuzza, ME and Princiotto, M and Sabbatinelli, J and Olivieri, F and Fiorillo, M and Chinigò, C and Muglia, L and Cozza, A and Beccacece, A and Gembillo, G and Bruschetta, G and Villalta Savedra, E and Lattanzio, F and Corsonello, A and Soraci, L},
title = {From necroptosis to neuroinflammation: Unraveling mechanisms and therapeutic targets in age-related cognitive decline.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {199},
number = {},
pages = {119326},
doi = {10.1016/j.biopha.2026.119326},
pmid = {42054746},
issn = {1950-6007},
abstract = {Aging is the major risk factor for several chronic conditions, including cognitive decline and dementia. It is accompanied by profound immune alterations characterized by a progressive decline in immune competence, a process known as immunosenescence. The resulting dysregulation of immune function leads to the overproduction of proinflammatory cytokines and fuels a persistent, low-grade inflammatory state termed inflammaging. This chronic inflammation contributes to dysfunction across the central and peripheral nervous systems, promoting neuronal damage and accelerating neurodegenerative processes such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other age-related cognitive disorders. Within this framework, prolonged activation of inflammatory pathways can trigger regulated forms of cell death. Among these, necroptosis has recently emerged as a potential mediator linking inflammaging to neurodegeneration. Its core molecular effectors, including the receptor-interacting protein kinases RIPK1 and RIPK3 and the mixed-lineage kinase domain-like protein (MLKL), are increasingly expressed in aged neural tissues, promoting the release of damage-associated molecular patterns (DAMPs) that amplify glial activation, oxidative stress, and blood-brain barrier disruption. Growing evidence suggests that necroptotic signaling may be upregulated in the aging brain and in neurodegenerative disorders, where it could contribute to neuronal loss and cognitive impairment. This review discusses the potential role of necroptosis in the continuum between inflammation and neurodegeneration, highlighting emerging diagnostic and therapeutic perspectives. Epigenetic and circulating biomarkers, such as phosphorylated MLKL and specific microRNAs, may support early detection, while pharmacological and nutraceutical strategies targeting necroptosis show promising neuroprotective effects in preclinical studies.},
}

@article {pmid42055109,
year = {2026},
author = {Zhu, Y and Zhang, H and Zhang, Z and Song, G and Fu, J and Wang, H},
title = {The role of ultrasound in addressing neurodegenerative diseases: A review of mechanisms, applications, and challenges.},
journal = {Neuroscience},
volume = {606},
number = {},
pages = {126-137},
doi = {10.1016/j.neuroscience.2026.04.024},
pmid = {42055109},
issn = {1873-7544},
abstract = {With the aging of the global population, neurodegenerative diseases have become a major public health challenge. Currently, there are many limitations in the traditional treatment of neurodegenerative diseases, such as medicine, deep brain stimulation, transcranial magnetic stimulation, and transcranial direct current stimulation, including the inability to penetrate the blood-brain barrier (BBB) accurately and challenges in achieving precise and quantitative control during the treatment process. Ultrasound is an emerging neural modulation technology that stands out for its non-invasive nature, precise targeting, and unique ability to penetrate the BBB, demonstrating tremendous application potential. In this review, we summarized the common types of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS), and the limitations of traditional treatments. It delves into the physical principles, classification, mechanisms, and unique advantages of ultrasound therapy in neuromodulation. It provides a detailed account of the current status of application of ultrasound in neurodegenerative diseases, and represents the advantages and challenges currently faced by ultrasound therapy, which offers insights into future research directions and technological improvements.},
}

@article {pmid42046889,
year = {2026},
author = {Martinez-Gonzalez, L and Sanchez-Santos, C and Huang, CS and Gil, C and Martinez, A},
title = {Innovative therapies under clinical development for ALS treatment: Small molecules.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543784.2026.2667249},
pmid = {42046889},
issn = {1744-7658},
abstract = {INTRODUCTION: The clinical trial landscape for Amyotrophic Lateral Sclerosis (ALS) is a rapidly evolving field, characterized by significant obstacles but also by an increasing volume of novel therapeutics entering clinical research. Expanding on our 2022 work, this review examines the current state of the ALS clinical pipeline. Given the high volume of ongoing trials, the diversity of their biological targets and the nature of their therapeutic approaches, we focus this comprehensive update in providing a comprehensive overview of the current state of small-molecule development, focusing on agents that have entered or progressed through clinical evaluation since 2022 to the end of 2025.

AREAS COVERED: Clinical trials for ALS registered within the United States (ClinicalTrials.gov) and European Union (EU Clinical Trials Register/CTIS) databases have been systematically reviewed and are detailed in this report.

EXPERT OPINION: The implementation of advanced clinical trial platforms has introduced more efficient, adaptive strategies, leading to a significant increase in the breadth of explored therapies for ALS. Furthermore, the advent of precision medicine, powered by Artificial Intelligence (AI) for enhanced patient selection and stratification, offers a critical pathway toward overcoming the challenges posed by this severe and heterogeneous disease.},
}

@article {pmid42049092,
year = {2026},
author = {Liu, C and Meng, L and Zhang, Z},
title = {Physiological and pathological functions of TAF15 in neurodegenerative diseases and cancers.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.04.066},
pmid = {42049092},
issn = {2090-1224},
abstract = {BACKGROUND: TATA-box binding protein associated factor 15 (TAF15) is a multifunctional DNA/RNA-binding protein that plays pivotal roles in transcription regulation, precursor mRNA splicing, and cellular stress responses. Accumulating evidence demonstrates that TAF15 is strongly implicated in two distinct pathological classes: neurodegenerative diseases and cancers. In neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), TAF15 undergoes abnormal cytoplasmic aggregation and mislocalization in neurons and glia, and TAF15 has been established as a candidate disease gene for ALS. In a wide range of cancers, TAF15 drives oncogenic transcriptional dysregulation either via wild-type protein dysfunction or the formation of oncogenic fusion proteins derived from chromosomal translocations.

AIM OF REVIEW: A central unresolved question is how TAF15 contributes to two mechanistically distinct disease entities. This review aims to provide a mechanistically integrated analysis of the physiological and pathological functions of TAF15. We use TAF15's intrinsic molecular properties as a unifying framework to connect its roles in neurodegeneration and cancer. We also summarize key pathogenic mechanisms and emerging therapeutic strategies targeting TAF15, with the goal of proposing a novel conceptual perspective to guide future research. Key scientific concepts of review. TAF15 may act as a biologically relevant molecular link between neurodegeneration and cancer through its intrinsic molecular characteristics, such as nucleic acid binding, phase separation, and nucleocytoplasmic shuttling. The "localization determines outcome" hypothesis offers a unifying framework to explain the connection between the two diseases. TAF15 holds promise as a target for novel biomarkers and precision therapeutics across both disease areas. Deepening mechanistic studies of TAF15 will not only advance understanding of its dual pathological roles but also illuminate the largely unexplored molecular link between neurodegenerative diseases and cancers.},
}

@article {pmid42043709,
year = {2026},
author = {Umar, M and Franjieh, K and White, AL and Ward-Dones, E and Ismael, S and Roskey, RC and Courseault, J and Bix, GJ},
title = {Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies.},
journal = {Current nutrition reports},
volume = {15},
number = {1},
pages = {},
pmid = {42043709},
issn = {2161-3311},
abstract = {PURPOSE OF REVIEW: Folate is a key regulator of one-carbon metabolism (OCM), which supports essential physiological processes, including DNA synthesis, repair, methylation, amino acid homeostasis, and redox balance. It is also crucial for brain health throughout life, from neural tube formation during early development to neurotransmitter synthesis, myelination, neuronal development, synaptic plasticity and cognitive function during later stages of life. Disruption of folate-mediated OCM (FOCM) can adversely affect brain health and contribute to neurodegeneration. In this review, we summarize current evidence linking FOCM dysregulation to neurodegenerative diseases, emphasizing disease-specific mechanisms and the therapeutic potential of modulating folate metabolism, as evidenced by experimental and clinical studies.

RECENT FINDINGS: Disruption of FOCM can lead to oxidative stress, impaired methylation, excitotoxicity, and neuroinflammation, thereby contributing to neurodegenerative diseases. In Alzheimer’s disease, impaired FOCM promotes amyloid-β accumulation, tau pathology, cognitive decline, and vascular dysfunction, consistent with low folate and elevated homocysteine observed clinically, though supplementation outcomes remain mixed. In Parkinson’s disease, folate deficiency and hyperhomocysteinemia exacerbate motor deficits and dopaminergic neurodegeneration via oxidative stress, mitochondrial dysfunction, and NLRP3-mediated inflammation and combined folate and vitamin B12 supplementation may reduce levodopa-associated risks. Elevated homocysteine and aberrant FOCM have also been reported in Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Huntington’s disease and are associated with neuroinflammation, demyelination, neuronal loss, and severe disease phenotypes in these conditions.

SUMMARY: Overall, maintaining optimal folate levels may be a promising strategy to support brain health and reduce the risk of neurodegenerative disorders.},
}

@article {pmid42043769,
year = {2026},
author = {Raafat, MA and Al-Hasnaawei, S and Mousa, HM and Hanumanthayya, M and Sahoo, S and Prathiba, S and Singh, G and Sinha, A},
title = {The central role of mitochondrial dysfunction in neurodegeneration: implications for therapy.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {42043769},
issn = {1573-4919},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, remain leading causes of disability and premature death. Although they present with distinct clinical phenotypes, they converge on several pathogenic processes. Among these, mitochondrial dysfunction has emerged as a key driver of neurodegeneration, encompassing impaired bioenergetic capacity, disturbed calcium handling, altered mitochondrial dynamics, insufficient mitophagy, and excessive production of reactive oxygen species (ROS). This review provides a focused synthesis of the ways in which mitochondrial pathology contributes to neurodegeneration across major neurodegenerative disorders and summarizes therapeutic strategies designed to target mitochondria. We outline disease-relevant mitochondrial abnormalities and connect them to neuronal loss, synaptic failure, and neuroinflammatory cascades, with particular attention to mitochondrial ROS and inflammatory signaling linked to mitochondrial DNA. The manuscript further evaluates current and emerging interventions, including mitochondria-targeted antioxidants, mitochondrial transfer/transplantation, exercise, dietary approaches, and nanotechnology-enabled delivery systems. For each strategy, we consider the mechanistic rationale, key preclinical findings, and barriers to translation. Across experimental models, many of these approaches confer measurable neuroprotection-often reflected by lower oxidative burden, stabilization of mitochondrial membrane potential, and partial restoration of ATP production. However, clinical findings have been inconsistent, suggesting that efficacy depends strongly on disease stage, patient heterogeneity, and the specific mitochondrial defect being targeted. By integrating mechanistic insights with therapeutic evidence, this review offers a structured perspective on shared and disease-specific features of mitochondrial dysfunction and highlights priorities for advancing mitochondria-centered interventions toward meaningful clinical benefit.},
}

@article {pmid41979429,
year = {2026},
author = {Patel, J and Eisenberg-Godsey, SR and Tipton, PW},
title = {Exploring the phenotypic spectrum of frontotemporal lobar degeneration.},
journal = {Neurologia i neurochirurgia polska},
volume = {60},
number = {2},
pages = {138-152},
doi = {10.5603/pjnns.109796},
pmid = {41979429},
issn = {0028-3843},
mesh = {Humans ; *Frontotemporal Lobar Degeneration/diagnosis/physiopathology/genetics ; Phenotype ; },
abstract = {Frontotemporal lobar degeneration (FTLD) refers to a spectrum of neuropathology preferentially affecting the frontal and temporal lobes manifesting with progressive behavioral, language, and motor impairment. These clinical symptoms linked to FTLD are collectively referred to as frontotemporal spectrum disorders (FTSD) and include behavioral-variant frontotemporal dementia, nonfluent/agrammatic primary progressive aphasia, semantic variant primary progressive aphasia, right temporal variant frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, and amyotrophic lateral sclerosis-frontotemporal spectrum disorders. While some patients with FTLD present with a single, well-defined syndrome, others exhibit features of multiple syndromes, and clinical phenotypes frequently evolve over time. Moreover, there is substantial phenotypic overlap between FTSD and other neurological disorders, contributing to frequent misdiagnosis and diagnostic delays. To address these challenges, we provide a practical, clinically oriented framework for the diagnosis of FTSD. We review common and nuanced clinical features, pertinent diagnostic testing, and the role of genetic testing in the context of current understanding of neuropathological correlates. Despite the absence of disease-modifying therapies, we also outline evidence-informed strategies for the symptomatic management of FTSD.},
}

Humans
*Frontotemporal Lobar Degeneration/diagnosis/physiopathology/genetics
Phenotype

@article {pmid42035914,
year = {2026},
author = {Li, F and Tao, S and Wang, S and Ren, T and Qiu, M and Xu, X},
title = {New Perspectives on oligodendrocytes: Guardians of iron homeostasis and defenders against ferroptosis.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.04.052},
pmid = {42035914},
issn = {2090-1224},
abstract = {BACKGROUND: Oligodendrocytes (OLs) play a pivotal role in preserving iron homeostasis within the central nervous system (CNS), as they harbor the largest cellular iron reservoir essential for myelination. However, this indispensable function places OLs at heightened risk of ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation. The susceptibility of OLs to ferroptosis has significant implications for CNS health, particularly in the context of neurodegenerative diseases where OL dysfunction exacerbates demyelination and accelerates disease progression.

AIM OF REVIEW: This review aims to systematically elucidate the mechanisms by which mature OLs balance their dual roles as guardians of iron homeostasis and defenders against ferroptosis. Furthermore, it aims to underscore the ramifications of impaired OL iron regulation in prominent neurodegenerative conditions and to investigate potential therapeutic interventions aimed at bolstering OL resilience.

Mature OLs employ a sophisticated, multi-layered defense system to maintain iron homeostasis and prevent ferroptosis, encompassing precise metabolic regulation of iron uptake and storage, alongside a specialized antioxidant network centered on selenoprotein synthesis. Disruption of this delicate balance renders OLs vulnerable in diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD), leading to a vicious cycle of OL death, iron dysregulation, and demyelination. Targeting OL iron homeostasis and anti-ferroptotic pathways through iron modulation, antioxidant reinforcement, or direct ferroptosis inhibition represents a promising strategy to promote remyelination and mitigating neurodegeneration.},
}

@article {pmid42038869,
year = {2025},
author = {Behroozinia, M and Khosrawi, S},
title = {Rehabilitation Interventions in Adults with Amyotrophic Lateral Sclerosis: A Review :.},
journal = {Galen medical journal},
volume = {14},
number = {},
pages = {e3708},
pmid = {42038869},
issn = {2322-2379},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common and rapidly devastating neurodegenerative disease, which causes impairment of motor neurons in the upper and lower limbs, as well as in the bulbar muscles among adults. This leads to progressive weakness of voluntary muscles. The median survival after the emergence of initial symptoms is typically three years. During this period, due to the worsening of general well-being and independence, patients and their caregivers experience significant emotional stress. Furthermore, there is currently no definitive treatment for ALS. Consequently, patients face various challenges associated with motor impairment, including mobility disturbances, respiratory dysfunction, speech difficulties, and limitations in activities of daily living. Therefore, rehabilitation plays a vital role as a component of multidisciplinary care for managing these issues and reducing the impact of the disease on patients and their families. It is considered the optimal choice for alleviating the discomfort of ALS patients until a curative treatment is discovered.This narrative review aims to provide an overview of different aspects of rehabilitation, including physical therapy, occupational therapy, speech therapy, and respiratory strategies focused on enhancing independence, functional abilities, and overall quality of life while minimizing disabilities and complications in patients coping with this debilitating condition.},
}

@article {pmid42040397,
year = {2026},
author = {Maia, ME and Carvalho, M and Sousa Gomes, C and Arruda, M and Antunes de Magalhães, AJ and Farias, D},
title = {Plant-Derived Peptides with Neuroprotective Activity: Advances and Perspectives in the Prevention of Neurodegenerative Diseases.},
journal = {ACS omega},
volume = {11},
number = {15},
pages = {22458-22478},
pmid = {42040397},
issn = {2470-1343},
abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, represent an increasing global public health challenge, driven by population aging and the lack of effective curative therapies. In this context, plant-derived peptides have emerged as promising bioactive compounds due to their multitarget neuroprotective properties and favorable safety profiles. This review provides a comprehensive overview of plant peptides with reported activity against neurodegeneration, highlighting their natural sources, biological activities, and mechanisms of action. Evidence from in vitro and in vivo models indicates that these peptides act through multiple complementary pathways, including attenuation of oxidative stress, modulation of neuroinflammation, regulation of apoptosis, preservation of mitochondrial function, and inhibition of toxic protein aggregation. Additionally, several peptides have been shown to enhance synaptic plasticity, modulate neurotransmission, and regulate ion channel activity, suggesting beneficial effects on neuronal communication and cognitive function. Some studies explored structural modifications, such as the introduction of specific residues or glycosylation, which have resulted in greater stability and enhanced efficacy against oxidative insults. Overall, plant-derived peptides demonstrate consistent neuroprotective effects and low toxicity; however, challenges related to the blood-brain barrier, bioavailability, and the understanding of molecular mechanisms must still be overcome to enable their clinical application.},
}

@article {pmid42041525,
year = {2026},
author = {Bertoni, G and Ristori, S and Monti, D},
title = {Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
pmid = {42041525},
issn = {2073-4409},
support = {DM 1557 11.10.2022//Next Generation EU/ ; },
mesh = {Humans ; *Immunosenescence/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; *Inflammation/immunology/pathology ; Animals ; *Aging/immunology ; *Neuroimmunomodulation ; },
abstract = {Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.},
}

Humans
*Immunosenescence/immunology
*Neurodegenerative Diseases/immunology/pathology/therapy
*Inflammation/immunology/pathology
Animals
*Aging/immunology
*Neuroimmunomodulation

@article {pmid42041816,
year = {2026},
author = {Kleinerova, J and Tully, J and Lope, J and Tan, EL and Toomey, A and Siah, WF and Bede, P},
title = {Driving with Motor Neuron Disease: Disease-Specific Considerations, Multi-Domain Assessments and Support Strategies.},
journal = {Brain sciences},
volume = {16},
number = {4},
pages = {},
pmid = {42041816},
issn = {2076-3425},
support = {HRB JPND-Cofund-2025-3/HRBI_/Health Research Board/Ireland ; JPND - 2025 "Qual-Bulb-MND"//EU Joint Programme - Neurodegenerative Disease Research/ ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; },
abstract = {Motor neuron diseases (MNDs) encompass a clinically heterogeneous group of neurodegenerative conditions with varying impact on dexterity, mobility, decision making, respiratory and bulbar dysfunction. While consensus best-practice recommendations exist for genetic screening, diagnostic work-up, pharmacological and respiratory management, disease-specific facets of driving safety, assessment approaches and intervention strategies to support patients for safe driving have not been comprehensively reviewed. MNDs have unique, phenotype-specific clinical features, which are distinct form other neuromuscular conditions which necessitate a careful and systematic approach to evaluate driving safety. While MNDs are primarily associated with progressive motor impairment, extrapyramidal, cerebellar, cognitive, behavioural, and respiratory manifestations of the disease also affect driving safety and necessitate comprehensive driving assessments and individualised strategies to enable patients to continue to drive. The majority of existing papers focus on amyotrophic lateral sclerosis, and low-incidence MND phenotypes, such as PLS, SBMA, PPS, are glaringly understudied from a driving safety perspective despite the relatively slower progression of these conditions. Beyond the review of specific aspects of driving in MNDs, the main objective of this review paper is to raise awareness of non-motor aspects of MNDs with regard to driving safety and to explore viable strategies to support patients to maintain their independence. Despite the considerable differences in driving regulations around the globe, there are core, disease-specific aspects of MND which are universal. The careful consideration of these clinical factors, comprehensive domain-by-domain assessments, and the implementation of practical, individualised adaptations may enable patients to continue driving safely, maintain their independence and enhance their quality of life.},
}

@article {pmid42042751,
year = {2026},
author = {Aguilera-Méndez, A and Aguilera-Manuel, K and Saavedra-Molina, A and Ríos-Chávez, P and Villafaña, S and Nieto-Aguilar, R and Godínez-Hernández, D and Ortega-Cuellar, D and Palomera-Sanchez, Z and Gauthereau-Torres, M},
title = {Alpha-Lipoic Acid and Biotin in Neurodegenerative Diseases: Convergent Mechanistic Insights from Preclinical Models to Clinical Perspectives.},
journal = {Neurology international},
volume = {18},
number = {4},
pages = {},
pmid = {42042751},
issn = {2035-8385},
support = {CIC-19443//CIC-UMSNH/ ; },
abstract = {BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, represent a major global health burden and share convergent pathogenic mechanisms, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, calcium imbalance, and neuronal loss. Despite advances in symptomatic management, effective disease-modifying therapies remain limited.

OBJECTIVES: This review aims to critically synthesize mechanistic, preclinical, and clinical evidence on α-lipoic acid and biotin as candidate neuroprotective agents in neurodegenerative diseases, with emphasis on shared signaling pathways, therapeutic potential, generally favorable safety profiles, and translational limitations.

METHODS: A narrative and integrative review was conducted, encompassing mechanistic studies, preclinical experimental models, and clinical trials and observational studies evaluating ALA and biotin in neurodegenerative diseases. The evidence was qualitatively analyzed with attention to biological plausibility, consistency across models, and clinical relevance.

RESULTS: ALA and biotin modulate key cellular pathways implicated in neurodegeneration, including mitochondrial metabolism, redox homeostasis, inflammatory signaling, and neurovascular function. Preclinical studies consistently report beneficial effects on mitochondrial efficiency, oxidative stress, and neuroinflammatory markers. In contrast, clinical evidence remains heterogeneous, with more extensive evaluation of biotin in progressive multiple sclerosis and more limited or exploratory findings for ALA across neurodegenerative disorders.

CONCLUSIONS: ALA and biotin exhibit mechanistic convergence across pathways relevant to neurodegeneration and generally favorable safety profiles. Although current evidence supports their biological plausibility as adjunctive or exploratory therapeutic strategies, clinical outcomes remain inconsistent and appear to be influenced by dosing regimens, disease stage at intervention, and endpoint selection. Well-designed clinical studies are required to define their efficacy, optimal dosing, and disease-specific applicability.},
}

@article {pmid42043421,
year = {2026},
author = {Cheng, T and Li, M and Yang, Y and Rao, Z and Yang, W},
title = {Glycolysis as a central pathological axis in neurodegenerative diseases.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42043421},
issn = {2191-0200},
abstract = {Glycolysis is increasingly recognized as a pathological backbone in neurodegenerative diseases rather than merely an accompanying epiphenomenon. This article first delineates the division of metabolic labor among neurons, astrocytes, microglia, and oligodendrocytes in the brain, with particular emphasis on cell type-specific glycolytic flux, lactate shuttling, and an integrated brain-periphery framework of energy metabolism. It then systematically compares alterations in glucose uptake, glycolytic intermediates, and lactate metabolism across Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Wilson disease (WD), Huntington's disease (HD), and multiple sclerosis (MS), highlighting pronounced heterogeneity across cell types, disease stages, and brain regions. These metabolic disturbances encompass not only global cerebral hypometabolism and an energy crisis, but also compensatory hyperglycolysis and inflammation-associated metabolic reprogramming in astrocytes and microglia, and extend further to systemic metabolic phenotypes involving peripheral blood cells, muscle, and liver. The article summarizes recent methodological advances for characterizing glycolytic reprogramming, including fluorodeoxyglucose positron emission tomography (FDG-PET), hyperpolarized carbon-13 magnetic resonance spectroscopy(ˆ13C-MRS), metabolomics, single-cell and spatial transcriptomics, genetically encoded metabolic sensors, and Seahorse assays. In addition, potential therapeutic strategies are discussed, focusing on targets such as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3), the astrocyte-neuron lactate shuttle (ANLS), microglial glycolysis and lactylation, as well as systemic metabolic modulation and nanodelivery approaches. Finally, key challenges are highlighted, including unclear causal relationships, biphasic and cell type-specific effects, insufficient brain-periphery integration, and the lack of standardized metrics, underscoring the need for longitudinal, multimodal, and stage-specific strategies to reposition glycolysis as a targetable therapeutic dimension in neurodegenerative diseases.},
}

@article {pmid42033202,
year = {2026},
author = {Yusuf, S and Allen, MD and Kang, H and Phillips, DE and Genge, A},
title = {Opportunities and challenges related to participant stratification and cohort enrichment in ALS clinical trials.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2659128},
pmid = {42033202},
issn = {2167-9223},
abstract = {Amyotrophic lateral sclerosis (ALS) is marked by substantial clinical heterogeneity. This heterogeneity has impacted clinical trials by obscuring treatment effects and causing inefficiency. In this review, we summarize potential approaches for addressing heterogeneity in ALS via patient stratification and cohort enrichment methods and highlight potential challenges and limitations. These categories include stratification based on genetics, clinical characteristics (e.g. pattern of weakness, ALS Functional Rating Scale rates of progression), wet biomarkers (e.g. neurofilament light chain), neuroimaging, and novel methods employing statistical modeling or machine learning. These stratification methods have yet to be fully leveraged in clinical trial design. But these strategies must be employed thoughtfully and judiciously due to potential issues stratification can introduce. Future clinical trials should explore how participant stratification and cohort enrichment strategies may improve our ability to identify treatment effects, which may ultimately aid in the quest to establish more personalized medicine for persons with ALS.},
}

@article {pmid42033865,
year = {2026},
author = {Wang, F},
title = {Polyphenols and physical activity stimulate gut microbiota mediated Nrf2 signaling to combat neurodegeneration.},
journal = {Pathology, research and practice},
volume = {283},
number = {},
pages = {156478},
doi = {10.1016/j.prp.2026.156478},
pmid = {42033865},
issn = {1618-0631},
abstract = {Polyphenols and regular physical activity are increasingly recognized as complementary lifestyle interventions that influence the gut-brain axis and contribute to neuroprotection. Emerging evidence highlights the central role of the gut microbiota in mediating these effects by transforming dietary and host-derived substrates into bioactive metabolites. These metabolites can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a key regulator of cellular antioxidant defenses, mitochondrial function, and anti-inflammatory responses processes that are critically impaired in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review synthesizes current mechanistic insights into how polyphenol-derived metabolites and exercise-induced alterations in gut microbial composition converge to modulate Nrf2 signaling. We discuss the roles of key microbiota-derived metabolites, including short-chain fatty acids, urolithins, and indole derivatives, in regulating oxidative stress, neuroinflammation, and synaptic function. Furthermore, we examine evidence from preclinical models supporting the synergistic effects of dietary polyphenols and physical activity on gut microbiota-mediated neuroprotection. Finally, we address translational challenges and highlight the potential of integrating dietary and exercise-based strategies to harness microbiota-dependent Nrf2 activation. This integrative framework provides a basis for developing personalized, microbiome-informed interventions aimed at delaying or mitigating neurodegeneration.},
}

@article {pmid42021677,
year = {2026},
author = {Mukhija, S and Lehner, F and Jung, HH},
title = {[Amyotrophic lateral sclerosis (ALS): current perspectives and the Swiss ALS Registry].},
journal = {Praxis},
volume = {115},
number = {4},
pages = {100-106},
doi = {10.23785/PRAXIS.2026.04.003},
pmid = {42021677},
issn = {1661-8157},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/epidemiology ; *Registries ; Switzerland ; Disease Progression ; Risk Factors ; Riluzole/therapeutic use ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease leading to muscle weakness, atrophy, and ultimately death. In addition to mutations in ALS-related genes, environmental and lifestyle factors may increase disease risk. Diagnosis is based on clinical evaluation, supplemented by electroneuromyography, imaging, and molecular genetic testing. No curative therapy exists, but Riluzole and Edaravone can slow progression, and genetic therapies offer promising perspectives in certain genetically determined forms. In practice, diagnosis is often delayed. The Swiss ALS Registry collects comprehensive data on environmental, lifestyle, clinical, genetic, and biomarker factors, aiming to improve understanding of risk, disease progression, and therapeutic approaches.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/epidemiology
*Registries
Switzerland
Disease Progression
Risk Factors
Riluzole/therapeutic use

@article {pmid42023099,
year = {2026},
author = {Galluzzi, G and Ruocco, G and Fornetti, E and Genovese, I},
title = {Modeling ALS in a dish: how organoids are transforming research.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1792336},
pmid = {42023099},
issn = {2296-858X},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. The multifactorial etiology of ALS, encompassing genetic mutations, protein aggregation, oxidative stress, excitotoxicity, and dysregulated RNA metabolism, has hindered the development of effective therapies. Traditional animal and 2D cell models have provided important mechanistic insights but often fail to fully capture the human-specific and multicellular aspects of disease pathophysiology. Recent advances in induced pluripotent stem cell (iPSC)-derived organoids offer a promising human-based platform for ALS research, enabling the generation of disease-relevant neural and neuromuscular subtypes in three-dimensional architectures. These models recapitulate key pathological features, including protein mis-localization, neuromuscular junction defects, synaptic impairments, and glial contributions to motor neuron degeneration, while also serving as platforms for drug screening and mechanistic studies. Importantly, spinal and neuromuscular organoids bridge the gap between simplified in vitro systems and the complex human nervous system, providing a unique framework to study ALS pathogenesis. This review provides a comprehensive overview of the various differentiation protocols, experimental strategies and key results obtained to date, with a primary focus on validating and benchmarking organoid models, while also highlighting their limitations, emerging clinical applications, translational potential, and opportunities for personalized therapeutic discovery.},
}

@article {pmid42024796,
year = {2026},
author = {Mei, J and Xia, M and Peng, L and Li, X},
title = {Alcohol and neurodegenerative diseases: a review of mechanistic insights and disease specific effects.},
journal = {The American journal of drug and alcohol abuse},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/00952990.2026.2645215},
pmid = {42024796},
issn = {1097-9891},
abstract = {Background: Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) represent a significant global public health problem. Alcohol consumption is a common lifestyle factor that has been implicated as both a risk factor and potential modifier of disease progression.Objectives: This review integrates evidence from human and experimental studies to characterize the effects of alcohol consumption on the onset and progression of major neurodegenerative diseases.Methods: A narrative review was undertaken examining the pathophysiological effects of alcohol on the brain and its disease-specific effects on neurodegenerative disorders, integrating findings from human cohort studies and mechanistic investigations in preclinical models.Results: Experimental evidence indicates that chronic alcohol consumption exacerbates neurodegeneration through multiple converging mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, inflammatory signaling, disruption of neurotrophic pathways, impairment of dopaminergic neurotransmission, and alcohol-induced gut microbiota dysbiosis with blood-brain barrier compromise. Epidemiological data suggest dose-dependent and disease-specific associations, with heavy and sustained consumption more consistently linked to increased risk or accelerated progression of AD and PD, while evidence in ALS and HD remains inconsistent.Conclusion: Alcohol exerts a multifaceted and context-dependent influence on neurodegenerative diseases. Accumulating evidence supports that long-term heavy alcohol consumption is associated with enhanced neurodegeneration. Minimizing alcohol consumption may present a pragmatic opportunity to reduce neurodegenerative risk.},
}

@article {pmid42026661,
year = {2026},
author = {Kuppens, A and Rogister, B and Neirinckx, V},
title = {Pharmacological modulation of CXCL12/CXCR4/ACKR3 for brain disorders - an overview.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02877-1},
pmid = {42026661},
issn = {1478-811X},
support = {7.6518.24//Fonds De La Recherche Scientifique - FNRS/ ; },
}

@article {pmid42027094,
year = {2026},
author = {McElvaney, R and Starrs, B},
title = {Adolescents' Positive Experiences of Psychotherapy Following Sexual Abuse: A Systematic Review.},
journal = {Trauma, violence & abuse},
volume = {},
number = {},
pages = {15248380261437090},
doi = {10.1177/15248380261437090},
pmid = {42027094},
issn = {1552-8324},
abstract = {While a small body of work focuses directly on young people's experiences of psychotherapy following sexual abuse, to our knowledge, there are no existing reviews of this literature. This systematic review was conducted using Siddaway et al.'s guidelines. Inclusion criteria were: published between 2000 and 2022; used qualitative methodologies; and captured adolescents' perspectives. Eleven studies were identified, representing an aggregated sample size of 72 young people aged 12 to 18. Methodologies used included thematic analysis, content analysis, conversation analysis, and narrative analysis. A total of 9 of the 11 studies addressed experiences of individual therapy using semi-structured interviews; 2 studies explored experiences of group therapy through focus groups. The review identified three key processes that reflect adolescents' experiences: engagement, ambivalence to trust; painful processing: exercising agency; and integrating: taking responsibility. Young people struggled to engage in therapy, and it took time to build trust; they experienced improvements in mood and general well-being, facilitated by psychoeducation, talking about the abuse, experiencing difficult emotions, and learning coping skills. They described integrating their abuse experience into their life story, discovering their inner strength and resilience. The therapeutic experience was underpinned by two key support processes: the therapeutic relationship and a supportive environment outside of therapy. This review supports the components of trauma-focused therapy alongside personalizing psychotherapy to the needs of adolescents for agency and autonomy.},
}

@article {pmid42030003,
year = {2026},
author = {Arslan, HN and Bozkul, G and Çelik, SŞ},
title = {Emotional, Ethical and Cultural Challenges in Percutaneous Endoscopic Gastrostomy (PEG) Decision-Making: A Systematic Review and Meta-Synthesis.},
journal = {Health expectations : an international journal of public participation in health care and health policy},
volume = {29},
number = {2},
pages = {e70294},
pmid = {42030003},
issn = {1369-7625},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Humans ; *Gastrostomy/ethics/psychology/methods ; *Decision Making/ethics ; *Emotions ; Qualitative Research ; Caregivers/psychology ; },
abstract = {BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is a critical intervention for patients with neurological and gastrointestinal conditions affecting oral intake. While clinical guidelines emphasise medical indications, they often overlook the intricate emotional, ethical and cultural concerns that shape decision-making. This gap in understanding leads to variability in clinical recommendations and uncertainty among patients and their families. A deeper exploration of these factors is necessary to support informed, patient-centred decision-making.

AIM: This systematic review and meta-synthesis aimed to explore the emotional, ethical and cultural challenges influencing PEG decision-making, while also considering the broader context of shared decision-making.

DESIGN: A systematic review and meta-synthesis of qualitative studies.

METHODS: The review was conducted by systematically searching six databases, including CINAHL, Scopus, Web of Science, MEDLINE, PubMed and TRDizin. Only qualitative studies published between 2004 and 2024 were included to capture subjective experiences related to PEG decision-making. Studies focusing only on clinical outcomes or utilising quantitative methodologies were excluded. The review considered perspectives from adult patients, family members, caregivers and healthcare professionals while paediatric studies were excluded due to differences in decision-making dynamics. Data were synthesised using thematic analysis to organise findings into main themes and sub-themes.

RESULTS: A total of 15 studies representing a variety of clinical settings and patient conditions, such as amyotrophic lateral sclerosis, advanced dementia and stroke, were included. These studies involved 141 patients (41.1%), 62 caregivers (18.1%) and 140 healthcare professionals (40.8%), ensuring a comprehensive analysis of perspectives on PEG decision-making. Seven major themes were identified: (1) emotional and psychological impact of decision-making, (2) ethical and moral considerations both patients and caregivers, (3) communication challenges and information gaps, (4) impact of healthcare professionals on decision-making, (5) ethical and emotional challenges in decision-making, (6) communication barriers and conflicting advice and (7) professional responsibility and advocacy. Family members and caregivers reported feelings of anxiety, guilt and regret, often due to uncertainty and inadequate communication. Healthcare professionals also faced challenges, including conflicting messages and a lack of comprehensive information.

CONCLUSION: Emotional, ethical and cultural factors significantly impact the PEG decision-making process involving patients, caregivers and healthcare professionals. Improving healthcare professionals' communication skills, developing decision aids and encouraging interdisciplinary collaboration are crucial for supporting informed and shared decision-making.

IMPLICATIONS FOR NURSING: Nurses play a central role in the PEG decision-making process, as they are the healthcare professionals with the most frequent and direct contact with patients and their family support networks. Addressing the gaps in communication and emotional support can help improve the quality of care provided to patients undergoing PEG. Implementing structured emotional support programmes, integrating psychological counselling into routine care and training healthcare professionals in empathetic communication strategies can significantly reduce patient and caregiver distress. Beyond providing clinical care, nurses act as essential advocates, educators and emotional support providers, ensuring that patients and families receive clear, consistent and compassionate guidance throughout the decision-making process. Their involvement in interdisciplinary collaboration and shared decision-making frameworks is crucial for aligning PEG decisions with patient values and preferences.

This review synthesised findings from studies capturing the experiences of patients, families, caregivers and healthcare professionals involved in PEG decision-making, ensuring their perspectives were represented.},
}

Humans
*Gastrostomy/ethics/psychology/methods
*Decision Making/ethics
*Emotions
Qualitative Research
Caregivers/psychology

@article {pmid42031063,
year = {2026},
author = {Shi, C and Jia, K and Guo, Y and Qian, S and Wang, B and Qiu, Y and Dan, L and Dang, Z and Xue, K and Gao, F and Zhao, L},
title = {Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116242},
doi = {10.1016/j.bbr.2026.116242},
pmid = {42031063},
issn = {1872-7549},
abstract = {Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress and cytoskeletal collapse under conditions of impaired reducing capacity. Neurodegenerative diseases (NDs), including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by oxidative stress, mitochondrial dysfunction, metabolic impairment, protein aggregation, and cytoskeletal instability-features that may provide a permissive intracellular context for disulfidptosis. However, its occurrence and pathological relevance in these disorders remain incompletely understood. In this review, we examine the potential involvement of disulfidptosis in neurodegenerative diseases from a disease-centered perspective. We emphasize that current evidence is largely indirect and based on mechanistic overlap rather than direct experimental validation in neural systems. Accordingly, we distinguish between direct evidence, indirect mechanistic support, and pathophysiological plausibility. We further discuss cell-type-specific susceptibility across neurons and glial cells, analyze its relationship with other cell death pathways, and consider potential therapeutic implications. Overall, disulfidptosis is best regarded as a context-dependent and emerging mechanism that may contribute to neuronal vulnerability under specific metabolic and redox constraints. Clarifying its disease relevance will be essential for determining its significance in neurodegeneration and its potential as a therapeutic target.},
}

@article {pmid42009215,
year = {2026},
author = {Nassar, JE and Knebel, A and Ammar, LA and Singh, M and Kuris, EO and Diebo, BG and Daniels, AH},
title = {Differentiating Neurologic Disorders from Spinal Conditions: Evidenced-Based History and Physical Examination Clues for the Orthopedic Clinic.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2026.04.017},
pmid = {42009215},
issn = {1555-7162},
abstract = {This narrative review highlights neurologic disorders that mimic or worsen degenerative spine disease and provides key clinical clues for recognition in spine surgery practice. A focused review examined amyotrophic lateral sclerosis, normal pressure hydrocephalus, multiple sclerosis, Parkinson's disease, Guillain-Barré syndrome, peripheral neuropathies, and transverse myelitis. These conditions frequently overlap with structural spinal pathology through motor, sensory, and gait disturbances. Amyotrophic lateral sclerosis presents with combined upper and lower motor neuron signs. Normal pressure hydrocephalus is characterized by gait impairment, urinary incontinence, and cognitive decline. Multiple sclerosis often causes relapsing multifocal deficits that do not localize to a single spinal level. Parkinson's disease is identified by bradykinesia, rigidity, tremor, and progressive postural deformity. Other mimics including Guillain-Barré syndrome, small and large fiber neuropathies, and transverse myelitis further complicate evaluation. Careful history and neurologic examination remain central, while disease-specific tools such as the 2017 McDonald criteria and the Dubousset Functional Test improve recognition. Early identification is essential to avoid unnecessary surgery, guide multidisciplinary referral, improve risk stratification, and optimize patient outcomes.},
}

@article {pmid42013476,
year = {2026},
author = {El-Agamy, SE and Mattedi, F and Fratta, P},
title = {Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics.},
journal = {Annual review of genomics and human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-genom-022024-011307},
pmid = {42013476},
issn = {1545-293X},
abstract = {TDP-43 is an RNA-binding protein that regulates multiple aspects of RNA processing, and its mislocalization from the nucleus to the cytoplasm is a defining feature of amyotrophic lateral sclerosis (ALS). While both loss- and gain-of-function mechanisms contribute to disease, the discovery of cryptic splicing has shed light on the downstream consequences of TDP-43 nuclear clearance for neuronal health. Here, we highlight how loss of nuclear TDP-43 can drive a cascade of events that lead to the impairment of cellular proteostasis and result in a positive feedback loop that perpetuates neuronal dysfunction. This sustains the appearance of cryptic splicing events in genes that are involved in key pathways for the maintenance of axonal homeostasis and synaptic transmission. In contrast to their detrimental effects on neuronal health, cryptic splicing mechanisms may be harnessed to develop novel therapeutic strategies, unprecedentedly expanding the availability of therapeutic avenues for TDP-43 proteinopathies.},
}

@article {pmid42003855,
year = {2026},
author = {Casey, M and Coghlan, D and Carroll, Á and Buckley, T and Stokes, D},
title = {Assessing Quality of Action Research Using the Quality Assessment Action Research Checklist (QuARC): A Hybrid Systematic Narrative Review.},
journal = {Journal of advanced nursing},
volume = {},
number = {},
pages = {},
doi = {10.1111/jan.70607},
pmid = {42003855},
issn = {1365-2648},
abstract = {AIM: To evaluate the quality of action research studies using the Quality Assessment Action Research Checklist (QuARC) and to assess its utility as a tool for quality appraisal.

DESIGN: A hybrid systematic narrative review following Turnbull et al.'s six-stage methodology and reported in accordance with PRISMA 2020 guidance.

DATA SOURCES: Scopus was searched for author self-identified action research studies published between January 2020 and March 2024.

REVIEW METHODS: Two reviewers independently selected studies meeting inclusion criteria: health science action research papers addressing any or all of QuARC's four quality factors. A scoring system was used to capture each of QuARC's 17 quality items, which was scored as 0 (absent), 0.5 (partial) or 1 (comprehensive). Narrative synthesis was undertaken across the four QuARC domains.

RESULTS: Thirty-two studies met the inclusion criteria. Reporting frequencies across QuARC were: Context (92.5%, mean = 3.7/4), Quality of Relationships (55% mean = 2.2/4), Quality of Action Research Process (62.5% mean = 2.5/4), and Quality of Outcomes (62.5% mean = 3.1/5). Reporting gaps were most evident in reflexive co-analysis, relational evaluation and explicit theoretical contribution.

CONCLUSION: Global reporting of rigour and quality in action research remains inconsistent. QuARC functioned both as an appraisal instrument and as an analytic lens, revealing systematic patterns in how action research privileges practical change over theoretical articulation and reflexive relational work. Further refinement and validation are recommended to strengthen its reliability as an appraisal tool.

IMPLICATIONS: Findings highlighted a critical need to establish a standardised, validated approach to assess quality in action research. Adoption of QuARC can enhance consistency, clarity and comparability across studies, strengthening the evidence base for action research methodologies.

IMPACT: This first systematic synthesis of QuARC's application provides an evidence base for its further development. This lays foundations for international standards in quality appraisal, strengthening the credibility, reproducibility and influence of action research.},
}

@article {pmid41398098,
year = {2026},
author = {Pieper, AA and Paul, BD},
title = {Hydrogen Sulfide Signaling in Neurodegenerative Movement Disorders.},
journal = {Handbook of experimental pharmacology},
volume = {292},
number = {},
pages = {65-93},
pmid = {41398098},
issn = {0171-2004},
support = {R01 AG071512/AG/NIA NIH HHS/United States ; R21 AG073684/AG/NIA NIH HHS/United States ; },
mesh = {*Hydrogen Sulfide/metabolism ; Humans ; *Signal Transduction ; Animals ; *Neurodegenerative Diseases/metabolism/physiopathology/drug therapy ; Brain/metabolism/physiopathology ; *Movement Disorders/metabolism ; Gasotransmitters/metabolism ; },
abstract = {Hydrogen sulfide (H2S) is a gaseous signaling molecule, also known as a gasotransmitter, present in nearly all mammalian organs. It plays crucial roles in regulating various physiological processes in both the brain and peripheral systems. The body maintains tight control over H2S levels, as both excessive and deficient levels can disrupt normal physiological functions and lead to disease. H2S has a significant impact on cognitive and motor functions, which are often compromised in neurodegenerative disorders. It modulates signaling and metabolism primarily by post-translationally modifying reactive cysteine residues on proteins through sulfhydration, also known as persulfidation. This chapter reviews the signaling mechanisms regulated by H2S in neurodegenerative diseases that significantly affect motor function, specifically focusing on Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), and Leigh syndrome (LS), as well as other mitochondrial disorders. While PD, HD, and SCA are linked to decreased levels of H2S, elevated levels of H2S are associated with ALS, DS, and LS. We also explore potential therapeutic applications of modulating H2S levels in the brain.},
}

*Hydrogen Sulfide/metabolism
Humans
*Signal Transduction
Animals
*Neurodegenerative Diseases/metabolism/physiopathology/drug therapy
Brain/metabolism/physiopathology
*Movement Disorders/metabolism
Gasotransmitters/metabolism

@article {pmid41994333,
year = {2026},
author = {Stein, DN and Gendelman, HE},
title = {CAR Treg therapies for neurodegenerative diseases.},
journal = {iScience},
volume = {29},
number = {3},
pages = {114988},
pmid = {41994333},
issn = {2589-0042},
abstract = {Regulatory T cells (Tregs) promote immune tolerance by recognizing non-foreign self-antigens. Consequently, Tregs suppress chronic immune responses and prevent autoimmunity. Chimeric antigen receptor Tregs (CAR Tregs) enhance Treg responses by genetic modification for cell-specific targeting. This can lead to effective treatments for autoimmune diseases, transplant rejection, and graft-versus-host disease. An extension of CAR Tregs involves their potential ability to regulate immune responses to misfolded and aggregated proteins, which drive neurodegenerative diseases. These protein aggregates can trigger immune responses that lead to neural injury. Early preclinical and translational strategies suggest CAR Treg therapies can treat Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In each case, a Treg-based approach transforms a neurotoxic, inflammatory environment through neurotrophic responses. By doing so, CAR Tregs may restore brain balance and slow disease progression. This review highlights ongoing efforts to develop CAR Treg strategies as potential therapies for neurodegenerative disorders.},
}

@article {pmid41996987,
year = {2026},
author = {Priya, R and Tanti, GK and Jain, BP},
title = {Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.},
journal = {Biochemical and biophysical research communications},
volume = {818},
number = {},
pages = {153723},
doi = {10.1016/j.bbrc.2026.153723},
pmid = {41996987},
issn = {1090-2104},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron loss, leading to muscle weakness, paralysis, and respiratory failure. Dysregulation of RNA metabolism and splicing has emerged as a central mechanism in ALS pathogenesis. TARDBP (TAR DNA-binding protein), FET family proteins (FUS, EWSR1, TAF15), SOD1 (Superoxide Dismutase 1), and C9orf72 (Chromosome 9 Open Reading Frame 72) are key genes associated with ALS that regulate RNA processing, alternative splicing, and nuclear-cytoplasmic transport. Mutations or mislocalization of these proteins result in nuclear loss-of-function and cytoplasmic gain-of-function toxicity, promoting protein aggregation, sequestering spliceosomal components, and impairing spliceosome assembly. This leads to the aberrant inclusion of cryptic exons in essential neuronal genes, such as STMN2 (Stathmin 2) and UNC13A (Unc-13 Homolog A), resulting in the production of truncated proteins, defective axonal maintenance, and impaired synaptic function. TDP-43 pathology, a hallmark of ALS, disrupts splicing and RNA transport, while C9orf72 repeat expansions and FET protein mutations exacerbate cytoplasmic aggregation and stress granule dynamics. Mutant SOD1 contributes via mitochondrial dysfunction, endoplasmic reticulum stress, and disrupted axonal transport. Therapeutic strategies targeting these mechanisms are advancing rapidly. Gene replacement therapy, which restores STMN2 expression, and antisense oligonucleotides (ASOs) targeting mutant transcripts show promise in preclinical and early clinical studies. Complementary approaches, including the inhibition of stress kinases and the activation of autophagy, reduce cytoplasmic protein aggregation and support neuronal homeostasis. This review provides a comprehensive overview of RNA splicing regulation, spliceosomal dysfunction, and cryptic exon incorporation in ALS. Understanding the interplay among splicing defects, RNA-binding protein pathology, and neuronal degeneration is critical for developing next-generation multimodal therapies to restore RNA processing, reduce toxic protein accumulation, and promote motor neuron survival.},
}

@article {pmid41998853,
year = {2026},
author = {Qian, W and Zhu, D and Yang, S},
title = {Spray Coating of Thick Perovskite Films for Photodetectors: The Aerosol-Liquid-Solid Mechanisms and Sensing Applications.},
journal = {Chemical record (New York, N.Y.)},
volume = {},
number = {},
pages = {e202500358},
doi = {10.1002/tcr.202500358},
pmid = {41998853},
issn = {1528-0691},
support = {22261160370//National Natural Science Foundation of China/ ; U2001217//National Natural Science Foundation of China/ ; 22579004//National Natural Science Foundation of China/ ; 12505294//National Natural Science Foundation of China/ ; 2508085QA021//Natural Science Foundation of Anhui Province/ ; KQTD2016053015544057//Shenzhen Peacock Plan/ ; SYSRD20250529113001002//Shenzhen Key Lab of Glass-based Optoelectronic Thin Film Materials/ ; //Shenzhen Bay Lab Concept Validation Fund/ ; },
abstract = {Spray coating has emerged as a transformative technique for fabricating high-quality perovskite thick films, which are essential for advanced photodetectors such as X-ray and narrowband sensors. This review surveys and systematically elucidates the physicochemical mechanisms underlying the aerosol-liquid-solid (ALS) transformation during spray deposition, focusing on three core stages: aerosol generation (via pneumatic, electrospray, or ultrasonic methods), droplet deposition and wetting dynamics, and liquid-to-solid crystallization. The interplay among precursor properties, spray parameters, and substrate characteristics dictates film morphology, crystallinity, and defect density. We highlight optimization strategies, including solvent engineering, additive incorporation, and process control, that enable the growth of dense, vertically aligned, and large-grained perovskite films with thicknesses up to hundreds of micrometers. Furthermore, the integration of dimensional engineering and heterojunction design through sequential spray deposition enhances charge transport, suppresses ion migration, and improves detection performance. Applications of these films are demonstrated in direct X-ray detectors and filter-free narrowband photodetectors with high sensitivity, low detection limits, and excellent spatial resolution. Remaining challenges are also discussed in understanding dynamic phase transitions and ensuring large-area uniformity of the spray-deposited films. Advancing in situ characterization and intelligent process control will accelerate the transition of spray coating from a laboratory technique to a scalable precision-manufacturing platform for next-generation perovskite optoelectronics.},
}

@article {pmid41654110,
year = {2026},
author = {Shen, Y and Shen, S and Luo, ZG},
title = {Gene-targeted versus broad-spectrum therapies in ALS: comparative lessons and strategic outlook.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jgg.2026.01.012},
pmid = {41654110},
issn = {1673-8527},
abstract = {Amyotrophic lateral sclerosis (ALS) is a relentless and fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and ultimately, respiratory failure. Despite a growing understanding of its complex pathophysiology, therapeutic options remain limited. This review critically analyzes recent clinical advances by comparing two divergent strategies, including precision gene-targeted therapies for monogenic ALS subtypes and broad-spectrum agents for the wider sporadic population. While gene therapies like tofersen demonstrate clear molecular target engagement, their translation to robust clinical benefit remains a challenge. In contrast, broad-spectrum agents have faced consistent late-stage failures, often due to the disease's underlying diversity, which undermines a one-size-fits-all approach. We argue that this heterogeneity, coupled with a lack of predictive biomarkers and the difficulty of late-stage intervention, represents the core barrier to progress. The future of ALS therapeutics therefore depends on a strategic pivot toward personalized medicine. This requires prospectively stratifying patients, developing rational combination therapies, and intervening earlier in the disease course, ultimately treating ALS as a syndrome of distinct molecular diseases rather than a single entity.},
}

@article {pmid41980219,
year = {2026},
author = {Galizzi, G},
title = {MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1342},
pmid = {41980219},
issn = {2152-5250},
abstract = {Aging is a natural process leading to the slow and progressive deterioration of numerous physiological functions. It is the main risk factor for several neurodegenerative diseases. Mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs) are essential and dynamic sites of contact between mitochondria and the endoplasmic reticulum (ER) and are involved in numerous cellular processes, such as calcium (Ca[2+]) homeostasis, reactive oxygen species (ROS) production, autophagy, inflammation, mitochondrial dynamics, apoptosis, lipid biosynthesis, and trafficking. As a result, they play a significant role in maintaining cellular functionality regulating metabolism and ensuring proper stress responses. Recently, MAMs have been widely investigated to understand their critical role in cell physiology as well as in different pathological conditions. Increasing evidence indicates that alterations in ER-mitochondria communication contribute to aging and the development of age-related diseases. However, the cellular mechanisms underlying this link remain unclear. Understanding how these interactions change with age could provide further insights into the aging process and the mechanisms underlying age-related diseases, suggesting potential new therapeutic strategies. This review summarizes the current knowledge on MAM biology, focusing on their role in the pathogenesis of age-related brain disorders. Their therapeutic potential in limiting the progression of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, and slowing the physiological aging process are also explored.},
}

@article {pmid41981822,
year = {2026},
author = {Luo, X and Alias, BS and Adnan, NH},
title = {Active learning strategies and student engagement in undergraduate medical education: A systematic review (2015-2025).},
journal = {Anatomical sciences education},
volume = {},
number = {},
pages = {},
doi = {10.1002/ase.70231},
pmid = {41981822},
issn = {1935-9780},
support = {JYZ202412//Hubei Enshi College/ ; },
abstract = {Active learning strategies (ALS) are increasingly employed in undergraduate medical education to promote student engagement across behavioral, emotional, and cognitive dimensions; however, there remains limited integrative understanding of the pedagogical mechanisms through which ALS activate engagement and the contextual conditions shaping this process. This systematic review synthesized empirical studies published between 2015 and June 2025 to examine how ALS activate multidimensional student engagement and to develop an integrative, mechanism-oriented framework for engagement activation in undergraduate medical education. Following PRISMA 2020 guidelines, six academic databases were systematically searched for quantitative, qualitative, and mixed-methods studies involving undergraduate medical students, yielding 22 eligible studies. Thematic synthesis indicated that strategies such as gamification, scenario-based learning, team-based learning, and audience response systems demonstrated robust engagement activation when instructional designs integrated authentic tasks, structured collaboration, and timely feedback, rather than through instructional format alone. Across studies, discrepancies were frequently observed between perceived engagement and actual learning outcomes, highlighting the limitations of relying on self-report measures. Contextual moderators, including instructional culture, facilitation practices, and learning environments, further shaped how engagement was activated, expressed, and sustained across settings. These findings informed the development of the Active Learning Engagement Activation model, which conceptualizes engagement as a dynamic, context-sensitive process arising from interactions among instructional design features, learner-interface mechanisms, and contextual moderators, providing a mechanism-oriented framework to support engagement-informed curriculum design and future research in undergraduate medical education.},
}

@article {pmid41992971,
year = {2026},
author = {Cheng, H and Zheng, G and Yang, Y and Xu, C and Tang, G and Huang, C},
title = {Incorporating artificial intelligence into morphological diagnosis of acute leukemias: Current landscape, challenges and prospects (Review).},
journal = {Oncology reports},
volume = {55},
number = {6},
pages = {},
doi = {10.3892/or.2026.9120},
pmid = {41992971},
issn = {1791-2431},
mesh = {Humans ; *Artificial Intelligence ; Machine Learning ; *Leukemia/diagnosis/pathology ; Microscopy/methods ; Data Mining/methods ; *Leukemia, Myeloid, Acute/diagnosis/pathology ; },
abstract = {Acute leukemias (ALs) are a diverse group of hematological malignancies characterized by the abnormal proliferation of immature cells. Microscopic observation of cell morphology based on the French‑American‑British classification remains a fundamental diagnostic method for ALs. However, manual screening from bone marrow smear images is often inefficient, laborious and prone to subjective bias, leading to potential misdiagnosis or missed diagnosis. Artificial intelligence (AI), particularly machine learning (ML), has expanded human capabilities in analyzing complex datasets, leading to breakthroughs in multiple fields, including medical research and clinical practice. Increasingly, ML applications are being developed to diagnose hematological diseases by extracting and aggregating morphological characteristics from peripheral blood and bone marrow smears. However, applying ML methods to recognize cell morphology in hematological diseases presents unique challenges compared with other pathology subspecialties. The present review provided an overview of AI and ML applications in ALs diagnosis, focusing on cell segmentation and data mining methods from microscopy images, and highlights their advantages over manual microscopy.},
}

Humans
*Artificial Intelligence
Machine Learning
*Leukemia/diagnosis/pathology
Microscopy/methods
Data Mining/methods
*Leukemia, Myeloid, Acute/diagnosis/pathology

@article {pmid41993642,
year = {2026},
author = {Zhou, H and Meng, T and Liang, D and Wang, Y},
title = {The effect of statins on the survival of patients with amyotrophic lateral sclerosis: a meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1753992},
pmid = {41993642},
issn = {1664-2295},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying therapies and a poor overall prognosis. Statins, are commonly used for dyslipidemia, and have been proposed to exert cholesterol-independent actions including anti-inflammatory and potential neuroprotective effects. Prior studies, However, existing studies offer conflicting results regarding their impact on ALS survival. This systematic review and meta-analysis aimed to evaluate the association between statin use and survival outcomes in patients with ALS.

METHODS: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science from inception to September 2025. Studies were included if they reported survival outcomes for statin users vs. non-users among patients with ALS. Data on hazard ratios (HRs) were extracted and pooled using fixed- or random-effects models, depending on heterogeneity. Meta-regression and sensitivity analyses were performed to explore the influence of covariates such as age and gender.

RESULTS: Six studies with 3,739 participants (889 statin users) met the inclusion criteria. The pooled analysis showed no statistical significant association between statin use and ALS survival [Log(HR) = -0.04; 95% CI: -0.18 to 0.10], with moderate heterogeneity (I [2] = 24.85%).

CONCLUSION: The pooled estimate in this meta-analysis did not show a statistically significant association between statin use and ALS survival; however, the evidence is limited by heterogeneity in statin exposure definitions and likely residual confounding in predominantly observational data. Further high-quality studies with large sample sizes are needed to determine whether specific subgroups may benefit/harm from statin therapy.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251160344; PROSPERO: CRD420251160344.},
}

@article {pmid41021520,
year = {2026},
author = {Yu, J and Du, H and Xue, E and Fu, Y and Chen, L and Shao, J},
title = {Effectiveness, ethics, and sustainability of nudge-based interventions for self-monitoring in patients with hypertension and type 2 diabetes: A systematic review.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {45},
number = {4},
pages = {387-401},
doi = {10.1037/hea0001564},
pmid = {41021520},
issn = {1930-7810},
support = {//Zhejiang Provincial Natural Science Foundation/ ; //National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/therapy ; *Hypertension/therapy ; *Self Care ; },
abstract = {OBJECTIVE: This study aims to assess the effectiveness, ethics, and sustainability of nudge-based interventions in improving self-monitoring behaviors among patients with hypertension (HTN) and type 2 diabetes mellitus (T2DM).

METHOD: A systematic search of seven databases (January 2008-October 2024) identified studies on nudge-based interventions for HTN and T2DM self-monitoring. Nudge strategies were categorized using Münscher et al.'s taxonomy of choice architecture, which includes "decision information," "decision architecture," and "decision assistance." The included nudge-based interventions were evaluated across three domains: effectiveness, ethical quality, and sustainability.

RESULTS: Seventeen studies (19 trials) were included in this review; 58% of the nudge-based interventions significantly improved self-monitoring adherence, and 47% yielded measurable improvements in clinical outcomes, such as reductions in blood pressure and glycated haemoglobin levels compared to usual care. Ethical evaluations revealed that the majority of nudge-based interventions exhibited above-average ethical quality. Regarding sustainability, while multicomponent interventions were common, they proved more difficult to implement due to higher resource demands.

CONCLUSIONS: This review highlights the potential of nudge-based interventions to improve self-monitoring adherence among patients with HTN and T2DM. However, balancing effectiveness, ethical considerations, and sustainability will be crucial for optimizing these interventions in real-world settings. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

Humans
*Diabetes Mellitus, Type 2/therapy
*Hypertension/therapy
*Self Care

@article {pmid41175111,
year = {2026},
author = {Sewell-Green, AR and Kuiper, M and Holdom, CJ and Beelen, A and Ngo, ST and Steyn, FJ and Matthews-Rensch, KL},
title = {Examining the impact and role of lipid classes on the risk of amyotrophic lateral sclerosis (ALS) onset: a systematic review and GRADE analysis of the evidence.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {27},
number = {3-4},
pages = {370-382},
doi = {10.1080/21678421.2025.2574685},
pmid = {41175111},
issn = {2167-9223},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/epidemiology/diagnosis ; *Lipids/blood/classification ; Risk Factors ; },
abstract = {BACKGROUND: This study aimed to synthesize existing research on pre-diagnostic blood lipid levels and the risk of amyotrophic lateral sclerosis (ALS) onset in adults, and the quality of this evidence.

METHODS: A systematic review was conducted (8 March 2024, updated 19 June 2025) across six databases (PubMed, Embase, CINAHL, Scopus, Cochrane Library, and Web of Science) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, identifying adult clinical studies of blood lipids measured prior to ALS onset. Studies with high risk of bias, assessed using the Quality in Prognostic Studies tool, were excluded. Standardized mean difference and 95% confidence intervals were calculated. Study outcomes were categorized by lipid class as indicating reduced, no effect, or increased ALS risk. Certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.

RESULTS: Of 7222 studies identified, eight (n = 7 sterol lipids, n = 1 fatty acids) met inclusion. No significant differences in sterol lipids were observed between ALS cases and controls (I[2] = 69.9-77.3%). Most studies reported no association or increased risk between ALS onset and higher total cholesterol, triglycerides, LDL-C, HDL-C, or LDL/HDL ratio. For HDL-C, two studies showed protective associations. A single fatty acid study reported increased disease risk with higher arachidonic acid and reduced risk with higher alpha-linoleic acid. Certainty of evidence was low to very low.

CONCLUSION: Circulating sterol lipid levels were inconsistently associated with ALS risk. The overall low certainty of evidence, and variability of findings across studies call for research using standardized designs, high-resolution lipid profiling, and robust causal inference approaches to clarify the role of lipids in ALS risk.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood/epidemiology/diagnosis
*Lipids/blood/classification
Risk Factors

@article {pmid41428860,
year = {2026},
author = {Curtis, SE and Tatlock, S and O'Hara, L and Seçinti, E and Mehdiyoun, NF and Ayala-Nunes, L and Flynn, J and Fernelius, K and Hodson, N and Delbecque, L},
title = {Patient experience and clinical outcome assessment validity in amyotrophic lateral sclerosis: a targeted literature review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {27},
number = {3-4},
pages = {285-300},
doi = {10.1080/21678421.2025.2604233},
pmid = {41428860},
issn = {2167-9223},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/diagnosis ; *Quality of Life/psychology ; *Outcome Assessment, Health Care/methods ; Reproducibility of Results ; },
abstract = {OBJECTIVE: To identify relevant concepts of measurement for people with amyotrophic lateral sclerosis (ALS) and to evaluate the face and content validity of clinical outcome assessments (COAs) that can be used to measure treatment benefits in ALS clinical trials.

METHODS: A targeted literature review was conducted to explore patient experience (stage 1) and COAs used in ALS research (stage 2). Abstracts were screened against predefined eligibility criteria; full-text articles were reviewed for eligible abstracts and relevant data were extracted. Face and content validity of the identified COAs were assessed.

RESULTS: Stage 1 searches identified 3,527 abstracts, of which 12 full-text articles, two summary reports, and one conference poster were included in this review. Twenty-five symptoms and 35 health-related quality of life (HRQoL) impacts were identified. Frequently reported symptoms included breathing and speech difficulties and muscle/limb weakness, each associated with a diverse range of impacts, including those related to emotional wellbeing, physical function, social and leisure activities, and activities of daily living. Stage 2 searches identified 119 COAs, of which 28 were reviewed. Many had acceptable face (13/28) and content validity (15/28), but 13 had not involved patients during development; only 10 were clearly worded and seven were lengthy, increasing patient burden risk.

CONCLUSIONS: This review identified wide-ranging symptoms and HRQoL impacts experienced by people with ALS, but detailed qualitative evidence is sparse. Multiple COAs were identified as potential measures in ALS clinical trials.},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology/therapy/diagnosis
*Quality of Life/psychology
*Outcome Assessment, Health Care/methods
Reproducibility of Results

@article {pmid41977439,
year = {2026},
author = {Bougea, A},
title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
pmid = {41977439},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; *RNA, Untranslated/genetics ; MicroRNAs/genetics ; RNA, Long Noncoding/genetics ; Genetic Therapy/methods ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.},
}

Humans
*Neurodegenerative Diseases/genetics/therapy
Animals
*RNA, Untranslated/genetics
MicroRNAs/genetics
RNA, Long Noncoding/genetics
Genetic Therapy/methods

@article {pmid41978251,
year = {2026},
author = {Malmström, N and Ozanne, A and Nilsson, S and Öhlén, J and Jakobsson Larsson, B},
title = {Support interventions for families facing parental life-threatening illness - A scoping review.},
journal = {Palliative & supportive care},
volume = {24},
number = {},
pages = {e78},
doi = {10.1017/S1478951526101837},
pmid = {41978251},
issn = {1478-9523},
mesh = {Humans ; Child ; *Parents/psychology ; *Social Support ; Infant ; },
abstract = {OBJECTIVES: Despite the urgent need for support interventions for families facing parental life-threatening illness, research is limited - particularly in progressive neurological diseases. This scoping review aimed to systematically map existing interventions to inform the development of tailored support in the neurological context.

METHODS: A scoping review was conducted, including articles published between 2013 and 2025, identified through searches in PubMed, CINAHL, PsycINFO, and Web of Science, along with manual screening of reference lists. Extracted data were systematically charted and descriptively summarized.

RESULTS: Of 5172 articles, 15 were included, describing 6 unique interventions aimed at supporting children (0-25 years) and/or parents in families where a parent had a life-threatening illness. While cancer was the predominant diagnosis among ill parents, progressive neurological diseases, such as amyotrophic lateral sclerosis (ALS) and Huntington's disease, were represented to a limited extent. The interventions targeted children (n = 4), parents in their parenting role (n = 4), or the entire family (n = 7) and were primarily based on psychosocial, psychoeducational, or peer support. Overall, the interventions were positively received by both children and parents and perceived as helpful in navigating their challenging life situations in various ways.

SIGNIFICANCE OF RESULTS: This review confirms a particular lack of knowledge and tailored support for families affected by progressive neurological diseases. While support interventions for other life-threatening illnesses are also limited, those that exist may offer valuable insights to inform the development of support within neurological care contexts. The findings underscore the need for early, proactive, and accessible approaches that address both individual and family needs across the disease trajectory, aligning with core principles of high-quality palliative care.},
}

Humans
Child
*Parents/psychology
*Social Support
Infant

@article {pmid41977262,
year = {2026},
author = {Mîndreanu, R and Chiș, IC and Sevastre-Berghian, A and Login, C and Stan, A and Stan, T and Clichici, S and Suciu, Ș},
title = {N-Acetylcysteine in Neurological Disorders: A Systematic Review of Clinical and Translational Evidence Across Seven Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
pmid = {41977262},
issn = {1422-0067},
mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy ; Translational Research, Biomedical ; Antioxidants/therapeutic use ; Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Multiple Sclerosis/drug therapy ; Brain Injuries, Traumatic/drug therapy ; },
abstract = {N-acetylcysteine (NAC) is a glutathione precursor with established antioxidant and anti-inflammatory properties that has been investigated as a neuroprotective agent across multiple neurological conditions. This systematic review systematically mapped the clinical evidence for NAC across seven neurological disorders. PubMed and Cochrane Library were searched for studies published between 1 January 1995 and 31 December 2025. Twenty-three studies were included: traumatic brain injury (TBI, n = 6), Alzheimer's disease (AD, n = 5), Parkinson's disease (PD, n = 5), multiple sclerosis (n = 4), amyotrophic lateral sclerosis (n = 2), and migraine (n = 1); no eligible epilepsy studies were identified. The strongest evidence emerged for acute mild TBI, where early NAC administration significantly improved symptom resolution, and for PD, where combined intravenous/oral NAC improved dopamine transporter binding. In AD, nutraceutical formulations including NAC and other active compounds showed trends toward cognitive stabilization. Most included studies had a high or serious risk of bias, and only eight of 23 assessed oxidative stress biomarkers. NAC demonstrated a favorable safety profile across all conditions. Despite fragmented and heterogeneous evidence, the encouraging signals identified warrant large-scale randomized controlled trials with a standardized biomarker assessment.},
}

*Acetylcysteine/therapeutic use/pharmacology
Humans
*Nervous System Diseases/drug therapy
*Neuroprotective Agents/therapeutic use
Parkinson Disease/drug therapy
Translational Research, Biomedical
Antioxidants/therapeutic use
Alzheimer Disease/drug therapy
Oxidative Stress/drug effects
Amyotrophic Lateral Sclerosis/drug therapy
Multiple Sclerosis/drug therapy
Brain Injuries, Traumatic/drug therapy

@article {pmid41974458,
year = {2026},
author = {Facciabene, A and Ellsworth, SG},
title = {Gut-targeted strategies at the intersection of radiotherapy and immunotherapy.},
journal = {Journal for immunotherapy of cancer},
volume = {14},
number = {4},
pages = {},
pmid = {41974458},
issn = {2051-1426},
mesh = {Humans ; *Gastrointestinal Microbiome/radiation effects/immunology ; *Immunotherapy/methods ; *Neoplasms/immunology/therapy/radiotherapy ; *Radiotherapy/methods ; },
abstract = {The gut microbiota has emerged as a critical determinant of therapeutic immunity, shaping responses to immune checkpoint inhibitors, adoptive cellular therapies, and radiotherapy (RT). Interest has grown in whether interventions targeting the microbiota might deliberately amplify anticancer immunity.Chen and colleagues recently proposed an unconventional approach: using low-dose intestinal irradiation (ILDR) to remodel the gut microbiota and thereby enhance responsiveness to programmed death-ligand 1 blockade in patients with metastatic cancer. Their report, though preliminary, suggests that directed RT to the intestine can in fact act to favorably modulate the intestinal microbiota. Importantly, current evidence remains largely correlative and does not establish a causal relationship between ILDR, microbiota remodeling, and enhanced systemic antitumor immunity. This concept is provocative, but it raises fundamental questions: does gut-directed RT truly enhance systemic antitumor immunity, or might additional confounding variables, organ-specific effects, and potential toxicities influence the signal?In this Commentary, we balance enthusiasm with caution. We first outline the conceptual framework linking RT, microbiota, and immune activation; then highlight the specific pitfalls revealed by Chen et al's study, including challenges in attribution, heterogeneity, and immunosuppression. We also discuss complementary translational approaches, including direct microbiota modulation through targeted antibiotics and other gut-directed strategies, as potential tools to experimentally interrogate the microbiota-RT-immunotherapy axis in patients.},
}

Humans
*Gastrointestinal Microbiome/radiation effects/immunology
*Immunotherapy/methods
*Neoplasms/immunology/therapy/radiotherapy
*Radiotherapy/methods

@article {pmid41960733,
year = {2026},
author = {Han, JJ and Hayward, LJ and Adams, C and Perez-Ibarra, J},
title = {Reachable Workspace as a Clinical Outcome for Upper Extremity Function: A Narrative Review.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70190},
pmid = {41960733},
issn = {1097-4598},
support = {U01 AR065113-01/AR/NIAMS NIH HHS/United States ; //Fulcrum Therapeutics/ ; },
abstract = {Motion sensing technology can be utilized to capture detailed upper extremity (UE) motion to reconstruct an individual's three-dimensional (3D) reachable workspace (RWS). The RWS can be quantified as relative surface area (RSA), providing an innovative surrogate measure to assess UE mobility and function. Numerous studies have shown that RSA can reliably distinguish between healthy and impaired UE function and also is able to detect clinically relevant longitudinal changes, with sufficient sensitivity to detect small differences even in slowly-progressive conditions. After more than a decade of experience in clinical studies, RWS has been shown to be a valid, reliable, and sensitive UE clinical outcome assessment (COA) tool, with clinical utility in various neuromuscular diseases in which UE impairment is significant, including facioscapulohumeral dystrophy (FSHD), Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis (ALS). RWS and its performance outcome (PerfO) measure RSA have demonstrated strong associations with established clinical measures of disease severity, patient-reported outcomes (PROs), and functional performance, further supporting its clinical relevance. As an UE functional assessment tool, RWS has also shown its generalizable application in various other conditions with UE impairment, such as stroke, orthopedic conditions, and other musculoskeletal disorders. With significant body of work supporting sensor-based RWS as a clinically useful assessment of UE function, future developments incorporating increasingly-capable mobile sensing technologies for remote monitoring and applying machine learning and artificial intelligence (AI) approaches to the sensor-acquired motion data promise further exciting possibilities to enhance clinical studies and patient care.},
}

@article {pmid41962593,
year = {2026},
author = {Ran, X and Wang, M and Huang, J and Kuang, N and Tian, P and Wu, J and Feng, F and Luo, Y and Huang, N},
title = {Mechanistic Research and Therapeutic Prospects of Alternative Splicing in Neurodegenerative Diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103133},
doi = {10.1016/j.arr.2026.103133},
pmid = {41962593},
issn = {1872-9649},
abstract = {One essential post-transcriptional regulatory mechanism that increases protein diversity in eukaryotes is alternative splicing. This process is crucial for maintaining nervous system function and is highly active in neurons. Dysregulation of alternative splicing is a common pathogenic factor in many neurodegenerative diseases. For example, splicing variants of tau protein and amyloid precursor protein are implicated in Alzheimer's disease; aberrant splicing of α-synuclein (SNCA) and upregulation of specific transcript variants of the Parkin (PARK2) gene occurs in Parkinson's disease; and aberrant splicing of Stathmin-2 (STMN2) pre-mRNA leads to the loss of axonal maintenance proteins in amyotrophic lateral sclerosis and frontotemporal dementia. This process is precisely regulated by trans-acting factors, a class of RBPs that specifically recognize and bind to cis-acting elements on precursor mRNA (pre-mRNA). These factors are primarily categorized into two major groups: serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). Although hnRNPs and SR proteins have been shown to regulate neuronal alternative splicing, their complex regulatory networks and associated disease mechanisms remain incompletely understood, hindering the development of targeted therapies. This review summarizes the molecular mechanisms of alternative splicing and its regulatory features in neurodegenerative diseases. It also summarizes recent advances in splicing-based therapies and biomarkers, providing insights into disease mechanisms and therapeutic development.},
}

@article {pmid41964193,
year = {2026},
author = {Grabarczyk, Ł},
title = {Comprehensive Review of Anesthetic Strategies for Patients With Neurodegenerative Diseases.},
journal = {Medical science monitor : international medical journal of experimental and clinical research},
volume = {32},
number = {},
pages = {e950453},
pmid = {41964193},
issn = {1643-3750},
mesh = {Humans ; *Neurodegenerative Diseases/surgery/physiopathology ; *Anesthesia/methods ; *Anesthetics/therapeutic use ; Neuromuscular Blockade/methods ; Perioperative Care/methods ; },
abstract = {Patients with neurodegenerative diseases (NDDs) represent a unique and challenging population from an anesthesiological perspective due to their neurological vulnerability. This issue is becoming increasingly relevant as the incidence of certain NDDs rises with population aging. Effective perioperative management in patients with NDDs requires detailed preoperative evaluation, with emphasis on neurological status, cardiopulmonary function, and a thorough review of current medications. Intraoperatively, careful selection of anesthetic agents and monitoring strategies is essential because of altered drug sensitivity, increased susceptibility to malignant hyperthermia, and potential drug interactions. Particular attention must be given to neuromuscular blockade. The use of nondepolarizing neuromuscular blocking agents is generally risky due to their potentially prolonged and unpredictable effects; their use may be considered under strictly controlled conditions. In contrast, propofol and inhalational agents have demonstrated safety and efficacy in this patient population. This article aims to review the perioperative anesthetic management of patients with NDDs, including Huntington disease, (spino)cerebellar ataxia, Friedreich ataxia, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis.},
}

Humans
*Neurodegenerative Diseases/surgery/physiopathology
*Anesthesia/methods
*Anesthetics/therapeutic use
Neuromuscular Blockade/methods
Perioperative Care/methods

@article {pmid41964251,
year = {2026},
author = {Anastasakis, DG and Hafner, M},
title = {RNA G-quadruplex-protein interactions: from nuclear RNA processing to cytoplasmic stress response and neurodegeneration.},
journal = {RNA biology},
volume = {23},
number = {1},
pages = {1-16},
pmid = {41964251},
issn = {1555-8584},
mesh = {*G-Quadruplexes ; Humans ; *Cytoplasm/metabolism/genetics ; Animals ; *RNA-Binding Proteins/metabolism ; *Cell Nucleus/metabolism/genetics ; *RNA Processing, Post-Transcriptional ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; *Stress, Physiological ; Protein Binding ; },
abstract = {RNA G-quadruplexes (rG4s) are stable secondary structures formed by non-canonical Hoogsteen base-pairing of guanine-rich sequences in precursor and mature messenger and non-coding RNAs. We review evidence that rG4s exist in two functionally distinct worlds. In the nucleus, rG4s fold co-transcriptionally to regulate gene expression and RNA processing and organizing membraneless organelles through liquid-liquid phase separation. Splicing regulation by rG4s is restricted to vertebrates and co-evolved with transcriptome complexity. In the cytoplasm, rG4s are actively maintained in an unfolded state by dedicated helicases and RNA-binding proteins, but fold upon stress to nucleate stress granules, that sequester mRNAs and sustain cell survival. When compartmentalization of rG4-protein interactions fails, cells lose both nuclear RNA processing control and cytoplasmic translational regulation and proper stress response. The same biophysical properties that make rG4s effective scaffolds for reversible phase separation in RNA processing, proteostasis, and acute stress become liabilities under chronic conditions: in ageing neurons, failure of rG4-protein homoeostasis transforms protective condensates into irreversible aggregates associated with α-synuclein, tau, TDP-43, and FUS pathology. We discuss the implications of a dynamic equilibrium of folded and unfolded rG4s in health and disease, with particular focus on their emerging roles in neurodegeneration.},
}

*G-Quadruplexes
Humans
*Cytoplasm/metabolism/genetics
Animals
*RNA-Binding Proteins/metabolism
*Cell Nucleus/metabolism/genetics
*RNA Processing, Post-Transcriptional
*Neurodegenerative Diseases/metabolism/genetics/pathology
*Stress, Physiological
Protein Binding

@article {pmid41466523,
year = {2026},
author = {Watabe, K},
title = {Praja1 E3 ubiquitin ligase and the role it plays in neurodegeneration.},
journal = {The FEBS journal},
volume = {293},
number = {8},
pages = {2208-2211},
doi = {10.1111/febs.70383},
pmid = {41466523},
issn = {1742-4658},
mesh = {Humans ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Neurodegenerative Diseases/genetics/pathology/enzymology/metabolism ; tau Proteins/metabolism/genetics ; Animals ; Ubiquitination ; alpha-Synuclein/metabolism/genetics ; },
abstract = {Protein aggregation and transmission are hallmarks of neurodegenerative diseases. Praja1 E3 ubiquitin ligase has been shown to suppress the aggregation of causative proteins in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Parkinson's disease, Huntington's disease, and spinocerebellar degeneration, which include transactivation response DNA-binding protein of 43 kDa, fused in sarcoma, superoxide dismutase 1, α-synuclein, huntingtin, and ataxin-3. Aoki et al. demonstrated that Praja1 ubiquitinates and degrades tau, a key molecule in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal syndrome, furthering our understanding of the role of Praja1 in neurodegenerative diseases and potential therapeutic approaches.},
}

Humans
*Ubiquitin-Protein Ligases/metabolism/genetics
*Neurodegenerative Diseases/genetics/pathology/enzymology/metabolism
tau Proteins/metabolism/genetics
Animals
Ubiquitination
alpha-Synuclein/metabolism/genetics

@article {pmid41955837,
year = {2026},
author = {Song, Y and Zhao, Z and Dai, Y and Li, C and He, X and Wang, Y and Xu, ZD and Yang, Y},
title = {The m7G modification: An emerging player in neurological diseases.},
journal = {Pathology, research and practice},
volume = {282},
number = {},
pages = {156465},
doi = {10.1016/j.prp.2026.156465},
pmid = {41955837},
issn = {1618-0631},
abstract = {With the growing researches on RNA epigenetics, the importance of 7-methylguanosine (m7G) modification is increasingly recognized. The m7G modification is known as a kind of post-transcriptional modifications of RNA and present in many types of RNAs, including mRNAs, microRNAs, ribosomal RNA, and transfer RNAs. Increasing evidence indicates that m7G modifications are involved in a variety of critical biological processes through affecting the stability of RNA, nucleoplasmic transfer and translation efficiency. In the central nervous system (CNS), m7G modification is catalyzed by three major methyltransferase complexes: METTL1/WDR4, RNMT/RAM, and WBSCR22/TRMT112. Dysregulation of this modification is tightly associated with the pathogenesis of various neurological diseases, such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), epilepsy, glioblastoma, ischemic stroke (IS), etc. Here, we review the current knowledge regarding the latest findings on the distribution, regulatory factors, detection techniques and prediction methods of m7G. We further highlight critical knowledge gaps, especially the limited understanding of m7G "readers," the absence of validated "erasers," and the scarcity of cell-type-resolved profiling in the brain. In addition, we also discuss the translational opportunities and challenges, including biomarker discovery, therapeutic targeting of m7G regulators, and specificity concerns in precision neurological medicine.},
}