@article {pmid41201719,
year = {2025},
author = {Gautam, P and Vishwakarma, RK and Nath, M and Nath, G and Pathak, A},
title = {Microbiota Dysbiosis in Amyotrophic Lateral Sclerosis: A Systematic Review of Human Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {10},
pmid = {41201719},
issn = {1559-1182},
mesh = {*Amyotrophic Lateral Sclerosis/microbiology/complications ; Humans ; *Dysbiosis/microbiology/complications ; *Gastrointestinal Microbiome/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Despite intensive research, its pathogenesis remains poorly understood. Recent insights suggest a pivotal role of the gut microbiota in modulating neuroinflammation and neurodegeneration via the gut-brain axis. This systematic review aims to synthesize clinical evidence on gut microbiota dysbiosis in ALS, exploring microbial and metabolic alterations and their associations with disease progression and severity. A comprehensive literature search was conducted across PubMed, Embase, Scopus, Web of Science, and other databases up to May 10, 2024, adhering to PRISMA 2020 guidelines. Eighteen eligible human studies were selected based on predefined inclusion criteria. Data on microbial diversity, taxonomic shifts, metabolite profiles, and clinical correlations were extracted and assessed using a modified Newcastle-Ottawa Scale. Most studies reported altered microbial diversity, reduced butyrate-producing bacteria (e.g., Faecalibacterium, Roseburia), and increased pro-inflammatory taxa (e.g., Escherichia coli, Bacteroides) in ALS. Integrated microbiome-metabolome analyses revealed disruptions in SCFAs, bile acids, and lipid metabolism, some correlating with ALSFRS-R scores and cognitive impairment. Although some studies showed minimal or no differences, the overall evidence supports a link between dysbiosis and ALS pathophysiology. Probiotic trials demonstrated limited efficacy, highlighting the need for targeted, patient-specific interventions. Gut microbiota dysbiosis is increasingly recognized as a contributor to ALS progression. However, methodological variability, small sample sizes, and limited longitudinal data restrict definitive conclusions. Future research should employ standardized, multi-omics approaches and larger cohorts to clarify causal links and develop microbiome-informed diagnostics and therapies for ALS.},
}

*Amyotrophic Lateral Sclerosis/microbiology/complications
Humans
*Dysbiosis/microbiology/complications
*Gastrointestinal Microbiome/physiology

@article {pmid41196032,
year = {2025},
author = {Mansoor, N and Heiman-Patterson, T and Feldman, EL and Wicks, P and Benatar, M and Vieira, F and Glass, J and Levine, T and Bertorini, T and Barkhaus, P and Mascias Cadavid, J and Jackson, C and Jhooty, S and Brown, A and Pattee, G and Sane, H and Mcdermott, CJ and Carter, G and Beauchamp, M and Wang, O and Ratner, D and Bedlack, R and Li, X},
title = {ALSUntangled #81: Pyridostigmine (mestinon[®]).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/21678421.2025.2582830},
pmid = {41196032},
issn = {2167-9223},
abstract = {Pyridostigmine (Mestinon[®], Bausch Health, Canada Inc.) increases acetylcholine availability at the neuromuscular junction, enhancing transmission. Preclinical studies suggest that neuromuscular junction dysfunction develops early in ALS, and pyridostigmine may temporarily improve neuromuscular transmission. However, altered neuromuscular junction transmission has uncertain benefits in ALS progression. Pyridostigmine does not have other plausible mechanisms that truly modify ALS pathophysiology. People with ALS (PALS) who have positive acetylcholine receptor autoantibodies and no myasthenia symptoms are unlikely to respond to pyridostigmine treatment. Clinical trials on pyridostigmine in PALS are lacking, but two clinical trials of other similar anticholinesterase agents did not effectively slow ALS progression. Muscarinic cholinergic side effects, including gastrointestinal symptoms, are common. Given the lack of mechanistic plausibility and efficacy, we do not support the use of pyridostigmine for slowing ALS progression.},
}

@article {pmid41194800,
year = {2025},
author = {Su, Z and Xiang, L},
title = {Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1639114},
pmid = {41194800},
issn = {1662-5099},
abstract = {The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.},
}

@article {pmid41194479,
year = {2025},
author = {Das, S and Patel, M and Khandelwal, S and Rawat, R and Shukla, S and Kumari, AP and Singh, K and Kumar, A},
title = {From Mutations to Microbes: Investigating the Impact of the Gut Microbiome on Repeat Expansion Disorders.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70278},
doi = {10.1111/jnc.70278},
pmid = {41194479},
issn = {1471-4159},
mesh = {*Gastrointestinal Microbiome/physiology/genetics ; Humans ; Animals ; *Mutation/genetics ; Dysbiosis/genetics ; *DNA Repeat Expansion/genetics ; },
abstract = {Repeat expansion disorders (REDs) are a diverse array of genetic disorders characterized by the expansion of specific DNA sequences. These expansions are frequently dynamic and are susceptible to further expansion across generations. They contribute to disease progression by leading symptoms to become more severe and manifest earlier in subsequent generations. Despite a substantial understanding of their molecular mechanisms, the exact etiology of REDs remains tricky. Emerging evidence indicates that gut microbiome dysbiosis significantly impacts REDs by regulating various biochemical pathways. Alterations in microbial diversity and composition have been observed across multiple REDs; however, a comprehensive understanding of the complete scenario remains a significant challenge. To elucidate these dynamic interactions, future research should utilize multifaceted approaches. This review focuses on the key modifications in the gut microbiome that contribute to the pathogenesis of REDs and discusses potential gut microbiome-targeted therapeutic strategies that could be effectively employed to treat these disorders.},
}

*Gastrointestinal Microbiome/physiology/genetics
Humans
Animals
*Mutation/genetics
Dysbiosis/genetics
*DNA Repeat Expansion/genetics

@article {pmid41192771,
year = {2025},
author = {Shima, S and Kondo, T and Inoue, H},
title = {iPSC-derived neural organoids in dementia research: recent advances and future directions.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104980},
doi = {10.1016/j.neures.2025.104980},
pmid = {41192771},
issn = {1872-8111},
abstract = {Neural organoids are self-assembled three-dimensionally shaped aggregates generated from pluripotent stem cells for the purpose of generating brain-like structures. Organoids derived from patient induced pluripotent stem cells (iPSCs) can recapitulate the features of the disease from molecular to functional levels, which are not fully reproduced by other culture systems or in vivo models. Neural organoids have been applied to model dementia including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia, and they have recapitulated aspects of their complex pathophysiology, including neuronal network dysfunction and accumulation of pathogenic proteins. Although there are some challenges for the research using neural organoids, including their heterogeneity and the lack of cells of non-neural lineage, researchers have tried to overcome these limitations and have demonstrated their utility in conjugation with gene editing technologies and the assembly system of organoids and specific types of cells. This article reviews current research on iPSC-derived organoids for dementia, discussing both the technical hurdles and the potential for translational applications.},
}

@article {pmid41165282,
year = {2025},
author = {Roedl, K and Genbrugge, C},
title = {Managing cardiac arrest in the intensive care unit.},
journal = {Current opinion in critical care},
volume = {31},
number = {6},
pages = {729-734},
doi = {10.1097/MCC.0000000000001319},
pmid = {41165282},
issn = {1531-7072},
mesh = {Humans ; *Heart Arrest/therapy/epidemiology/etiology/mortality ; *Intensive Care Units ; *COVID-19/epidemiology ; *Cardiopulmonary Resuscitation/methods ; SARS-CoV-2 ; *Critical Care/methods ; },
abstract = {PURPOSE OF REVIEW: This review aims to explore the distinct clinical characteristics, epidemiology, treatment approaches, and research needs concerning cardiac arrest in the intensive care unit (ICU-CA), a specific subset of in-hospital cardiac arrest (IHCA). While IHCA remains a major cause of mortality, recent data indicate improved outcomes, with a notable variation in incidence and survival depending on the location, particularly within the ICU setting.

RECENT FINDINGS: Recent studies underscore that ICU-CA differs significantly from general IHCA in etiology, monitoring, and treatment environment. Although incidence rates vary widely (4-78 per 1000 ICU admissions), recent data suggest a stabilization. Causes of ICU-CA often involve noncardiac factors such as septic shock and respiratory failure. Treatment is typically guided by general advanced life support (ALS) protocols, but ICU-specific resources such as real-time monitoring, invasive pressure measurements, transesophageal echocardiography, and the potential for extracorporeal cardiopulmonary resuscitation offer unique advantages. The COVID-19 pandemic highlighted the vulnerability of ICU patients, with respiratory causes dominating and extremely poor outcomes reported.

SUMMARY: In summary, ICU-CA represents a distinct clinical entity requiring tailored research. Future directions should prioritize international registries, validation of predictive models using artificial intelligence, and clarification of do-not-resuscitate practices to improve outcomes and resource allocation in this critically ill population.},
}

Humans
*Heart Arrest/therapy/epidemiology/etiology/mortality
*Intensive Care Units
*COVID-19/epidemiology
*Cardiopulmonary Resuscitation/methods
SARS-CoV-2
*Critical Care/methods

@article {pmid41191158,
year = {2025},
author = {Pal, B and Panda, S and Bashir, B and Vishwas, S and Chaitanya, M and Hussain, MS and Gupta, G and Kumbhar, P and Gupta, S and Singh, SK},
title = {Nanomedicine-enabled neuroprotection: therapeutic role of berberine in neurodegenerative diseases.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {49},
pmid = {41191158},
issn = {1573-4978},
mesh = {Humans ; *Berberine/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nanomedicine/methods ; Animals ; *Neuroprotection/drug effects ; Nanoparticles/chemistry ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Amyotrophic lateral sclerosis, Huntington's, and Parkinson's, present an increasingly widespread health burden globally with limited curative or treatment modalities, mostly having symptomatic attenuation. Berberine (BBR) is an isoquinoline alkaloid that occurs naturally and has been proposed as a potential neuroprotectant, since it has been found to exert multiple effects to modulate most of the pathological hallmarks of NDs, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and protein aggregation. Although it shows promise, the practical utilization of BBR is marred by low oral bioavailability, high rate of oxidation, and low blood-brain barrier permeability. To combat these issues, recent developments in nanotechnology, especially in the use and creation of lipidic, inorganic, and polymeric nano-particles, have dramatically altered the pharmacokinetics and pharmacodynamics of BBR. This article summarizes recent advances in BBR-based nanoformulations and emphasizes the translational potential of BBR-based nanopreparations to improve treatment response in NDs. It also describes the molecular foundation of the neuroprotective effects of BBR and its possible place in clinical practice. Future nanocarrier development and investigation of BBR mechanisms will be essential to the development of the next generations of therapeutics in NDs.},
}

Humans
*Berberine/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
*Nanomedicine/methods
Animals
*Neuroprotection/drug effects
Nanoparticles/chemistry
Oxidative Stress/drug effects
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41190025,
year = {2025},
author = {Alhassan, HH and Janiyani, K and Surti, M and Adnan, M and Patel, M},
title = {The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1693805},
pmid = {41190025},
issn = {1663-9812},
abstract = {Glycogen Synthase Kinase-3 Beta (GSK3β), a multifunctional serine/threonine kinase, plays a central role in cellular signaling pathways and autophagy regulation, processes critical to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS). Dysregulation of autophagy leads to the toxic accumulation of misfolded proteins and damaged organelles, contributing to neuronal loss in these disorders. This review explores the mechanistic interplay between GSK3β and autophagy, highlighting its modulation through key pathways, including mTOR, AMPK and Bcl-2 and its direct impact on autophagy-related proteins such as Beclin-1 and LC3. This review systematically discusses the disease-specific roles of GSK3β in autophagy dysregulation and protein aggregation, providing evidence from recent studies on neurodegenerative models. Additionally, therapeutic approaches targeting GSK3β are evaluated, including preclinical and clinical trials of GSK3β inhibitors and combination therapies with autophagy modulators, emphasizing their potential for improving neuroprotection and cellular homeostasis. Despite its promise, challenges such as off-target effects and pathway complexity remain significant. This review highlights the importance of GSK3β as both a therapeutic target and a biomarker, offering avenues for future research into selective GSK3β modulators that enhance autophagy and mitigate ND progression.},
}

@article {pmid41189652,
year = {2025},
author = {Guo, H and Yang, Z and Zhang, G and Lv, L and Zhao, X},
title = {Meta analysis of the diagnostic efficacy of transformer-based multimodal fusion deep learning models in early Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1641548},
pmid = {41189652},
issn = {1664-2295},
abstract = {INTRODUCTION: This study aims to systematically evaluate the diagnostic efficacy of Transformer-based multimodal fusion deep learning models in early Alzheimer's disease (AD) through a Meta-analysis, providing a scientific basis for clinical applications.

METHODS: Following PRISMA guidelines, databases such as PubMed and Web of Science were searched, and 20 eligible clinical studies (2022-2025) involving 12,897 participants were included. Study quality was assessed using the modified QUADAS-2 tool, statistical analyses were performed with Stata 16.0, effect sizes were pooled via random-effects models, and subgroup analyses, sensitivity analyses, and publication bias tests were conducted.

RESULTS: Results showed that Transformer-based multimodal fusion models exhibited excellent overall diagnostic performance, with a pooled AUC of 0.924 (95% CI: 0.912-0.936), sensitivity of 0.887 (0.865-0.904), specificity of 0.892 (0.871-0.910), and accuracy of 0.879 (0.858-0.897), significantly outperforming traditional single-modality methods. Subgroup analyses revealed that: Three or more modalities achieved a higher AUC (0.935 vs. 0.908 for two modalities, p =0.012). Intermediate fusion strategies (feature-level, AUC=0.931) significantly outperformed early (0.905) and late (0.912) fusion (p <0.05 for both). Multicenter data improved AUC (0.930 vs. 0.918 for single-center, p =0.046), while sample size stratification (<200 vs. ≥200 cases) showed no significant difference (p =0.113). Hybrid Transformer models (Transformer +CNN) trended toward higher AUC (0.928 vs. pure Transformer 0.917, p =0.068) but did not reach statistical significance.

DISCUSSION: Notable studies included Khan et al.'s (2024) Dual-3DM[3]AD model (AUC=0.945 for AD vs. MCI) and Gao et al.'s (2023) generative network (AUC=0.912 under data loss), validating model robustness and feature complementarity. Sensitivity analysis confirmed stable results (AUC range: 0.920-0.928), and Egger's test (p =0.217) and funnel plot symmetry indicated no significant publication bias. Limitations included a high proportion of single-center data and insufficient model interpretability. Future research should focus on multicenter data integration, interpretable module development, and lightweight design to facilitate clinical translation. Transformer-based multimodal fusion models demonstrate exceptional efficacy in early AD diagnosis, with multimodal integration, feature-level fusion, and multicenter data application as key advantages. They hold promise as core tools for AD "early diagnosis and treatment" but require further optimization for cross-cohort generalization and clinical interpretability.},
}

@article {pmid41187881,
year = {2025},
author = {Ge, TQ and Wang, P and Guan, PP},
title = {Targeting the C5-C5aR1 axis: A promising therapeutic strategy for Alzheimer's disease and amyotrophic lateral sclerosis by unlocking neuroprotection.},
journal = {Biochemical pharmacology},
volume = {243},
number = {Pt 1},
pages = {117518},
doi = {10.1016/j.bcp.2025.117518},
pmid = {41187881},
issn = {1873-2968},
abstract = {C5aR1 is a G protein-coupled receptor (GPCR) which is involved in exacerbating neurodegenerative diseases, including Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). This review highlights the critical role of the C5-C5aR1 axis, in the pathogenesis of neurodegenerative diseases such as AD and ALS. In AD and ALS, abnormal protein aggregates activate the complement system (CS), leading to increased production of C5a. C5a activates C5aR1 on microglia, triggering the release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) that induce synaptic loss. Concurrently, the C5-C5aR1 axis impairs microglial phagocytic capacity, promoting damage-associated molecular patterns (DAMPs) accumulation and forming a vicious cycle of inflammation and complement activation. Additionally, excessive complement molecule assembles into the terminal complement complex (TCC), which exerts direct neurotoxic effects and drives neuronal apoptosis. Preclinical studies show that C5aR1 antagonists, such as PMX205, mitigate disease progression in AD and ALS animal models by reducing neuroinflammation and preserving synaptic function. These findings underscore the C5-C5aR1 axis as a promising target for neurodegenerative disease therapy and highlight the need for further development of potential antagonists of C5aR1.},
}

@article {pmid41117139,
year = {2025},
author = {Pedro, KM and Alvi, MA and Goulart, GR and Fehlings, MG},
title = {Riluzole as a pharmacological therapy for spinal cord injury: where does this therapy stand?.},
journal = {Current opinion in neurology},
volume = {38},
number = {6},
pages = {625-634},
doi = {10.1097/WCO.0000000000001434},
pmid = {41117139},
issn = {1473-6551},
mesh = {*Riluzole/therapeutic use/pharmacology ; Humans ; *Spinal Cord Injuries/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; },
abstract = {PURPOSE OF REVIEW: Spinal cord injury (SCI) remains a disabling condition associated with long term neurological impairment, functional disability, and reduced quality of life. Despite decades of research, pharmacological interventions with proven clinical efficacy remain limited. This review critically evaluates the current evidence supporting riluzole as a neuroprotective agent for acute traumatic and nontraumatic SCI. We synthesize findings from preclinical and clinical studies, assess the progress towards clinical translation, and outline key challenges and research opportunities for future implementation.

RECENT FINDINGS: Riluzole, an FDA-approved agent for amyotrophic lateral sclerosis (ALS), inhibits voltage-gated sodium channels and modulates glutaminergic transmission, two mechanisms central to the pathogenesis of secondary injury in SCI and in nerve cell degeneration in nontraumatic forms of SCI, including degenerative cervical myelopathy (DCM). Preclinical studies consistently demonstrate functional and histopathological improvements following riluzole administration. Phase I/II trials have provided evidence for its safety and tolerability in acute SCI patients, while the RISCIS and CSM-PROTECT trials, two landmark multicenter randomized controlled studies, along with their secondary analyses, revealed promising multidomain improvements in motor function, independence, and quality of life indices. Sub-studies have also established pharmacokinetic and pharmacodynamic frameworks for individualized dosing, and early biomarker analysis suggests potential for predictive stratification.

SUMMARY: Riluzole represents a promising candidate for neuroprotection in traumatic and nontraumatic SCI. The consistency of favorable trends across multiple domains and strong support from preclinical studies highlight riluzole's value in orphan diseases such as SCI. Future directions should focus on refining the therapeutic window, optimizing PK/PD modeling, and identifying patient subgroups most likely to benefit. Its implementation in a multimodal treatment paradigm for acute SCI will be crucial for optimizing management protocols in this highly disabling condition.},
}

*Riluzole/therapeutic use/pharmacology
Humans
*Spinal Cord Injuries/drug therapy
*Neuroprotective Agents/therapeutic use/pharmacology
Animals

@article {pmid40960157,
year = {2025},
author = {Wang, J and Dai, L and Zhang, Z},
title = {Protein aggregation in neurodegenerative diseases.},
journal = {Chinese medical journal},
volume = {138},
number = {21},
pages = {2753-2768},
pmid = {40960157},
issn = {2542-5641},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; Animals ; *Protein Aggregates/physiology ; },
abstract = {Neurodegenerative diseases constitute a group of chronic disorders characterized by the progressive loss of neurons. Major neurodegenerative conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Pathologically, these diseases are marked by the accumulation of aggregates formed by pathological proteins such as amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. These proteins assemble into amyloid fibrils that undergo prion-like propagation and dissemination, ultimately inducing neurodegeneration. Understanding the biology of these protein aggregates is fundamental to elucidating the pathophysiology of neurodegenerative disorders. In this review, we summarize the molecular mechanisms underlying the aggregation and transmission of pathological proteins, the processes through which these protein aggregates trigger neurodegeneration, and the interactions between different pathological proteins. We also provide an overview of the current diagnostic approaches and therapeutic strategies targeting pathological protein aggregates.},
}

Humans
*Neurodegenerative Diseases/metabolism
alpha-Synuclein/metabolism
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
*Protein Aggregation, Pathological/metabolism
DNA-Binding Proteins/metabolism
Animals
*Protein Aggregates/physiology

@article {pmid40794569,
year = {2025},
author = {Benatar, M and Staffaroni, AM and Wuu, J and McDermott, MP and Quintana, M and Swidler, J and Andersen, G and Huey, ED and Turner, MR and Macklin, EA and Berry, JD and McMillan, CT and Gendron, T and Onyike, C and Rosen, H and Heuer, HW and Grignon, AL and Dave, KD and Balas, C and Gleixner, A and Satlin, A and Dunn, B and Dacks, P and Boxer, AL},
title = {Design considerations for C9orf72 disease prevention trials.},
journal = {Brain : a journal of neurology},
volume = {148},
number = {11},
pages = {3844-3855},
doi = {10.1093/brain/awaf290},
pmid = {40794569},
issn = {1460-2156},
support = {//Association for Frontotemporal Degeneration/ ; //ALS Association/ ; },
mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/prevention & control ; *Frontotemporal Dementia/genetics/prevention & control ; *Clinical Trials as Topic/methods ; DNA Repeat Expansion/genetics ; Research Design ; },
abstract = {The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10%-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and The ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities and the broader drug development community.},
}

Humans
*C9orf72 Protein/genetics
*Amyotrophic Lateral Sclerosis/genetics/prevention & control
*Frontotemporal Dementia/genetics/prevention & control
*Clinical Trials as Topic/methods
DNA Repeat Expansion/genetics
Research Design

@article {pmid41186720,
year = {2025},
author = {Aijaz, M and Ahmad, M and Ahmad, S and Afzal, M and Kothiyal, P},
title = {The gut-brain axis: role of gut microbiota in neurological disease pathogenesis and pharmacotherapeutics.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41186720},
issn = {1432-1912},
abstract = {The gut-brain axis is a highly complex, bidirectional communication link between the gut and the central nervous system (CNS), mainly through neural, endocrine, immunological, and metabolic pathways. This review outlines the growing contribution of gut microbiota in the remediation of neurological health and also emphasizes the controlling role of gut microbiota on the synthesis of neurotransmitters. Emerging evidence indicates that dysbiosis of the gut is related to a variety of neurodegenerative and neuropsychiatric diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), autism spectrum disorders (ASD), depression, and glioblastoma. Mechanistic understandings show that gut microbes critically contribute to neuroimmune and blood-brain barrier (BBB) signaling. The peripheral association of gut microflora, networked with inflammasome activation, nuclear factor kappa B (NF-κB), and type-I IFN pathways highlights their role in CNS inflammation. Microbiota-targeted interventions with probiotics, prebiotics, synbiotics, antibiotics, dietary modifications, and fecal microbiota transplantation are examined for their therapeutic potential. These strategies appear to be promising to reinstate microbial balance, enhance neuroplastic responses, and ameliorate the disease symptoms. The review highlights personalized microbiome-based algorithms, underpinned by integrated multi-omics technologies and machine-learning-driven diagnostics. Future research should address underlying microbial mechanisms and perform large, randomized controlled trials in order to establish microbiota-based therapies for neurological disorders.},
}

@article {pmid41184709,
year = {2025},
author = {Kiecka, A and Szczepanik, M},
title = {Dietary modulation of the gut microbiome as a supportive strategy in the treatment of amyotrophic lateral sclerosis - a narrative review.},
journal = {Pharmacological reports : PR},
volume = {},
number = {},
pages = {},
pmid = {41184709},
issn = {2299-5684},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to permanent damage to the central and peripheral motor neurons. Currently, there is no effective treatment for ALS, and therapy focuses solely on slowing the progression of the disease. Recent studies show that gut microbiota plays an important role in the development of neurodegenerative diseases. Altered gut microbiota has also been found in ALS. These changes have prompted the search for alternative forms of ALS treatment, focusing on changing the microbial composition of the gut. It has been noted that diet, probiotics, prebiotics and vitamins can all influence the course of ALS. Another interesting issue is fecal microbiota transplantation, which is already used in the treatment of certain intestinal diseases and could potentially be useful in the treatment of ALS. This review summarizes current knowledge on the impact of gut microbiota on the neurodegenerative process in ALS, with particular emphasis on the role of diet and probiotics. It also discusses potential mechanisms and highlights future research directions in this emerging field.},
}

@article {pmid41183377,
year = {2025},
author = {Morris, AC and Seker, A and Telesia, L and Wickersham, A and Ching, BC and Roy, R and Epstein, S and Matcham, F and Sonuga-Barke, E and Downs, J},
title = {Adherence to Actigraphic Devices in Elementary School-Aged Children: Systematic Review and Meta-Analysis.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e79718},
doi = {10.2196/79718},
pmid = {41183377},
issn = {1438-8871},
mesh = {Humans ; Child ; *Actigraphy/instrumentation ; *Patient Compliance/statistics & numerical data ; Child, Preschool ; Female ; Schools ; Male ; },
abstract = {BACKGROUND: Consistent wear is essential for valid and reliable actigraphy data. Adherence to actigraphy may be challenging in primary school children due to developmental and design considerations, yet no quantitative synthesis of adherence in this age group exists.

OBJECTIVE: The aim of this study was to provide the first pooled estimate of actigraphy adherence in primary school-aged children and examine the impact of individual, device, and study-specific factors on adherence.

METHODS: We searched seven electronic databases for studies reporting adherence to actigraphy in primary school-aged children. Searches were conducted in Embase, MEDLINE, PsycINFO, Social Policy and Practice via OVID, Education Resources Information Center, British Education Index, and CINAHL via EBSCO using database-specific search strategies conducted between January 2018 and January 24, 2023. Forward and backward citation searches were completed on the Web of Science Core Collection and Google Scholar. Gray literature searches were undertaken in PsycEXTRA and Healthcare Management Information Consortium. Empirical studies reporting quantitative data on adherence to community-based actigraphy in children aged 5-11 years (or if ≥50% of the average age fell within this range) were included. Eligible studies were written in English and could be published or unpublished. Risk of bias was assessed using an 8-item checklist adapted from Berger et al's actigraphy reporting standards. All included studies were narratively synthesized, and adherence data were pooled in a proportional meta-analysis. Adherence was calculated as the proportion of children meeting wear-time criteria to be included in the analysis compared to the number of children invited to use the device at baseline. Meta-regression was used to examine the impact of individual, device, and study-specific factors on adherence. Prediction intervals were calculated to estimate the range of adherence expected across future studies.

RESULTS: Data were extracted from 235 studies (N=148,161); of these, 135 studies (n=64,541) provided adherence data for proportional meta-analysis. Pooled adherence, measured across 1-140 days, was 81.6% (95% CI 78.7%-84.4%; I2=98.8%). The prediction intervals (42.8%-100%) indicated substantial variability in adherence estimates across studies. Meta-regression suggested that individual characteristics contributed to observed heterogeneity as children with a physical health diagnosis (b=0.236, 95% CI 0.009-0.464; P=.04) and those with neurodevelopmental or mental health diagnosis (b=0.395, 95% CI 0.125-0.665; P=.004) demonstrated higher adherence than undiagnosed children, though these effects were of modest magnitude. No significant effects were found for age, placement, protocol length, protocol deviation, or incentivization. Reporting quality was poor, with only 3.4% of studies satisfying all criteria.

CONCLUSIONS: This review demonstrates generally high actigraphy adherence in primary school-aged children, particularly those with health conditions. However, observed variability indicates that adherence was much lower in some contexts, underscoring that the reported pooled adherence cannot be assumed across future actigraphy applications within this age group. Future research should use standardized adherence reporting and should plan for adherence variability.},
}

Humans
Child
*Actigraphy/instrumentation
*Patient Compliance/statistics & numerical data
Child, Preschool
Female
Schools
Male

@article {pmid41182353,
year = {2025},
author = {Cai, Y and Huang, S and Dong, Y and Li, S and Jin, X},
title = {PIWI-Interacting RNAs in brain health and disease: biogenesis, mechanisms, and therapeutic horizons.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41182353},
issn = {1432-2072},
support = {81971083//National Natural Science Foundation of China/ ; 25JCLZJC00190//Tianjin Natural Science Foundation Project/ ; },
abstract = {PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.},
}

@article {pmid41180593,
year = {2025},
author = {Civita, E and Nicolella, V and Fiorenza, M and Cosimato, V and Castaldo, G and Morra, VB and Moccia, M and Terracciano, D},
title = {Advancing Clinical Use of Neurofilament Light Chain: Translational Insights From Research to Routine Practice.},
journal = {Biomarker insights},
volume = {20},
number = {},
pages = {11772719251364018},
pmid = {41180593},
issn = {1177-2719},
abstract = {Neurofilament Light Chain (NfL) has emerged as a promising biomarker for neurological diseases. NfL, a structural component of axons, is released into cerebrospinal fluid (CSF) and blood following neuro-axonal damage. Highly sensitive immunometric assays have enabled its reliable quantification in blood, facilitating non-invasive monitoring. Several studies demonstrated strong correlations between NfL levels and the risk of developing different neurological diseases and, in individuals already living with a neurological disease, with the risk of worsening. However, interpretation is affected by factors like age, BMI, renal function, and comorbidities. NfL is already utilized as a diagnostic and prognostic biomarker in clinical practice, particularly in specialized centers and research settings, although no FDA-cleared assay is currently available for routine use. Recent research has highlighted that NfL may represent the first of a new generation of neurological biomarkers, with many more ready to come, such as glial fibrillary acidic protein (GFAP), further improving diagnostic and prognostic accuracy. Despite its promising role in the landscape of biomarkers, challenges remain to implement NfL in daily clinical practice, including standardization of assays, defining reference values, and ensuring methodological consistency. Addressing these limitations will be essential for integrating NfL into routine clinical practice, ultimately advancing precision medicine in neurology.},
}

@article {pmid41180498,
year = {2025},
author = {Shamsi, A and Alrouji, M and AlOmeir, O and Tasqeruddin, S and Dinislam, K and Zuberi, A},
title = {CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1681891},
pmid = {41180498},
issn = {1662-5102},
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, ALS, and spinocerebellar ataxia are becoming more prevalent as populations age, posing major global health challenges. Despite decades of research, effective treatments that halt or reverse these conditions remain elusive. Aging is the most significant risk factor in the development of these diseases, intertwining with molecular processes like DNA damage, mitochondrial dysfunction, and protein aggregation. Recent advances in gene-editing technologies, particularly CRISPR-Cas9, are beginning to shift the therapeutic landscape. This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone. In this review, we explore how CRISPR-Cas9 is being leveraged to target key genes implicated in various neurodegenerative conditions and how it may overcome barriers posed by aging biology. We also examine the delivery systems and safety challenges that must be addressed before clinical application. With continued progress, CRISPR-Cas9 could mark a turning point in our ability to treat or even prevent age-related neurological decline.},
}

@article {pmid41179113,
year = {2025},
author = {Luo, Y and Xu, Z and Li, Z},
title = {Advances in Induced Pluripotent Stem Cell Reprogramming and Its Application in Amyotrophic Lateral Sclerosis: A Review.},
journal = {FASEB bioAdvances},
volume = {7},
number = {11},
pages = {e70065},
pmid = {41179113},
issn = {2573-9832},
abstract = {Since Yamanaka's landmark achievement in reprogramming somatic cells into induced pluripotent stem cells (iPSCs) using the four key transcription factors-OCT4, SOX2, KLF4, and c-Myc (OSKM)-iPSC technology has made significant strides. Notable advancements include refining reprogramming factors, delivery systems, somatic cell selection, and optimization of reprogramming conditions, along with developing chemical reprogramming methods. With their unparalleled proliferative capacity and near-pluripotent differentiation potential, iPSCs have become invaluable tools for investigating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Neuronal models derived from ALS patient-specific iPSCs, particularly iPSC-derived motor neurons (iPSC-MNs), offer a robust platform to recapitulate disease-specific pathology and investigate the molecular mechanisms underpinning ALS, thereby accelerating the discovery of novel therapeutic strategies. This review highlights the evolution of iPSC technology and its transformative applications in ALS modeling, drug discovery, and therapeutic development.},
}

@article {pmid41178826,
year = {2025},
author = {Stern, C and Semendric, I and Shrestha, N and Beasley-Hall, J and Hasanoff, S and Barker, T and Pollock, D and Schubert, C and Giles, L and Vucic, S and Merlin, T and Munn, Z},
title = {Guidelines addressing Motor Neurone Disease (MND): a scoping review.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/17582024.2025.2573608},
pmid = {41178826},
issn = {1758-2032},
abstract = {INTRODUCTION: Motor Neurone Disease (MND) is a debilitating neurodegenerative condition affecting individuals, families, and carers. Evidence-informed care can improve outcomes, and guidelines play a key role in supporting this. A preliminary search showed limited guidelines exist, with none developed for the Australian context. This review aimed to identify existing health and social care guidelines for MND.

METHODS: A scoping review was conducted using Joanna Briggs Institute (JBI) methodology. Guidelines addressing health and social care for people with MND, gene carriers, family members, or carers were included regardless of publication status. Five databases and additional sources were searched. Two reviewers independently screened citations, and data were extracted and analysed descriptively, with qualitative content analysis grouping guideline questions. Reporting followed PRISMA-ScR.

RESULTS: Forty-two guidelines covering 133 questions were included. Most focused on symptom management for people with MND and were produced by professional bodies. Few used GRADE methodology or systematic reviews, and only seven assessed risk of bias. No guideline was developed for Australia.

CONCLUSIONS: A high-quality, evidence-based MND guideline following best practice development methods is needed.},
}

@article {pmid41178159,
year = {2025},
author = {Mosna, S and Dormann, D},
title = {TDP-43 Phosphorylation: Pathological Modification or Protective Factor Antagonizing TDP-43 Aggregation in Neurodegenerative Diseases?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e70084},
doi = {10.1002/bies.70084},
pmid = {41178159},
issn = {1521-1878},
support = {//Deutsche Forschungsgemeinschaft (DFG)/ ; //VERUM Foundation/ ; },
abstract = {TDP-43 is a ubiquitously expressed RNA-binding protein that aggregates in the brains of patients suffering from neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease. Aggregated TDP-43 in these diseases is hyperphosphorylated in its C-terminal intrinsically disordered region, while physiological TDP-43 is normally unphosphorylated. Whether TDP-43 phosphorylation is a pathological driver, or rather a protective antagonist of TDP-43 aggregation and consequently neurodegeneration, is still debated and a matter of ongoing research. Here, we review current knowledge about TDP-43 phosphorylation in disease and the kinases and phosphatases that regulate this post-translational modification. We discuss how TDP-43 phosphorylation is thought to shape TDP-43's phase separation, aggregation and toxicity in neurodegenerative diseases. We highlight recent research that provides evidence that hyperphosphorylation antagonizes TDP-43 phase separation and aggregation, and speculate about a potential role of condensates in TDP-43 phosphorylation.},
}

@article {pmid41176929,
year = {2025},
author = {Akan, T and Akan, S and Alp, S and Ledbetter, CR and Tafti, AP and Arevalo, O and Bhuiyan, MAN},
title = {Deep Learning in neuroimaging for neurodegenerative diseases: State-of-the art, Challenges, and Opportunities.},
journal = {Journal of the neurological sciences},
volume = {478},
number = {},
pages = {123735},
doi = {10.1016/j.jns.2025.123735},
pmid = {41176929},
issn = {1878-5883},
abstract = {Neuroimaging is commonly used to diagnose neurodegenerative diseases (NDDs), providing crucial insights into brain changes before clinical symptoms manifest. Deep learning (DL) for neuroimaging can improve early diagnosis and disease monitoring. Clinical implementation of DL faces challenges in accurately representing real-world data. Recent models, particularly those focused on diagnostic categorization, have achieved high accuracy, but their applicability to patients is limited. Conflicting inferences have been reported, with findings from small cohorts generalizing conclusions without considering inter-scanner, intra- and inter-site variations. A theoretically feasible method involves gathering a comprehensive dataset that encompasses all patient demographics, but this presents practical challenges including harmonization, data incompleteness, class imbalance, and substantial costs. Existing research has also mostly focused on common NDDs like Alzheimer's Disease (AD) and Parkinson's Disease (PD). This contribution expands the literature by looking at a wider range of NDDs, exploring the latest advancements in applying deep learning algorithms to neuroimaging analysis for the diagnosis and monitoring of NDDs, including AD, Frontotemporal Dementia (FTD), Lewy Body Dementia, PD, Huntington's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. We emphasize how these approaches are handling spatial/temporal information available in brain volume imaging data. We conclude by discussing the challenges associated with the use of voxel-based, patch-based, ROI-based, and slice-based approaches in brain volume imaging. These challenges are further compounded by issues such as inter-site and inter-scanner variability, class imbalances in medical datasets, and the scarcity of accurately annotated data, all of which impact the performance and generalizability of deep learning models.},
}

@article {pmid41165792,
year = {2025},
author = {Goerdt, LA and Brandl, C and Schuster, AK and Rauscher, FG and Finger, RP and Mauschitz, MM},
title = {[Neurodegeneration and retinal changes-A literature overview].},
journal = {Zeitschrift fur Gerontologie und Geriatrie},
volume = {},
number = {},
pages = {},
pmid = {41165792},
issn = {1435-1269},
abstract = {BACKGROUND: The eyes and the central nervous system (CNS) develop from the same embryonic tissue which explains why retinal changes have been observed in various neurological and neurodegenerative diseases. These changes can be visualized in vivo on a cellular and subcellular level using optical coherence tomography (OCT). This article summarizes which retinal changes occur and how these could be used as potential biomarkers of neurodegenerative diseases.

OBJECTIVE: The article gives an overview of the literature on the relationship between neurodegeneration, OCT-based retinal characteristics and cognitive functions.

METHODS: A literature search was carried out in PubMed until February 2025. The search terms "neurodegeneration", "dementia", "mild cognitive impairment", "mild neurocognitive disorder", "OCT", "OCT angiography (OCT-A)", "retinal biomarkers", "retinal layer", "RNFLT", and "GCL" were used. Relevant publications were reviewed, analyzed and summarized.

RESULTS: In OCT‑A Alzheimer's disease, frontotemporal dementia, vascular dementia, amyotrophic lateral sclerosis, multiple sclerosis (MS) and Parkinson's disease demonstrate an association with a reduced retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) thickness as well as an enlarged foveal avascular zone.

CONCLUSION: So far retinal changes could not be specifically assigned to a particular form of neurodegenerative disease,; however, they could be meaningful in neuropsychological/radiological examinations and for longitudinal monitoring, as already recommended for MS. Further longitudinal studies are needed to identify and validate retinal biomarkers (patterns).},
}

@article {pmid40975951,
year = {2025},
author = {von Quednow, E and Husain, N and Łajczak, P and Linha Secco, G and Koppanatham, A},
title = {Diagnostic accuracy of the Gold Coast Criteria for amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {179},
number = {},
pages = {2111005},
doi = {10.1016/j.clinph.2025.2111005},
pmid = {40975951},
issn = {1872-8952},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Sensitivity and Specificity ; },
abstract = {OBJECTIVE: To compare the diagnostic accuracy of Gold Coast Criteria (GCC) with Revised El Escorial Criteria (rEEC) and Awaji Criteria (AC) in suspected amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, and Google Scholar were searched through December 2024. Eligible studies assessed patients using GCC, rEEC, and/or AC, reporting or allowing calculation of sensitivity and specificity. Quality was evaluated using QUADAS-2 and STARD. "Probable+" included probable and definite classifications; "Possible+" encompassed possible to definite. Sensitivity analyses excluded the largest study with imputed data and included a sensitivity-only model. PRISMA-DTA compliant; PROSPERO CRD42025623678.

RESULTS: Nine studies (n = 9656), all from ALS referral centers, were included. GCC showed higher sensitivity (∼95 %) than rEEC and AC Probable+ (59 % and 54 %) and Possible+ (84 % and 85 %), but lower specificity (66 %) vs. rEEC (Probable+ 94 %, Possible+ 77 %) and AC (Probable+ 94 %, Possible+ 82 %). GCC achieved the highest AUC (0.95) and diagnostic odds ratio (36.1). Sensitivity-only analysis confirmed GCC performance (97 %).

CONCLUSIONS: GCC demonstrated superior sensitivity, potentially facilitating earlier recognition and trial inclusion. Their lower specificity requires caution, particularly in low-prevalence contexts. Applicability in unselected neurology populations remains uncertain.

SIGNIFICANCE: GCC may enable earlier ALS diagnosis and timely trial enrollment in referral centers.},
}

*Amyotrophic Lateral Sclerosis/diagnosis
Humans
Sensitivity and Specificity

@article {pmid40998074,
year = {2025},
author = {Fischer, I},
title = {Considering Big tau as a novel and specific biomarker for spinal motor neuron pathology.},
journal = {Neurobiology of disease},
volume = {216},
number = {},
pages = {107118},
doi = {10.1016/j.nbd.2025.107118},
pmid = {40998074},
issn = {1095-953X},
mesh = {Humans ; *tau Proteins/metabolism ; Biomarkers/metabolism ; *Motor Neurons/pathology/metabolism ; Animals ; *Spinal Cord/pathology/metabolism ; *Motor Neuron Disease/metabolism/pathology/diagnosis ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; },
abstract = {Big tau is an isoform of tau that includes the large 4 A exon, resulting in an extended projection domain and an overall increase in apparent molecular weight from 40 to 65 kDa to 95-110 kDa. Its expression is highly restricted to the peripheral and autonomic nervous systems and select regions of the central nervous system. Although the precise function of Big tau remains unclear, we have proposed that the expanded projection domain of low molecular weight (LMW) tau by 250 amino acids of exon 4a and its structural properties may enhance axonal transport in long-projecting neurons and confer resistance to aggregation. Here, we propose a clinical perspective based on the properties of Big tau: the selective expression of Big tau in spinal motor neurons, but not in upper motor neurons or other spinal neuronal populations, is likely to make Big tau a specific biomarker for spinal motor neuron pathology. This expression pattern may be particularly valuable for tracking disease prognosis and progression in conditions such as amyotrophic lateral sclerosis (ALS) and related disorders, to identify when degeneration advances to lower motor neurons. Big tau could thus serve as a more specific biomarker to neurofilament or LMW tau proteins or can be used in combination with other biomarkers to enhance the specificity and sensitivity. This hypothesis can be readily tested using existing samples and assays applied to cerebrospinal fluid (CSF) and blood samples from patients. If validated through clinical studies, Big tau may provide clinicians with a new tool to better diagnose and monitor a variety of motor neuron degenerative disorders. To accelerate research in this area, I offer to share experimental data and an inventory of polyclonal antibodies specific to Big tau to the research community to enable further investigation of Big tau as a clinical biomarker.},
}

Humans
*tau Proteins/metabolism
Biomarkers/metabolism
*Motor Neurons/pathology/metabolism
Animals
*Spinal Cord/pathology/metabolism
*Motor Neuron Disease/metabolism/pathology/diagnosis
Amyotrophic Lateral Sclerosis/metabolism/pathology

@article {pmid41164103,
year = {2025},
author = {},
title = {Edaravone for amyotrophic lateral sclerosis.},
journal = {Australian prescriber},
volume = {48},
number = {5},
pages = {182-183},
pmid = {41164103},
issn = {0312-8008},
}

@article {pmid41158661,
year = {2025},
author = {Tao, F and Lin, M and Meng, X and Huang, L and Zhuo, B and Jiang, S and Deng, S and Meng, Z and Shi, J},
title = {Copper homeostasis and cuproptosis: implications for neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1688554},
pmid = {41158661},
issn = {1663-4365},
abstract = {Copper (Cu) is a vital trace element required for sustaining life and is involved in numerous critical metabolic processes within the body. Cuproptosis, a newly recognized type of Cu-dependent cell death, is mechanistically distinct from apoptosis, autophagy, pyroptosis, and ferroptosis. It is characterized by abnormal Cu accumulation and aberrant interactions with key enzymes of the tricarboxylic acid (TCA) cycle, which lead to protein aggregation, loss of iron-sulfur cluster proteins, and proteotoxic stress, ultimately leading to cell death. Recent studies have revealed that Cu dyshomeostasis and cuproptosis are intricately linked to the pathological progression of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Wilson's disease (WD), and Menkes disease (MD). In this review, we systematically elucidate the systemic Cu metabolism, the molecular mechanisms of cuproptosis, and its intricate interplay with different neurodegenerative disorders. We also examined the relationship between cuproptosis and other types of cell death. Finally, we discuss therapeutic strategies targeting cuproptosis and Cu dyshomeostasis to combat neurodegenerative diseases and propose potential directions for future research.},
}

@article {pmid40975292,
year = {2025},
author = {Lewis, KN and Gonsalvez, DG and Turner, BJ and Barton, SK},
title = {Schwann cells as a therapeutic target for amyotrophic lateral sclerosis: A TDP-43 focussed review.},
journal = {Neurochemistry international},
volume = {190},
number = {},
pages = {106055},
doi = {10.1016/j.neuint.2025.106055},
pmid = {40975292},
issn = {1872-9754},
mesh = {Humans ; *Schwann Cells/metabolism/drug effects/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/therapy/pathology ; Animals ; *DNA-Binding Proteins/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable, lethal neurodegenerative disease and a proteinopathy with >97 % of cases characterised by pathological accumulation of TDP-43. TDP-43 is ubiquitously expressed and its pathological accumulation has now been identified in non-neuronal cells in both the central and peripheral nervous systems. Thus, the expansion to exploring other cells and their contribution to ALS pathogenesis may be the key to finding more effective treatments. Schwann cells are the myelinating cells of the peripheral nervous system, that encase neuronal axons to propagate action potentials, maintain neuronal health, and respond to neuronal activity in the extracellular environment. Despite Schwann cells being identified to exhibit aberrant TDP-43 proteinopathy in ALS patients, their role in disease remains elusive. Here, we review the potential contributions of Schwann cells to ALS as well as the prospective benefits of harnessing Schwann cells treat the disease.},
}

Humans
*Schwann Cells/metabolism/drug effects/pathology
*Amyotrophic Lateral Sclerosis/metabolism/therapy/pathology
Animals
*DNA-Binding Proteins/metabolism

@article {pmid41157172,
year = {2025},
author = {Carata, E and Destino, M and Tenuzzo, BA and Panzarini, E},
title = {Inter-Organ Crosstalk in Neurodegenerative Disease.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/life15101499},
pmid = {41157172},
issn = {2075-1729},
abstract = {Inter-organ communication plays a vital role in the pathogenesis of neurodegenerative diseases (ND), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS). Emerging research highlights the involvement of the gut-brain axis, immune system, and peripheral metabolic systems in modulating neuroinflammation, protein misfolding, and neuronal dysfunction by releasing cytokines, adipokines, growth factors, and other soluble factors, which in turn affect neuronal health and systemic inflammation. This review explores the complex bidirectional interactions between the brain and peripheral organs, including the gut, adipose tissue, liver, muscle, bone and immune system. Notably, the gut microbiome's role in neurodegenerative diseases through the gut-brain axis, the impact of adipose tissue in inflammation and metabolic regulation, and the muscle-brain axis with its neuroprotective myokines are also discussed. Additionally, we examine the neuro-immune axis, which mediates inflammatory responses and exacerbates neurodegeneration, and liver-brain axis that is implicated in regulating neuroinflammation and promoting disease progression. Dysregulation of inter-organ pathways contributes to the systemic manifestations of neurodegenerative diseases, offering insights into both potential biomarkers and therapeutic targets, and, in turn, promising strategies for preventing, diagnosing, and treating neurodegenerative diseases.},
}

@article {pmid41155689,
year = {2025},
author = {Ruffo, P and Perrone, B and Perrone, F and De Amicis, F and Iuliano, R and Bucci, C and Messina, A and Conforti, FL},
title = {The Other Side of the Same Coin: Beyond the Coding Region in Amyotrophic Lateral Sclerosis.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101573},
pmid = {41155689},
issn = {1424-8247},
support = {2022XTM2S3//Ministero dell'università e della ricerca/ ; P20225J5NB//Ministero dell'università e della ricerca/ ; },
abstract = {Transposable elements (TEs), once regarded as genomic "junk," are now recognized as powerful regulators of gene expression, genome stability, and innate immunity. In the context of neurodegeneration, particularly Amyotrophic Lateral Sclerosis (ALS), accumulating evidence implicates TEs as active contributors to disease pathogenesis. ALS is a fatal motor neuron disease with both sporadic and familial forms, linked to genetic, epigenetic, and environmental factors. While coding mutations explain a subset of cases, advances in long-read sequencing and epigenomic profiling have unveiled the profound influence of non-coding regions-especially retrotransposons such as LINE-1, Alu, and SVA-on ALS onset and progression. TEs may act through multiple mechanisms: generating somatic mutations, disrupting chromatin architecture, modulating transcriptional networks, and triggering sterile inflammation via innate immune pathways like cGAS-STING. Their activity is normally repressed by epigenetic regulators, including DNA methylation, histone modifications, and RNA interference pathways; however, these controls are compromised in ALS. Taken together, these insights underscore the translational potential of targeting transposable elements in ALS, both as a source of novel biomarkers for patient stratification and disease monitoring, and as therapeutic targets whose modulation may slow neurodegeneration and inflammation. This review synthesizes the current knowledge of TE biology in ALS; integrates findings across molecular, cellular, and systems levels; and explores the therapeutic potential of targeting TEs as modulators of neurodegeneration.},
}

@article {pmid41155541,
year = {2025},
author = {Perez, DM},
title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101425},
pmid = {41155541},
issn = {1424-8247},
support = {RO1AG066627/GF/NIH HHS/United States ; },
abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.},
}

@article {pmid41155167,
year = {2025},
author = {Sharbafshaaer, M and Pepe, R and Notariale, R and Canale, F and Tedeschi, G and Tessitore, A and Bergamo, P and Trojsi, F},
title = {Beyond Antioxidants: The Emerging Role of Nrf2 Activation in Amyotrophic Lateral Sclerosis (ALS).},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209872},
pmid = {41155167},
issn = {1422-0067},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *NF-E2-Related Factor 2/metabolism/genetics ; Animals ; *Antioxidants/metabolism ; Oxidative Stress ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial-neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1-Nrf2 protein-protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2's therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots.},
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics
Humans
*NF-E2-Related Factor 2/metabolism/genetics
Animals
*Antioxidants/metabolism
Oxidative Stress

@article {pmid41154657,
year = {2025},
author = {Nhieu, J and Wei, LN},
title = {Targeting CRABP1 Signalosomes in Managing Neurodegeneration.},
journal = {Biomolecules},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/biom15101428},
pmid = {41154657},
issn = {2218-273X},
support = {R01NS132277//National Institute of Health/ ; },
mesh = {Humans ; Animals ; *Receptors, Retinoic Acid/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/drug therapy ; Signal Transduction/drug effects ; Tretinoin/metabolism/pharmacology ; },
abstract = {Retinoic acid (RA) binds RA (RAR) and Retinoid X (RXR) receptors to elicit biological effects by regulating transcription. RA is also known to have non-canonical activities mediated, primarily, by cellular retinoic acid-binding protein 1 (CRABP1) which forms protein complexes named "CRABP1 signalosomes" to regulate cytosolic signaling independent of RARs/RXRs. This review focuses on therapeutic applications in neurodegeneration by targeting CRABP1 signalosomes including CRABP1-MAPK, CRABP1-CaMKII, CRABP1-eIF2α, and others recently identified from our proteomic studies. The mouse Crabp1 gene is regulated by various epigenetic factors and is important for the health of multiple cell types including motor neurons (MNs). In humans, CRABP1 gene expression is reduced in ALS- and SMA-patient MNs. RA is a therapeutic agent for leukemias and dermatological disorders and is being investigated for managing neurodegenerative diseases, but its therapeutic effects are accompanied by RAR-mediated toxic effects. We have uncovered a novel class of synthetic retinoids that bind CRABP1 without acting on RARs, circumventing RAR-mediated toxic effects. These first-generation CRABP1-selective compounds C3, C4, and C32 target CRABP1-MAPK and/or CRABP1-CaMKII signalosomes. This knowledge, together with emerging structural information, sheds lights on the strategies in designing next-generation CRABP1-signalosome-selective retinoids for the management of neurodegenerative diseases.},
}

Humans
Animals
*Receptors, Retinoic Acid/metabolism/genetics
*Neurodegenerative Diseases/metabolism/drug therapy
Signal Transduction/drug effects
Tretinoin/metabolism/pharmacology

@article {pmid41151740,
year = {2025},
author = {Bhatia, T and Godad, A},
title = {Disrupted proteostasis and ionic imbalance in TDP-43 and tauopathies: Dual drivers of neurodegeneration.},
journal = {Life sciences},
volume = {382},
number = {},
pages = {124055},
doi = {10.1016/j.lfs.2025.124055},
pmid = {41151740},
issn = {1879-0631},
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's Disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal dysfunction and protein aggregation. There is a growing body of evidence suggesting that the collapse of proteostasis, the failure of protein homeostasis, is an important contributor to neurotoxicity. In this review, we suggest that this collapse is exacerbated by ionic dysregulation, an important but under-addressed cause of neurodegeneration. Importantly, breakdowns in chloride, bicarbonate, sodium, and calcium homeostasis alter fundamental aspects of cellular physiology, including important aspects of TDP-43 phase separation and tau hyperphosphorylation and aggregation. We suggest that the relationship of proteostasis failure and ionic dysregulation is a bidirectional feedback loop that accelerates the progression of neurodegeneration. Some therapeutic strategies aimed at correcting these mechanisms-including small-molecule chaperone inducers, autophagy inducers, and ion-channel modulators-might hold the potential for disease modification. In this review, we document the complex intersections of proteostasis failure and ionic dysregulation in TDP-43 and tauopathies and provide new ideas for therapies and future studies.},
}

@article {pmid41149991,
year = {2025},
author = {Kwiatkowska, A and Grzeczkowicz, A and Lipko, A and Kazimierczak, B and Granicka, LH},
title = {Emerging Approaches to Mitigate Neural Cell Degeneration with Nanoparticles-Enhanced Polyelectrolyte Systems.},
journal = {Membranes},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/membranes15100313},
pmid = {41149991},
issn = {2077-0375},
abstract = {Counteracting neurodegenerative diseases (NDs) presents a multifaceted challenge in the aging societies of Western countries. Each year, millions of people worldwide are affected by such ailments as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), spinal cord injury, ischemic stroke, motor neuron disease, spinal muscular atrophy, spinocerebellar ataxia, and amyotrophic lateral sclerosis (ALS). Advancements in modern biomaterial technologies present substantial opportunities for the field of regenerative medicine. Nevertheless, limitations arise from the requirement that biomaterial design be tailored to the specific biological parameters of the target cell types with which they are intended to interact. Such an opportunity creates nanomaterials involving nanoparticles. The surface chemistry of nanoparticles, especially when functionalized with bioactive agents, enhances biocompatibility and facilitates interactions with nervous cells. Herein, we review contemporary strategies in the application of biomaterials for nerve regeneration, with particular emphasis on nanomaterials and biocompatible polyelectrolyte layers, which the authors identify as having the most significant potential to drive transformative advances in regenerative medicine in the near future.},
}

@article {pmid41149102,
year = {2025},
author = {Mauriello, L and Cuozzo, A and Pezzella, V and Isola, G and Spagnuolo, G and Iorio-Siciliano, V and Ramaglia, L and Blasi, A},
title = {Oral Health Status in Patients with Amyotrophic Lateral Sclerosis: A Scoping Review.},
journal = {Dentistry journal},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/dj13100455},
pmid = {41149102},
issn = {2304-6767},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome which often leads to progressive muscular dysfunction and therefore oral health deterioration. The aim of this scoping review is to evaluate oral health status in ALS patients focusing on the importance of dental care in improving patient's quality of life. Methods: A comprehensive literature search was conducted on PubMed, Scopus, Web of Science, and Embase databases until June 2025 using a combination of keywords and MeSH terms related to ALS and oral health. Studies were screened and selected based on inclusion and exclusion criteria, focusing on human clinical data reporting oral health outcomes in ALS. Results: Eight studies met the inclusion criteria. The findings showed a high prevalence of oral complications in bulbar-onset ALS patients. Common issues included reduced tongue mobility, poor oral hygiene, sialorrhea, and decreased masticatory function were evaluated. Conclusions: Oral health impairment in ALS patients frequently contributes to systemic risks and reduced quality of life. A dental expert may play an important role in multidisciplinary care teams in terms of early diagnosis and conservative treatment of oral diseases ranging from periodontal disease to temporomandibular disorders (TMD). Personalized oral hygiene strategies and adjunctive therapies may serve as key elements in maintaining overall health and patient comfort in ALS. Therefore, the objective of the following review was to evaluate oral health complication in patients with ALS, highlighting the impact of oral care on patients' quality of life.},
}

@article {pmid41148800,
year = {2025},
author = {Salmaso, V and Menin, S and Moro, S and Spalluto, G and Federico, S},
title = {Adenosine Receptors in Neuroinflammation and Neurodegeneration.},
journal = {Cells},
volume = {14},
number = {20},
pages = {},
doi = {10.3390/cells14201585},
pmid = {41148800},
issn = {2073-4409},
mesh = {Humans ; *Receptors, Purinergic P1/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism ; Adenosine/metabolism ; *Inflammation/metabolism ; },
abstract = {Adenosine plays a crucial role in various pathophysiological conditions, including neuroinflammation and neurodegeneration. Neuroinflammation can be either beneficial or detrimental to the central nervous system, depending on the intensity and duration of the inflammatory response. Across a wide range of brain disorders, neuroinflammation contributes to both the onset and progression of disease. Notably, neuroinflammation is not limited to conditions primarily classified as neuroinflammatory but is also a key factor in other neurological disorders, including life-threatening neurodegenerative diseases. All four adenosine receptor subtypes (A1, A2A, A2B, and A3) are implicated, to varying degrees, in these conditions. This review aims to summarize the roles of individual adenosine receptor subtypes in neuroinflammation and neurodegenerative diseases, emphasizing their therapeutic potential. While some therapeutic applications are well-established with clinically approved drugs, others warrant further investigation due to their promising potential.},
}

Humans
*Receptors, Purinergic P1/metabolism
*Neurodegenerative Diseases/metabolism
Animals
*Neuroinflammatory Diseases/metabolism
Adenosine/metabolism
*Inflammation/metabolism

@article {pmid41148458,
year = {2025},
author = {Goel, F and Kumar, D and Singh, P and Rai, SN and Yadav, DK},
title = {Molecular crosstalk between miRNAs and lncRNAs in neurodegenerative disease pathways.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {16},
pmid = {41148458},
issn = {1573-4978},
mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; Gene Expression Regulation ; Animals ; Signal Transduction ; Gene Regulatory Networks ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal degeneration and dysfunction. Of recent interest, a series of studies have been targeting the role of non-coding RNAs, particularly miRNAs and lncRNAs, in regulating gene expression and influencing cellular pathways that may play a critical role in the pathogenesis of these diseases. miRNAs regulate many biological processes by degrading or repressing the translation of target mRNAs, whereas lncRNAs act as scaffolds, sponges, and guides to control gene expression and cellular activities. Both miRNAs and lncRNAs participate in neurodegenerative mechanisms such as protein aggregation, inflammation, oxidative stress, and neuroinflammation. While targeting miRNAs and lncRNAs holds promise for potential therapeutic benefits, problems persist with their efficient delivery, specificity, and off-target effects. New techniques like viral vectors, lipid nanoparticles, and CRISPR-based gene editing will further enhance the development of therapies based on miRNA and lncRNA. Moreover, their interaction with regulatory networks may present new avenues toward understanding disease mechanisms and guiding therapeutic design. This review covers the role of miRNAs and lncRNAs in neurodegenerative disorders, their therapeutic potential, challenges, and future directions in ncRNA-based treatment approaches.},
}

Humans
*RNA, Long Noncoding/genetics/metabolism
*MicroRNAs/genetics/metabolism
*Neurodegenerative Diseases/genetics/metabolism/therapy
Gene Expression Regulation
Animals
Signal Transduction
Gene Regulatory Networks

@article {pmid41146616,
year = {2025},
author = {Roberts, L and Trakman, G and Furness, K and Farrugia, E},
title = {Risks and Benefits of Gastrostomy in Non-Motor Neurone Disease Progressive Neurological Diseases: A Systematic Review.},
journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association},
volume = {38},
number = {6},
pages = {e70144},
doi = {10.1111/jhn.70144},
pmid = {41146616},
issn = {1365-277X},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Humans ; *Gastrostomy/adverse effects/methods ; Parkinson Disease/surgery ; Risk Assessment ; Enteral Nutrition ; Multiple Sclerosis/surgery/therapy ; *Nervous System Diseases/surgery ; Adult ; Huntington Disease/surgery ; },
abstract = {OBJECTIVES: This review aimed to synthesise current evidence on the effects of gastrostomy in Parkinson's disease (PD) and parkinsonism, Multiple Sclerosis (MS) and Huntington's disease (HD).

PURPOSE: Evidence regarding the risks and benefits of gastrostomy insertion and use in progressive neurological diseases, excluding Motor Neurone Disease (MND), is lacking, causing gastrostomy decision-making discussions to arise as a matter of debate in practice.

METHODS: Three databases (Web of Science, Ovid Medline and Embase) were searched for research on the impacts of gastrostomy, including survival, complication rates, nutrition changes, in adults with progressive neurological diseases, excluding MND. Quality was assessed using the Academy of Nutrition and Dietetics Quality Criteria Checklist: Primary Research, and a narrative synthesis was conducted.

RESULTS: Twelve (n = 12) studies were eligible for inclusion, with either retrospective cohort (n = 12) or cross-sectional (n = 1) design, examining the effects of percutaneous endoscopic gastrostomy (PEG) (n = 8), radiologically inserted gastrostomy (RIG) (n = 1) or gastrostomy not further defined (n = 4) in adults with PD (n = 6), parkinsonism (n = 3), MS (n = 3), or HD (n = 3). There was variability in outcomes and comparators with inconclusive results. Quality was assessed as positive (n = 3) or neutral (n = 9). Gastrostomy appears to be associated with increased care needs in the population of interest.

CONCLUSIONS: Gastrostomy insertion and use in this cohort is poorly investigated. High-quality prospective studies, especially with well-defined nutrition-related outcome measures, and robust statistical analyses are needed to determine the potential benefits of gastrostomy in this population.

TRIAL REGISTRATION: PROSPERO: CRD42024604136.},
}

Humans
*Gastrostomy/adverse effects/methods
Parkinson Disease/surgery
Risk Assessment
Enteral Nutrition
Multiple Sclerosis/surgery/therapy
*Nervous System Diseases/surgery
Adult
Huntington Disease/surgery

@article {pmid41144030,
year = {2025},
author = {Yang, D and Lei, X and Yang, L and He, D},
title = {A novel frameshift mutation in the NEK1 gene causing amyotrophic lateral sclerosis: A case report and literature review.},
journal = {Neurogenetics},
volume = {26},
number = {1},
pages = {75},
pmid = {41144030},
issn = {1364-6753},
mesh = {Humans ; *NIMA-Related Kinase 1/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Frameshift Mutation ; Male ; Aged ; Female ; Middle Aged ; },
abstract = {To investigate a novel NIMA Related Kinase 1 (NEK1) frameshift mutation in amyotrophic lateral sclerosis (ALS), assess its pathogenicity using computational algorithms and genetic databases, and analyze the clinical manifestations of cases carrying the NEK1 genetic mutation. A 65-year-old man with sporadic ALS (sALS) carrying a NEK1 c.2413dup (p.Thr805Asnfs*7) mutation was studied. Clinical and genetic data were evaluated using Mutation Taster and ACMG guidelines. A literature review was conducted in PubMed and CNKI to identify ALS cases with NEK1 mutations. Whole-exome sequencing identified a NEK1 mutation, c.2413dup (p.Thr805Asnfs*7),which is predicted to lead to a truncated protein. A literature review found 19 articles covering 89 mutation sites. Among the recorded cases, sex was reported for 79 cases (47 male,32 female), and age of onset was available for 80 cases, with an average of 56.94 ± 11.88 years. Onset type data were available for 77 cases, of which 49.35% (38/77) had lower motor neuron onset,41.56% (32/77) had upper motor neuron onset, and 9.09% (7/77) had both. Among those with lower motor neuron onset (n = 38),28.95% (11/38) had bulbar onset, and 2.63% (1/38) had respiratory onset. The c.2413dup (p.Thr805Asnfs*7) frameshift mutation in the NEK1 gene is likely pathogenic and may contribute to the onset of ALS. ALS associated with NEK1 mutations appears to be more common in men than women and typically affects individuals in late middle age.},
}

Humans
*NIMA-Related Kinase 1/genetics
*Amyotrophic Lateral Sclerosis/genetics
*Frameshift Mutation
Male
Aged
Female
Middle Aged

@article {pmid41141079,
year = {2025},
author = {Jeong, E and Li, D},
title = {Antisense Oligonucleotide Therapy for Amyotrophic Lateral Sclerosis (ALS): An Umbrella Review.},
journal = {Cureus},
volume = {17},
number = {9},
pages = {e93140},
pmid = {41141079},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, is a fatal neurodegenerative disease prominent in the elderly population. To this point, no completely effective treatments have been procured; however, antisense oligonucleotide therapies, or ASOs, are a promising venue. In order to investigate the efficacy of ASOs in the treatment of ALS by targeting specific genetic mutations, we conducted an umbrella review utilizing keywords such as "ALS" and "ASO" in the PubMed database, excluding sources published more than 10 years ago for relevance. Results revealed that of multiple tentative ASO treatments, for multiple specific gene mutations, only one, Tofersen, was approved for the wider population. The main cause of failure was an inability to meet efficacy endpoints, resulting in the discontinuation of the product. Tofersen is able to treat mutations in the SOD1 gene, but not any others. While initially discouraging, the production of ASOs is a relatively new and advanced process, and slow progress is expected. However, there remains the problem of identifying and treating the much more prevalent sporadic ALS, which is much more common compared to familial ALS.},
}

@article {pmid41140053,
year = {2025},
author = {Obara, K and Ito, D and Nilsson, C and Janelidze, S and Santillo, A and Katsuno, M and Mattsson-Carlgren, N},
title = {Diagnostic and Prognostic Value of Blood and Cerebrospinal Fluid Biomarkers in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.},
journal = {European journal of neurology},
volume = {32},
number = {10},
pages = {e70382},
doi = {10.1111/ene.70382},
pmid = {41140053},
issn = {1468-1331},
support = {//Elsa Schmitz stiftelse för neurologisk och neurokirurgisk forskning/ ; JPMJSP2125//Japan Science and Technology Agency (JST) SPRING/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood/diagnosis ; Biomarkers/cerebrospinal fluid/blood ; Prognosis ; Neurofilament Proteins/cerebrospinal fluid/blood ; },
abstract = {BACKGROUND: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are urgently needed due to diagnostic and prognostic challenges. This systematic review and meta-analysis aimed to synthesize recent evidence on the utility of blood and cerebrospinal fluid (CSF) biomarkers for ALS.

METHODS: We systematically reviewed studies published from January 1, 2019 to March 25, 2025, that evaluated blood or CSF biomarkers for ALS. Eligible studies reported diagnostic performance, group-level biomarker values, hazard ratios (HRs) for survival, or correlations with functional rating scales or disease progression rates. Study quality was assessed using the QUADAS-2 and QUIPS frameworks. Random-effects models were employed to pool summary receiver operating characteristic (SROC) curves, HRs, standardized mean differences, and correlation coefficients.

RESULTS: We included 47 studies in the SROC analysis and 27 in the HR analysis, covering 9078 participants (5556 ALS and 3522 controls). Neurofilament light chain (NfL) consistently demonstrated the highest diagnostic accuracy (sensitivity/specificity: 0.81-0.87 vs. ALS mimics) and high prognostic value (pooled HRs: 2.8-4.3) in both blood and CSF. CSF chitinases and the p-tau/t-tau ratio showed moderate utility. Other biomarkers, including interleukins, had limited clinical relevance. Most studies showed moderate to high risk of bias, with methodological heterogeneity and limited transparency.

CONCLUSIONS: NfL is the most validated biomarker for ALS diagnosis and prognosis, in both blood and CSF. However, its limited accuracy when used alone carries a considerable risk of misclassification. Future studies should adopt prevalence-specific strategies and integrate biomarkers within multimodal frameworks to enhance diagnostic and prognostic precision.},
}

Humans
*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood/diagnosis
Biomarkers/cerebrospinal fluid/blood
Prognosis
Neurofilament Proteins/cerebrospinal fluid/blood

@article {pmid41136086,
year = {2025},
author = {Tran, K and Lussier, BL},
title = {Noninvasive Ventilation in Amyotrophic Lateral Sclerosis.},
journal = {Sleep medicine clinics},
volume = {20},
number = {4},
pages = {547-555},
doi = {10.1016/j.jsmc.2025.07.007},
pmid = {41136086},
issn = {1556-4088},
mesh = {*Amyotrophic Lateral Sclerosis/therapy/complications ; Humans ; *Noninvasive Ventilation/methods ; *Respiratory Insufficiency/therapy/etiology ; },
abstract = {This article explores the role of early noninvasive ventilation in improving the quality of life and survival rates in patients with amyotrophic lateral sclerosis (ALS). It discusses how the goals of ventilatory support may vary depending on whether hospitalization is elective or emergent. The article emphasizes the importance of protocol-based optimization of nocturnal noninvasive positive pressure ventilation, focusing on patient tolerance and neuromuscular considerations. Additionally, it highlights the different approaches required for nocturnal and daytime ventilatory support, underscoring the need for tailored management strategies in ALS care.},
}

*Amyotrophic Lateral Sclerosis/therapy/complications
Humans
*Noninvasive Ventilation/methods
*Respiratory Insufficiency/therapy/etiology

@article {pmid39328135,
year = {2025},
author = {Sharma, S and Mehan, S and Khan, Z and Tiwari, A and Kumar, A and Gupta, GD and Narula, AS and Kalfin, R},
title = {Exploring the Neuroprotective Potential of Icariin through Modulation of Neural Pathways in the Treatment of Neurological Diseases.},
journal = {Current molecular medicine},
volume = {25},
number = {8},
pages = {962-979},
pmid = {39328135},
issn = {1875-5666},
support = {CRG/2021/001009//DST-SERB, Govt. Of India/ ; },
mesh = {Humans ; *Flavonoids/therapeutic use/pharmacology/chemistry ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; Signal Transduction/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; },
abstract = {Neuropathological diseases involve the death of neurons and the aggregation of proteins with altered properties in the brain. Proteins are used at the molecular level to categorize neurodegenerative disorders, emphasizing the importance of protein-processing mechanisms in their development. Natural herbal phytoconstituents, such as icariin, have addressed these neurological complications. Icariin, the principal compound in Epimedium, has been studied for its antineuroinflammatory, anti-oxidative, and antiapoptotic properties. Recent scientific investigations have shown that icariin exhibits promising therapeutic and preventive properties for mental and neurodegenerative disorders. In preclinical, icariin has been shown to inhibit amyloid development and reduce the expression of APP and BACE-1. Previous preclinical studies have demonstrated that icariin can regulate proinflammatory responses in neurological conditions like Parkinson's disease, depression, cerebral ischemia, ALS, and multiple sclerosis. Studies have shown that icariin possesses neuroprotective properties by modulating signaling pathways and crossing the blood-brain barrier, suggesting its potential to address various neurocomplications. This review aims to establish a foundation for future clinical investigations by examining the existing literature on icariin and exploring its potential therapeutic implications in treating neurodegenerative disorders and neuropsychiatric conditions. Future research may address numerous concerns and yield captivating findings with far-reaching implications for various aspects of icariin.},
}

Humans
*Flavonoids/therapeutic use/pharmacology/chemistry
*Neuroprotective Agents/therapeutic use/pharmacology
Animals
Signal Transduction/drug effects
*Nervous System Diseases/drug therapy/metabolism
*Neurodegenerative Diseases/drug therapy/metabolism

@article {pmid41135633,
year = {2025},
author = {Vu, TD and Sung, H},
title = {Endoplasmic reticulum in the axon: Insights into structural dynamics and implications in neurodegeneration.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107152},
doi = {10.1016/j.nbd.2025.107152},
pmid = {41135633},
issn = {1095-953X},
abstract = {The endoplasmic reticulum (ER) is an interconnected and highly dynamic organelle essential for multiple cellular functions. In neurons, the ER extends into axons, where it plays a pivotal role in maintaining neuronal polarity. The unique structural and dynamic adaptations of the axonal ER enable it to meet the specialized demands of neurons, ranging from compartmentalized physiological regulation to long-distance intracellular communication. Recent studies have shown that axonal ER supports the regulation of organelle remodeling and trafficking in a spatiotemporal manner, processes that become compromised in aged neurons. Moreover, disruptions in the structure and dynamics of the axonal ER have increasingly become associated with neurodegenerative diseases, including hereditary spastic paraplegia, amyotrophic lateral sclerosis, and peripheral neuropathies. This review synthesizes current knowledge of axonal ER biology, highlighting its structural and dynamic characteristics, its impact on organelle arrangement and distribution, and its pathological implications in neurodegeneration. By consolidating recent advances, this review outlines emerging questions and future directions in axonal ER research, a field gaining recognition for its contribution to neuronal dysfunction and neurodegenerative pathomechanisms.},
}

@article {pmid41133655,
year = {2025},
author = {Di Fronzo, P and Gaetti, G and Marcassa, D and Gervasi, V and Dardour, O and Pedretti, A and Gambolò, L},
title = {The Impact of ACLS Training in the Management of Cardiac Arrest: A Narrative Review.},
journal = {Epidemiologia (Basel, Switzerland)},
volume = {6},
number = {4},
pages = {},
doi = {10.3390/epidemiologia6040061},
pmid = {41133655},
issn = {2673-3986},
abstract = {BACKGROUND: Cardiac arrests can occur both in and out of hospital settings. Over the years, several protocols have been developed to standardize the behavior of healthcare professionals called upon to deal with these emergencies. Advanced Cardiac Life Support (ACLS) algorithms enable healthcare professionals to effectively manage cardiac arrest and achieve better patient outcomes, particularly at the time of discharge.

METHODS: We conducted a narrative review. Three databases (PubMed, Embase, Cochrane) were searched for relevant articles. The articles were screened and analyzed in accordance with the PRISMA guidelines.

RESULTS: A total of 1252 articles were initially identified. After screening, 11 papers were included in the review. From the selected studies, it has emerged that ACLS training had several positive effects, including an overall decrease in mortality rates. Adherence to ACLS protocols throughout an event is associated with increased Return of Spontaneous Circulation (ROSC) in the setting of In-Hospital Cardiac Arrest (IHCA). Advanced Life Support (ALS) response interval in out-of-hospital cardiac arrest was associated with decreased survival and a favorable neurological outcome. ALS response ≤ 10 min was associated with improved survival and favorable neurological outcomes.

CONCLUSIONS: This review underscores the importance of adherence to ALS/ACLS guidelines in the resuscitation of patients who suffer in-hospital and out-of-hospital cardiac arrest.},
}

@article {pmid41131592,
year = {2025},
author = {Theunissen, F and Flynn, L and Iacoangeli, A and Al Khleifat, A and Al-Chalabi, A and Giordano, JJ and Strømme, M and Akkari, PA},
title = {Entering the era of precision medicine to treat amyotrophic lateral sclerosis.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {111},
pmid = {41131592},
issn = {1750-1326},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Precision Medicine/methods ; },
abstract = {With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy
Humans
*Precision Medicine/methods

@article {pmid41126230,
year = {2025},
author = {Lai, YH and Lin, KH and Huang, HK and Huang, TW and Kuo, YS},
title = {The first case of diaphragm pacing system implantation in a patient with high cervical spinal cord injury in taiwan: a case report and literature review.},
journal = {Journal of cardiothoracic surgery},
volume = {20},
number = {1},
pages = {377},
pmid = {41126230},
issn = {1749-8090},
mesh = {Humans ; *Diaphragm/innervation/physiopathology ; *Spinal Cord Injuries/complications ; Taiwan ; Male ; Laparoscopy/methods ; Middle Aged ; Cervical Vertebrae/injuries ; *Electric Stimulation Therapy/methods ; *Respiratory Insufficiency/etiology/therapy ; },
abstract = {INTRODUCTION: This report presents the first case of a patient with high cervical spinal cord injury who underwent successful laparoscopic implantation of a diaphragm pacing system in Taiwan. It also compares the pros and cons of laparoscopic and thoracoscopic implantation and discusses postoperative care.

BACKGROUND: The diaphragm pacing system (DPS) represents a substantial advancement in respiratory support technology, particularly for patients with chronic respiratory insufficiency. It electrically stimulates the phrenic nerve, which in turn activates the diaphragm-the primary muscle involved in respiration [1]. This stimulation mimics the natural neural impulses that drive diaphragmatic contractions, thereby promoting inhalation and a more efficient lung ventilation. The DPS typically consists of implanted electrodes, an external pulse generator, and connecting leads [2]. It is mainly used in patients with high spinal cord injuries, amyotrophic lateral sclerosis, and central hypoventilation syndrome. These conditions often result in compromised neural control of the diaphragm, leading to severe respiratory insufficiency. By restoring diaphragm function, DPS can enhance the patients' quality of life, reduce dependence on mechanical ventilators, and lower the risk of ventilator-associated complications [3]. Despite its benefits, DPS is not without challenges. Patient selection and the surgical approach are critical to perform successful DPS implantation for the restoration of diaphragm function [4]. This report presents the first case of a patient with cervical spine injury who underwent successful laparoscopic implantation of DPS in Taiwan. Furthermore, it discusses postoperative ICU care and reviews the pros and cons of different surgical approaches to performing DPS implantation.},
}

Humans
*Diaphragm/innervation/physiopathology
*Spinal Cord Injuries/complications
Taiwan
Male
Laparoscopy/methods
Middle Aged
Cervical Vertebrae/injuries
*Electric Stimulation Therapy/methods
*Respiratory Insufficiency/etiology/therapy

@article {pmid41124800,
year = {2025},
author = {Sergeeva, OS and Neklesova, MV and Reushev, VA and Artemov, AV and Kuznetsova, IM and Turoverov, KK and Uversky, VN and Fonin, AV},
title = {On the potential roles of TDP-43 in the formation of membraneless organelles and their transformation into toxic aggregates.},
journal = {Biochemical and biophysical research communications},
volume = {788},
number = {},
pages = {152808},
doi = {10.1016/j.bbrc.2025.152808},
pmid = {41124800},
issn = {1090-2104},
abstract = {Trans-activation response (TAR) DNA-binding protein 43 (TDP-43) is an RNA-binding protein involved in the processing, transport, and regulation of mRNA translation. It is distributed in many tissues, including the brain, where it is found mainly in hippocampal neurons. Abnormal localization, hyperphosphorylation, and aggregation of TDP-43 are pathological signs of a group of neurodegenerative diseases known as TDP-43 proteinopathies. Despite the growing understanding of the physiological role of TDP-43 in ensuring neuronal plasticity and the formation of long-term memory, to date, there is no comprehensive data on the molecular and cellular mechanisms of the transformation of functional membraneless organelles (MLOs) containing TDP-43 into toxic aggregates and the pathogenesis of associated diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This review is devoted to highlighting the role of MLOs in the formation of irreversible aggregates, the role of TDP-43 in the formation of MLOs and their relationship with pathological forms of TDP-43, most often found in people suffering from neurodegenerative diseases.},
}

@article {pmid41122379,
year = {2025},
author = {Takahashi, H and Kasai, T and Miyagawa-Hayashino, A and Ohara, T},
title = {Emerging roles of primary cilia in the pathogenesis of amyotrophic lateral sclerosis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1688839},
pmid = {41122379},
issn = {1662-4548},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons, for which effective disease-modifying therapies remain elusive. Primary cilia are solitary microtubule-based organelles critical for signal transduction and have recently been implicated in ALS pathogenesis. In this review, we provide a basic overview of the structure, dynamics, and functions of primary cilia, particularly in the brain. We highlight accumulating evidence from ALS models showing altered ciliary structure and function and explore how mutations in ALS-associated genes such as NEK1, C21orf2, and C9orf72 disrupt ciliogenesis and ciliary signaling. Moreover, we examine the interplays between primary cilia dysfunction and known ALS-related mechanisms, including loss of proteostasis, abnormal RNA metabolism, microtubule dysfunction, neuroinflammation, and mitochondrial dysfunction. Collectively, the evidence suggests a bidirectional relationship in which ciliary impairment and ALS pathomechanisms reinforce one another in a vicious cycle. We further discuss emerging therapeutic strategies targeting ciliary function, as well as the potential for primary cilia as novel clinical applications. Our review highlights primary cilia as a previously underappreciated yet potentially important component of ALS biology, offering novel insights into disease mechanisms and future therapeutic development.},
}

@article {pmid41118343,
year = {2025},
author = {Cheng, YH and Ho, MS},
title = {Disease-associated microglia in neurodegenerative diseases: Friend or foe?.},
journal = {PLoS biology},
volume = {23},
number = {10},
pages = {e3003426},
pmid = {41118343},
issn = {1545-7885},
mesh = {*Microglia/metabolism/pathology ; Humans ; Animals ; *Neurodegenerative Diseases/pathology/metabolism ; Alzheimer Disease/pathology/metabolism ; Mice ; Disease Models, Animal ; Aging ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Phagocytosis/genetics ; Lipid Metabolism ; Transcriptome ; },
abstract = {Recent advances in single-cell transcriptomics have led to the identification of disease-associated microglia (DAM) as a distinct, conserved microglia state associated with mouse models of Alzheimer's disease (AD) and amyotrophic lateral sclerosis, and with aging. DAM are characterized by downregulation of homeostatic genes and upregulation of lipid metabolism and phagocytosis genes, including key risk factors for AD in humans. Although characterized in models of AD, whether DAM acts as universal sensor across all neurodegenerative diseases remains unknown. This Essay discusses the dynamics, origins, and therapeutic potential of DAM in neurodegeneration, alongside evidence supporting a protective role for them in regulating disease processes.},
}

*Microglia/metabolism/pathology
Humans
Animals
*Neurodegenerative Diseases/pathology/metabolism
Alzheimer Disease/pathology/metabolism
Mice
Disease Models, Animal
Aging
Amyotrophic Lateral Sclerosis/pathology/metabolism
Phagocytosis/genetics
Lipid Metabolism
Transcriptome

@article {pmid41016762,
year = {2025},
author = {Riku, Y and Kobayashi, R},
title = {[Pathomechanisms of frontotemporal lobar degeneration: from view of clinical neuropathology].},
journal = {Rinsho shinkeigaku = Clinical neurology},
volume = {65},
number = {10},
pages = {711-720},
doi = {10.5692/clinicalneurol.cn-002103},
pmid = {41016762},
issn = {1882-0654},
mesh = {Humans ; *Frontotemporal Lobar Degeneration/pathology/genetics/etiology ; tau Proteins/metabolism ; },
abstract = {Frontotemporal lobar degeneration (FTLD) encompasses frontotemporal dementia and related neurological disorders including motor neuron disease and movement disorders. During the 21th century, analyses of aggregative proteins suggested powerful hypotheses of gain-of-neurotoxicity or loss-of-function for aggregation-related proteins. However, recent translational researches in collaboration of basic studies and human pathology indicate that FTLD arises from more complex molecular mechanisms than dyshomeostasis of single molecules. Additionally, accumulation of clinicopathological evidences from various countries, genetic backgrounds or clinical specialties (e.g. neurology and psychiatry), suggests diverse phenotypes of FTLD, which are indicative of future paradigm-shift in the concept of FTLD. In this paper, we discuss FTLD pathomechanism on the basis of human pathology.},
}

Humans
*Frontotemporal Lobar Degeneration/pathology/genetics/etiology
tau Proteins/metabolism

@article {pmid41113933,
year = {2025},
author = {Wang, Z and Cao, W and Fan, D},
title = {Role of lipocalin-2 in amyotrophic lateral sclerosis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1672903},
pmid = {41113933},
issn = {1663-4365},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized pathologically by degeneration of upper and lower motor neurons, ultimately leading to muscle weakness and respiratory failure. Lipocalin-2 (LCN2) is a secreted protein involved in lipid transport that plays a key role in inflammatory responses and the regulation of iron homeostasis. The role of LCN2 in ALS has attracted increasing attention, as significantly elevated LCN2 expression has been observed in the blood and postmortem tissues of ALS patients. Functionally, LCN2 participates in neuroinflammation, iron dysregulation, cell death, and peripheral immune immunity, proposing a central-peripheral linkage hypothesis mediated by LCN2. Clinically, LCN2 shows promise as both a biomarker and a therapeutic target, with multiple strategies demonstrating potential to mitigate ALS pathology. Moving forward, it is essential to integrate multi-omics to deeply decipher LCN2-mediated molecular networks, advance patient stratification, and accelerate its clinical translation.},
}

@article {pmid41113424,
year = {2025},
author = {Maidina, A and Wang, F},
title = {[Advances in the Structure and Function of Neurofilament Protein and Its Application in Early Diagnosis of Amyotrophic Lateral Sclerosis].},
journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition},
volume = {56},
number = {4},
pages = {1145-1151},
pmid = {41113424},
issn = {1672-173X},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Humans ; *Neurofilament Proteins/chemistry/metabolism/physiology ; Early Diagnosis ; Biomarkers ; },
abstract = {Neurofilament proteins (NFs), defined as a type Ⅳ intermediate filaments, are important components of the neuronal cytoskeleton. They play a key physiological role in maintaining the structural integrity and plasticity of axons and in ensuring the axonal transport function. Under pathological conditions, NFs detach from axons and undergo abnormal aggregation, causing axonal transport dysfunction. In addition, some components of the detached NFs leak into the peripheral circulation system. In patients with amyotrophic lateral sclerosis (ALS), the concentration of NFs is significantly elevated in the cerebrospinal fluid and blood, and the changes in NFs concentration is significantly positively correlated with the disease progression of ALS, suggesting the potential of NFs being used as early diagnostic biomarkers for ALS. In this review, we explored the relationship between NFs structure, assembly, and physiological function, focusing on the molecular mechanisms and clinical manifestations of ALS caused by abnormal assembly of NFs. We comprehensively summarized recent advances in the application of NFs as a new humoral biomarkers for early diagnosis and therapeutic monitoring of ALS. Key challenges in biomarker development-including undefined pathological neurofilament light chain (NFL) fragments, limited antibody availability, and poor assay reproducibility-are discussed. Strategies, including ultrasensitive detection technologies such as single molecule array (Simoa), antibody optimization based on pathological fragment identification, and multi-omics biomarker panels, should be integrated. These approaches may lead to breakthroughs, pave the way for precision-based ALS diagnosis, provide theoretical support for promoting its clinical translation and application, and offer ideas for future research.},
}

*Amyotrophic Lateral Sclerosis/diagnosis/metabolism
Humans
*Neurofilament Proteins/chemistry/metabolism/physiology
Early Diagnosis
Biomarkers

@article {pmid41110100,
year = {2025},
author = {Yu, H and Chen, X and Yang, Y and Gu, M and Ren, K and Wei, Z},
title = {Decoding Glycosylation in Neurodegenerative Diseases: Mechanistic Insights and Therapeutic Opportunities.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {20},
pages = {e71160},
pmid = {41110100},
issn = {1530-6860},
support = {82301342//MOST | National Natural Science Foundation of China (NSFC)/ ; 82201455//MOST | National Natural Science Foundation of China (NSFC)/ ; 82470403//MOST | National Natural Science Foundation of China (NSFC)/ ; 82204389//MOST | National Natural Science Foundation of China (NSFC)/ ; },
mesh = {Humans ; Glycosylation ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *Protein Processing, Post-Translational ; Animals ; Biomarkers/metabolism ; },
abstract = {Glycosylation is a highly dynamic and complex post-translational modification that plays a pivotal role in regulating protein folding, trafficking, stability, and function. Accumulating evidence indicates that aberrant glycosylation is intimately involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review provides a comprehensive overview of the molecular mechanisms by which the two predominant forms of glycosylation, N-glycosylation and O-GlcNAcylation, contribute to protein misfolding, synaptic dysfunction, neuroinflammation, and impaired stress responses in the diseased nervous system. We further explore the diagnostic potential of glycosylation biomarkers and emerging therapeutic strategies targeting glycosylation pathways. Special emphasis has been placed on recent advances in glycomic technologies, artificial intelligence-driven analytics, and nanocarrier-based drug delivery platforms. By integrating mechanistic insights with translational applications, this review highlights glycosylation as both a pathological driver and a promising therapeutic target in neurodegenerative disorders.},
}

Humans
Glycosylation
*Neurodegenerative Diseases/metabolism/therapy/pathology
*Protein Processing, Post-Translational
Animals
Biomarkers/metabolism

@article {pmid41107992,
year = {2025},
author = {Wu, S},
title = {Fixed-effect or random-effect models? A methodological reappraisal of subgroup analyses in mesenchymal stem cell therapy for knee osteoarthritis.},
journal = {Stem cell research & therapy},
volume = {16},
number = {1},
pages = {572},
pmid = {41107992},
issn = {1757-6512},
mesh = {Humans ; *Osteoarthritis, Knee/therapy ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/cytology ; },
abstract = {We commend Cao et al. for their systematic review demonstrating the efficacy of intra-articular mesenchymal stem cell (MSC) therapy in alleviating pain and improving function in patients with non-surgical knee osteoarthritis (OA). However, we reanalyzed their subgroup analyses to evaluate the methodological implications of statistical model selection (fixed-effect vs. random-effect models) on result reliability. In dose-stratified analyses, Cao et al. applied fixed-effect models to low-dose (I[2] = 0%) and high-dose (I[2] = 80%) MSC subgroups. Upon reanalysis using random-effect models, the high-dose group showed no statistically significant differences in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total scores compared to the control group at 6 months [MD = 8.75; 95% CI (-2.10, 19.61); P = 0.11] or 12 months [MD = 12.68; 95% CI (-4.96, 30.32); P = 0.16], contrasting with Cao et al.'s original findings. The low-dose subgroup, with no heterogeneity, yielded identical results across both models. Similarly, in cell-source stratification (adipose-derived MSCs [ADMSCs] vs. bone marrow-derived MSCs [BM-MSCs]), reanalysis of ADMSCs using random-effect models demonstrated significant 6-month WOMAC improvement [MD = 9.32; 95% CI (3.73, 14.92); P = 0.001] but non-significant 12-month differences [MD = 12.90; 95% CI (-1.76, 27.55); P = 0.08], diverging from Cao et al.'s conclusions. BM-MSCs results remained consistent due to negligible heterogeneity (I[2] = 0%). These findings underscore that fixed-effect models artificially narrow confidence intervals in heterogeneous populations, overestimating clinical significance. Our results align with Cochrane guidelines, emphasizing that random-effect models better accommodate inter-study diversity, yielding conservative and clinically generalizable estimates. This critique reinforces the necessity of transparent statistical model selection in meta-analyses, particularly when subgroup heterogeneity may influence therapeutic interpretations.},
}

Humans
*Osteoarthritis, Knee/therapy
*Mesenchymal Stem Cell Transplantation/methods
*Mesenchymal Stem Cells/cytology

@article {pmid41104042,
year = {2025},
author = {Yassin, LK and Skrabulyte-Barbulescu, J and Alshamsi, SH and Saeed, S and Alkuwaiti, SH and Almazrouei, S and Alnuaimi, A and BaniYas, S and Aldhaheri, D and Alderei, M and Shehab, S and Hamad, MIK},
title = {The microbiota-gut-brain axis in mental and neurodegenerative disorders: opportunities for prevention and intervention.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1667448},
pmid = {41104042},
issn = {1663-4365},
abstract = {The microbiota-gut-brain axis (MGBA) is increasingly recognized as a critical regulator of brain health, influencing both neurodevelopment and age-related neurological decline. Disruptions in this axis, driven by gut dysbiosis, have been implicated in the pathogenesis of a wide range of neurodegenerative and neuropsychiatric disorders. This review synthesizes current evidence linking microbiota alterations to Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and stroke-including post-stroke cognitive impairment (PSCI), as well as major depressive disorder (MDD), bipolar disorder (BD), anxiety disorders, post-traumatic stress disorder (PTSD), and chronic fatigue syndrome (CFS). Common findings include reduced microbial diversity, depletion of short-chain fatty acid (SCFA)-producing genera, and enrichment of pro-inflammatory taxa. These changes contribute to neuroinflammation, blood-brain barrier (BBB) dysfunction, microglial activation, and neurotransmitter imbalances. The review further explores the neurotoxic effects of external factors such as radiation and xenobiotics on the MGBA. Despite disorder-specific variations, shared microbial and immunological mechanisms emerge across the spectrum of conditions. Importantly, we present current and emerging strategies aimed at restoring gut-brain communication, including dietary interventions such as fiber-rich and Mediterranean diets, SCFA supplementation, probiotics, and fecal microbiota transplantation (FMT). These approaches show promise in alleviating cognitive and emotional symptoms, modulating immune responses, and potentially slowing disease progression. By integrating mechanistic insights with therapeutic perspectives, this review underscores the gut microbiota as a modifiable factor in neuropsychiatric and neurodegenerative disease. Targeting the MGBA offers a novel, translational approach to intervention that may ultimately contribute to healthier brain aging and improved outcomes across the lifespan.},
}

@article {pmid41102629,
year = {2025},
author = {Masbi, M and Tavkoli, N and Payrovi, H and Dowlati, M},
title = {Special care services delivery at disaster scenes: a systematic review.},
journal = {International journal of emergency medicine},
volume = {18},
number = {1},
pages = {206},
pmid = {41102629},
issn = {1865-1372},
abstract = {BACKGROUND: Disasters create strain on health systems and require significant preparedness to reduce mortality and morbidity. Special care services; e.g. Advanced Life Support, critical care interventions (intubation; vasopressor therapy) and point of care diagnostics (ultrasound) may be provided in disaster-settings, although actual use of services is dependent on logistical, operational and contextual issues. This systematic review identifies an important gap to understand the effectiveness, feasibility and barriers to, special care services.The overall aim of this systematic review is to synthesise global evidence on the evidence-based practices and improve disaster response.

METHODS: This systematic review utilized PubMed, Scopus, Web of Science, Embase, and grey literature from the time of inception of the different databases to January 2025, from which a total of 4465 records were identified. After a thorough, organized review of the identified records based on our exclusion criteria and inclusion criteria, a total of 31 articles were retained. The systematic review followed PRISMA 2020, and searched for studies on special care services in a pre-hospital disaster setting, and included primary research and review articles that described advanced interventions, and which had no time restrictions on date of publication. Articles that were waived from the cost of in-app purchasing were excluded due to limited resources and could limit the studies that were included. Quality assessment using STROBE, SANRA and checklists, along with the categories of findings using a thematic content analysis based on the dimensions of prehospital care.

RESULTS: Thematic analysis revealed six broad themes: Patient Care and Clinical Management, Operational Efficiency and Logistics, Personnel and Training, Technology and Equipment, System Coordination and Preparedness, and Ethical and Contextual Considerations. Advanced functions like REBOA, ultrasound and AI-related diagnostics improved survival and neurological outcomes, However, they were restricted due to limited resources, lack of training, and lack of coordination, particularly in low resource contexts.

CONCLUSIONS: The reviewed literature demonstrated that critical-care services such as Advanced Life Support (ALS), intubation, and ultrasound resulted in improved morbidity and mortality outcomes in disaster settings but were limited due to resource constraints, lack of training and inadequate coordination all the more pertinent to low-resource settings.

CLINICAL TRIAL NUMBER: Not applicable.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12245-025-01041-9.},
}

@article {pmid41103971,
year = {2025},
author = {Arachchige, ASPM},
title = {Rethinking ALS: Current understanding and emerging therapeutic strategies.},
journal = {AIMS neuroscience},
volume = {12},
number = {3},
pages = {391-405},
pmid = {41103971},
issn = {2373-7972},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons, which leads to muscle atrophy, spasticity, and ultimately respiratory failure. The etiology of ALS remains unclear, though a combination of genetic and environmental factors is suspected. Advances in understanding ALS pathophysiology, including the role of RNA metabolism, mitochondrial dysfunction, and glutamate toxicity, have paved the way for new research directions. While Riluzole offers limited survival benefits, there is no cure, and treatment remains mostly supportive. This article summarizes the current understanding of ALS in terms of its pathophysiology, epidemiology, risk factors, clinical presentation, and treatment strategies.},
}

@article {pmid41101301,
year = {2025},
author = {Sasidharan, A and Somayaji, Y and Fernandes, R},
title = {Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00159},
pmid = {41101301},
issn = {1948-7193},
abstract = {Neurodegenerative disorders are marked by the gradual degeneration of neurons and deterioration of cognitive function. One key underlying factor in these diseases is neuroinflammation. An essential component of this process is microglia, which are the innate immune cells that maintain homeostasis in the brain. A common outcome of microglial dysregulation in neurodegenerative diseases is chronic neuroinflammation, which exacerbates neuronal damage and impairs synaptic function. This review focuses on the dual roles that disease-associated microglia (DAMs) play in neural inflammation and neuroprotection as well as their distinct transcriptional profile in neurodegenerative diseases. DAMs engage in phagocytosis to remove debris, in addition to releasing cytokines that promote inflammation. To create an effective medicine, it is imperative to comprehend these dual functions. The roles of DAMs in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are discussed, along with the mechanisms (such as the TREM2-APOE pathway) causing their activation. This review attempts to highlight the important aspects that could direct future investigations and treatment development by clarifying the interactions between DAMs and neurodegenerative diseases.},
}

@article {pmid41099730,
year = {2025},
author = {Polu, PR and Mishra, S},
title = {Genetic convergence in brain aging and neurodegeneration: from cellular mechanisms to therapeutic targets.},
journal = {Journal of neurogenetics},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/01677063.2025.2571127},
pmid = {41099730},
issn = {1563-5260},
abstract = {The distinction between normal brain aging and neurodegeneration has traditionally been viewed as a binary classification, yet emerging evidence reveals a complex continuum of shared genetic mechanisms underlying both processes. This review synthesises current understanding of conserved molecular pathways that contribute to age-related neural decline across the spectrum from healthy aging to pathological neurodegeneration. We examine how fundamental cellular processes including protein quality control, mitochondrial dysfunction, inflammation, and synaptic maintenance are genetically regulated and become progressively dysregulated during aging. Key genetic pathways, such as insulin/IGF signalling, autophagy-lysosomal networks, and stress response mechanisms demonstrate remarkable conservation from model organisms to humans, suggesting evolutionary constraints on neural aging processes. The review highlights how genetic variants in these pathways can determine individual trajectories along the aging-neurodegeneration continuum, influencing susceptibility to diseases like Alzheimer's, Parkinson's, and ALS. We discuss evidence from comparative studies in C. elegans, Drosophila, rodents, and human populations that illuminate shared vulnerability genes and protective factors. Understanding these convergent mechanisms offers unprecedented opportunities for therapeutic intervention, as strategies targeting fundamental aging processes may simultaneously address multiple neurodegenerative conditions. This integrated perspective challenges traditional disease-centric approaches and supports the development of unified therapeutic strategies for promoting healthy brain aging while preventing neurodegeneration.},
}

@article {pmid41098540,
year = {2025},
author = {Dafsari, HS and Schuler, J and Schober, E and Möller, B and Antebi, A and Fanto, M and Jungbluth, H},
title = {The space-time continuum in neurological disorders of the autophagosome-lysosome fusion machinery.},
journal = {Autophagy reports},
volume = {4},
number = {1},
pages = {2560903},
pmid = {41098540},
issn = {2769-4127},
abstract = {Autophagy is a highly conserved cellular pathway for the degradation and recycling of defective intracellular cargo and plays a vital role in the homeostasis of post-mitotic tissues, particularly the nervous system. Autophagosome-lysosome fusion represents the final critical step in macroautophagy with a tightly regulated process mediated by a complex molecular machinery of tethering vesicles for degradation. Since the first reports of human autophagy disorders, the scientific and clinical focus condensed on severe phenotypes with biallelic-truncating genotypes as monogenic models of near-complete autophagy perturbation. Recent reports suggest a much wider disease spectrum with defective autophagy, ranging from neurodevelopmental disorders to neurodegenerative phenotypes with later manifestation due to "milder" genotypes, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In addition, recent evidence identified molecular connections between physiological autophagy regulation during normal aging and pathophysiological hallmarks of aging-related disorders. These translational observations led to a more comprehensive understanding of autophagy at health and disease, in particular: 1) genetic location and allelism of pathogenic variants ("genomic space"); 2) protein-protein interaction in functional protein complexes ("proteomic space"); 3) metabolic autophagic flux with positive and negative regulators ("metabolomic space"); 4) age-related phenotypic progression over time. Here, we review the autophagosome-lysosome fusion machinery as a key structure both on the molecular level and with regards to the pathogenesis of the autophagy-related disease spectrum. We highlight the clinicopathological signature of disorders in the autophagosome-lysosome fusion machinery, in particular features warranting awareness from clinicians and geneticists to inform adequate diagnosis, surveillance, and patient guidance.},
}

@article {pmid41097145,
year = {2025},
author = {Tuigunov, D and Sinyavskiy, Y and Nurgozhin, T and Zholdassova, Z and Smagul, G and Omarov, Y and Dolmatova, O and Yeshmanova, A and Omarova, I},
title = {Precision Nutrition and Gut-Brain Axis Modulation in the Prevention of Neurodegenerative Diseases.},
journal = {Nutrients},
volume = {17},
number = {19},
pages = {},
doi = {10.3390/nu17193068},
pmid = {41097145},
issn = {2072-6643},
support = {Grant No. AP23489983//This research is funded by the Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/microbiology ; *Gastrointestinal Microbiome/physiology ; *Brain ; *Precision Medicine/methods ; *Brain-Gut Axis/physiology ; Prebiotics/administration & dosage ; Probiotics/administration & dosage ; },
abstract = {In the recent years, the accelerating global demographic shift toward population aging has been accompanied by a marked increase in the prevalence of neurodegenerative disorders, notably Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Among emerging approaches, dietary interventions targeting the gut-brain axis have garnered considerable attention, owing to their potential to modulate key pathogenic pathways underlying neurodegenerative processes. This review synthesizes current concepts in precision nutrition and elucidates neurohumoral, immune, and metabolic regulatory mechanisms mediated by the gut microbiota, including the roles of the vagus nerve, cytokines, short-chain fatty acids, vitamins, polyphenols, and microbial metabolites. Emerging evidence underscores that dysbiotic alterations contribute to compromised barrier integrity, the initiation and perpetuation of neuroinflammatory responses, pathological protein aggregations, and the progressive course of neurodegenerative diseases. Collectively, these insights highlight the gut microbiota as a pivotal target for the development of precision-based dietary strategies in the prevention and mitigation of neurodegenerative disorders. Particular attention is devoted to key bioactive components such as prebiotics, probiotics, psychobiotics, dietary fiber, omega-3 fatty acids, and polyphenols that critically participate in regulating the gut-brain axis. Contemporary evidence on the contribution of the gut microbiota to the pathogenesis of Alzheimer's disease, Parkinson's disease, and multiple sclerosis is systematically summarized. The review further discusses the prospects of applying nutrigenomics, chrononutrition, and metagenomic analysis to the development of personalized dietary strategies. The presented findings underscore the potential of integrating precision nutrition with targeted modulation of the gut-brain axis as a multifaceted approach to reducing the risk of neurodegenerative diseases and preserving cognitive health.},
}

Humans
*Neurodegenerative Diseases/prevention & control/microbiology
*Gastrointestinal Microbiome/physiology
*Brain
*Precision Medicine/methods
*Brain-Gut Axis/physiology
Prebiotics/administration & dosage
Probiotics/administration & dosage

@article {pmid41097004,
year = {2025},
author = {Daponte, A and Koros, C and Skarlis, C and Siozios, D and Rentzos, M and Papageorgiou, SG and Anagnostouli, M},
title = {Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199739},
pmid = {41097004},
issn = {1422-0067},
mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurofilament Proteins/metabolism/blood ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Neuroinflammatory Diseases/metabolism/diagnosis ; Animals ; },
abstract = {Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism/blood
*Neurofilament Proteins/metabolism/blood
*Neurodegenerative Diseases/metabolism/diagnosis
*Neuroinflammatory Diseases/metabolism/diagnosis
Animals

@article {pmid41096667,
year = {2025},
author = {Skarlis, C and Angelopoulou, E and Rentzos, M and Papageorgiou, SG and Anagnostouli, M},
title = {Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199398},
pmid = {41096667},
issn = {1422-0067},
mesh = {Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/immunology ; Animals ; *Central Nervous System Diseases/drug therapy/immunology ; Neuromyelitis Optica/drug therapy ; Central Nervous System/drug effects/immunology ; Multiple Sclerosis/drug therapy ; },
abstract = {Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer's disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson's disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety.},
}

Humans
*Antibodies, Monoclonal/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/immunology
Animals
*Central Nervous System Diseases/drug therapy/immunology
Neuromyelitis Optica/drug therapy
Central Nervous System/drug effects/immunology
Multiple Sclerosis/drug therapy

@article {pmid41095520,
year = {2025},
author = {Whelan, BM and Aldridge, D and Ruhle, J and Whitelock, P and Taubert, S and Collins, A and Kearney, E and Charania, S and Henderson, RD and Wallace, SJ and Mitchell, C and Stipancic, KL and Kuruvilla-Dugdale, M and Vogel, AP},
title = {To Treat or Not to Treat: A Scoping Review of Speech Treatment for Dysarthria in Amyotrophic Lateral Sclerosis (ALS).},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {19},
pages = {},
doi = {10.3390/healthcare13192434},
pmid = {41095520},
issn = {2227-9032},
support = {N/A//University of Queensland, School of Health and Rehabilitation Sciences, New Staff Research Start-Up Fund/ ; },
abstract = {BACKGROUND: Speech loss is recognised as one of the most devastating outcomes for individuals with ALS, yet active speech intervention is rarely targeted in this population. Clinicians face significant challenges in managing dysarthria associated with ALS due to the rapidly progressive nature of the disease, historical concerns around intensive exercise accelerating decline, and an absence of direction on restorative and compensatory intervention strategies in current clinical care guidelines. This review evaluates the scope and quality of evidence for speech treatments in ALS to identify knowledge gaps and establish research priorities to guide clinical care.

METHODS: Studies were retrieved from six electronic databases (PubMed, CINAHL, Embase, Cochrane library, Web of Science, and PsycINFO).

RESULTS: Four studies met inclusion criteria. Treatment approaches included: music-based speech therapy; multisubsystem speech rehabilitation program, tongue strengthening and articulation training; and Lee Silverman Voice Treatment-LOUD[®] combined with additional voice and articulation therapy. Sample sizes were small, with all studies demonstrating notable methodological weaknesses. The limited evidence base, marked by conflicting results and methodological flaws, prevents any reliable conclusions about treatment effectiveness.

CONCLUSIONS: Despite the prevalence and impact of dysarthria in this population, evidence for speech treatment remains sparse, of generally low quality, and provides limited guidance for clinical practice. The changing perspective on exercise in ALS warrants rigorous investigation of tailored dysarthria interventions for this population that are minimally fatiguing and enhance speech by making use of residual physiologic support.},
}

@article {pmid41092899,
year = {2025},
author = {Ruiz de Almodovar, C and Dupraz, S and Bonanomi, D},
title = {Neurovascular dynamics in the spinal cord from development to pathophysiology.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.09.017},
pmid = {41092899},
issn = {1097-4199},
abstract = {The vasculature is increasingly recognized as an active regulator of homeostasis and repair, beyond conventional roles in nutrient delivery. In the central nervous system, vascular cells adopt region-specific traits tailored to the distinct demands of the brain, retina, and spinal cord. Despite long-standing interest in the spinal cord as a model for neural development and injury, its vascular organization and properties remain understudied. The assumption that spinal cord and brain neurovascular systems are built and function in the same way has limited progress. Here, we challenge this view by examining specific properties underlying spinal cord vascular development, physiology, and pathology. We highlight unique angioarchitecture and homeostatic mechanisms, and discuss how neurovascular disruption contributes to spinal disorders and regenerative failure after injury. Identifying critical knowledge gaps, we aim to stimulate new research in spinal cord neurovascular biology, redefining its importance for health and disease.},
}

@article {pmid41092810,
year = {2025},
author = {Lopez-Mateos, D and Harris, BJ and Hernández-González, A and Yarov-Yarovoy, V and Wulff, H},
title = {Recent advances in the pharmacology of voltage-gated ion channels.},
journal = {Pharmacological reviews},
volume = {77},
number = {6},
pages = {100090},
doi = {10.1016/j.pharmr.2025.100090},
pmid = {41092810},
issn = {1521-0081},
abstract = {Voltage-gated ion channels (VGICs) are critical regulators of membrane potential, cellular excitability, and calcium signaling in both excitable and nonexcitable tissues and constitute important drug targets for neurological, cardiovascular, and immunological diseases. This review describes recent progress in the pharmacology of voltage-gated Na[+], voltage-gated Ca[2+], and voltage-gated K[+] channels, highlighting clinical-stage compounds, emerging therapeutic modalities, and new strategies in VGIC drug discovery, emphasizing the increasingly central role of protein structures and artificial intelligence. Several compounds targeting VGICs have progressed to clinical trials for epilepsy, atrial fibrillation, psoriasis, and difficult-to-treat disorders, such as chronic pain, schizophrenia, major depression, and amyotrophic lateral sclerosis. The therapeutic landscape for VGIC-related disorders is expanding beyond traditional small molecules and antisense oligonucleotides and gene therapies targeting VGICs at the mRNA or gene level are currently in both early and late clinical trial stages for Dravet syndrome and developmental epileptic encephalopathy. The progression of such varied modalities suggests that the extensive efforts dedicated to elucidating VGIC biophysics and structure, coupled with rigorous target validation, are beginning to translate into therapeutic advancements. Furthermore, we discuss emerging discovery strategies, including the growing impact of VGIC structures, computational structural modeling, virtual screening of focused and ultralarge libraries, and artificial intelligence-driven redesign and de novo design of biologics. Although these approaches are poised to substantially accelerate the early stages of ion channel drug discovery, the clinical stages will continue to require careful selection of indications and thoughtful clinical trial design to fully realize the long-held potential of VGICs as drug targets. SIGNIFICANCE STATEMENT: Drug development for voltage-gated ion channels is widely considered to be challenging. This article reviews recent advances in the pharmacology of voltage-gated Na[+], voltage-gated Ca[2+], and voltage-gated K[+] channels by examining compounds currently in clinical trials, including emerging new therapeutic approaches such as antisense oligonucleotides and gene therapy. We then discuss noteworthy recent developments, including the increasing availability and impact of ion channel structures, structural modeling, virtual screening, and artificial intelligence-assisted protein design, which are likely to accelerate the early stages of ion channel drug discovery. Success of the later stages will continue to rely on rigorous target validation, and proper choices of clinical candidates and clinical trial design.},
}

@article {pmid41090732,
year = {2025},
author = {Brocard, F and Dingu, N},
title = {Calpains at the Crossroads of Spinal Cord Physiology, Plasticity, and Pathology.},
journal = {Cells},
volume = {14},
number = {19},
pages = {},
pmid = {41090732},
issn = {2073-4409},
support = {ANR-24-CE16-1548//Agence National de la recherche/ ; ANR-21-CE17-0060//Agence National de la Recherche/ ; },
mesh = {*Calpain/metabolism ; Humans ; Animals ; *Spinal Cord/pathology/physiopathology/physiology/metabolism ; *Neuronal Plasticity/physiology ; },
abstract = {Calcium-dependent cysteine proteases, known as calpains, emerge as important regulators of spinal cord physiology, plasticity, and pathology. First characterized in the brain, they influence a wide range of processes in the spinal cord, maintaining neuronal homeostasis, shaping both synaptic and intrinsic plasticity, and modulating glial responses. When dysregulated, calpains contribute to the pathophysiology of traumatic and neurodegenerative spinal cord disorders, as well as to their associated motor and sensory complications, including spasticity and neuropathic pain. A recurring feature of these conditions is calpain-mediated proteolysis of ion channels, transporters, and cytoskeletal proteins, which promotes disinhibition and neuronal hyperexcitability. The resultant protein fragments are examined as prospective biomarkers for damage and disease progression. Meanwhile, promising strategies for neuroprotection and functional recovery in the clinic emerge as a result of innovative pharmacological and genetic approaches to modulate calpain activity. In this review, we present the current state of knowledge regarding the functions and regulation of calpains in the spinal cord and assess their translational potential as both therapeutic targets and effectors in spinal cord disorders.},
}

*Calpain/metabolism
Humans
Animals
*Spinal Cord/pathology/physiopathology/physiology/metabolism
*Neuronal Plasticity/physiology

@article {pmid40762148,
year = {2025},
author = {Mascias Cadavid, J and Mena Bravo, A and Barkhaus, P and Barnes, B and Benatar, M and Breevoort, S and Brown, A and Carter, GT and Crayle, J and Foucher, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Mcdermott, C and Pattee, G and Pierce, K and Pioro, E and Ratner, D and Rivner, M and Tito, E and Wicks, P and Bedlack, R},
title = {ALSUntangled #80: ISRIB (Integrated stress response InhiBitor).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {7-8},
pages = {821-824},
doi = {10.1080/21678421.2025.2542919},
pmid = {40762148},
issn = {2167-9223},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; Animals ; Stress Granules/drug effects/metabolism ; },
abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we assess ISRIB, a molecule that attenuates the integrated stress response (ISR). The ISR is an intracellular signaling network through which cells normally respond to stress, but in ALS it appears to be overactive, leading to the formation of "stress granules" which some but not all investigators believe can triggerapoptotic cell death. ISRIB can attenuate the formation of these stress granules while still allowing parts of protein synthesis to continue. Pre-clinical data demonstrate that ISRIB is beneficial in cell models of ALS. A small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects, though we have not been able to independently verify these benefits. There are no clinical trials evaluating ISRIB in any condition and questions about its solubility and bioavailability have arisen. Currently, we do not have enough evidence to endorse the use of ISRIB for treating ALS. We support further research in disease models and clinical trials to study pharmacokinetics, safety and efficacy.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/metabolism
Humans
Animals
Stress Granules/drug effects/metabolism

@article {pmid41090725,
year = {2025},
author = {Vishnumukkala, T and Che Mohd Nassir, CMN and Hein, ZM and Kalerammana Gopalakrishna, P and Karikalan, B and Alkatiri, A and Jagadeesan, S and Naik, VR and Thomas, W and Mohd Moklas, MA and Kamaruzzaman, MA},
title = {Glial Cells as Emerging Therapeutic Targets in Neurodegenerative Diseases: Mechanistic Insights and Translational Perspectives.},
journal = {Cells},
volume = {14},
number = {19},
pages = {},
doi = {10.3390/cells14191497},
pmid = {41090725},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology ; *Neuroglia/metabolism/pathology/drug effects ; Animals ; *Translational Research, Biomedical ; Biomarkers/metabolism ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis share converging mechanisms of neuronal dysfunction, including protein aggregation, oxidative stress, and chronic neuroinflammation. Glial cells, once considered passive supporters, are now recognized as central drivers of these processes, offering both pathogenic triggers and therapeutic opportunities. Yet, despite compelling preclinical evidence, the translation of glial-targeted therapies into clinical success has been limited. This review provides a critical synthesis of current knowledge by examining therapeutic strategies through the lens of their translational challenges and failures. This narrative review highlights how interspecies variability of glial phenotypes, shifting neuroprotective versus neurotoxic states, limited biomarker stratification, and delivery barriers have constrained trials, such as anti-triggering receptor expressed on myeloid cells 2 (anti-TREM2) antibodies in AD and glial cell line-derived neurotrophic factor (GDNF) in PD. By analyzing these obstacles across major neurodegenerative disorders, this review argue that the next stage of glial medicine requires precision approaches that integrate stage-specific phenotyping, biomarker-guided patient selection, and innovative delivery platforms. Understanding not only what has been tried but why translation has stalled is essential to chart a roadmap for effective, disease-modifying glial therapies in the aging brain.},
}

Humans
*Neurodegenerative Diseases/therapy/pathology
*Neuroglia/metabolism/pathology/drug effects
Animals
*Translational Research, Biomedical
Biomarkers/metabolism

@article {pmid41090678,
year = {2025},
author = {Jing, W and Shan, Y and Wu, H and Li, T and Tang, H and Sun, Y and Napattharin, V and Loong, S and Qin, B and Pan, W},
title = {Integrative treatment of the motor neuron disease amyotrophic lateral sclerosis, efficacy of pharmacotherapy, traditional Chinese medicine and importance of respiratory support, life-style, and gastrostomy-assisted nutrition: A review.},
journal = {International journal of clinical pharmacology and therapeutics},
volume = {63 (Suppl. 1)},
number = {},
pages = {S14-S25},
pmid = {41090678},
issn = {0946-1965},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/etiology/physiopathology ; *Gastrostomy ; *Medicine, Chinese Traditional ; *Life Style ; *Integrative Medicine/methods ; Treatment Outcome ; },
abstract = {Currently, there are no effective treatments for amyotrophic lateral sclerosis (ALS), a chronic progressive neurodegenerative disease. Although the etiology of ALS is unknown, it is thought that factors such as diet, the environment, and lifestyle habits play a role. The pathogenesis of ALS includes alterations in glutamate neurotransmission, oxidative stress, mitochondrial dysfunction. Drugs such as riluzole, edaravone, dextromethorphan/quinidine combinations, and the administration of tofersen by injection are approved treatment options for ALS although a number of other agents are being examined in clinical trials. Despite these developments, the availability of effective treatment options is limited. This review summarizes the etiology and pathogenesis of ALS and describes treatments in detail as an integrative medicine approach and including traditional Chinese medicine together with the importance of the timing for interventions, precautions necessary for noninvasive ventilator and gastrostomy surgery, and precautions for dealing with respiratory issues with the overall aim of providing state-of-the-art clinical recommendations for the care and therapy of ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/etiology/physiopathology
*Gastrostomy
*Medicine, Chinese Traditional
*Life Style
*Integrative Medicine/methods
Treatment Outcome

@article {pmid41088409,
year = {2025},
author = {Ward, EL and Benowitz, L and Brunner, TM and Bu, G and Cayouette, M and Canto-Soler, V and Dá Mesquita, S and Di Polo, A and DiAntonio, A and Duan, X and Goldberg, JL and He, Z and Hu, Y and Liddelow, SA and La Torre, A and Margeta, M and Quintana, F and Shekhar, K and Stevens, B and Temple, S and Venkatesh, H and Welsbie, D and Flanagan, JG},
title = {Modeling neurodegeneration in the retina and strategies for developing pan-neurodegenerative therapies.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {108},
pmid = {41088409},
issn = {1750-1326},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology ; Animals ; *Glaucoma/therapy ; Disease Models, Animal ; *Retina/pathology ; },
abstract = {BACKGROUND: Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting "Solving Neurodegeneration," (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 "Solving Neurodegeneration 2" meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research.

MAIN BODY: We summarize the recent progress in the field of neurodegenerative disease research and present the newest challenges and opportunities moving forward. While translatability and disease complexity continue to pose major challenges, important progress has been made in identifying neuroprotective targets and understanding neuron-glia-vascular cell interactions. New challenges involve improving our understanding of the disease microenvironment and timeline, identifying the optimal approach(es) to neuronal replacement, and finding the best drug combinations and synergies for neuroprotection. We propose solutions to common research questions, provide prescriptive recommendations for future studies, and detail methodologies, strategies, and approaches for addressing major challenges at the forefront of neurodegenerative disease research.

CONCLUSIONS: This review is intended to serve as a research framework, offering recommendations and approaches to validating neuroprotective targets, investigating rare cell types, performing cell-specific functional characterizations, leveraging novel adaptations of scRNAseq, and performing single-cell sorting and sequencing across neurodegenerative diseases and disease models. We focus on modeling neurodegeneration using glaucoma and other neurodegenerative pathologies to investigate the temporal and spatial dynamics of neurodegenerative disease pathogenesis, suggesting researchers aim to identify pan-neurodegenerative drug targets and drug combinations leverageable across neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/therapy/pathology
Animals
*Glaucoma/therapy
Disease Models, Animal
*Retina/pathology

@article {pmid41084041,
year = {2025},
author = {Hassan, YM and Wanas, A and Ali, AA and El-Sayed, WM},
title = {Integrating artificial intelligence with nanodiagnostics for early detection and precision management of neurodegenerative diseases.},
journal = {Journal of nanobiotechnology},
volume = {23},
number = {1},
pages = {668},
pmid = {41084041},
issn = {1477-3155},
abstract = {BACKGROUND: Neurodegenerative diseases—including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS)—as well as autoimmune disorders with neurodegenerative features such as multiple sclerosis (MS), present an escalating global challenge. Current diagnostics often detect pathology too late, and most treatments focus on symptom relief rather than disease modification. There is an urgent need for tools that enable early detection and precision-targeted intervention.

MAIN BODY: Nanotechnology offers unique advantages in this space, enabling early molecular detection, targeted drug delivery, and theranostic systems. Engineered nanocarriers, biosensors, and responsive nanodevices are being tailored to disease-specific features such as oxidative stress in AD or neuroinflammation in MS. Yet, issues like biocompatibility, clinical scalability, and long-term safety remain barriers to translation. Artificial intelligence (AI) enhances nanomedicine by improving biomarker sensitivity, stratifying patients, and enabling predictive disease modeling. From AI-guided nanoparticle design to closed-loop delivery systems and digital twin models, these technologies work synergistically to support real-time, personalized care. Still, critical challenges—including algorithmic bias, lack of explainability, heterogeneous datasets, and limited regulatory clarity—impede clinical integration. Additionally, high system complexity and cost risk excluding low-resource settings unless inclusive, scalable alternatives are pursued.

CONCLUSION: The convergence of AI and nanotechnology is reshaping neurodegenerative disease care, moving from reactive to proactive, personalized neurology. Realizing this promise requires cross-sector collaboration, ethical foresight, and translational rigor to ensure these innovations are safe, equitable, and accessible to all patients.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid41079430,
year = {2025},
author = {Argelazi, RL and Graça, SC and Thomazoni, PV and Moura, CB and Gomes, AC and Kormanski, MK and de Almeida, SSC and Ferreira, YD and Santos, DH},
title = {TBK1 mutation and its role in frontotemporal dementia and amyotrophic lateral sclerosis in Brazilian families.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {},
pages = {e20240227},
pmid = {41079430},
issn = {1980-5764},
abstract = {UNLABELLED: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are progressive neurodegenerative diseases with unclear etiology. Mutations in the TBK1 gene are associated with an increased risk of both FTD and ALS, presenting a diverse phenotype that includes the behavioral variant of FTD, primary progressive aphasia, and pure ALS. This mutation is rare, and to date, only one case report on TBK1-related clinical manifestations has been published in Brazil.

OBJECTIVE: To investigate the association between TBK1 gene mutations and the clinical manifestations of FTD and ALS in a Brazilian family, documenting the clinical history and disease progression of three first-degree relatives. Additionally, to conduct a literature review to better understand the impact of this mutation and its implications for neurological practice.

METHODS: Clinical data were collected from three patients in the same family who were receiving care at Dom Pedro II Geriatric Hospital and Central Hospital of the Irmandade da Santa Casa de Misericordia de São Paulo, including information on clinical symptoms, disease progression, and complementary exams - particularly genetic testing to detect and confirm the diagnosis. A detailed analysis of the existing literature on the disease was also conducted to better understand the implications of this mutation.

RESULTS: Three siblings affected by the TBK1 gene mutation were documented, with a unique family history suggesting that this genetic alteration has affected the lineage for several generations.

CONCLUSION: Although rare, frontotemporal dementia with accompanying motor deficits is of significant relevance to neurologists due to its poor prognosis and the potential familial impact on descendants.},
}

@article {pmid41073371,
year = {2025},
author = {Liu, RY and Yin, KF and He, SY and Su, WM and Duan, QQ and Wen, XJ and Chen, T and Shen, C and Li, JR and Cao, B and Chen, YP},
title = {Viral infections and the risk of neurodegenerative diseases: a comprehensive meta-analysis and systematic review.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {388},
pmid = {41073371},
issn = {2158-3188},
mesh = {Humans ; *Neurodegenerative Diseases/epidemiology/virology ; *Virus Diseases/epidemiology/complications ; *Amyotrophic Lateral Sclerosis/epidemiology/virology ; *Parkinson Disease/epidemiology/virology ; Risk Factors ; *Alzheimer Disease/epidemiology/virology ; },
abstract = {BACKGROUND: Viral infections have been implicated in the pathogenesis of neurodegenerative diseases (NDs); however, evidence linking specific viruses to Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) remains inconclusive. This study conducted a meta-analysis and systematic review to investigate these associations.

METHODS: Thorough searches were conducted across Embase, PubMed, Cochrane Library, Web of Science and Scopus until May 18, 2025, to identify observational studies investigating the relationship between viral infections and the risk of NDs, including AD, PD, and ALS. Meta-analyses were executed using a random-effects model with Stata MP18.0.

RESULTS: A total of 34,417 articles were identified, of which 73 met the eligibility criteria for inclusion in the meta-analysis, and 48 were included in the systematic review. The analysis demonstrated that infections with cytomegalovirus (CMV) (odds ratio [OR] = 1.41; 95% confidence interval [CI]: 1.03, 1.93), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (OR = 1.88; 95% CI: 1.53, 2.32), hepatitis C virus (HCV) (OR = 1.39; 95% CI: 1.14, 1.69), and human herpesvirus (HHV) (OR = 1.24; 95% CI: 1.02, 1.51) were associated with an increased risk of AD. Regarding PD, infections with hepatitis B virus (HBV) (OR = 1.18; 95% CI: 1.04, 1.35) and HCV (OR = 1.29; 95% CI: 1.18, 1.41) were identified as risk factors. Conversely, no significant correlation was found between any viral infection and the risk of ALS.

CONCLUSION: This meta-analysis supports the role of select viral infections in AD and PD pathogenesis. However, no association was found between viral infections and ALS, warranting further large, multicenter, and longitudinal studies to elucidate mechanisms and confirm causality.},
}

Humans
*Neurodegenerative Diseases/epidemiology/virology
*Virus Diseases/epidemiology/complications
*Amyotrophic Lateral Sclerosis/epidemiology/virology
*Parkinson Disease/epidemiology/virology
Risk Factors
*Alzheimer Disease/epidemiology/virology

@article {pmid41063391,
year = {2025},
author = {Inoue, K and Toyooka, K and Fujimura, H and Ueda, K and Kaido, M and Yamamoto, Y and Izumi, Y},
title = {Familial ALS With p. L127S (L126S) Variant of the Cu/Zn SOD1 Gene: A Report of Two New Cases and Literature Review.},
journal = {Neuropathology : official journal of the Japanese Society of Neuropathology},
volume = {45},
number = {6},
pages = {e70028},
pmid = {41063391},
issn = {1440-1789},
support = {25wm0625126s0301//Japan Agency for Medical Research and Development/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Middle Aged ; Female ; *Superoxide Dismutase-1/genetics ; Male ; Adult ; Motor Neurons/pathology ; Inclusion Bodies/pathology ; },
abstract = {Herein, we report two autopsy cases of familial ALS with a p. L127S (L126S) SOD1 variant. Case 1 involved a 62-year-old woman who presented with lower-extremity muscle weakness with lower motor neuron signs. The patient developed bulbar palsy and died of respiratory failure 9 years after onset. Case 2 (the second son of Case 1) presented with lower-extremity muscle weakness at the age of 38 years, with upper and lower motor neuron signs and died of respiratory failure 8 years after onset. The pathological findings in both cases predominantly consisted of lower motor neuron loss and degeneration of the lateral and posterior funiculi. Numerous conglomerate hyaline inclusions (CHIs) were observed in the remaining motor neurons. Vacuole formation was observed inside the inclusions, sometimes with granular structures. Some inclusions were positive for ubiquitin, p62, and SOD1. Electron microscopy revealed that CHIs were composed of neurofilaments and expanded mitochondria. By literature review, ALS with p. L127S disclosed a male-dominant incidence rate, a variety of ages at onset, and low penetrance. The initial symptom was exclusively lower limb weakness. One-third of the patients only showed lower motor neuron signs and half did not present with bulbar symptoms. The neuropathological findings commonly observed in ALS with p. L127S variants were mainly the degeneration of lower motor neurons and the sensory system, including the posterior column, Clarke's nucleus, and the associated cerebellar system. The formation of intracytoplasmic hyaline inclusions was also a prominent feature. ALS with p. L127S variant should be included in the possible diagnosis of slowly progressive muscle weakness in the lower extremities, with or without family history or upper motor neuron signs. The loss of lower motor neurons and the accumulation of neurofilaments in the remaining neurons are key to the pathological diagnosis for ALS with p. L127S variant.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology
Middle Aged
Female
*Superoxide Dismutase-1/genetics
Male
Adult
Motor Neurons/pathology
Inclusion Bodies/pathology

@article {pmid41062721,
year = {2025},
author = {Ramasubramanian, B and Ganguly, D and Rao, RP and Ramakrishna, S},
title = {Progress, pitfalls, and prospects in emerging materials for aluminum-sulfur batteries.},
journal = {Communications chemistry},
volume = {8},
number = {1},
pages = {301},
pmid = {41062721},
issn = {2399-3669},
abstract = {Aluminium-sulfur (Al-S) batteries have emerged as a promising post-lithium alternative owing to aluminium's abundance, safety, and high theoretical capacity. However, their practical implementation is impeded by key challenges such as sluggish Al[3+] redox kinetics, polysulfide shuttle effects, and volumetric changes of the electrodes during cycling. This review critically analysis recent advancements in host structural design engineering, new electrocatalysts, and electrolyte aimed at overcoming these limitations. Advanced host frameworks include 2D/3D porous structures, MXene-based multilayers, and single-atom doped materials that facilitate efficient sulfur confinement, enhance conductivity, and catalyse redox reactions. Embedded catalysts like Mo6S8 and CoS2 within nitrogen-doped carbons lower the decomposition barrier of Al2S3, promote stable Al-polysulfide conversion, and extend cycle life. Electrolyte optimization through ionic liquids, molten salts, and halide-modified systems further enhances ion mobility, suppresses passivation, and supports stable sulfur utilization. Emerging hybrid electrolytes combining high-donicity solvents with ionic or molten salt phases offer synergistic gains in redox kinetics and thermal stability. Density functional theory (DFT) guided designs elucidate key host-electrolyte-polysulfide interactions, revealing pathways for tailored material selection and performance enhancement. These integrated strategies pave the way for high-energy, long-lasting Al-S batteries that perform reliably at both room and elevated temperatures.},
}

@article {pmid41053519,
year = {2025},
author = {Amiri, M and Afshary, H and Bezaatpour, A and Hatamikia, S and Wei, J and Boukherroub, R and Szunerits, S},
title = {A critical review on neurodegenerative biomarker diagnostics: where is the field heading to?.},
journal = {Analytical and bioanalytical chemistry},
volume = {},
number = {},
pages = {},
pmid = {41053519},
issn = {1618-2650},
abstract = {Neurodegenerative diseases (NDD), a collection of disorders with different underlying causes and clinical presentations, are recognized as a major area of concern of our society today. The most common NDD are Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, each one of them being characterized by the progressive degradation of nerve cells and accumulation of misfolded and aggregated proteins in the affected brain region. Diagnosing NDD is challenging, due to the heterogeneity of the disease and the overlap of symptoms. Yet, early detection and accurate diagnosis are crucial for effective NDD management. With the emergence of disease-modifying therapies for AD, monitoring disease progression and treatment success is becoming essential. The future of NND diagnostics is focusing on developing less invasive, cost-effective strategies that enable early NDD identification and detection with improved patient outcomes. The integration of biotechnology and nanotechnology is seen as crucial for advancing the analytical science aspect of NDD. The creation of these innovative tools and methodologies is on the verge of enabling new possibilities for clinical diagnostics, but is also faced with several hurdles that will be critically evaluated.},
}

@article {pmid40906311,
year = {2025},
author = {Oubari, H and Berkane, Y and Jeljeli, M and Lellouch, AG and Smadja, DM},
title = {Engineering the Future of Stem Cells in Vascular Reconstruction: A Leap Towards Functional Endothelialized Tissue-Engineered Vascular Conduits.},
journal = {Stem cell reviews and reports},
volume = {21},
number = {8},
pages = {2796-2806},
pmid = {40906311},
issn = {2629-3277},
mesh = {Humans ; *Tissue Engineering/methods ; *Induced Pluripotent Stem Cells/cytology ; *Blood Vessel Prosthesis ; *Endothelial Cells/cytology ; Animals ; Tissue Scaffolds ; },
abstract = {The transition from reconstructive to regenerative strategies in vascular surgery has intensified the need for grafts that are biocompatible, growth-capable, and resistant to thrombosis. Addressing this challenge, Park et al. introduce a groundbreaking method for engineering fully biological, endothelialized tissue-engineered vascular conduits (TEVCs) using decellularized human umbilical arteries (dHUAs) coated with human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs). These constructs undergo shear stress training in bioreactors, mimicking physiological blood flow to enhance endothelial functionality and anti-thrombotic properties. Upon implantation in animal models, the grafts showed long-term patency, resistance to thrombosis, and progressive replacement of hiPSC-ECs by host endothelial cells, highlighting their regenerative and integrative potential. The study emphasizes the pivotal role of hemodynamic conditioning and key regulators such as KLF2 in promoting endothelial quiescence and vascular homeostasis. It further explores alternative strategies like endothelial colony-forming cells (ECFCs) and microfluidic systems for flow-induced maturation. Clinically, this approach offers a promising, scalable avenue for patient-specific, immune-compatible vascular grafts applicable in congenital heart disease, dialysis access, vascular grafts and coronary bypass. While challenges such as long-term durability and mechanical reinforcement remain, this research marks a transformative step toward functional, off-the-shelf vascular grafts. Park et al.'s work bridges biomimicry with regenerative medicine, paving the way for next-generation vascular therapies rooted in endothelial mechanobiology and personalized bioengineering.},
}

Humans
*Tissue Engineering/methods
*Induced Pluripotent Stem Cells/cytology
*Blood Vessel Prosthesis
*Endothelial Cells/cytology
Animals
Tissue Scaffolds

@article {pmid40304712,
year = {2025},
author = {Freisem, D and Hoenigsperger, H and Catanese, A and Sparrer, KMJ},
title = {Inborn errors of canonical autophagy in neurodegenerative diseases.},
journal = {Human molecular genetics},
volume = {34},
number = {R1},
pages = {R23-R34},
doi = {10.1093/hmg/ddae179},
pmid = {40304712},
issn = {1460-2083},
support = {CA 2915/4-1//German Research Foundation/ ; CRC1506//German Research Foundation/ ; CRC1279//German Research Foundation/ ; SP 1600/7-1//German Research Foundation/ ; SP 1600/9-1//German Research Foundation/ ; },
mesh = {Humans ; *Autophagy/genetics ; *Neurodegenerative Diseases/genetics/pathology/metabolism ; Animals ; Mitophagy/genetics ; Parkinson Disease/genetics/pathology ; Mutation ; Proteostasis/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; },
abstract = {Neurodegenerative disorders (NDDs), characterized by a progressive loss of neurons and cognitive function, are a severe burden to human health and mental fitness worldwide. A hallmark of NDDs such as Alzheimer's disease, Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and prion diseases is disturbed cellular proteostasis, resulting in pathogenic deposition of aggregated protein species. Autophagy is a major cellular process maintaining proteostasis and integral to innate immune defenses that mediates lysosomal protein turnover. Defects in autophagy are thus frequently associated with NDDs. In this review, we discuss the interplay between NDDs associated proteins and autophagy and provide an overview over recent discoveries in inborn errors in canonical autophagy proteins that are associated with NDDs. While mutations in autophagy receptors seems to be associated mainly with the development of ALS, errors in mitophagy are mainly found to promote PD. Finally, we argue whether autophagy may impact progress and onset of the disease, as well as the potential of targeting autophagy as a therapeutic approach. Concludingly, understanding disorders due to inborn errors in autophagy-"autophagopathies"-will help to unravel underlying NDD pathomechanisms and provide unique insights into the neuroprotective role of autophagy, thus potentially paving the way for novel therapeutic interventions.},
}

Humans
*Autophagy/genetics
*Neurodegenerative Diseases/genetics/pathology/metabolism
Animals
Mitophagy/genetics
Parkinson Disease/genetics/pathology
Mutation
Proteostasis/genetics
Amyotrophic Lateral Sclerosis/genetics/pathology

@article {pmid41051689,
year = {2025},
author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A},
title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41051689},
issn = {1590-3478},
abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.},
}

@article {pmid41050540,
year = {2025},
author = {Bøgard, H and Green Knakkergaard, S and Simonÿ, C and Tang, LH and Christensen, JR and Dalhoff Pedersen, A and Luijk, A and Gundtoft Roikjær, S},
title = {Implementation of cross-sectoral rehabilitation in the Nordic countries: a scoping review.},
journal = {Frontiers in health services},
volume = {5},
number = {},
pages = {1662230},
pmid = {41050540},
issn = {2813-0146},
abstract = {INTRODUCTION: Rehabilitation needs are rising in the Nordic countries due to an aging population and declining health profiles. Nordic healthcare systems share common features, including universal access, organization, and substantial tax-based financing. Due to the organization of the healthcare system, patients often experience transitions between sectors as part of the rehabilitation program. This fragmented setup undermines the continuity and quality of rehabilitation, making implementation more difficult. To inform future implementation processes, this scoping review examines the factors that influence cross-sectoral rehabilitation in settings with comparable healthcare systems.

METHODS: This Scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. The search strategy aimed to identify published, peer-reviewed primary studies on interventions implemented in adult rehabilitation within Nordic countries. Data were charted following Levac et al.'s framework and analyzed using Elo & Kyngäs' content analysis to identify factors influencing implementation. Key study characteristics and implementation approaches were synthesized narratively and in tables.

RESULTS: Thirty-six papers were identified. Most studies described the implementation of rehabilitation transitioning from the secondary to the primary sector. A top-down implementation approach was predominantly reported and appears more facilitating than a bottom-up approach. Implementation of rehabilitation across sectors is influenced by an interplay of factors: (1) Organization & Resources: alignment of context with intervention, involvement from front-line personnel, time & resources, the workplace itself, and managers, and (2) Collaboration & Communication, including knowledge and competence, attitudes, communication, patients, and families.

CONCLUSION: While this scoping review conveys that collaboration, communication, resources, and organization have a central role affecting the implementation of cross-sectoral rehabilitation, it further identifies knowledge gaps, such as the lack of the patients' perspective, the use of a framework or other systematic approach to ensure the success of the implementation.},
}

@article {pmid41047006,
year = {2025},
author = {Stefano, GB and Büttiker, P and Weissenberger, S and Raboch, J and Anders, M},
title = {Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101217},
doi = {10.1016/j.yfrne.2025.101217},
pmid = {41047006},
issn = {1095-6808},
abstract = {While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.},
}

@article {pmid41046979,
year = {2025},
author = {Puspita, L and Deline, M and Shim, JW},
title = {DUAL SMAD INHIBITION AS A VERSATILE PLATFORM IN HUMAN PLURIPOTENT STEM CELL-BASED NEUROSCIENCE AND REGENERATIVE MEDICINE.},
journal = {Molecules and cells},
volume = {},
number = {},
pages = {100284},
doi = {10.1016/j.mocell.2025.100284},
pmid = {41046979},
issn = {0219-1032},
abstract = {Dual SMAD inhibition is a robust and widely adopted protocol for directing human pluripotent stem cells (hPSCs) toward neuronal lineages by blocking transforming growth factor-beta and bone morphogenetic protein pathways. Suppressing TGF-β and BMP signaling enables efficient and reproducible induction of neuroectoderm, serving as the foundation for generating diverse brain region-specific neuronal subtypes. This review outlines the mechanistic basis and major achievements of the dual SMAD inhibition strategy, including its application in two recent clinical trials for Parkinson's disease, and its role in preclinical studies targeting conditions, such as spinal cord injury, retinal degeneration, and amyotrophic lateral sclerosis. In addition to its significant contribution to the generation of transplantation-ready grafts from hPSCs, the protocol serves as a valuable platform for disease modeling across various neurological and metabolic disorders. The key strengths include high efficiency, technical simplicity that enables precise control of cell fate using small molecules, versatility in both two- and three-dimensional culture systems, and reproducibility across various hPSC lines. This review also addresses key limitations, such as restricted gliogenic capacity and limited neural progenitor cell expansion. Future research should focus on incorporating emerging technologies to advance stem cell-based applications. Overall, dual SMAD inhibition represents a powerful and versatile platform for stem cell-based neuroscience and regenerative medicine.},
}

@article {pmid41042709,
year = {2025},
author = {Hall, HK and Austin, E and Hutchinson, K and Cheek, C and Clay-Williams, R},
title = {A Systematic Review of Management of Cramping Pain in Patients with Amyotrophic Lateral Sclerosis.},
journal = {European neurology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/000548820},
pmid = {41042709},
issn = {1421-9913},
abstract = {BACKGROUND/INTRODUCTION: Pain, particularly cramping, in people living with Amyotrophic Lateral Sclerosis (ALS) is often underrecognized and under-treated. Despite affecting over 70% of people living with ALS (plwALS), cramping pain remains inadequately managed due to its complex nature and the difficulties plwALS face in communicating their symptoms as the disease progresses. This systematic review explores both pharmacological and non-pharmacological treatments for cramping pain in ALS, aiming to assess and compare their efficacy.

METHODS: The systematic review was conducted following PRISMA guidelines and the protocol was registered with PROSPERO (ID CRD42024521649). A comprehensive search was performed across MEDLINE, Embase, Scopus, and Cochrane databases from inception until February 1, 2024, using specific search terms related to ALS and cramping.

RESULTS: The search resulted in the identification of 368 studies. After duplicates were removed, abstracts screened, and full texts reviewed, nine studies were included. Pharmacological interventions such as Mexiletine demonstrated significant reductions in cramp frequency and intensity in several trials, with varying doses showing distinct levels of effectiveness. Other medications like Dronabinol and Levetiracetam were also tested but showed limited efficacy in reducing cramp severity. Among non-pharmacological options, supervised exercise programs, particularly those incorporating stretching and functional mobility, were effective in reducing cramping pain intensity, while unsupervised home exercise programs did not show significant improvements.

CONCLUSION: The review demonstrates the scarcity of high-quality research on cramping pain management in ALS. Mexiletine emerged as the most promising pharmacological intervention, providing notable relief, while supervised exercise therapy demonstrated beneficial effects.},
}

@article {pmid41037122,
year = {2025},
author = {Thakur, A and Sharma, R and Sharma, R and Devi, A},
title = {Neurodegeneration and aging: pathophysiology, diagnosis, and therapeutic targets.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41037122},
issn = {1568-5608},
abstract = {Aging is the greatest risk factor for AD, ALS, PD, FTD, and HD. Neurons in the brain experience many changes as people age, negatively affecting their structure and function. It examines the key processes behind brain aging, such as age-related death of cells, failure of the cells' powerhouses, oxidative stress, incorrect protein shapes, brain inflammation, difficulty in cleaning the brain, and deterioration of blood vessels, and shows their impact on neurodegeneration. With age, there are difficulties in brain-blood circulation, less synaptic change, and fewer new neurons, which make the disease even worse. Informed by human and animal trials, we see that mitochondria work less efficiently in aging brain cells, while oxidative damage to DNA increases doubly to triply. In addition, too much tau, amyloid-β, and α-synuclein building up is tied to declining mental abilities in the elderly. We further evaluate new tests that help with early detection and classification, for example, using biomarkers in cerebrospinal fluid (CSF), blood panels, detailed brain scans, and AI algorithms. It stresses that more aging-specific trials, better integration of multi-omics, and increased interest in research on the gut-brain axis are important. The communication between the aging of the body and the brain is also explained. This article covers the main cellular, molecular, and clinical issues linked to brain aging and highlights important future research areas needed to develop effective treatments for aging people.},
}

@article {pmid41032625,
year = {2025},
author = {Rosenberg, GM and Murray, KA and Sawaya, MR and Jiang, YX and Geschwind, DH and Eisenberg, DS},
title = {Genetic and structural aspects of amyloid diseases.},
journal = {Science translational medicine},
volume = {17},
number = {818},
pages = {eadp3378},
doi = {10.1126/scitranslmed.adp3378},
pmid = {41032625},
issn = {1946-6242},
mesh = {Humans ; *Amyloidosis/genetics ; *Amyloid/chemistry/genetics/metabolism ; Mutation/genetics ; Animals ; },
abstract = {The conversion of proteins into insoluble fibrillar aggregates known as amyloid occurs in a wide variety of diseases, e.g., Alzheimer's disease, amyotrophic lateral sclerosis, systemic transthyretin amyloidosis, and multisystem atrophy. There are more than 60 disease-associated amyloid-forming proteins, and amyloid formation can occur sporadically or can be induced or accelerated by genetic mutations. This Review discusses structural mechanisms by which genetic changes promote amyloid formation and thereby influence disease outcomes. By dividing amyloid-forming proteins into six types according to the genetic mutations they carry and analyzing mutation-induced structural changes in amyloid fibrils, a better understanding of inheritance patterns of amyloid diseases (amyloidoses) can be obtained.},
}

Humans
*Amyloidosis/genetics
*Amyloid/chemistry/genetics/metabolism
Mutation/genetics
Animals

@article {pmid40581671,
year = {2025},
author = {Ono, S and Nakamura, M and Ikegami, T and Kajiyama, Y and Kume, K and Takahashi, Y and Takahashi, M and Mochizuki, H and Mizusawa, H and Kawakami, H and Yakushiji, Y},
title = {Spinocerebellar ataxia type 2 followed by amyotrophic lateral sclerosis due to a pure CAG repeat expansion in ATXN2: a case report and literature review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {46},
number = {10},
pages = {5417-5421},
pmid = {40581671},
issn = {1590-3478},
mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/complications/diagnostic imaging ; Female ; *Ataxin-2/genetics ; *Spinocerebellar Ataxias/genetics/complications/diagnostic imaging ; *Trinucleotide Repeat Expansion/genetics ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia caused by abnormal CAG expansions (≥ 34 repeats) in the ATXN2 gene (ATXN2), whereas intermediate CAG expansions (27-33 repeats) have been linked to amyotrophic lateral sclerosis (ALS).

CASE DESCRIPTION: A 53-year-old woman with longstanding cerebellar ataxia developed progressive upper limb weakness and muscle atrophy at the age of 51 years. On neurological examination, she was found to have ataxic dysarthria, slow saccadic eye movements, tongue atrophy with fasciculations, muscle atrophy and weakness in both upper limbs, hyperreflexia with Babinski's sign, and limb and gait ataxia. Brain magnetic resonance imaging (MRI) showed brainstem and cerebellar atrophy. Genetic analysis identified an expanded CAG-repeat of 39/22 in ATXN2, and screening for other known ALS-related gene mutations was negative, leading to a diagnosis of both SCA2 and ALS associated with ATXN2.

CONCLUSIONS: SCA2 is typically associated with uninterrupted CAG-repeat expansions, whereas ALS-related ATXN2 expansions usually contain at least one CAA triplet. However, despite carrying an uninterrupted CAG-repeat expansion, this patient developed ALS. This case shows that ALS can emerge several decades after SCA2 onset, even in patients with pure CAG-repeats, underscoring the need for long-term monitoring in SCA2 patients. Further research is needed to clarify the roles of repeat length, CAA interruptions, and other factors in ATXN2-related ALS.},
}

Humans
Middle Aged
*Amyotrophic Lateral Sclerosis/genetics/complications/diagnostic imaging
Female
*Ataxin-2/genetics
*Spinocerebellar Ataxias/genetics/complications/diagnostic imaging
*Trinucleotide Repeat Expansion/genetics
Magnetic Resonance Imaging

@article {pmid41024175,
year = {2025},
author = {Bamber, R and Carlton, J and McDermott, C and Stavroulakis, T},
title = {Understanding health-related quality of life of informal carers in amyotrophic lateral sclerosis: a scoping review and conceptual framework.},
journal = {Health and quality of life outcomes},
volume = {23},
number = {1},
pages = {90},
pmid = {41024175},
issn = {1477-7525},
support = {NIHR301648//National Institute for Health and Care Research/ ; NIHR301648//National Institute for Health and Care Research/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/nursing ; *Quality of Life/psychology ; *Caregivers/psychology ; Patient Reported Outcome Measures ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, life-limiting neurodegenerative disease. Informal carers provide extensive support, significantly impacting their health-related quality of life (HRQoL). Current HRQoL measurement using person-reported outcome measures (PROMs) in ALS carers lacks consistency and comprehensiveness, hindering robust assessment and synthesis. There is evident need for a comprehensive conceptual framework of HRQoL, to fully capture the multidimensional nature of caregiving in ALS. Such a framework is essential to inform research and clinical practice, ensuring relevant measurement and meaningful clinical discussions. This study aimed to develop this evidence-based framework.

METHODS: This study comprised two stages. Firstly, a scoping review was undertaken in March 2024 using Medline, Embase, and CINAHL to identify primary articles exploring HRQoL in ALS carers. Qualitative, mixed methods and quantitative articles using multi-item PROMs to assess HRQoL in informal ALS carers were included. Relevant themes and subthemes were extracted from articles and PROMs and mapped onto an existing conceptual framework for people with ALS (Quality of Life in ALS, QuALS), which covers physical, psychological, and social HRQoL domains in people with ALS. The Carer-QuALS framework was subsequently developed and refined using existing literature and consultation with ALS carers. PROMs within this review were then indexed against the finalised Carer-QuALS framework.

RESULTS: From 715 search results, 82 articles and 44 PROMs were eligible for inclusion. One new subtheme 'physical caring activities' emerged, while seven subthemes lacked support from the literature. In three structured consultation sessions, nine ALS carers, reviewed the draft Carer-QuALS framework (consisting of seven themes and 43 subthemes). Based on their input, one new subtheme 'privacy' was added, six subthemes were removed, and one was retained, despite lacking support from review literature. The final Carer-QuALS framework includes 37 subthemes: 8 physical, 6 social, and 23 psychological.

CONCLUSIONS: This review presents a comprehensive conceptual framework encompassing the multidimensional impact of ALS caregiving on the HRQoL of informal carers. The framework provides a resource that can be used by researchers, clinicians, and patient advocacy groups for multiple purposes (e.g., to support PROM selection to measure HRQoL, to guide future PROM development, and to facilitate discussions between informal carers and clinicians).},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology/nursing
*Quality of Life/psychology
*Caregivers/psychology
Patient Reported Outcome Measures

@article {pmid41022359,
year = {2025},
author = {Liu, C and Lai, FF and Zhang, T and Mao, KJ and Wan, HT and He, Y},
title = {Roles and therapeutic potential of PARP-1 in neurodegenerative diseases.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117373},
doi = {10.1016/j.bcp.2025.117373},
pmid = {41022359},
issn = {1873-2968},
abstract = {Poly(ADP-ribose) polymerase 1 (PARP-1) was first discovered in the 1960 s, and over the past few decades, there has been growing evidence that PARP-1 plays a key role in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. With DNA damage detection and repair as its main function, PARP-1 is activated by regulation in the early stages of neurodegenerative diseases, quickly and effectively repairs mild DNA damage, and protects nerve cells from death. However, as the disease progresses, severe DNA damage causes PARP-1 to overactivate, resulting in neuronal cell death, including apoptosis, necrosis, and parthanatos, further exacerbating the disease progression. PARP-1 is also involved in the pathological process of neurodegenerative diseases, such as pathological protein aggregation, neuroinflammation, mitochondrial dysfunction, autophagy disorder, and damage to the blood-brain barrier. According to a large number of studies, PARP-1 inhibition has shown great therapeutic potential for neurodegenerative diseases, and the development of PARP-1 inhibitors has received increasing attention. Here, we review the role of PARP-1 in the process of neurodegenerative diseases and summarize the latest research progress and application of PARP-1 inhibitors in neurodegenerative diseases.},
}

@article {pmid41019550,
year = {2025},
author = {Chen, KQ and Cao, WJ and Liu, Z and Liu, RZ},
title = {Mini-review: Processed red meat intake and risk of neurodegenerative diseases.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1663647},
pmid = {41019550},
issn = {2296-861X},
abstract = {Neurodegenerative diseases (NDDs) are a group of disorders characterized by the progressive loss of neurons in specific areas of the central nervous system. In recent years, more and more research has focused on the influence of diet on NDDs. As a common food, processed red meat is widely consumed worldwide. Many studies have shown that processed red meat may increase the risk of cancer, diabetes and cardiovascular disease. Unfortunately, it is unclear whether processed red meat affects NDDs. Therefore, we reviewed the existing literature on the role of processed meats in NDDs. We concluded that intake of processed meat may have an adverse effect on NDDs.},
}

@article {pmid41018945,
year = {2025},
author = {Vucic, S and Shahrizaila, N and Kano, O and Menon, P and Agustini, S and Kulkantrakorn, K and Atchayaram, N and Lee, YC and Prado, MB and Ng, KWP and Chai, J and Son, B and Talman, P and Nghia, HTT and Tuan, LTQ and Shibuya, K and Izumi, Y and Atsuta, N and Henderson, RD and Cui, L and Liu, M and Ohnmar, O and Rabani, R and Hong, YH and Sung, JJ and Fan, D and Raykar, V and Kuwabara, S and Kim, SH and Sobue, G and Kiernan, MC},
title = {Pan-Asian consortium for treatment and research in ALS (PACTALS) guidelines for management of amyotrophic lateral sclerosis.},
journal = {The Lancet regional health. Western Pacific},
volume = {62},
number = {},
pages = {101684},
pmid = {41018945},
issn = {2666-6065},
abstract = {The Pan-Asian Consortium for Treatment and Research in ALS (PACTALS) guidelines were developed for the management of amyotrophic lateral sclerosis (ALS) patients living in the Asia-Pacific countries, taking into consideration the ethnic, racial and economic diversity of the region. The majority of patients reside in low-income (limited-resource setting) and middle-income countries. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was utilised for development of the PACTALS management guidelines. Nine broad research questions, divided into sections, were addressed. Evidence was derived from existing Cochrane reviews, systematic reviews, meta-analysis, and randomized controlled trials (RCT) along with consensus when evidence was limited. Recommendations were provided for diagnostic pathways, use of disease modifying therapies, appropriateness of multidisciplinary care models, management of respiratory dysfunction, communication and nutrition, addressing symptoms that affect the quality of life, managing cognitive, behavioural and emotional symptoms as well as appropriate implementation of palliative care services and addressing end-of-life issues. The PACTALS guidelines provide a much-needed framework for the management of ALS patients living in the Asia-Pacific region. The management guidelines will be updated as the treatment landscape evolves and evidence of novel management approaches becomes available.},
}

@article {pmid41017972,
year = {2025},
author = {Feng, J and Hu, X and Liu, J and Wang, W and Chen, L and Pang, R and Zhang, A},
title = {Akkermansia muciniphila in neurological disorders: mechanisms and therapeutic potential via the gut-brain axis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1650807},
pmid = {41017972},
issn = {1662-4548},
abstract = {In recent years, the role of Akkermansia muciniphila (A. muciniphila) in neurological diseases has attracted increasing attention. As a probiotic, A. muciniphila is closely associated with host health, metabolism, and immunity, demonstrating therapeutic potential in various conditions such as obesity, atherosclerosis, inflammatory bowel disease, diabetes, and liver disorders. In the context of neurological diseases, A. muciniphila significantly influences the host brain through the microbiota-gut-brain axis (MGBA). This review summarizes the roles and mechanisms of A. muciniphila and its active components (e.g., the outer membrane protein Amuc_1100, extracellular vesicles AmEVs, and short-chain fatty acids SCFAs) in various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), depression, cerebral palsy (CP), epilepsy (EP), autism spectrum disorder (ASD), and amyotrophic lateral sclerosis (ALS). It exerts protective effects by enhancing the intestinal barrier, regulating lipid metabolism, producing SCFAs, secreting neuroactive substances, and inhibiting neuroinflammation, thereby suggesting novel therapeutic avenues for neurological disorders. However, due to limited data from large-scale human clinical trials and the complexity of disease mechanisms and host-microbiota interactions, its clinical translation faces considerable challenges. Future efforts should focus on multicenter randomized controlled trials and in-depth mechanistic studies utilizing technologies such as metabolomics to facilitate evidence-based clinical application.},
}

@article {pmid41011076,
year = {2025},
author = {Della Toffola, J and Ricci, E and Quagliotto, M and Manganotti, P and Benussi, A},
title = {Non-Invasive Brain Stimulation for Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {9},
pages = {},
pmid = {41011076},
issn = {1648-9144},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology ; *Transcranial Magnetic Stimulation/methods/trends/standards ; *Transcranial Direct Current Stimulation/methods/trends/standards ; Brain/physiopathology ; },
abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, with a bleak prognosis and few treatment options. Non-invasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), represent emerging approaches aimed at modulating cortical hyperexcitability, a relevant pathogenetic mechanism in ALS. Materials and Methods: A systematic review of the literature was conducted following the PRISMA guidelines, exploring the Scopus and PubMed databases from April to June 2025 with terms related to ALS and NIBS. A total of 18 relevant studies were selected from the initial 708 articles, analysing stimulation protocols, clinical and neurophysiological outcomes, and associated biomarkers; their validity was assessed using the revised Cochrane risk-of-bias (RoB2) tool. Results: The selected studies were extremely heterogeneous, with NIBS techniques, including magnetic (rTMS, cTBS, tSMS) and electrical (tDCS) stimulation, showing variable effects. Low-frequency protocols (1 Hz rTMS) and cTBS showed a slight slowing of clinical progression, while prolonged home stimulation with tDCS and tSMS showed more significant improvements in terms of efficacy, tolerability, and adherence. The main limitations concern the heterogeneity of patients and protocols and the lack of standardised biomarkers, which is why the analysis remained at a descriptive level. The use of telemonitoring and caregiver training are essential to ensure safety and accessibility. Conclusions: NIBS represents a promising therapeutic approach for ALS, but further multicentre, standardised studies with prolonged follow-up are needed. Future strategies should include customisation of stimulation, combination with other therapies, and extension of application to pre-symptomatic phases.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/physiopathology
*Transcranial Magnetic Stimulation/methods/trends/standards
*Transcranial Direct Current Stimulation/methods/trends/standards
Brain/physiopathology

@article {pmid41009734,
year = {2025},
author = {Genchi, G and Catalano, A and Carocci, A and Sinicropi, MS and Lauria, G},
title = {Copper, Cuproptosis, and Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {18},
pages = {},
doi = {10.3390/ijms26189173},
pmid = {41009734},
issn = {1422-0067},
mesh = {*Copper/metabolism/toxicity ; Humans ; *Neurodegenerative Diseases/metabolism/etiology/pathology ; Animals ; Homeostasis ; },
abstract = {Copper is a vital micronutrient for animals and plants acting as a crucial cofactor in the synthesis of numerous metabolic enzymes and contributing to mitochondrial respiration, metabolism, oxido-reductive reactions, signal transmission, and oxidative and nitrosative damage. In the cells, copper may exist in the Cu[+] and Cu[++] oxidation states and the interconversion between these two states may occur via various redox reactions regulating cellular respiration, energy metabolism, and cell growth. The human body maintains a low level of copper, and copper deficiency or copper excess may adversely affect cellular functions; therefore, regulation of copper levels within a narrow range is important for maintaining metabolic homeostasis. Recent studies identified a new copper-dependent form of cell death called cuproptosis. Cuproptosis occurs due to copper binding to lipoylated enzymes (for instance, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the tricarboxylic acid Krebs cycle. In recent years, extensive studies on copper homeostasis and copper-induced cell death in degenerative disorders, like Menkes, Wilson, Alzheimer, Parkinson's, Huntington's diseases, and Amyotrophic Lateral Sclerosis, have discussed the therapeutic potential of targeting cuproptosis. Copper contamination in the environment, which has increased in recent years due to the expansion of agricultural and industrial activities, is associated with a wide range of human health risks. Soil used for the cultivation of grapes has a long history of copper-based fungicide application (the Bordeaux mixture is rich in copper) resulting in copper accumulation at levels capable of causing toxicity in plants that co-inhabit the vineyards. Phytoremediation, which uses plants and biological solutions to remove toxic heavy metals and pesticides and other contaminants from soil and water, is an environmentally friendly and cost-effective technology used for the removal of copper. It requires plants to be tolerant of high levels of copper and capable of accumulating metal copper in plants' aerial organs and roots. This review aims at highlighting the importance of copper as an essential metal, as well as its involvement in cuproptosis and neurodegenerative diseases.},
}

*Copper/metabolism/toxicity
Humans
*Neurodegenerative Diseases/metabolism/etiology/pathology
Animals
Homeostasis

@article {pmid41009457,
year = {2025},
author = {Scognamiglio, A and Corvino, A and Caliendo, G and Fiorino, F and Perissutti, E and Santagada, V and Severino, B},
title = {Druggability of Sodium Calcium Exchanger (NCX): Challenges and Recent Development.},
journal = {International journal of molecular sciences},
volume = {26},
number = {18},
pages = {},
doi = {10.3390/ijms26188888},
pmid = {41009457},
issn = {1422-0067},
mesh = {*Sodium-Calcium Exchanger/metabolism/antagonists & inhibitors/chemistry ; Humans ; Animals ; Protein Isoforms/metabolism ; Calcium/metabolism ; },
abstract = {Na[+]/Ca[2+] exchangers (NCXs) are membrane transporters crucial for calcium homeostasis in excitable tissues, particularly in the central nervous system. Growing evidence indicates that NCX dysfunction contributes to calcium overload and neuronal damage in several neurological conditions. Thus, pharmacological modulation of NCX isoforms (NCX1, NCX2, and NCX3) has emerged as a potential therapeutic strategy for disorders such as stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). However, the identification of selective modulators directed at specific NCX isoforms, or even different splice variants, remains challenging and limits their clinical validation. This Review aims to provide an updated overview of small-molecule NCX modulators, described over the last two decades. Chemical structures, mechanisms of action, and isoform specificity are discussed, along with the most commonly used biological assays for their functional evaluation.},
}

*Sodium-Calcium Exchanger/metabolism/antagonists & inhibitors/chemistry
Humans
Animals
Protein Isoforms/metabolism
Calcium/metabolism

@article {pmid41008559,
year = {2025},
author = {Steffan, D and Pezzini, C and Esposito, M and Franco-Romero, A},
title = {Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.},
journal = {Biomolecules},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/biom15091252},
pmid = {41008559},
issn = {2218-273X},
mesh = {Humans ; *Mitochondria/metabolism/pathology/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Aging/metabolism/pathology ; *Central Nervous System/metabolism/pathology ; Animals ; DNA, Mitochondrial/genetics/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Mitophagy ; Mitochondrial Dynamics ; },
abstract = {Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration.},
}

Humans
*Mitochondria/metabolism/pathology/genetics
*Neurodegenerative Diseases/metabolism/pathology/genetics
*Aging/metabolism/pathology
*Central Nervous System/metabolism/pathology
Animals
DNA, Mitochondrial/genetics/metabolism
Oxidative Stress
Reactive Oxygen Species/metabolism
Mitophagy
Mitochondrial Dynamics

@article {pmid41008528,
year = {2025},
author = {Tian, Z and Jin, F and Geng, Z and Xu, Z and Shao, Q and Liu, G and Ji, X and Liu, J},
title = {Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases.},
journal = {Biomolecules},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/biom15091221},
pmid = {41008528},
issn = {2218-273X},
support = {20230484436//the Beijing Nova Program/ ; CX23YQ01//the Chinese Institutes for Medical Research, Beijing/ ; 22JCZXJ00190//Beijing-Tianjin-Heibei Basic Research Cooperation Project/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Hemoglobins/metabolism ; *Hypoxia/metabolism/complications ; Animals ; Mitochondria/metabolism ; },
abstract = {Hypoxic stress is increasingly recognized as a convergent pathological factor in various age-related neurodegenerative diseases (NDDs), encompassing both acute events such as stroke and traumatic brain injury (TBI), and chronic disorders including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Recent studies have revealed that hemoglobin (Hb), beyond its classical oxygen-transport function, exhibits unexpected expression and functional relevance within the central nervous system. Notably, both cerebral and circulating Hb appear to be dysregulated under hypoxic and aging conditions, potentially influencing disease onset and progression of these diseases. However, Hb's impact on neurodegeneration appears to be context-dependent: in acute NDDs, it may exert neuroprotective effects by stabilizing mitochondrial and iron homeostasis, whereas in chronic NDDs, aberrant Hb accumulation may contribute to toxic protein aggregation and neuronal dysfunction. This review provides an integrative overview of the emerging roles of Hb in hypoxia-related NDDs, highlighting both shared and distinct mechanisms across acute and chronic conditions. We further discuss potential therapeutic implications of targeting Hb-related pathways in NDDs and identify key gaps for future investigation.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Hemoglobins/metabolism
*Hypoxia/metabolism/complications
Animals
Mitochondria/metabolism