@article {pmid42457567,
year = {2026},
author = {Akiyama, T and Aoki, M},
title = {Cracking a New Era of Therapeutic Development in ALS.},
journal = {The Tohoku journal of experimental medicine},
volume = {269},
number = {4},
pages = {437-447},
doi = {10.1620/tjem.2026.J082},
pmid = {42457567},
issn = {1349-3329},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; Animals ; Biomarkers/metabolism ; *Drug Development ; Induced Pluripotent Stem Cells ; },
abstract = {Recent advances in genetics, RNA biology, disease modeling, biomarkers, and clinical trial methodology have fundamentally transformed therapeutic development in amyotrophic lateral sclerosis (ALS). Recent clinical successes, including edaravone, ultrahigh-dose methylcobalamin, and antisense oligonucleotide (ASO) therapies such as tofersen, have demonstrated that therapeutic success depends not only on effective drugs but also on improved therapeutic development strategies. These advances have highlighted several fundamental principles, including patient enrichment, intervention during appropriate therapeutic windows, biomarker-guided drug development, and innovative clinical trial design. At the biological level, human genetics and molecular neuropathology have revealed that genetically diverse forms of ALS converge on a limited number of shared pathogenic pathways. In particular, TDP-43 proteinopathy has emerged as the central molecular hallmark of ALS, linking protein aggregation, RNA dysregulation, and neuronal dysfunction. The discovery of TDP-43-dependent cryptic splicing has transformed RNA dysregulation into a therapeutically actionable target and accelerated the development of RNA-targeted therapeutics and mechanism-based biomarkers. In parallel, patient-derived induced pluripotent stem cell (iPSC) models, multi-omics technologies, and computational approaches have fundamentally altered therapeutic discovery and target validation. Furthermore, neurofilament biomarkers, adaptive platform trials, and digital technologies are reshaping clinical evaluation and accelerating therapeutic development. In this review, we discuss how advances in genetics, RNA biology, disease modeling, biomarkers, and clinical trial methodology are collectively redefining therapeutic development in ALS and shaping the next generation of precision medicine for neurodegenerative diseases.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/genetics
Animals
Biomarkers/metabolism
*Drug Development
Induced Pluripotent Stem Cells

@article {pmid42749235,
year = {2026},
author = {Knezovic, A and Krsnik, A and Homolak, J and Babic Perhoc, A and Deskin, A and Virag, D and Salkovic-Petrisic, M and Osmanovic Barilar, J},
title = {From systems to cells: Metabolic mechanisms underlying risk divergence in Alzheimer's disease and amyotrophic lateral sclerosis.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {106982},
doi = {10.1016/j.neubiorev.2026.106982},
pmid = {42749235},
issn = {1873-7528},
abstract = {Epidemiological studies show an inverse relationship between metabolic disorders and two major neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Obesity, type 2 diabetes (T2DM), and reduced physical activity increase AD risk, whereas in ALS cardiometabolic factors, particularly T2DM, show inverse, age-dependent associations with disease risk. This review integrates epidemiological, clinical, and experimental evidence to suggest that cell-type-specific energy metabolism underlies these contrasting risk profiles. Neurons and skeletal muscle differ in metabolic organization, substrate use, and redox capacity. Neurons rely mainly on glucose and lactate and have limited fatty acid oxidation, making them vulnerable to lipid overload, insulin resistance, and oxidative stress, hallmarks of AD. In contrast, skeletal muscle is metabolically flexible, efficiently oxidizes fatty acids, and has strong antioxidant defenses, which may protect against ALS. These cell-type-specific metabolic profiles are proposed to causally shape disease susceptibility: neuronal lipid overload and impaired redox homeostasis promote amyloid and tau pathology in AD, whereas preserved muscle fatty acid oxidation and antioxidant capacity support neuromuscular junction stability and delay motor neuron degeneration in ALS. Hypermetabolism, hypothalamic dysfunction, glial-neuronal coupling and lactate shuttling may further shape disease susceptibility. Overall, these patterns likely reflect distinct cellular responses to metabolic stress.},
}

@article {pmid42522997,
year = {2026},
author = {Stanley, LM and Scott, JA},
title = {Single-case design interventions for deaf disabled students: a systematic literature review.},
journal = {Journal of deaf studies and deaf education},
volume = {31},
number = {4},
pages = {563-576},
doi = {10.1093/jdsade/enag045},
pmid = {42522997},
issn = {1465-7325},
mesh = {Humans ; *Deafness/rehabilitation/psychology ; *Single-Case Studies as Topic ; *Persons with Hearing Disabilities/rehabilitation ; Students ; *Education of Persons with Hearing Disabilities/methods ; },
abstract = {This systematic review examined single-case design (SCD) interventions for Deaf and Hard-of-Hearing students with co-occurring disabilities (i.e., who are Deaf Disabled). Ten peer-reviewed studies met the inclusion criteria, targeting communication, behavior, or academic outcomes. Behavioral interventions demonstrated more durable generalization, while academic gains often required continued reinforcement. Study quality evaluated using Horner et al.'s indicators revealed two high-quality studies, four acceptable, and four below minimum standards, indicating notable methodological limitations. Findings highlight a significant gap in rigorous, language-focused SCD research. Improved methodological quality is needed to better inform multidisciplinary teams in designing individualized, evidence-based supports, while also considering how normative assumptions shape definitions of "improvement" and influence interpretations of effectiveness.},
}

Humans
*Deafness/rehabilitation/psychology
*Single-Case Studies as Topic
*Persons with Hearing Disabilities/rehabilitation
Students
*Education of Persons with Hearing Disabilities/methods

@article {pmid42742812,
year = {2026},
author = {Codron, P and Miranda, M and Garnier, M and He, S and Gouju, J and Cassereau, J and Leblanc, P and Letournel, F},
title = {Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42742812},
issn = {1432-0533},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *TDP-43 Proteinopathies/pathology/metabolism ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Cytoplasmic accumulation of phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathological hallmark of most ALS cases. While ALS has traditionally been viewed as a disease confined to the brain, spinal cord and motor nerves, recent studies have reported pTDP-43 pathology in multiple other tissues (skeletal and cardiac muscle, skin, minor salivary glands, gastrointestinal tract and lymph nodes), referred to as peripheral pathology. The detection of pTDP-43 beyond the nervous system suggests that ALS-associated TDP-43 proteinopathy may be more widespread than previously recognized and raises fundamental questions regarding the spatial and temporal landscape of ALS pathology. Peripheral pTDP-43 accumulation may reflect a systemic biological susceptibility affecting multiple tissues, propagation of pathological TDP-43 species between anatomical compartments, or a combination of both mechanisms. While its biological significance is yet to be determined, the presence of pTDP-43 in peripheral tissues broadens the current conceptual framework of ALS. It may also provide new opportunities for pathology-based biomarkers, therapeutic monitoring, and mechanistic studies aimed at understanding disease initiation and progression. However, current evidence is derived from small and methodologically heterogeneous cohorts, and peripheral pTDP-43 pathology is not restricted to ALS, emphasizing the need for larger standardized studies.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/metabolism
*DNA-Binding Proteins/metabolism
*TDP-43 Proteinopathies/pathology/metabolism
Animals

@article {pmid42745716,
year = {2026},
author = {Kokubo, Y},
title = {[A New Understanding of the Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex in the Kii Peninsula, Japan, 2026].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {9},
pages = {1023-1029},
doi = {10.11477/mf.188160960780091023},
pmid = {42745716},
issn = {1881-6096},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Japan/epidemiology ; *Parkinsonian Disorders/epidemiology/genetics ; *Dementia/epidemiology/genetics ; },
abstract = {The distribution of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) in the Kii Peninsula of Japan exhibits regional variations, with ALS/PDC in the Hohara focus closely resembling that in Guam and ALS in the Kozagawa focus. Recent structural analysis using cryo-electron microscopy revealed that the tau filaments in patients with ALS/PDC in Kii have a chronic traumatic encephalopathy (CTE) fold, confirming the disease's distinct pathological identity and commonality with the Guam focus. While the exact causal genes remain unidentified, research utilizing patient-derived induced pluripotent stem cells and proteomic analysis has uncovered endogenous mitochondrial dysfunction, specifically involving decreased expression of CHCHD2 and SSBP1. The presence of migrant cases further suggests that ALS/PDC is a multifactorial disorder triggered by environmental factors that influence genetic vulnerability. Although the incidence of ALS in Kozagawa and Hohara districtst has declined, new cases with PDC continue to emerge in Hohara. Identifying these modifiable environmental triggers is crucial for preventing and eradicating neurological disorders.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/genetics
Japan/epidemiology
*Parkinsonian Disorders/epidemiology/genetics
*Dementia/epidemiology/genetics

@article {pmid42745993,
year = {2026},
author = {Buck, SA and Madhavan, SS and Sanders, LH},
title = {Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {38},
pmid = {42745993},
issn = {3059-4944},
support = {R01 NS119528/NS/NINDS NIH HHS/United States ; T32 AG000029/AG/NIA NIH HHS/United States ; },
abstract = {Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.},
}

@article {pmid42748981,
year = {2026},
author = {Zhang, C and Yang, Z},
title = {The double-edged sentinel: cGAS-STING as a context-dependent regulator of microglial senescence and neuronal genotoxic stress in neurodegeneration.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112118},
doi = {10.1016/j.brainresbull.2026.112118},
pmid = {42748981},
issn = {1873-2747},
abstract = {BACKGROUND: Neurodegenerative diseases may continue to progress even when a pathogenic protein aggregate is reduced, suggesting that downstream inflammatory and genotoxic circuits can become partly autonomous. This narrative review examines cGAS-STING as a context-dependent regulator of DNA-stress responses in the ageing and proteinopathic brain.

METHODS: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for mechanistic, translational, and human-tissue studies of cGAS-STING, DNA damage, mitochondrial quality control, neuroinflammation, and major neurodegenerative diseases. Evidence was separated into biochemical or cellular, animal, and human observations, and contradictory findings were retained.

RESULTS: Mitochondrial DNA leakage is a recurrent candidate trigger, while activity-induced nuclear DNA breaks, defective repair, retrotransposon-derived cDNA, and micronuclear rupture provide conditional inputs. Microglial evidence is currently more extensive and causally developed than neuron-specific evidence; neuronal STING is most firmly supported in selected contexts such as excitotoxic or ischemic stress. Across Alzheimer disease, Parkinson disease, ALS/FTD, multiple sclerosis, and Huntington disease, cGAS-STING-associated inflammation is plausible but not uniform, and human validation remains limited. Therapeutic strategies therefore require cell-, source-, and stage-aware modulation rather than indiscriminate pathway ablation.

CONCLUSION: cGAS-STING is best regarded as a testable kinetic-bottleneck model, not a universal driver of neurodegeneration. Longitudinal human studies and cell-resolved biomarkers are needed to determine when recalibration can suppress pathological inflammation while preserving antiviral and homeostatic functions.},
}

@article {pmid42740981,
year = {2026},
author = {Xie, G and Guo, Y and Wang, Z},
title = {Prevalence of and associated factors for sleep disorders in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1889217},
pmid = {42740981},
issn = {1664-2295},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications ; *Sleep Wake Disorders/epidemiology/etiology ; Prevalence ; },
abstract = {BACKGROUND: Sleep disorders stand as prevalent non-motor symptoms in individuals with amyotrophic lateral sclerosis (ALS) and may be linked to respiratory muscle weakness, neurodegenerative changes, and disruption of sleep architecture. Existing studies have reported considerable variability in the prevalence of sleep disorders in ALS patients, and findings regarding associated factors remain inconsistent. Therefore, this study intended to integrate the existing evidence through a meta-analysis to further clarify the prevalence of sleep disorders and their clinical relevant factors.

METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from database inception to January 10, 2026. Cross-sectional, cohort, and case-control studies involving clinically diagnosed adult patients with ALS were included. A random-effects model was used to estimate the pooled prevalence of sleep disorders. Subgroup analyses were performed according to sex, site of onset, age, disease duration, body mass index (BMI), sleep disorder category based on the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), sleep-related treatment status, and assessment method (polysomnography [PSG] versus questionnaire-based assessment).

RESULTS: A total of 31 studies involving 2,762 patients with ALS were included. The pooled prevalence of sleep disorders was 50% (95% confidence interval [CI], 45-56%). Patients with sleep disorders were significantly older than those without sleep disorders (mean difference [MD] = 3.72 years, 95% CI, 2.39-5.05), whereas no significant associations were observed for sex, body mass index (BMI), disease duration, or site of onset. The prevalence did not differ significantly across the ICSD-3-TR categories (p = 0.7367), whereas questionnaire-based studies yielded a significantly higher pooled prevalence than PSG-based studies (p = 0.0367). Sensitivity analyses confirmed the robustness of the findings.

CONCLUSION: Approximately half of ALS patients have sleep disorders. Age may be related to the occurrence of sleep disorders, whereas no substantial relations were identified for sex, BMI, disease duration, or site of onset. Routine screening and early intervention for sleep issues should be strengthened in clinical management. Large-scale, multicenter prospective studies are still needed to further clarify the underlying mechanisms and clinical implications.

The publicly accessible registration URL is: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261287352. The systematic review was registered with PROSPERO (registration number: CRD420261287352).},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/complications
*Sleep Wake Disorders/epidemiology/etiology
Prevalence

@article {pmid42739287,
year = {2026},
author = {Chen, M and Li, H and Jin, Q},
title = {Presymptomatic Amyotrophic Lateral Sclerosis: From Early Biomarker Detection to Phenoconversion Prediction.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {17},
pages = {},
pmid = {42739287},
issn = {2075-4418},
support = {81671117//National Natural Science Foundation of China/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) usually enters diagnostic pathways after motor symptoms emerge, by which time neural injury has been ongoing. Long-term hereditary ALS cohorts show that some pathogenic-variant carriers may show elevated neurofilament light chain (NfL), mild motor impairment (MMI), electromyographic abnormalities, or imaging changes before clinical manifestation. Since 2022, research has shifted from detecting presymptomatic abnormalities to identifying observable prodromal phenotypes and predicting phenoconversion timing. Operational MMI criteria, longitudinal imaging in chromosome 9 open reading frame 72 (C9orf72) expansion carriers, TAR DNA-binding protein 43 (TDP-43)-related fluid biomarkers, and plasma proteomic models spanning prediction horizons have broadened early identification. The ATLAS study, a trial of tofersen initiated in clinically presymptomatic carriers of superoxide dismutase 1 (SOD1) variants, incorporated specific SOD1 variants and within-person NfL increases into risk monitoring and used these criteria to select participants for the randomized treatment phase. Evidence remains concentrated in a few genetic subtypes, and no single marker accurately predicts individual phenoconversion. Identification requires genotype-specific natural history, serial clinical examinations and biomarker testing, with clinical utility validated in independent longitudinal cohorts and prevention trials.},
}

@article {pmid42736511,
year = {2026},
author = {Soliman, AR and Guirguis, KJ and Kamal, NA},
title = {From fundus to filtration: AI-driven retinal phenotyping as a framework for non-invasive prediction of kidney pathological categories (the "virtual renal biopsy" concept)- a narrative review.},
journal = {International urology and nephrology},
volume = {},
number = {},
pages = {},
pmid = {42736511},
issn = {1573-2584},
abstract = {BACKGROUND: The burden of chronic kidney disease (CKD) continues to grow, affecting over 850 million individuals globally. Current methods to precisely and definitively classify CKD still rely on renal biopsy, a procedure with a 5.1% rate of major complications, and further cost and access complications in low-resource settings. The retina, containing the only accessible microvasculature for direct and non-invasive visualization, shares deep developmental and structural features with, and biologically plausible pathogenic overlap with, the kidney (see Sect. 3 for the distinction between established and hypothesized components of this relationship). Oculomics, an emerging discipline that incorporates AI to analyze retinal images to identify systemic disease, has shown promising results for binary CKD screening, with AUC scores of 0.83-0.93; this is distinct from, and should not be conflated with, the prediction of specific renal pathological categories discussed below. A 2025 study introducing the Kidney Intelligent Diagnosis System (KIDS) was among the first to demonstrate that specific renal pathological categories-IgA nephropathy, idiopathic membranous nephropathy, arterionephrosclerosis, diabetic nephropathy, and a combined idiopathic minimal change disease/focal segmental glomerulosclerosis category-could be predicted from retinal images using five separate binary prediction tasks, reporting AUC values of 0.790-0.932 (internal and, for a subset, external validation; hybrid image-plus-clinical-data models performed at the higher end of this range). This is best regarded as an early proof-of-concept for a non-invasive risk-stratification tool, conceptually described in this review as a 'virtual renal biopsy'-a metaphor for a proposed research framework, not a claim of diagnostic equivalence with tissue histopathology (Meng et al.'s DeepDKD model had earlier used retinal images to distinguish biopsy-defined diabetic from non-diabetic kidney disease, so KIDS is best described as an early multi-category model rather than the first retinal-AI study in this space).

AIM: This narrative review aims to consolidate various biological, technological, and clinical components of AI-driven retinal phenotyping and outline the path toward non-invasive prediction of kidney pathological categories. This includes the aspects of continuous progression from binary screening of CKD towards predicting specific histopathologies while considering the current state of explainability of AI, the performance metrics beyond AUC that are required for clinical deployment, and offering a detailed clinical research roadmap.

METHODS: Narrative synthesis was utilized to integrate data on CKD and deep learning, retinal vascular research, research on retinal-renal connections, AI explainability, and the KIDS model. A structured search of PubMed/MEDLINE, Embase, Scopus, and Google Scholar was performed for English-language, peer-reviewed original studies, systematic reviews, and clinical guidelines relevant to retinal-renal biology, oculomics, and AI-based renal pathology prediction; representative search terms, eligibility criteria, and the handling of preprints are detailed in Sect. 2. The data were organized by biological plausibility, evolution of modeling, integration of imaging technologies, metrics required for clinical validation, and research in translational barriers.

CONCLUSIONS: The combination of the biological plausibility of a retinal signature of renal injury, the advances in oculomics, AI, and early multi-category models such as KIDS lays a preliminary foundation for research toward non-invasive prediction of kidney pathological categories. In order to advance this research agenda, numerous multidisciplinary clinical studies are required along with the integration of different imaging technologies, rigorous reporting of calibration and clinically relevant performance metrics, and the creation of ethical and regulatory frameworks. The 'virtual renal biopsy' concept will not replace histopathology and is not yet supported by evidence sufficient for clinical deployment; if the underlying research agenda is executed rigorously, it may in time provide an adjunctive, non-invasive risk-stratification tool for the hundreds of millions of patients who do not have access to renal histopathological diagnosis.},
}

@article {pmid42737854,
year = {2026},
author = {Ginanni, F and Nicoletti, F and Meoni, C and Becattini, L and Mancuso, M and Carlesi, C and Bianchi, F},
title = {Cognitive and Behavioural Profile of SOD1-ALS Across the ALS-FTD Spectrum: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {17},
pages = {},
pmid = {42737854},
issn = {1422-0067},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; *Superoxide Dismutase-1/genetics ; *Frontotemporal Dementia/genetics/psychology ; *Cognition ; Mutation ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is increasingly recognized as a multisystem disorder. However, SOD1-associated ALS has traditionally been regarded as an exclusively motor phenotype. This systematic review challenges that paradigm by characterizing the cognitive and behavioural profiles of SOD1 mutation-related ALS. Following PRISMA guidelines, a systematic PubMed search identified 17 eligible studies. Across the included studies, encompassing 222 patients with SOD1 variants, three of the analyzed subjects fulfilled the diagnostic criteria for frontotemporal dementia (FTD), and a larger proportion exhibited multidomain cognitive deficits, including executive dysfunction, language impairment, and working memory decline. Behavioural disturbances, such as apathy, emotional lability, and mental rigidity, were also prominent. The historical assumption that SOD1 mutations completely spare cognitive networks likely reflects an under-recognition of subtle manifestations, compounded by the limited sensitivity of earlier screening tools. These findings indicate that cognitive and behavioural involvement can occur in SOD1-ALS, highlighting a highly heterogeneous phenotype. Encompassing varying degrees of severity-from subtle differences in neuropsychological test scores to formal FTD diagnoses-the current evidence points towards possible variant-specific phenotypes rather than a uniform cognitive syndrome. Routine multidomain cognitive screening is crucial in this population. Properly characterizing these non-motor features allows for more accurate disease staging, better monitoring of clinical progression, and the implementation of truly personalized care strategies.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/psychology
*Superoxide Dismutase-1/genetics
*Frontotemporal Dementia/genetics/psychology
*Cognition
Mutation

@article {pmid42738833,
year = {2026},
author = {Ayupova, AI and Sidorova, AS and Luzina, EA and Sufianov, AA and Sufianova, GZ and Zaynutdinov, AM and Rizvanov, AA and Solovyeva, VV},
title = {Application of Mesenchymal Stromal Cells and Their Exosomes in Neurodegenerative Diseases and Lysosomal Storage Diseases.},
journal = {Cells},
volume = {15},
number = {17},
pages = {},
pmid = {42738833},
issn = {2073-4409},
support = {FZSM-2026-0022//The Ministry of Education and Science of the Russian Federation/ ; },
mesh = {Humans ; *Exosomes/metabolism ; *Neurodegenerative Diseases/therapy/metabolism ; *Mesenchymal Stem Cells/metabolism/cytology ; *Lysosomal Storage Diseases/therapy/metabolism ; Animals ; *Mesenchymal Stem Cell Transplantation/methods ; },
abstract = {Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic platform for central nervous system disorders, including neurodegenerative diseases and lysosomal storage disorders (LSDs). This review examines MSC mechanisms of action-paracrine activity, immunomodulation, antioxidant effects, TFEB-mediated autophagy regulation, and enzymatic cross-correction in LSDs-while critically assessing translational challenges. We provide a comparative analysis of MSC sources, administration routes, dosing regimens, and safety profiles, with emphasis on hemocompatibility and thrombotic risks. The evidence base for MSC efficacy in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and LSDs is systematically reviewed, highlighting both promising signals and limitations. MSC-derived extracellular vesicles are discussed as a cell-free alternative with improved safety and potential blood-brain barrier interaction. We propose an individualized monitoring framework integrating clinical scales, biomarkers, and neuroimaging. Despite preclinical promise, the field faces major hurdles: product standardization, optimal dosing, and the need for large, randomized controlled trials. The most rational path forward lies in combination strategies-MSCs as adjuncts to gene or enzyme replacement therapy-and engineered platforms for sustained delivery. This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice.},
}

Humans
*Exosomes/metabolism
*Neurodegenerative Diseases/therapy/metabolism
*Mesenchymal Stem Cells/metabolism/cytology
*Lysosomal Storage Diseases/therapy/metabolism
Animals
*Mesenchymal Stem Cell Transplantation/methods

@article {pmid42738864,
year = {2026},
author = {Ma, X and Liu, J and Guan, Y and Xu, C and Li, M and Zhang, X and Li, Z and Zhang, L and Wang, X and Zhang, H and Chen, Y},
title = {Lactate Metabolism and Signaling in Amyotrophic Lateral Sclerosis.},
journal = {Cells},
volume = {15},
number = {17},
pages = {},
pmid = {42738864},
issn = {2073-4409},
support = {No.82571627//National Natural Science Foundation of China/ ; No.82271483//National Natural Science Foundation of China/ ; No. ZR2024MH112//Shandong Province Natural Science Foundation of China/ ; 202402010641//Shandong Provincial Medical and Health Science and Technology Development Plan/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Lactic Acid/metabolism ; *Signal Transduction ; Animals ; Motor Neurons/metabolism/pathology ; Energy Metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons (MNs). Although the specific pathogenesis of ALS is not yet fully understood, there is increasing evidence that abnormal energy metabolism plays a key role in the onset and progression of the disease. Lactate has traditionally been considered a metabolic by-product of glycolysis and has received increasing attention in recent years. Research has shown that lactate is not only an important energy substrate but also a signaling molecule that regulates a variety of physiological processes, including neuron-glia metabolic coupling, neuroprotection and inflammatory responses. In ALS, abnormalities in lactate metabolism, dysfunction of the lactate shuttle, and dysregulation of lactate-related signaling pathways may jointly lead to neuronal energy deficits and increased neuroinflammation, thereby promoting MN degeneration. This review summarizes the latest advances in lactate metabolism and lactate-mediated signaling in ALS, with particular emphasis on their roles in neuronal energy regulation, neuroprotection and inflammatory regulation. In addition, we also discuss potential therapeutic strategies for lactate metabolism and its related pathways, aiming to provide new insights into the pathogenesis of ALS and the development of treatment methods for lactate-related metabolism.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology
*Lactic Acid/metabolism
*Signal Transduction
Animals
Motor Neurons/metabolism/pathology
Energy Metabolism

@article {pmid42738890,
year = {2026},
author = {Wolozin, B and Best, M and Ellini, M and Ma, Y and Bok, S and Hwang, D and Filipponi, C},
title = {The Paradox of Tau and RNA-Binding Proteins: How Adaptive Stress Granule Regulation Becomes Pathological with Aging.},
journal = {Cells},
volume = {15},
number = {17},
pages = {},
pmid = {42738890},
issn = {2073-4409},
support = {AG080810, AG072577, AG082665, AG095773, AG096052 and AG064932/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Stress Granules/metabolism ; *tau Proteins/metabolism ; *RNA-Binding Proteins/metabolism ; *Aging/metabolism/pathology ; Animals ; Stress, Physiological ; DNA-Binding Proteins/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; },
abstract = {RNA-binding proteins (RBPs) are a large class of proteins that form biological condensates to facilitate their functions. Chronic stress, such as occurs in neurodegenerative diseases, stimulates persistent accumulation of particular RBP condensates as part of the translational stress response, termed stress granules (SGs). These persistent SGs serve as a nidus for aggregation of RBPs to form pathologies that appear in neurodegenerative diseases, such as the occurrence of Tar DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis. Many of the RBPs that accumulate in SGs are also associated with mutations that are linked to neurodegenerative diseases. The microtubule-associated protein tau is the major intracellular pathology that occurs in Alzheimer's disease. Tau is phosphorylated with stress, whereupon it functions to regulate SG biology; conversely, SGs serve as a crucible for the accumulation of toxic oligomeric tau. The regulation of stress by tau is an inherent part of biology that normally occurs during development and hibernation; however, with aging it becomes pathological, possibly because of the reduced proteostasis associated with aging.},
}

Humans
*Stress Granules/metabolism
*tau Proteins/metabolism
*RNA-Binding Proteins/metabolism
*Aging/metabolism/pathology
Animals
Stress, Physiological
DNA-Binding Proteins/metabolism
Neurodegenerative Diseases/metabolism/pathology

@article {pmid42721706,
year = {2026},
author = {Viljoen, S and Chaves, JCS and Peall, I and White, AR and Oikari, LE},
title = {Dysfunction of the blood-brain barrier and neurovascular unit in amyotrophic lateral sclerosis - From advanced human models to treatments.},
journal = {Journal of the neurological sciences},
volume = {490},
number = {},
pages = {126168},
doi = {10.1016/j.jns.2026.126168},
pmid = {42721706},
issn = {1878-5883},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, characterized by the degeneration of motor neurons, resulting in progressive and eventually complete loss of motor function. The phenotypical heterogeneity of ALS poses a challenge to early diagnosis and treatment, with currently available therapeutics only capable of relieving symptoms and slowing progression. While ALS is classified as a motor neuron disease (MND), research has identified significant impairment to the blood-brain barrier (BBB) and neurovascular unit (NVU) of ALS patients. The BBB along with supporting cells of the NVU selectively control the entry of substances into the central nervous system (CNS) and maintain brain homeostasis, with its many cellular components demonstrating impaired function, specifically relating to inflammation, oxidative stress and TDP-43 proteinopathy. The advent of more advanced in vitro techniques as well as use of patient-derived BBB cells has presented a promising alternative to recreate the in vivo structure of the BBB/NVU in a highly controlled platform. Such approaches have ranged from simple 2-dimensional (2D) cell culture to intricate 3-dimensional (3D) co-culture systems, as well as microfluidic systems and organoids, with a potential to investigate ALS associated BBB/NVU dysfunction and drug discovery. This review provides a comprehensive assessment of known BBB/NVU dysfunction in ALS and methods of investigating this using in vitro and in vivo platforms with a focus on inflammation, oxidative stress and pathological TDP-43 expression. This review also presents a future perspective to overcoming barriers to treatment of ALS using new patient-derived BBB/NVU model systems.},
}

@article {pmid42723096,
year = {2026},
author = {Persico, M and Tuithung, S and Lorenzo, A and Crawford, D and Eleuteri, S and Simon, DK},
title = {Retromer-targeted therapy for neurodegenerative diseases.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42723096},
issn = {1750-1326},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Vesicular Transport Proteins/metabolism ; *Endosomes/metabolism ; Mitochondria/metabolism ; Lysosomes/metabolism ; },
abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases characterized by dysfunction of the endosomal-lysosomal system (ELS). Four shared neurodegenerative mechanisms across ALS, PD and AD are regulated by the ELS, namely proteostasis and related protein misfolding, mitochondrial function, neurotransmission and neuroinflammation. These mechanisms are interconnected, contributing to neurodegeneration in a "snowball" manner. The retromer, a multimeric, evolutionarily conserved protein complex involved in intracellular protein trafficking, is at the crossroad of these neurodegenerative processes. This narrative review focuses on exploring the retromer structure, function as a master regulator of the ELS, and how this impacts proteostasis, mitochondrial biogenesis and homeostasis, neurotransmission and neuroinflammation across neurodegenerative diseases. We explore how alterations in retromer function can play an important role in neurodegeneration and discuss the impact of genetic and pharmacological manipulations of VPS35, one of the main retromer subunits. In vitro and in vivo studies have identified that the retromer enhances the activity of protein degradation pathways via the ELS, namely macroautophagy, chaperone-mediated autophagy, and the ELS itself, with concomitant reduction in misfolded protein levels. Also, in some model systems, when the retromer role is enhanced or restored, mitochondrial function is rescued, dysfunctional neurotransmission is restored, and the damaging effects of neuroinflammation are dampened. Lastly, we highlight the role of a novel pharmacological class of agents that enhance retromer function as a strategy for potentially slowing the progression of these neurodegenerative diseases in in vivo models of PD and ALS. We discuss the challenges in targeting the retromer, current limitations and potential off-target effects of retromer enhancement. Overall, the retromer regulates shared mechanisms across neurodegenerative diseases and retromer enhancers could represent a novel disease-modifying strategy in AD, PD and ALS.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
Animals
*Vesicular Transport Proteins/metabolism
*Endosomes/metabolism
Mitochondria/metabolism
Lysosomes/metabolism

@article {pmid42724165,
year = {2026},
author = {Alauddin, W and Srivastava, C and Goyal, P and Shukla, M and Garg, DK and Prajesh, BR and Singh, S and Shaikh, FI and Khairnar, S},
title = {Gut Microbiota, Neuroinflammation, and Autonomic Dysfunction in Neurodegenerative Diseases: A Systematic Review of Mechanistic and Translational Evidence.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114312},
pmid = {42724165},
issn = {2168-8184},
abstract = {Neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, multiple system atrophy, and amyotrophic lateral sclerosis, are increasingly recognized as complex conditions arising from interactions among the gut microbiota, immune system, and autonomic nervous system. Growing evidence indicates that disruption of the intestinal microbial ecosystem may contribute to neuroinflammatory processes, autonomic impairment, and progressive neurodegeneration through the microbiota-gut-brain axis, although the underlying mechanisms and their translational implications remain incompletely understood. This systematic review was conducted in accordance with the PRISMA 2020 guidelines to comprehensively evaluate the evidence linking gut microbiota dysbiosis with neuroinflammation and autonomic dysfunction across neurodegenerative diseases. A systematic search of PubMed/MEDLINE, Scopus, Web of Science, EMBASE, EBSCOhost, CINAHL, PsycINFO, CENTRAL, Google Scholar, and major grey literature sources yielded 2,769 records. After duplicate removal and eligibility screening, 62 full-text reports underwent detailed assessment, of which 11 studies met the predefined eligibility criteria and were included in the qualitative synthesis. The evidence encompassed human observational, animal experimental, and in vitro approaches, with several studies integrating complementary clinical, microbiome, and experimental methodologies. Most included studies focused on Parkinson's disease and multiple system atrophy. Across studies, microbial dysbiosis was characterized by reduced abundance of short-chain fatty acid (SCFA)-producing bacteria alongside increased representation of pro-inflammatory microbial taxa. These microbial alterations were associated with disruption of intestinal barrier integrity, activation of inflammatory signaling pathways, microglial activation, elevated pro-inflammatory cytokine production, α-synuclein aggregation, and autonomic manifestations such as gastrointestinal dysmotility and cardiovascular autonomic dysfunction. Experimental studies provided biological support for the microbiota-gut-brain axis, whereas clinical investigations consistently demonstrated associations without establishing causality. Overall, current evidence suggests that gut microbial dysbiosis is closely associated with neuroinflammation and autonomic dysfunction in neurodegenerative diseases and may represent a promising avenue for biomarker discovery and therapeutic intervention. Nevertheless, the available literature is constrained by methodological heterogeneity, limited sample sizes, and the predominance of observational and preclinical studies. Future large-scale longitudinal investigations and rigorously designed randomized controlled trials are required to determine causal relationships and define the clinical utility of microbiome-targeted strategies.},
}

@article {pmid42725023,
year = {2026},
author = {Xiao, X and Cao, G and Hou, S and Yin, H},
title = {P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {613821},
pmid = {42725023},
issn = {1178-7031},
abstract = {Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca[2+]overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca[2+]-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.},
}

@article {pmid42727710,
year = {2026},
author = {Inoue, Y and Tanaka, M and Oguchi, T and Sasaki, A and Saito, K and Inoue, A and Otsuka, N},
title = {Selective neuroprotection in the ALS-FTD spectrum: Mechanisms of neuronal resilience and translational perspectives.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112111},
doi = {10.1016/j.brainresbull.2026.112111},
pmid = {42727710},
issn = {1873-2747},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as part of a broader clinico-pathological continuum encompassing frontotemporal dementia (FTD). Despite progressive degeneration across motor and cognitive neural systems associated with TDP-43 pathology, specific neuronal populations-including the oculomotor and abducens nuclei, Onuf's nucleus, and sensory dorsal column pathways-remain relatively preserved.

OBJECTIVE: Selectively preserved neuronal structures in ALS have largely been described as isolated neuropathological observations without sufficient mechanistic integration. This review aims to synthesize candidate intrinsic and microenvironmental mechanisms that may contribute to selective neuronal preservation and propose a translational framework for understanding neuronal resilience in the ALS-FTD spectrum.

METHODS: We conducted a comprehensive critical review of the literature addressing selective neuronal vulnerability and resistance in ALS-FTD, integrating comparative observations from related neurodegenerative and neuromuscular disorders. Particular emphasis was placed on candidate mechanisms associated with neuronal resilience, including Nrf2/ARE signaling, calcium homeostasis, glutamatergic receptor composition, glial-mediated neurotrophic support, and emerging transcriptomic evidence relevant to selective neuronal vulnerability.

RESULTS: Selective preservation of specific neuronal populations represents a distinctive biological characteristic of the ALS-FTD spectrum. Current evidence suggests that enhanced antioxidant defense, tightly regulated intracellular calcium dynamics, protective microenvironmental interactions, and other stress-response pathways may collectively contribute to resistance against TDP-43 proteinopathy. These findings may provide a mechanistic framework for understanding selective neuronal resilience and suggest potential avenues for future neuroprotective therapeutic development.

CONCLUSIONS: Integrating mechanisms of selective neuroprotection with translational neurobiological perspectives may provide a conceptual framework for ALS research. Leveraging preserved neural systems may not only inform biologically grounded supportive care strategies but also help identify mechanistically relevant targets for future disease-modifying interventions.},
}

@article {pmid42728797,
year = {2026},
author = {Sanghai, N and Pierce, K and Sharma, N and Leggett, S and Yadav, TC and Masrori, P and Atukorallaya, D and Palaniyandi, S and Marcogliese, PC and Tranmer, GK},
title = {Recent Advancements in Drug Delivery Across the Blood-Brain Barrier in Amyotrophic Lateral Sclerosis (ALS).},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71078},
pmid = {42728797},
issn = {1755-5949},
support = {RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant/ ; 202210PJT-495295/CAPMC/CIHR/Canada ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Blood-Brain Barrier/drug effects/metabolism ; Animals ; *Drug Delivery Systems/methods/trends ; Blood-Spinal Cord Barrier/drug effects/metabolism ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neurodegenerative disease with limited therapeutic options. The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) present major obstacles to central nervous system (CNS) drug delivery, restricting the effectiveness of many potential therapies. Increasing evidence suggests that BBB and BSCB dysfunction are not only barriers to treatment but also important contributors to ALS pathophysiology.

OBJECTIVE: To examine current evidence regarding BBB and BSCB dysfunction in ALS and evaluate the implications of stage-dependent barrier alterations for CNS drug delivery and therapeutic outcomes.

METHODS: Recent mechanistic, pathological, preclinical, and clinical studies examining BBB and BSCB alterations in ALS were reviewed. Evidence on tight junction disorganization, endothelial dysfunction, vascular leakage, altered transporter activity, and emerging therapeutic and drug delivery strategies was analyzed.

RESULTS: Converging evidence indicates that BBB and BSCB dysfunction are intrinsic and progressive features of ALS pathophysiology rather than passive consequences of neurodegeneration. Barrier impairment emerges early in the disease course and evolves across clinical stages. Disruption of barrier integrity may increase motor neuron vulnerability while modulating CNS drug exposure. Emerging strategies that bypass, exploit, or restore barrier function hold promise for enhancing CNS bioavailability and improving therapeutic outcomes.

CONCLUSIONS: Improved understanding of barrier alterations may facilitate development of more effective CNS-targeted therapies and improve therapeutic outcomes in ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
*Blood-Brain Barrier/drug effects/metabolism
Animals
*Drug Delivery Systems/methods/trends
Blood-Spinal Cord Barrier/drug effects/metabolism

@article {pmid42734724,
year = {2026},
author = {Steger, L and Rothhammer, V and Zunke, F},
title = {Astrocytes in Neurodegeneration: Spatial States, Crosstalk, and Emerging Therapies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42734724},
issn = {1559-1182},
support = {S3- AstroFinder//Interdisziplinäres Zentrum für Klinische Forschung; IZKF, Erlangen/ ; 505539112//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Astrocytes/pathology/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/pathology/therapy/metabolism ; *Nerve Degeneration/pathology/therapy ; },
abstract = {Astrocytes are increasingly recognized as active drivers of neurodegeneration rather than passive responders. Single-cell and spatial transcriptomic analyses reveal that astrocytes occupy heterogeneous, regionally patterned states that align closely with selective neuronal vulnerability. Across Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, and rare primary astrocytopathies, astrocytes consistently converge on dysfunction across four mechanistic axes: breakdown of glutamate homeostasis, impaired ion and water buffering, lysosomal, and autophagic insufficiency, as well as maladaptive inflammatory-stress signaling. Spatial multi-omics demonstrates that these disruptions are not uniformly distributed but instead map to discrete niches, including plaque-adjacent astrocytes in Alzheimer's disease, CD44-high fibrotic-like astrocytes in the substantia nigra in Parkinson's disease, and EAAT2-low ventral horn astrocytes in ALS, consistent with patterns of selective neuronal vulnerability. Primary astrocytopathies including Alexander disease, vanishing white matter disease, and megalencephalic leukoencephalopathy illuminate the causal power of perturbing individual astrocytic modules, revealing how isolated disruptions in proteostasis, translation control, or ion-water coupling can initiate widespread neurodegeneration. By integrating neuropathological, imaging, and transcriptomic evidence across studies, we derive a consensus-based regional framework of astrocytic vulnerability across neurodegenerative diseases. Together, these findings define a unifying framework in which astrocytes transition from homeostatic regulators to pathological amplifiers, highlighting astrocyte states as tractable, region-specific therapeutic targets and illustrating how integration of spatial atlases with mechanistic insights might help develop a framework for targeted astrocyte therapies.},
}

*Astrocytes/pathology/metabolism
Animals
Humans
*Neurodegenerative Diseases/pathology/therapy/metabolism
*Nerve Degeneration/pathology/therapy

@article {pmid42721110,
year = {2026},
author = {Alrabadi, B and Matar, HI and Bandak, N and Yaseen, S and Badwan, A and Alomari, O},
title = {Non-invasive brain stimulation in amyotrophic lateral sclerosis: a systematic review and meta-analysis of transcranial direct current stimulation and transcranial magnetic stimulation.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17582024.2026.2731195},
pmid = {42721110},
issn = {1758-2032},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited disease-modifying treatments. Noninvasive brain stimulation techniques have been investigated as potential neuromodulatory interventions targeting cortical hyperexcitability in ALS.

OBJECTIVE: To systematically evaluate the clinical efficacy, neurophysiological effects, and safety of tDCS and TMS-based interventions in ALS.

METHODS: A systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Scopus, Web of Science, and Cochrane Library were searched from inception to March 2026.

RESULTS: Thirty studies involving ALS patients were included. Pooled analyses showed no significant difference between active stimulation and sham in ALSFRS-R at 6 months (MD = 0.58, 95% CI - 0.16 to 1.31) or at end of follow-up (MD = 0.20, 95% CI - 0.49 to 0.89). No significant effect was observed for manual muscle testing. Considerable heterogeneity was noted across studies. However, several studies demonstrated modulation of cortical excitability and intracortical inhibitory circuits, particularly with repeated stimulation protocols. Both tDCS and TMS were consistently safe and well tolerated, with no serious adverse events reported.

CONCLUSION: Noninvasive brain stimulation in ALS does not significantly improve functional outcomes, but induces measurable neurophysiological changes with a strong safety profile. Further studies should optimize protocols and identify responsive subgroups.},
}

@article {pmid42720979,
year = {2026},
author = {Huang, CS and Sanchez-Santos, C and Martinez-Gonzalez, L and Gil, C and Martinez, A},
title = {Innovative therapies under clinical development for ALS treatment. Part 2: biologics and natural products.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/13543784.2026.2729512},
pmid = {42720979},
issn = {1744-7658},
abstract = {INTRODUCTION: The clinical trial landscape for Amyotrophic Lateral Sclerosis (ALS) is rapidly expanding despite ongoing translational challenges. Following our 2022 analysis and as a continuation of Part 1, which focused on small molecules, this review provides a structured overview of biologics and natural products in the ALS clinical pipeline. Particular emphasis is placed on candidates that entered, advanced through, or completed clinical evaluation between 2022 and the end of 2025.

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

EXPERT OPINION: Modern biotechnology, ethnopharmacology, and classical pharmacology are increasingly converging in ALS therapeutic development, making this one of the most active areas of neurodegenerative disease research. Nevertheless, major challenges remain, including central nervous system (CNS) penetration, long-term safety, interpatient variability, limited clinical evidence, and the need for reliable biomarkers. Emerging technologies, such as big data analytics and artificial intelligence, may help accelerate and optimize therapeutic development, as well as improve patient recruitment and stratification.},
}

@article {pmid42713279,
year = {2026},
author = {Kassubek, J and Müller, HP},
title = {Magnetic resonance imaging applications to amyotrophic lateral sclerosis beyond the central nervous system.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1849783},
pmid = {42713279},
issn = {1664-2295},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; },
abstract = {Traditionally, in amyotrophic lateral sclerosis (ALS) and other motor neuron disorders, the diagnostic and research focus in the domain of magnetic resonance imaging (MRI) has been targeted on the brain and spinal cord. Nevertheless, structures outside the central nervous system (CNS) are core structures of the pathological processes and are also assessible by imaging approaches. Advanced imaging of structures like bodyfat and muscles can considerably contribute to the pathophysiological understanding and disease monitoring of ALS. The multiparametric combination of MRI approaches that capture these changes could be very helpful in future studies, especially when machine learning algorithms are used. This review summarizes the current state of the art and the role of imaging beyond the CNS in ALS, examining its diagnostic and monitoring potential and how it might ultimately lead to improved management strategies for patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging
*Magnetic Resonance Imaging/methods

@article {pmid42716045,
year = {2026},
author = {Teunissen, CE and Vermunt, L and Barthélemy, NR and Benzinger, TLS and Graff-Radford, J and Verberk, IMW and Zetterberg, H and Schindler, SE and Jack, CR},
title = {Fluid biomarkers in the evolving care landscape of Alzheimer's disease and related disorders.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {926-938},
doi = {10.1016/S1474-4422(26)00246-2},
pmid = {42716045},
issn = {1474-4465},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood ; tau Proteins/cerebrospinal fluid ; Animals ; },
abstract = {Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, α-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/diagnosis/blood
tau Proteins/cerebrospinal fluid
Animals

@article {pmid42719214,
year = {2026},
author = {Mittal, D and Solanki, P and Jain, GK and Jhawat, V and Kesharwani, P and Dutt, R and Arora, S and Singh, RP},
title = {Herbal nanoparticles in the treatment of neurodegeneration: from molecular mechanisms to therapeutic translation.},
journal = {3 Biotech},
volume = {16},
number = {10},
pages = {420},
pmid = {42719214},
issn = {2190-572X},
abstract = {UNLABELLED: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss involving multiple pathological mechanisms, including protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although conventional therapies provide symptomatic relief, they fail to halt disease progression and are limited by poor blood-brain barrier (BBB) penetration, off-target effects, and systemic toxicity. Likewise, several herbal bioactives, such as curcumin, resveratrol, quercetin, and epigallocatechin gallate, exhibit promising neuroprotective properties but suffer from poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate brain delivery. Nanotechnology-based delivery systems have emerged as a promising approach to overcome these pharmacokinetic limitations by enhancing stability, controlled release, BBB transport, and brain accumulation of herbal therapeutics. This review critically summarizes recent advances in herbal nanoformulations, emphasizing disease-specific molecular targets, BBB-targeting strategies, comparative nanocarrier systems, pharmacokinetic optimization, intracellular trafficking, and translational challenges. Unlike previous reviews, it integrates recent evidence on nanotoxicology, manufacturing scalability, quality control, regulatory considerations, and emerging technologies, including biomimetic nanoparticles and extracellular vesicles. Despite encouraging preclinical outcomes, clinical evidence remains limited, and no herbal nanoformulation has yet demonstrated definitive efficacy or received regulatory approval for neurodegenerative diseases. Future clinical translation will require standardized formulations, rigorous safety evaluation, and well-designed clinical trials. Unlike previous reviews that primarily summarize individual nanocarrier systems or herbal therapeutics, the present review provides a comprehensive and critical synthesis of the current evidence by integrating disease-specific molecular mechanisms, herbal bioactives, nanocarrier design strategies, blood-brain barrier transport mechanisms, intracellular trafficking, pharmacokinetic considerations, translational barriers, regulatory challenges, clinical evidence, and emerging technologies. Furthermore, the review identifies major knowledge gaps and future research priorities to facilitate the successful clinical translation of herbal nanoformulations for neurodegenerative disorders.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05048-8.},
}

@article {pmid42719350,
year = {2026},
author = {Imashuku, S},
title = {Literature review of pediatric Erdheim-Chester disease (ECD) and mixed histiocytosis (Langerhans cell histiocytosis/ECD).},
journal = {Annals of translational medicine},
volume = {14},
number = {4},
pages = {53},
pmid = {42719350},
issn = {2305-5839},
abstract = {BACKGROUND AND OBJECTIVE: Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD) are more commonly observed in childhood; however, Erdheim-Chester disease (ECD) predominantly affects adults, making pediatric ECD extremely rare. To find out the incidence and characteristics of ECD in children, a review article was prepared.

METHODS: A literature review was conducted to estimate the incidence of pediatric ECD and characterize its clinical features, using PubMed and Crossref, during 1990 to June 2026, with searched terms "Childhood or Pediatric", "Erdheim-Chester disease", "Mixed histiocytosis".

KEY CONTENT AND FINDINGS: A total of 28 pediatric ECD cases were collected, which compared with previously reported pediatric ECD case series (Pegoraro et al., n=21; Romano et al., n=16). Based on these reports, it was estimated that more than 30 pediatric ECD cases have been described to date. Pediatric ECD appears to be characterized by relatively high rates of central nervous system involvement (53-67%) and mixed histiocytosis (20-38%). In addition, ophthalmologic involvements in the Yeager et al.'s study in 45% (adult 30%) of pediatric ECD should be recognized as an important manifestation in the eyes even in children. Regarding prognosis, most pediatric patients with ECD were reported as alive with disease (AWD) at the time of publication, suggesting a more favorable outcome than that observed in adult cases.

CONCLUSIONS: Diagnosing ECD in children remains challenging; however, this rare entity should be considered in the differential diagnosis of pediatric histiocytosis, particularly in cases with central nervous system and ophthalmologic involvement.},
}

@article {pmid40660446,
year = {2026},
author = {Singh, D},
title = {Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.},
journal = {Current drug safety},
volume = {21},
number = {2},
pages = {94-107},
doi = {10.2174/0115748863375490250626163609},
pmid = {40660446},
issn = {2212-3911},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles ; *Mitochondrial Diseases/drug therapy ; },
abstract = {Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Targeted drug delivery to mitochondria represents a promising therapeutic strategy to mitigate neuronal degeneration and preserve mitochondrial function in these devastating conditions. This review provides a comprehensive overview of recent advances in targeted drug delivery solutions for mitochondrial dysfunction in neurodegenerative disorders. The mechanisms underlying mitochondrial dysfunction in AD, PD, HD, and ALS are explored, highlighting the specific challenges and opportunities for therapeutic intervention. Emerging drug delivery technologies are discussed, including mitochondriaresponsive systems, nanoparticles, peptides, and viral vectors, designed to deliver therapeutic agents directly to mitochondria along with suitable case studies. Furthermore, preclinical and clinical studies evaluating the efficacy and safety of mitochondria-targeted therapeutics are reviewed, and future directions and challenges in the field are outlined. By elucidating the intersection of mitochondrial biology and drug delivery, this review aims to inspire further research and innovation toward effective treatments for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/drug therapy/physiopathology/metabolism
*Mitochondria/drug effects/metabolism/pathology
Animals
*Drug Delivery Systems/methods
Nanoparticles
*Mitochondrial Diseases/drug therapy

@article {pmid41572777,
year = {2026},
author = {Liu, X and Lv, Z and Xu, G and Chen, Y and Liu, H and Xu, P},
title = {Investigating the Multiple Regulatory Mechanisms and Therapeutic Targets of PHLDA1 in Neurological Diseases.},
journal = {Current neuropharmacology},
volume = {24},
number = {8},
pages = {1206-1223},
pmid = {41572777},
issn = {1875-6190},
mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Transcription Factors/metabolism ; Signal Transduction/physiology ; },
abstract = {PHLDA1 (pleckstrin homology-like domain family A member 1) is a pleiotropic regulatory protein that affects key biological processes such as apoptosis, pyroptosis, immune inflammation, autophagy, metabolism, and oxidative stress. PHLDA1 plays a significant role in the pathological mechanisms of neurological diseases. This article systematically reviews the molecular characteristics of PHLDA1 and its core role in cerebrovascular diseases such as cerebral ischemia/ reperfusion injury, cerebral hemorrhage, subarachnoid hemorrhage, epilepsy, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Studies have shown that PHLDA1 promotes disease progression by regulating signalling pathways such as the NF-κB, MAPK, NLRP3 inflammasome, PPARγ, and Nrf2 pathways, thereby exacerbating neuroinflammation, mitochondrial dysfunction, endoplasmic reticulum stress, and pyroptosis in neurons. Its expression is regulated by the dynamic balance of miRNAs (such as miR-194 and miR-101), transcription factors (Egr1 and BHLHE40), and heat shock proteins (HSPs/HSF1). In addition, PHLDA1 has become a potential target for intervention in neurodegenerative and ischemic injuries by inhibiting FundC1-mediated mitochondrial autophagy, regulating microglial polarization, and activating TRAF6-dependent neuroinflammation. This article not only clarifies the pathogenic mechanism of PHLDA1 but also summarizes the relevant intervention strategies targeting PHLDA1, hoping to provide a corresponding theoretical basis and reference for the development of precision therapies for neurological diseases.},
}

Humans
Animals
*Nervous System Diseases/metabolism/drug therapy
*Transcription Factors/metabolism
Signal Transduction/physiology

@article {pmid42702895,
year = {2026},
author = {Uysal, SP and Dudley, KA and Sullivan, S and Brizzi, KT and Burke, KM and Hall, S and Pease, K and Goldstein, JN and Berry, JD and Ho, DT},
title = {Emergencies in Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70398},
pmid = {42702895},
issn = {1097-4598},
abstract = {Emergencies are frequent in people living with amyotrophic lateral sclerosis (pALS), especially as the disease progresses, and can necessitate urgent evaluation and intervention. Progressive weakness in ALS inevitably increases fall risk, making discussion of fall prevention strategies integral to caring for pALS. Thromboembolic events and respiratory failure may present insidiously in ALS, requiring a high index of clinical suspicion, and management strategies differ from those for individuals without ALS. Bulbar impairment in ALS can give rise to aspiration, laryngospasm, and malnutrition leading to emergency department (ED) visits, underscoring the need for early consideration of gastrostomy tube placement. PALS face an increased risk of serious infections, making vigilant monitoring for any acute change essential. Tracheostomy and gastrostomy, although life-sustaining measures in ALS, may require ED care when complications arise. Proactive assessment and management are critical to prevent complications related to constipation, urinary dysfunction, cognitive and behavioral issues. Although serious adverse events from ALS treatments are very rare, potential immune-mediated neurologic complications are a consideration with tofersen use. Importantly, ALS emergencies should be viewed as potential indicators of disease progression, prompting timely serious illness discussions and reassessment of goals of care. Anticipation of potential complications and emergencies, combined with an understanding of appropriate evaluation and evidence-based management, constitute critical components of caring for pALS. Early recognition and proactive management of these emergencies can improve safety, reduce avoidable hospitalizations, and support goal-concordant, patient-centered care.},
}

@article {pmid42707600,
year = {2026},
author = {Zhang, Z and Lu, Y and Yang, J and Li, M and Yang, M and Xu, Y and Ullah, MS and Wan, Q and Bao, B and Yu, W and Liu, X},
title = {Neurotoxic mechanisms of cadmium in neurodegenerative diseases.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1899381},
pmid = {42707600},
issn = {2296-634X},
abstract = {Cadmium (Cd) is a highly toxic, bioaccumulative heavy metal increasingly implicated in the pathogenesis of neurodegenerative disorders. This review systemically characterizes the molecular mechanisms underlying Cd-induced neurotoxicity, with particular emphasis on oxidative stress-mediated pathways that initiate interconnected processes including ferroptosis, mitochondrial impairment, disruption of calcium homeostasis, and chronic neuroinflammation. Evidence indicates that Cd exerts both convergent and disease-specific effects in neurodegenerative conditions. In Alzheimer's disease (AD), Cd exposure has been associated with enhanced amyloid-β (Aβ) deposition and increased tau hyperphosphorylation. In Parkinson's disease (PD), Cd disrupts metabolic homeostasis via the gut-liver-brain axis and promotes aberrant conformational changes and aggregation of α-synuclein (α-Syn). Within the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum, Cd contributes to TDP-43 proteinopathy and impairs nucleocytoplasmic transport mechanisms. Therapeutic strategies targeting Cd-induced neurotoxicity are also explored, including upstream approaches like metal chelation and downstream interventions aimed at restoring autophagic flux, modulating the neuroimmune microenvironment, and enhancing neuronal repair. Although emerging platforms such as brain organoids provide valuable mechanistic insights, translating findings from in vitro models to real-world chronic exposure scenarios remains a significant challenge. This review provides a comprehensive framework for the development of early-warning systems and precision-based interventions for Cd-related neurodegeneration.},
}

@article {pmid42709165,
year = {2026},
author = {Hamzeh, LH and Seyed, E and Elgendy, MA and Heib, D and Sadek, BI and Mohammed, COS and El Refaei, K and Soliman, YF and Eldmrdash, N and Abdelgalil, MS and Elsayed, MM},
title = {Efficacy and safety of memantine in adults with amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42709165},
issn = {1435-1463},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Memantine, an N-methyl-D-aspartate receptor antagonist, has been investigated in ALS, but its safety remains unclear. This study systematically assessed the safety of memantine in adults with ALS. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines, searching PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials of memantine in adults with ALS. Outcomes included ALSFRS-R and FVC decline, adverse neurological events, total and serious adverse events, treatment discontinuation, and all-cause mortality. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Because of heterogeneous reporting and missing variance estimates, ALSFRS-R and FVC outcomes were synthesized narratively; only safety outcomes were pooled quantitatively. Three randomized controlled trials (706 participants) met the inclusion criteria. Functional and respiratory outcomes could not be pooled because of heterogeneous reporting, and no consistent benefit was observed. Memantine showed lower headache incidence than placebo (RR 0.43; 95% CI 0.19-0.96), with no significant differences in constipation, falls, dizziness, treatment discontinuation, or all-cause mortality. Memantine showed a borderline increase in serious adverse events (RR 1.52; 95% CI 1.00-2.31) and a higher risk of total adverse events (RR 1.19; 95% CI 1.09-1.30). Memantine was associated with a small but significant increase in total adverse events and a trend toward more serious adverse events, without improving functional decline, respiratory function, or survival in ALS. Current evidence does not support its use as a disease-modifying or adjunctive therapy. Trial registration: PROSPERO CRD420261277874.},
}

@article {pmid42709336,
year = {2026},
author = {Colosimo, C},
title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {42709336},
issn = {1179-1918},
abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.},
}

@article {pmid42713005,
year = {2026},
author = {Belaidi, AA and Furtado, DL and Alves, F and Nisbet, RM and Ayton, S and Bush, AI},
title = {Engineering mRNA-LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases.},
journal = {Exploration (Beijing, China)},
volume = {},
number = {},
pages = {70223},
pmid = {42713005},
issn = {2766-2098},
abstract = {Messenger RNA (mRNA) therapeutics delivered by lipid nanoparticles (LNPs) have advanced from concept to clinic at unprecedented speed, yet their promise for neurodegenerative diseases remains largely untapped. Currently intractable age-related proteinopathies such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis demand new therapies that combine molecular precision with scalable manufacturing. This review surveys recent advances in engineering LNPs that traverse the blood-brain barrier (BBB), evade innate immune surveillance, and achieve cell-selective expression in the ageing brain. We highlight emerging chemistries, including BBB-shuttling ionizable lipids, peptide-functionalized shells, and liver-detargeted formulations that enable systemic or minimally invasive delivery to the central nervous system (CNS) in animal models. Although no CNS-directed mRNA-LNP has yet reached clinical trials, first-in-human studies for rare metabolic disorders demonstrate favourable safety, manufacturability, and durable protein replacement. Drawing lessons from COVID-19 mRNA vaccines and ongoing liver-targeted programmes, we outline a translational roadmap for brain applications. Major hurdles that are critically assessed include efficient endosomal escape in aged neurons, heterogeneity of the senescent BBB, chronic-dose immunogenicity, and large-scale synthesis of next-generation lipids. Finally, we propose design rules and analytical standards to address outstanding knowledge gaps in expression durability and age-related BBB alterations. Together, these insights chart a path for engineering mRNA-LNP therapeutics capable of meeting the rising burden of neurodegenerative diseases in an ageing global population.},
}

@article {pmid42697520,
year = {2026},
author = {Sharma, A and Jatana, N},
title = {Microbiota-derived metabolite-GPCR signalling in neurodegeneration.},
journal = {Neuroscience},
volume = {615},
number = {},
pages = {312-333},
doi = {10.1016/j.neuroscience.2026.09.001},
pmid = {42697520},
issn = {1873-7544},
abstract = {The gut microbiome acts as a primary regulator of host homeostasis, influencing the entire body through bidirectional communication along the gut-brain axis (GBA). Dysbiosis, which is defined as a state of microbial imbalance involving alterations in community composition and function, can disrupt the synthesis of important microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids and neurotransmitter precursors. This can lead to impaired essential host signalling pathways. There is growing evidence that metabolic alterations associated with dysbiosis contribute to the onset and progression of neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). In this context, G protein-coupled receptors (GPCRs) act as essential molecular transducers that link microbial metabolites to intracellular signalling networks. Aberrant GPCR activation, driven by altered metabolite profiles, modulates key downstream pathways including cAMP, MAPK, PI3K/Akt, NF-κB and Ca2 + signalling. This promotes neuroinflammation, oxidative stress, mitochondrial dysfunction and pathological protein aggregation - hallmark processes underlying neurodegeneration. By identifying convergent and disease-specific signalling pathways, the review highlights mechanistic nodes of therapeutic relevance and discusses GPCR-centric emerging and other microbiome-targeted strategies aimed at restoring metabolic and signalling homeostasis in neurodegenerative disorders.},
}

@article {pmid42698179,
year = {2026},
author = {Dhar, A and Sharar, AD and Papisetty, S and Bydon, M and Moinuddin, FM},
title = {The Therapeutic Potential of Purmorphamine Across Disease Models.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {17},
pages = {e71349},
pmid = {42698179},
issn = {1582-4934},
mesh = {Humans ; Animals ; *Purines/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Hedgehog Proteins/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Morpholines ; },
abstract = {Purmorphamine (PUR) is a trisubstituted purine compound that selectively activates Smoothened receptor, thereby initiating Sonic Hedgehog (Shh) signalling-a pathway critical for embryonic patterning, neuronal specification and tissue regeneration across multiple organ systems. Dysregulation of Shh signalling has been implicated in degenerative diseases yet therapeutic interventions targeting this pathway remain limited. PUR demonstrates broad therapeutic efficacy across diverse preclinical disease models by activating both canonical GLI-mediated transcription and non-canonical Shh pathways, resulting in neuroprotection, reduced neuroinflammation, enhanced blood-brain barrier integrity and tissue regeneration. In contrast to previous assumptions that Shh pathway activation requires endogenous ligand binding, PUR bypasses this requirement through direct Smoothened engagement, offering a pharmacologically tractable approach to pathway modulation. Preclinical studies demonstrate that PUR enhances motor neuron survival in amyotrophic lateral sclerosis models, protects dopaminergic neurons in Parkinson's disease, reverses behavioural abnormalities in autism spectrum disorder, promotes neurovascular repair following stroke, restores myelin integrity in multiple sclerosis models and drives osteogenic differentiation in bone tissue engineering applications. Beyond its established Smoothened agonist activity, recent evidence identifies PUR as a positive allosteric modulator of the secretin receptor, expanding its therapeutic scope to include cardiovascular applications such as hypertension management through enhanced nitric oxide bioavailability.},
}

Humans
Animals
*Purines/therapeutic use/pharmacology
Signal Transduction/drug effects
Hedgehog Proteins/metabolism
Disease Models, Animal
Neuroprotective Agents/pharmacology/therapeutic use
Morpholines

@article {pmid42701950,
year = {2026},
author = {Morgillo, F and Digennaro, V and Panciera, A and Benvenuti, L and Carbone, N and Ferri, R and Zielli, SO and Faldini, C},
title = {Torsional deformities and anterior knee pain: a systematic review and clinical approach to miserable malalignment syndrome.},
journal = {Musculoskeletal surgery},
volume = {},
number = {},
pages = {},
pmid = {42701950},
issn = {2035-5114},
abstract = {Despite advancements in understanding and treating anterior knee pain linked to lower limb torsional deformities, a definitive consensus on diagnostic criteria, clinical indications, and therapeutic strategies for "miserable malalignment syndrome" remains elusive. This systematic review synthesizes current research to unify understanding of this complex condition. Findings highlight varied definitions and surgical approaches, underscoring standardization challenges. This systematic review aimed to synthesize current research to provide a more unified understanding of this complex condition. While studies report favorable anatomical correction and symptomatic relief, inconsistent clinical outcome scores and limited long-term follow-up hinder robust comparisons. Conservative measures are often ineffective due to underlying mechanical imbalance; surgical interventions, primarily derotational osteotomies of the femur and/or tibia, offer the most direct anatomical correction. However, optimal level, extent, and timing of these osteotomies-whether single or double level, staged or simultaneous-are debated. Liße et al.'s proposed diagnostic criteria offer a valuable step towards standardized identification of true miserable malalignment syndrome. Future research, particularly robust multi-center studies with standardized outcome measures, is critically needed to establish clearer, evidence-based guidelines, ultimately improving patient care and long-term outcomes for this challenging condition.},
}

@article {pmid41510716,
year = {2026},
author = {Bano, A and Khan, AA and Kushwaha, SP and Aleena, and Zaidi, SMH and Misbahul Hasan, S and Fatima, A},
title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure- Activity Relationships and Drug-Receptor Interactions.},
journal = {Mini reviews in medicinal chemistry},
volume = {26},
number = {13},
pages = {1046-1069},
pmid = {41510716},
issn = {1875-5607},
mesh = {Humans ; *Indoles/chemistry/chemical synthesis/pharmacology/therapeutic use ; Structure-Activity Relationship ; *Nervous System Diseases/drug therapy ; Animals ; *Neuroprotective Agents/chemical synthesis/chemistry/pharmacology/therapeutic use ; Molecular Structure ; },
abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.},
}

Humans
*Indoles/chemistry/chemical synthesis/pharmacology/therapeutic use
Structure-Activity Relationship
*Nervous System Diseases/drug therapy
Animals
*Neuroprotective Agents/chemical synthesis/chemistry/pharmacology/therapeutic use
Molecular Structure

@article {pmid41588889,
year = {2026},
author = {Thakur, A and Chowdhury, KR and Kumar, A and Sharma, VV and Bhatia, R},
title = {Targeting Non-coding RNAs in Neurodegeneration: Advances in Therapeutic RNA Modalities and Next-Gen Delivery Technologies.},
journal = {Current Alzheimer research},
volume = {23},
number = {4},
pages = {245-269},
pmid = {41588889},
issn = {1875-5828},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics ; *RNA, Untranslated/therapeutic use/genetics ; Animals ; MicroRNAs ; *Genetic Therapy/methods ; Drug Delivery Systems ; },
abstract = {Non-coding RNA (ncRNA)-based therapies represent an emerging and transformative approach in the treatment of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND). This review explored the potential for targeting microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, reinforced by promising results from clinical trials demonstrating their capacity to modulate disease pathways. The incorporation of cutting-edge computational methodologies, including RNA structure prediction and gene regulatory network analysis, has been at the forefront in enhancing the efficacy of ncRNA-based treatments. Moreover, chemical methods have improved RNA molecules' stability, accuracy, and directed delivery, enhancing their therapeutic effects. Moreover, cutting-edge RNA editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats/CRISPRassociated protein 13 (CRISPR/Cas13) are advancing our ability to directly manipulate ncRNA expression, offering a powerful avenue for addressing the molecular origins of neurodegeneration. Despite these advances, challenges persist, particularly in ensuring the specificity, delivery efficiency, and long-term efficacy of these treatments. Nanotechnology provides innovative solutions to these obstacles, facilitating more efficient and precise RNA delivery, especially to neuronal tissue. In conclusion, ncRNA-based therapies, while still in nascent stages, represent a hopeful frontier in the fight against NDs. With ongoing research and technological advancements, these therapies could not only halt disease progression but also redefine the future of ND treatment, offering new avenues for patients' care and clinical success.},
}

Humans
*Neurodegenerative Diseases/therapy/genetics
*RNA, Untranslated/therapeutic use/genetics
Animals
MicroRNAs
*Genetic Therapy/methods
Drug Delivery Systems

@article {pmid42526365,
year = {2026},
author = {Ahsan, A and Ou, JC and Majumder, P and Chiang, YH and Huang, JK and Huang, CS},
title = {A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.},
journal = {Journal of neuroimmunology},
volume = {420},
number = {},
pages = {579028},
doi = {10.1016/j.jneuroim.2026.579028},
pmid = {42526365},
issn = {1872-8421},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; *Tomography, Optical Coherence/methods ; *Retina/diagnostic imaging/pathology ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS.

METHODS: A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I[2] statistic.

RESULTS: A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant.

CONCLUSION: This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder.

PROSPERO identifier CRD420251076035.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/complications
*Tomography, Optical Coherence/methods
*Retina/diagnostic imaging/pathology

@article {pmid42580558,
year = {2026},
author = {Armoundas, AA and Piperi, C},
title = {Epigenetic drift and LINE-1 activation in aging brain: Implications for neurodegenerative disease.},
journal = {Mechanisms of ageing and development},
volume = {233},
number = {},
pages = {112235},
doi = {10.1016/j.mad.2026.112235},
pmid = {42580558},
issn = {1872-6216},
mesh = {Humans ; *Long Interspersed Nucleotide Elements ; *Epigenesis, Genetic ; *Aging/genetics/metabolism/pathology ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Brain/metabolism/pathology ; *DNA Methylation ; Animals ; },
abstract = {Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.},
}

Humans
*Long Interspersed Nucleotide Elements
*Epigenesis, Genetic
*Aging/genetics/metabolism/pathology
*Neurodegenerative Diseases/genetics/metabolism/pathology
*Brain/metabolism/pathology
*DNA Methylation
Animals

@article {pmid42694478,
year = {2026},
author = {Cui, Q and Zheng, K and Liu, Q and Wang, L and Liu, Y and Bai, R and Zhang, W and Guo, J and Chang, X and Wang, J},
title = {From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1921079},
pmid = {42694478},
issn = {1662-5099},
abstract = {Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.},
}

@article {pmid42694654,
year = {2026},
author = {Wu, Y and Duan, L and Zhang, L and Wang, S and Yan, H and He, M and Wang, T and Li, L and Gao, Y},
title = {TREM2 as a central hub of neuroimmune-metabolic crosstalk in central nervous system disorders: from microglial biology to therapeutic targeting.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1912989},
pmid = {42694654},
issn = {1664-3224},
mesh = {Humans ; *Microglia/metabolism/immunology ; *Receptors, Immunologic/metabolism/genetics/immunology ; *Membrane Glycoproteins/metabolism/genetics/immunology ; Animals ; *Central Nervous System Diseases/metabolism/immunology/therapy ; Signal Transduction ; *Neuroimmunomodulation ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched immunoreceptor that functions as a central regulator of microglial adaptation by integrating immune surveillance, lipid sensing, metabolic reprogramming, and phagocytic responses in the central nervous system (CNS). Through association with the adaptor protein DAP12, TREM2 activates interconnected signaling networks involving the SYK pathway, PLCγ2-mediated Ca[2+] signaling, PI3K-AKT-mTOR signaling, NF-κB activation and inflammatory regulatory pathways, thereby shaping microglial survival, migration, clearance capacity, and interactions with surrounding neural and immune cells. Increasing evidence from genetic studies, single-cell transcriptomics, spatial analyses, and human-derived microglial models indicates that TREM2 dysfunction contributes to diverse CNS disorders; however, its biological consequences are highly dependent on disease stage, pathological substrate, cellular context, and microenvironmental cues. In Alzheimer's disease, TREM2 regulates amyloid-β-associated microglial responses, lipid metabolism, and synaptic remodeling, while its effects on tau-driven neurodegeneration remain controversial. In Parkinson's disease, stroke, epilepsy, and amyotrophic lateral sclerosis, TREM2 influences α-Syn clearance, inflammatory resolution, tissue repair, and microglial state transitions, but may exert beneficial or maladaptive effects depending on temporal dynamics and disease-specific stressors. Emerging clinical evidence, including TREM2 variants, soluble TREM2 (sTREM2) biomarkers, and human multi-omics studies, highlights both the translational potential and complexity of targeting this pathway. Herein, this review summarizes the molecular mechanisms, physiological functions, and disease-specific roles of TREM2 in CNS disorders, critically discusses unresolved controversies and species-specific challenges, and evaluates emerging therapeutic strategies toward biomarker-guided and stage-specific modulation of TREM2 signaling. Understanding how to restore appropriate microglial adaptability rather than simply enhance or suppress TREM2 activity may provide a foundation for precision therapies in CNS disorders.},
}

Humans
*Microglia/metabolism/immunology
*Receptors, Immunologic/metabolism/genetics/immunology
*Membrane Glycoproteins/metabolism/genetics/immunology
Animals
*Central Nervous System Diseases/metabolism/immunology/therapy
Signal Transduction
*Neuroimmunomodulation

@article {pmid42697379,
year = {2026},
author = {Mohammad, SI and Vasudevan, A and Oriquat, G and Gajjar, TB and Hanumanthayya, M and Shukla, SK and Tailor, NK and Baig, MR and Fadaam, O and Abdul, AS},
title = {Extracellular Vesicles in Neurodegenerative Diseases: A New Frontier in Diagnosis and Therapy.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116455},
doi = {10.1016/j.bbr.2026.116455},
pmid = {42697379},
issn = {1872-7549},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.},
}

@article {pmid41416937,
year = {2026},
author = {Jensen, TR and Jacobs, I and Kverková, K and Lalić, L and Polonyiová, A and Stehlík, P and Reber, SA and Osvath, M},
title = {T. rex cognition was T. rex-like-A critical outlook on diverging views of the neurocognitive evolution in dinosaurs.},
journal = {Anatomical record (Hoboken, N.J. : 2007)},
volume = {309},
number = {10},
pages = {2541-2559},
doi = {10.1002/ar.70074},
pmid = {41416937},
issn = {1932-8494},
mesh = {Animals ; *Dinosaurs/physiology/anatomy & histology ; *Cognition/physiology ; *Biological Evolution ; *Brain/physiology/cytology ; Neurons/physiology/cytology ; },
abstract = {A recent debate has emerged between Caspar et al. (2024) and Herculano-Houzel (2023) on inferring extinct dinosaur cognition by estimating brain neuron counts. While thought-provoking, the discussion largely overlooks the function of cognition, as well as partly neglects the difficulties involved in estimating neuron numbers, which according to us leads to oversimplified conclusions. We use this exchange as a springboard to further explore how extinct cognition might be studied and the potential pitfalls involved. One of the main emphases is on introducing basic concepts and contemporary views of cognition and its evolution. In relation to this, we highlight the shift in thermobiology during the Mesozoic-from ectothermy to endothermy-and its major impact on cognition and brain evolution. We also examine the challenges of estimating neuron counts in extinct dinosaurs based on current knowledge and take issue with several aspects of the approaches used by both Caspar et al. and Herculano-Houzel. At the same time, we challenge Caspar et al.'s claim that telencephalic neuron numbers, if estimable, would be largely uninformative about extinct dinosaur cognition, while also disagreeing with Herculano-Houzel's somewhat reductive view. We further emphasize the value of comparative cognitive studies in extant animals, alongside neural correlates, to infer the cognitive evolution of non-avian dinosaurs. We briefly outline how cognition is studied in living species and the extent to which such research can inform evolutionary inference. Our focus here is on non-avian theropods, as they are central to the current debate and belong to the lineage that led to modern birds.},
}

Animals
*Dinosaurs/physiology/anatomy & histology
*Cognition/physiology
*Biological Evolution
*Brain/physiology/cytology
Neurons/physiology/cytology

@article {pmid42694267,
year = {2026},
author = {Heffernan, ÁB and Do, F and Carter, E and Al-Tameemi, F and Selvaraj, BT and Stavrou, M},
title = {Disrupted astrocyte-neuron metabolic coupling in amyotrophic lateral sclerosis.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1899307},
pmid = {42694267},
issn = {2296-634X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive loss of motor neurons. In addition to neurodegeneration, ALS is increasingly recognised as a disorder associated with widespread metabolic dysfunction, including hypermetabolism, weight loss, and dyslipidaemia, all of which correlate with disease progression and survival. Astrocytes play a central role in maintaining metabolic homeostasis in the central nervous system by supporting neuronal energy demands, regulating glutamate levels, buffering oxidative stress, and maintaining lipid balance. Emerging evidence suggests that disruption of these supportive astrocytic functions may contribute directly to motor neuron vulnerability in ALS. In this mini-review, we discuss how alterations in astrocyte metabolism may impair astrocyte-neuron metabolic coupling in ALS. We summarise work from human studies and experimental models demonstrating abnormalities in astrocytic glycolysis, mitochondrial function, lactate shuttling, lipid metabolism, and glutamate homeostasis. We highlight growing evidence implicating mitochondrial dysfunction and impaired lipid handling in astrocytes as important contributors to disease progression. We explore how these changes may deprive motor neurons of metabolic and antioxidant support while also promoting excitotoxicity, oxidative stress, and lipotoxicity. We also discuss how recent advances in human induced pluripotent stem cell models, metabolomics, and single-cell transcriptomics are improving our understanding of astrocyte dysfunction in ALS. Finally, we consider current and emerging therapeutic strategies aimed at restoring astrocytic metabolic function. Together, these findings support the idea that progressive failure of astrocyte-mediated metabolic support is an important component of ALS pathogenesis and may represent a promising therapeutic target.},
}

@article {pmid42693185,
year = {2026},
author = {Dalakas, MC and Lünemann, JD},
title = {Role of complement and complement-targeted therapeutics in neurological diseases.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42693185},
issn = {1759-4766},
abstract = {Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.},
}

@article {pmid42689185,
year = {2026},
author = {Sun, L and Yu, X and Yin, H and Bi, J and Lou, H and Pei, H},
title = {A recent review on ginseng's effects on neurodegenerative diseases: active ingredients, mechanisms of action, applications, and delivery strategies.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1912520},
pmid = {42689185},
issn = {2296-861X},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) pose a major health challenge due to their high prevalence and the lack of effective treatments; ginseng, as medicine and food homology, has potential neuroprotective effects.

METHODS: This article provides a systematic review of research conducted over the past five years on the use of ginseng to treat NDDs, summarizing and analyzing the findings in four key areas: active components, mechanisms of action, clinical applications, and novel delivery strategies.

RESULTS: Ginsenosides are the core active ingredients in ginseng, while polysaccharides, essential oils, and peptides also exert synergistic effects through various pathways; their mechanisms of action include regulating Aβ/tau protein aggregation, inhibiting microglial activation, reducing glutamate excitotoxicity, and restoring mitochondrial function and antioxidant balance. In models of AD, PD, HD, and ALS, ginseng's active components have been shown to improve both behavioral and pathological indicators, while novel delivery strategies (nanoparticles, exosomes, and engineered cellular carriers) can significantly enhance blood-brain barrier permeability and brain-targeting efficiency.

CONCLUSION: Ginseng exhibits protective effects against NDDs through multiple mechanisms of action. However, current evidence is largely limited to preclinical studies, and future efforts should focus on advancing the clinical translation of safe and effective brain-targeted delivery systems.},
}

@article {pmid42677779,
year = {2026},
author = {Ali, A and Arif, M and Ashraf, U and Elahi, S and Mustafa, A and Yasir, MB and Sarfraz, W and Ansari, AU and Masood, HMY and Shabbir, MA and Abdullah, A and Sharma, MK},
title = {CSF Tau and Amyloid Biomarkers in Cognitive Impairment Across the ALS-FTD Spectrum: A Systematic Narrative Review and Evidence Map.},
journal = {Brain and behavior},
volume = {16},
number = {9},
pages = {e71740},
pmid = {42677779},
issn = {2162-3279},
mesh = {Humans ; *tau Proteins/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/complications ; Biomarkers/cerebrospinal fluid ; *Frontotemporal Dementia/cerebrospinal fluid/complications ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/etiology ; },
abstract = {INTRODUCTION: Cognitive impairment is an important non-motor manifestation of amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (ALS-FTD) spectrum. Cerebrospinal fluid (CSF) tau and amyloid biomarkers may reflect nonspecific neurodegenerative injury, concomitant Alzheimer disease (AD) pathology, or distinct cognitive phenotypes. However, available evidence remains limited, fragmented, and methodologically heterogeneous.

METHODS: This systematic narrative review and semi-quantitative evidence map was conducted according to PRISMA 2020 recommendations. PubMed, Scopus, Web of Science, and Google Scholar were searched from database inception through May 2026. Eligible observational studies reported cognition-specific associations between CSF tau, amyloid, or related neurodegenerative biomarkers and cognitive outcomes in ALS-spectrum populations. Two reviewers independently screened studies, extracted quantitative effect estimates, and assessed risk of bias using the Newcastle-Ottawa Scale. Cross-study consistency was summarized using an exploratory semi-quantitative evidence-coding framework.

RESULTS: Four observational studies comprising 638 ALS-spectrum participants fulfilled the eligibility criteria. Total tau and p-tau181 showed the most reproducible associations with cognition. Total tau correlated with ECAS total (r = -0.398, P < 0.001) and ALS-specific cognition (r = -0.403, P < 0.001), while adjusted multicenter analyses demonstrated associations between p-tau181 and ECAS total (β = -0.03, p = 0.006) and memory performance (β = -0.04, p = 0.003). Both biomarkers received ++ evidence-map coding. Amyloid findings were more heterogeneous; lower Aβ42/Aβ40 was associated with poorer memory performance (β = 0.20, p = 0.044), but continuous amyloid-cognition associations were not consistently replicated across cohorts (± evidence). Broader CSF protein-ratio findings remained exploratory. Clinical, cognitive, assay, and analytical heterogeneity precluded meta-analysis.

CONCLUSIONS: The available evidence, although limited and heterogeneous, suggests that total tau may primarily reflect broader neurodegenerative injury, whereas p-tau181 and Aβ42/Aβ40 may be more informative for selected cognitive phenotypes or possible AD co-pathology. These biomarkers should remain research tools until larger, standardized, longitudinal multicenter studies establish their pathological specificity, predictive value, and clinical utility.},
}

Humans
*tau Proteins/cerebrospinal fluid
*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/complications
Biomarkers/cerebrospinal fluid
*Frontotemporal Dementia/cerebrospinal fluid/complications
*Amyloid beta-Peptides/cerebrospinal fluid
*Cognitive Dysfunction/cerebrospinal fluid/etiology

@article {pmid42677831,
year = {2026},
author = {Basak, B and Riley, JF and Nataraj, NM and Holzbaur, EL},
title = {Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.},
journal = {The Journal of clinical investigation},
volume = {136},
number = {17},
pages = {},
pmid = {42677831},
issn = {1558-8238},
mesh = {Humans ; *Mitophagy ; Animals ; *Neurons/pathology/metabolism ; *Mitochondria/pathology/metabolism/genetics ; PTEN-Induced Putative Kinase ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Protein Kinases/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Signal Transduction ; },
abstract = {Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.},
}

Humans
*Mitophagy
Animals
*Neurons/pathology/metabolism
*Mitochondria/pathology/metabolism/genetics
PTEN-Induced Putative Kinase
*Neurodegenerative Diseases/metabolism/pathology/genetics
Protein Kinases/metabolism/genetics
Ubiquitin-Protein Ligases/metabolism/genetics
*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics
Signal Transduction

@article {pmid42681667,
year = {2026},
author = {Sowoidnich, L and Norman, AL and Gerstner, F and Siemund, JK and Buettner, JM and Pagiazitis, JG and Dreilich, V and Pilz, K and Tian, D and Sumner, CJ and Paradis, A and Mentis, GZ and Simon, CM},
title = {A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42681667},
issn = {2051-5960},
mesh = {Animals ; Humans ; *Motor Neurons/pathology ; *Neurodegenerative Diseases/pathology ; *Spinal Cord/pathology ; Muscular Atrophy, Spinal/pathology ; Mice ; Disease Models, Animal ; },
abstract = {Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, for which spinal cord sampling emerged as a major contributor. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.},
}

Animals
Humans
*Motor Neurons/pathology
*Neurodegenerative Diseases/pathology
*Spinal Cord/pathology
Muscular Atrophy, Spinal/pathology
Mice
Disease Models, Animal

@article {pmid42684942,
year = {2026},
author = {Huang, D and Zhang, Z and Gong, X},
title = {Context-dependent roles of osteopontin in aging-related neurological disorders.},
journal = {The Journal of international medical research},
volume = {54},
number = {9},
pages = {3000605261476190},
pmid = {42684942},
issn = {1473-2300},
mesh = {Humans ; *Osteopontin/metabolism ; *Aging/pathology/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Brain/pathology/metabolism ; Alzheimer Disease ; Microglia/metabolism ; },
abstract = {Osteopontin (encoded by secreted phosphoprotein 1) is a multifunctional matricellular phosphoglycoprotein that has emerged as an important mediator in the aging nervous system. During aging, osteopontin interacts with microglial priming, vascular remodeling, myelin repair, and innate immune responses and is consistently implicated in major late-life neurological disorders. However, its biological effects are highly context dependent. Depending on its cellular source, proteolytic processing, receptor interactions, anatomical distribution, and disease stage, osteopontin may either exacerbate chronic neuroinflammation and tissue injury or promote phagocytic clearance, neuronal survival, remyelination, neuroplasticity, and tissue repair. This review critically synthesizes studies indexed in PubMed and Google Scholar through 3 April 2026 on the role of osteopontin in brain aging, Alzheimer's disease and related dementias, Parkinson's disease and Lewy body disorders, cerebrovascular disease, vascular cognitive impairment, cerebral small vessel disease, and amyotrophic lateral sclerosis. In Alzheimer's disease, cerebrospinal fluid and plasma osteopontin concentrations increase from the prodromal to symptomatic stages, whereas microglial or perivascular secreted phosphoprotein 1 expression correlates with amyloid pathology, synaptic remodeling, and cognitive decline. However, under specific conditions, osteopontin also enhances macrophage-mediated amyloid-beta clearance. In stroke, elevated circulating osteopontin predicts poor clinical outcomes, whereas experimental studies demonstrate that appropriately timed exogenous osteopontin, regulatory T cell-derived osteopontin, and osteopontin-mediated autophagic and reparative pathways promote white-matter repair, peri-infarct plasticity, and blood-brain barrier integrity. Evidence from Parkinson's disease, Lewy body disease, frontotemporal dementia, and amyotrophic lateral sclerosis further supports the role of osteopontin as both a candidate biomarker and a regulator of selective neuronal vulnerability. Rather than being uniformly detrimental or protective, osteopontin should be regarded as a context-dependent regulator of age-related neuroimmune remodeling. This perspective reconciles seemingly conflicting findings and supports the development of therapeutic strategies that are tailored to disease stage, protein fragment, and cell type rather than broadly targeting osteopontin.},
}

Humans
*Osteopontin/metabolism
*Aging/pathology/metabolism
Animals
*Nervous System Diseases/metabolism/pathology
Brain/pathology/metabolism
Alzheimer Disease
Microglia/metabolism

@article {pmid42685299,
year = {2026},
author = {Benatar, M and Rothstein, JD and Snow, K and Sethi, N and Taylor, DM and Dave, KD and McDermott, CJ and Cochrane, TI},
title = {Repairing the Amyotrophic Lateral Sclerosis Trial Credibility Gap.},
journal = {Neurology},
volume = {107},
number = {7},
pages = {e218471},
doi = {10.1212/WNL.0000000000218471},
pmid = {42685299},
issn = {1526-632X},
mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Clinical Trials as Topic/standards ; *Research Design/standards ; },
abstract = {There is a long history of early- and mid-phase amyotrophic lateral sclerosis (ALS) clinical trial data being used to make claims of clinical benefit that fail to translate into successful phase 3 outcomes. It is suggested that fallacious scientific reasoning is being encouraged by perverse incentives arising from a "clinical trial industrial complex" that greatly influences trial design, data interpretation, and results communication. Recurring fallacies include false premises underlying outcome comparisons, misuse and incorrect interpretation of biomarkers, mismatches between study design and stated objectives, selective reporting of outcomes, over-reliance on post hoc analyses and open-label extension data, and overly optimistic framing of inconclusive data. We argue that these practices, reinforced by misaligned incentives across industry and academia, lead to premature claims of therapeutic promise and tangible harm to patients. To address the resulting ALS clinical trial credibility gap, we call for rigorous adherence to established standards for reporting clinical trial results, clearer distinction between hypothesis generation and hypothesis testing, more measured description of trial results, and more disciplined triage of phase 2 programs. A cultural shift toward scientific skepticism and methodological rigor is essential to accelerate the development of genuinely effective ALS therapies.},
}

*Amyotrophic Lateral Sclerosis/therapy
Humans
*Clinical Trials as Topic/standards
*Research Design/standards

@article {pmid42686219,
year = {2026},
author = {Liu, J and Lin, J and Liu, H and Soh, K and Ju, Q and Soh, K and Dong, X},
title = {Efficacy of Antimicrobial Lock Solutions on Central Line-Associated Bloodstream Infection and Catheter Survival in Hemodialysis Patients: A Systematic Review and Meta-Analysis.},
journal = {Seminars in dialysis},
volume = {},
number = {},
pages = {},
doi = {10.1111/sdi.70046},
pmid = {42686219},
issn = {1525-139X},
support = {202301A014//Chengde Science and Technology Program/ ; GJXH2021-126//Hebei Higher Education Association "14th Five-Year Plan" Research Project/ ; H2026406068//Hebei Natural Science Foundation/ ; 202307//Chengde Medical university Project/ ; 202404//Chengde Medical university Project/ ; },
abstract = {Hemodialysis (HD) catheters carry a high risk of life-threatening bloodstream infections and failure. Antimicrobial lock solutions (ALS) are used to reduce this risk, but their overall efficacy on key outcomes like infection rates and catheter survival requires comprehensive evaluation. This systematic review and meta-analysis assess the impact of ALS on preventing catheter-related bloodstream infections (including incidence and density) and on improving catheter survival. A systematic search was conducted across the databases of PubMed, Embase, Scopus, Cochrane Library, and Google Scholar. A meta-analysis was conducted using STATA software. A total of 1183 studies were screened based on title and abstract, and further 282 studies were evaluated in full text. Eventually, 14 studies with 15 treatment arms were included. Key outcomes including central line-associated bloodstream infection (CLABSI), exit infection, and catheter-free survival were conducted separately. ALS demonstrated statistically significant benefits on CLABSI infection and catheter-free survival compared to nonantimicrobial solutions, showing a reduction in CLABSI density with a pooled log odd ratio (logOR) of -1.29 (95% CI: -1.59 to -0.99), lower CLABSI rates (pooled logOR = -1.50, 95% CI: -1.85 to -1.15), and improved catheter-free survival with log hazard ratio (logHR) of -1.11 (95% CI: -1.41 to -0.8). Consistent treatment effects were observed across all lock types with no significant heterogeneity detected. ALS demonstrate statistically significant and clinically important efficacy in reducing CLABSI incidence and density while improving catheter survival in HD patients, establishing them as an essential preventive strategy in clinical practice.},
}

@article {pmid42676195,
year = {2026},
author = {Arbuzova, EE and Seksyaev, NE and Karakulova, YV and Selyanina, NV and Danilova, MA},
title = {[Atypical forms of amyotrophic lateral sclerosis].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {8},
pages = {13-20},
doi = {10.17116/jnevro202612608113},
pmid = {42676195},
issn = {1997-7298},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification ; Phenotype ; Diagnosis, Differential ; Disease Progression ; Motor Neurons/pathology ; },
abstract = {This article provides a comprehensive overview of contemporary concepts regarding the classical and atypical phenotypes of amyotrophic lateral sclerosis (ALS), with a particular focus on critical diagnostic challenges. The classical variant of the disease is characterized by the progressive involvement of both upper and lower motor neurons, typically presenting with an asymmetric onset and a predictable progression. However, several atypical phenotypes are identified, including syndromes predominantly affecting the lower motor neurons, such as the «hanging hands» and «hanging legs» syndromes, isolated bulbar paralysis, ALS with respiratory onset, and forms with a predominance of upper motor neuron involvement. These atypical variants often mimic other neurological conditions-such as cervical myelopathy, multifocal motor neuropathy, and myasthenia gravis-which can result in significant delays in the accurate diagnosis of ALS. Atypical forms of ALS represent a major source of diagnostic errors in clinical practice. Enhancing healthcare professionals' understanding of the spectrum of phenotypic presentations, alongside the application of contemporary diagnostic criteria, facilitates more timely diagnoses, optimized patient care pathways, and the prompt initiation of pathogenetic therapies, ultimately improving both survival rates and quality of life for affected individuals.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification
Phenotype
Diagnosis, Differential
Disease Progression
Motor Neurons/pathology

@article {pmid42667453,
year = {2026},
author = {Liu, C and Zhang, Y},
title = {Ginsenosides: potential therapeutic implications in neurodegenerative diseases by inhibiting ferroptosis.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42667453},
issn = {1573-4978},
mesh = {Humans ; *Ginsenosides/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Ferroptosis/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Amyotrophic Lateral Sclerosis/drug therapy ; },
abstract = {A positive correlation exists between the accelerating pace of population aging and the increasing prevalence of neurodegenerative diseases. Conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) profoundly compromise patient quality of life, yet efficacious clinical interventions remain notably limited. The prevention and management of neurodegenerative diseases represent a critical global public health imperative. A comprehensive literature search was performed across PubMed, Web of Science, and Scopus to identify studies on the biological functions, molecular mechanisms, and clinical implications of ginsenosides. The search strategy incorporated MeSH terms and free-text keywords, encompassing "neurodegenerative disease", "ferroptosis", "ginsenosides", "Parkinson's disease", "Alzheimer's disease", "amyotrophic lateral sclerosis", "Huntington's disease" and "multiple sclerosis". From an initial pool of over 400 papers (1998-2026), 107 were selected in this narrative review. Ferroptosis is intricately linked to the pathogenesis of neurodegenerative diseases. Ginsenosides constitute the principal bioactive triterpenoid saponins extracted from plants of the Panax genus, demonstrating broad-spectrum pharmacological efficacy encompassing antitumor, immunomodulatory, anti‑inflammatory, anti‑allergic, anti‑atherosclerotic, antihypertensive, antidiabetic, antistress, and neuroprotective activities. Ginsenosides exert their neuroprotective effects against AD, PD, and ALS predominantly through the modulation of ferroptosis. Herein, this article provides a review of the molecular mechanisms, genetic determinants, signaling cascades, and functional implications of ferroptosis. Ginsenosides represent promising therapeutic agents in neurodegenerative diseases via modulation of iron homeostasis; this paper elucidates mechanistic insights into disease pathogenesis and evaluates their translational therapeutic potential. This narrative review highlights emerging insights that provide novel therapeutic perspectives for neurodegenerative diseases.},
}

Humans
*Ginsenosides/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
*Ferroptosis/drug effects
Animals
Neuroprotective Agents/pharmacology/therapeutic use
Amyotrophic Lateral Sclerosis/drug therapy

@article {pmid42670527,
year = {2026},
author = {Pan, L and Liu, B and Xu, J and Mu, X and Fan, L},
title = {Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {628071},
pmid = {42670527},
issn = {1178-2013},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Extracellular Vesicles/transplantation ; *Mesenchymal Stem Cells/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; },
abstract = {Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.},
}

Humans
*Neurodegenerative Diseases/therapy
*Extracellular Vesicles/transplantation
*Mesenchymal Stem Cells/cytology
*Mesenchymal Stem Cell Transplantation/methods
Animals

@article {pmid42673727,
year = {2026},
author = {Aladwan, S and Jasim, A and Qassem, TA and Gajjar, TB and Hanumanthayya, M and Tripathi, V and Maharana, L and Bainsal, N},
title = {Human health risk assessment of toxic and non-toxic elements in various oily, cream, and powder cosmetics in Arab countries- A systematic literature review.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {97},
number = {},
pages = {127946},
doi = {10.1016/j.jtemb.2026.127946},
pmid = {42673727},
issn = {1878-3252},
abstract = {Oily, cream, and powder cosmetics (OCPCs) are widely used worldwide, especially in Arab nations, highlighting the need for ongoing heavy metal (HM) monitoring. This systematic review examined 16 HM concentrations in 14 OCPC product categories across 11 of the 22 Arab countries, selected countries based on predefined inclusion and exclusion criteria, and evaluated their associated health risks for only 9 of the 14 OCPCs for which sufficient data were available. The analysis included 24 papers published between June 1, 2007, and January 30, 2026, selected according to prescribed inclusion and exclusion criteria. International authorities like the WHO and the EU set acceptable limits (ALs) for HM levels. According to EPA criteria, all detected HMs underwent a health risk assessment (HRA). Saudi Arabia and Jordan had the highest HM detection rates in OCPCs among the 11 Arab countries analyzed, underscoring the need for stronger regulation. Moisturizing creams, toners, cosmetic masks, and oils were mostly contaminated with non-toxic HMs, whereas facial foundation and face cream samples were contaminated with toxic HMs. Despite exceedances of WHO and EU ALs for several elements, the EPA-based dermal risk indices remained below acceptable thresholds, reflecting the distinction between concentration-based regulatory limits and exposure-based health risk assessment. Arab regulatory agencies should establish monitoring systems to limit HMs in OCPCs, in line with WHO and EU guidelines on HM ALs in cosmetics, before market access.},
}

@article {pmid42675240,
year = {2026},
author = {Ma, S and Luo, S and Zhong, H},
title = {Artificial Intelligence in Neuromuscular Diseases: Opportunities for a Data-Scarce Field.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42675240},
issn = {2193-8253},
support = {Open research fund: gect-2025-Z01//Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases/ ; },
abstract = {Neuromuscular diseases (NMDs) encompass over 800 distinct entities affecting approximately one in 1000 individuals worldwide, with progressive muscle weakness, atrophy, and motor impairment as primary clinical manifestations. The rarity of most NMDs creates fundamental challenges for artificial intelligence (AI) and machine learning (ML) applications that typically require large-scale datasets. In this narrative review we synthesize the literature published between 2018 and 2025 on AI applications across the NMD spectrum, organized by clinical application domain. We examine how AI has advanced diagnostic capabilities through genetic variant interpretation, muscle magnetic resonance imaging analysis, electromyography-based classification, and computational pathology. In disease monitoring and prognosis, wearable-derived digital biomarkers have achieved regulatory qualification (US Food and Drug Administration [FDA] and European Medicines Agency [EMA]) as clinical trial endpoints for Duchenne muscular dystrophy, while AI-driven survival models for amyotrophic lateral sclerosis (ALS) have been validated across 14 European centers. Proteomic and multi-omics analyses using ML have identified diagnostic panels for ALS. However, most reported models were developed and internally validated on single-center datasets, and few have undergone external or prospective validation or clinical implementation. Despite these achievements, research intensity varies dramatically across NMD subtypes, with ALS and Duchenne muscular dystrophy dominating while myotonic dystrophy, congenital myopathies, and metabolic myopathies remain virtually unexplored. Critical gaps persist in computational pathology, multi-center validation, and clinical translation. In this review, we discuss how federated learning, international collaborative networks (TREAT-NMD, Solve-RD, EURO-NMD), and foundation models can address these challenges, and propose directions for future AI-enhanced clinical studies in this data-scarce field.},
}

@article {pmid42656917,
year = {2026},
author = {Zhang, J and Tang, P and Huang, L and Lv, J and Chen, Y and Wang, Y and Luo, Y},
title = {Multifaceted roles of S100A6 in neurological disorders: expression, interaction networks, and clinical implications.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1890559},
pmid = {42656917},
issn = {1663-9812},
abstract = {S100A6 (calcyclin) is a multifunctional Ca[2+]/Zn[2+]-binding protein of the S100 family, widely expressed in neurons and glia with a developmentally regulated and cell-type-specific pattern. This review synthesizes current knowledge on its roles in the nervous system. We detail its complex interactome, which includes cytoskeletal regulators, molecular chaperones, nuclear transport proteins, and cell surface receptors, positioning S100A6 as a central signaling hub. Furthermore, we examine its dynamic and context-dependent involvement in major neurological disorders. In Alzheimer's disease and amyotrophic lateral sclerosis, it functions as a glial-derived factor linking protein aggregation, metal dyshomeostasis, and neuroinflammation. In neuro-oncology, S100A6 exhibits dual roles, acting as a promoter of malignancy and immunosuppression in glioblastoma, an epigenetically silenced marker in medulloblastoma, and a diagnostic aid for peripheral nerve sheath tumors. Its expression is also altered in epilepsy, traumatic brain injury, and autoimmune encephalitis. Understanding the nuanced functions of S100A6 offers significant potential for developing novel diagnostic biomarkers and targeted therapeutic strategies for a range of challenging neurological conditions.},
}

@article {pmid42657487,
year = {2026},
author = {da Silva, AA and Pupe, CCB and Dos Santos, JCC},
title = {High-dose methylcobalamin in amyotrophic lateral sclerosis: mechanistic rationale, translational evidence, and clinical implications.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2026.2713755},
pmid = {42657487},
issn = {1758-2032},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by selective degeneration of upper and lower motor neurons, driven by converging mechanisms including glutamatergic excitotoxicity, mitochondrial dysfunction, oxidative stress, calcium dyshomeostasis, impaired RNA metabolism, and neuroinflammation. In the absence of effective disease-modifying therapies, high-dose methylcobalamin has emerged as a candidate intervention based on its pleiotropic neurobiological effects. A structured literature search was conducted in PubMed/MEDLINE and ScienceDirect to identify peer-reviewed studies published between January 2017 and December 2025 addressing the mechanistic, preclinical, and clinical effects of methylcobalamin in ALS. Preclinical evidence suggests that methylcobalamin modulates homocysteine metabolism, supports S-adenosylmethionine-dependent methylation pathways, preserves mitochondrial integrity, attenuates oxidative stress, and promotes axonal regeneration. Experimental and translational findings further indicate that its therapeutic effects may be strongly dose dependent, particularly under ultra-high-dose regimens capable of overcoming limitations in central nervous system delivery. Clinical trials evaluating ultra-high-dose methylcobalamin demonstrate a potential attenuation of functional decline in patients treated during early disease stages, although effects on survival and respiratory outcomes remain inconsistent. This narrative review integrates molecular mechanisms, experimental evidence, biomarker research, and clinical trial data to examine the translational relevance, stage dependency, and therapeutic implications of high-dose methylcobalamin in ALS.},
}

@article {pmid42661656,
year = {2026},
author = {Praharaj, S and Chakraborty, E and Mahalingam, G},
title = {Ultraviolet radiation and neurodegeneration: molecular mechanisms underlying dual neuroprotective and neurotoxic effects.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1909393},
pmid = {42661656},
issn = {1662-5102},
abstract = {Ultraviolet radiation exhibits a complex, often contradictory link to neurodegeneration risk/progression, spanning clinically diagnosed diseases [Parkinson's Disease (PD), Alzheimer's Disease (AD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS)] or intermediate phenotypes (decreased neurogenesis, loss of hippocampal volume). The aim of this review is to highlight the dual impact of UV radiation by collecting and synthesizing experimental (preclinical and translational) evidence as well as epidemiological evidence. Current literature exhibits a clear dichotomy: while Vitamin D is capable of exerting a potent neuroprotective effect via anti-oxidant and anti-inflammatory pathways, chronic and intense UV radiation exposure actually hastens the progression or even drives neurodegeneration via a variety of mechanisms. UV radiation exerts its effects through various interconnected pathways: DNA damage pathways, ROS mediated pathways, vitamin D signaling and the skin-brain axis, which unifies both protective and degenerative effects of UV radiation. Owing to the increasing occurrence of neurodegenerative diseases in the general population, these pathways and mechanisms must be leveraged in future research to develop novel therapeutic and preventive strategies. Investigation of biomarkers linked to certain genetic and environmental factors that could provide a link to predisposition toward neurodegeneration and standardization of UV radiation dosimetry (exposure dose/duration) across experimental or pre-clinical studies must also be prioritized.},
}

@article {pmid42666355,
year = {2026},
author = {Wei, Y and Wang, J and Ji, Y and Shang, T and Shen, Y and Sun, H and Cai, Y},
title = {Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {626069},
pmid = {42666355},
issn = {1177-8881},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Precision Medicine ; Animals ; *Clinical Trials as Topic ; *Neuroprotective Agents/therapeutic use ; *Research Design ; Genetic Therapy ; Drug Development ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous and fatal neurodegenerative disorder, for which clinical management and drug development have long faced formidable challenges. Since the approval of riluzole and edaravone, dozens of promising drug candidates that showed efficacy in preclinical models have failed in Phase III trials, highlighting an urgent need for systematic re-evaluation of the field. This review provides a comprehensive summary of the major limitations of current clinical therapies for ALS. These include the modest survival benefit of riluzole, the narrow eligible population for edaravone, and the complex trajectory of sodium phenylbutyrate-taurursodiol, which received accelerated approval but was subsequently voluntarily withdrawn after its confirmatory Phase III trial failed to meet its primary endpoints. On this basis, we discuss four major challenges that contribute to clinical trial failures: disease heterogeneity, paucity of reliable biomarkers, insufficient translational validity of preclinical models, and inherent flaws in conventional trial designs. Subsequently, we discuss emerging therapeutic strategies, encompassing precision medicine and gene therapy (exemplified by the development of the antisense oligonucleotide tofersen for SOD1-ALS), targeting protein homeostasis, modulation of neuroinflammation, metabolic and energetic support, neuroprotection and regeneration, as well as multi-target combination approaches. Innovative trial designs, including adaptive platform trials (exemplified by the HEALEY ALS Platform Trial), enrichment designs, sequential designs, N-of-1 trials, and virtual clinical trials are fundamentally reshaping the drug development paradigm in ALS. In conclusion, ALS treatment is at a historic turning point from a "one-size-fits-all" approach toward "precisely stratified" medicine. Future success depends on establishing multimodal biomarker panels, implementing genetic testing-guided individualized therapy, developing combination regimens, and integrating patient-reported outcomes with palliative care. Although substantial challenges remain, the clinical success of Tofersen provides evidence that precision therapeutic strategies may gradually transform ALS management toward a more individualized and disease-modifying approach.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/therapy
Humans
*Precision Medicine
Animals
*Clinical Trials as Topic
*Neuroprotective Agents/therapeutic use
*Research Design
Genetic Therapy
Drug Development

@article {pmid42653407,
year = {2026},
author = {Rosenfeld, J and Salomon-Zimri, S and Tracik, F},
title = {Combination Pharmacology for ALS: A Mechanistic Rationale.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
pmid = {42653407},
issn = {1422-0067},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Drug Therapy, Combination ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; },
abstract = {Amyotrophic lateral sclerosis (ALS) involves multiple converging pathogenic mechanisms, including glutamate excitotoxicity, oxidative and endoplasmic-reticulum stress, mitochondrial dysfunction, neuroinflammation, iron dysregulation, and altered microRNA processing. Expecting a single pharmacologic intervention to meaningfully alter such a complex disease has proven overly optimistic and is reflected by the modest clinical benefits of approved monotherapies. This review outlines the mechanistic foundation and translational rationale for combination pharmacology in ALS. Drawing from paradigms in oncology, infectious disease, and other neurological disorders, it explores how rational multi-target strategies, whether synergistic, complementary, or pathway-divergent, may better address the multifactorial biology of ALS. The review also discusses recent mechanistic examples and design principles for advancing this therapeutic paradigm.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
Animals
Drug Therapy, Combination
Oxidative Stress/drug effects
Mitochondria/metabolism/drug effects

@article {pmid42656624,
year = {2026},
author = {Soberano, JI and Montayre, J},
title = {Social frailty and related social vulnerabilities among older adults in the Philippines: A narrative review.},
journal = {International journal of nursing studies advances},
volume = {11},
number = {},
pages = {100655},
pmid = {42656624},
issn = {2666-142X},
abstract = {OBJECTIVES: To synthesize the evidence on social frailty among older adults in the Philippines, with attention to sociocultural and structural determinants, assessment approaches, and policy and program responses, and to derive implications for nursing practice and research.

METHODS: A narrative review with scoping elements was informed by the Scale for the Assessment of Narrative Review Articles (SANRA), with selected PRISMA-ScR items used to enhance reporting transparency. Electronic searches of PubMed, CINAHL, Web of Science, PsycINFO, and Google Scholar identified peer-reviewed and relevant verifiable discussion papers written in English from January 2015 to December 2025 (final search: 5 January 2026). The search, title, and abstract screening, full-text review, and data extraction were performed independently by two reviewers, with disagreements resolved through consensus. Eligible studies focused on community-dwelling Filipinos aged ≥60 years and examined social frailty or closely related constructs, including social networks, participation, support, isolation, loneliness, and social determinants of health and functioning. Data were synthesized thematically using Bunt et al.'s four domains of social frailty.

RESULTS: Thirty-five studies were included, most using qualitative or cross-sectional designs. Evidence clustered in the domains of general resources and social behavior activities, particularly access, participation, mobility, disaster related disruption, and emerging digital engagement. Fewer studies addressed social resources and self-management abilities. Family, kinship, and faith-based networks, and community organization were important protective systems, but were increasingly strained by migration, economic insecurity, service limitations, and environmental disruption.

CONCLUSIONS: Social frailty among older Filipinos emerges at the intersection of structural disadvantage, changing informal support systems, community participation, digital access, and self-management capacities. Addressing social frailty requires multidimensional assessment, culturally grounded measurement, and coordinated nursing, community and policy responses.},
}

@article {pmid42652600,
year = {2026},
author = {Davies, A and Bentley, A and Bikov, A},
title = {The Role of Neurofilaments in Diagnosis and Monitoring of Amyotrophic Lateral Sclerosis.},
journal = {Journal of clinical medicine},
volume = {15},
number = {16},
pages = {},
pmid = {42652600},
issn = {2077-0383},
abstract = {Background: Amyotrophic lateral sclerosis (ALS), the most common type of motor neurone disease (MND), is a devastating diagnosis that often leads to mortality within 2-5 years of symptom onset. Respiratory failure and aspiration pneumonia both associated with respiratory muscle weakness are the most common causes of death. Difficult to diagnose and devastating in its prognosis, much research has aimed to identify a reliable biomarker to diagnose ALS, prognosticate and improve enrolment into clinical trials to further research efforts. Over the last few decades, neurofilaments (NFs) have emerged as promising biomarkers, especially neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). This review aims to summarise the current evidence for use of NFs as biomarkers in ALS. Current Evidence: Higher levels of NFL and pNFH are measured in CSF than in serum, and levels in CSF and serum are correlated. High CSF NFL, serum NFL and CSF pNFH levels could differentiate patients with ALS from healthy controls, other neurological disease, neurodegenerative controls (without MND), other MND subtypes and ALS disease mimics; however, studies reported a high degree of heterogeneity irrespective of which media or NFs have been used. The number of studies examining NFs to predict respiratory failure in patients with ALS is low. Conclusions and Future Directions: Despite numerous studies consistently reporting higher NF levels in ALS compared to various controls, their clinical value is limited due to high heterogeneity of the results and inconsistencies in proving its prognostic value. Further understanding the relationship between NF levels and respiratory failure is paramount to improve the quality of life of patients with ALS and increase survival.},
}

@article {pmid42653169,
year = {2026},
author = {Terribile, G and Pedrinazzi, M and Frigerio, I and Sancini, G and Combi, R},
title = {Theranostic Innovative Strategies for Brain Diseases: New Insights on Neurovascular Unit-Associated Pathological Changes in Neurodegenerative Disorders and Aging.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
pmid = {42653169},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology/diagnosis ; *Aging/pathology ; Animals ; Blood-Brain Barrier/metabolism/pathology ; *Theranostic Nanomedicine/methods ; *Brain Diseases/therapy/diagnosis/pathology ; Nanoparticles ; MicroRNAs/genetics ; Nanotechnology ; },
abstract = {Central nervous system (CNS) disorders represent a significant healthcare challenge, with aging as the primary risk factor. Current clinical management remains predominantly symptomatic, as late-stage diagnosis and the blood-brain barrier (BBB) limit therapeutic efficacy. This review synthesizes emerging innovations in neurotheranostics-integrated diagnostic and therapeutic platforms-focusing on the neurovascular unit (NVU) as a central pathogenic driver and target. Evidence indicates that NVU and BBB dysfunction are early events in Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases, often preceding classic neuropathological hallmarks. The review highlights the potential of nanotechnology, engineered nanoparticles (NPs) and microRNAs (miRNAs) as precision tools for early detection and targeted CNS delivery. Additionally, it discusses the transformative impact of artificial intelligence (AI) in facilitating personalized, predictive care. Transitioning from a generic "one-pill-for-one-disease" model to a patient-centered strategy targeting early NVU alterations is essential. Integrating AI, nanotechnology and NVU-focused strategies offers a promising path toward effective, personalized disease-modifying therapies.},
}

Humans
*Neurodegenerative Diseases/therapy/pathology/diagnosis
*Aging/pathology
Animals
Blood-Brain Barrier/metabolism/pathology
*Theranostic Nanomedicine/methods
*Brain Diseases/therapy/diagnosis/pathology
Nanoparticles
MicroRNAs/genetics
Nanotechnology

@article {pmid42652164,
year = {2026},
author = {Karbownik, M and Fidura, M and Perlikowska, R},
title = {Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?.},
journal = {Biomedicines},
volume = {14},
number = {8},
pages = {},
pmid = {42652164},
issn = {2227-9059},
support = {564-20-100//Medical University of Lodz/ ; },
abstract = {Canonical signal peptides (SPs) are short N-terminal sequences that direct nascent proteins into the secretory pathway, but their role extends far beyond protein targeting. Advances in sequencing and computational tools have enabled their systematic identification across proteomes, highlighting SPs as critical regulators of protein biogenesis, including endoplasmic reticulum (ER) targeting, translocation, folding, and proteostasis. Clinically, mutations affecting SP function underlie a distinct group of human disorders, while SP-derived fragments are emerging as diagnostic biomarkers and therapeutic targets. In biotechnology, SPs are engineered to enhance recombinant protein production and serve as molecular tags for intracellular delivery. Together, these developments position SPs at the intersection of fundamental cell biology, medicine, and biotechnology. While this review primarily focuses on canonical SPs, it also considers selected non-canonical targeting and topogenic sequences whose dysfunction contributes to protein misfolding, impaired ER translocation, disrupted degradation pathways, and altered intracellular trafficking in neurodegenerative diseases. Aberrations involving both conventional SPs and alternative targeting/topogenic elements contribute to pathological protein aggregation, a hallmark of major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington Disease (HD), prion diseases, and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); in multiple sclerosis (MS) is primarily an inflammatory demyelinating disease, where abnormal protein exposure, potentially linked to misprocessed SPs, can activate immune responses. By synthesizing current knowledge, the review explores how alterations in targeting determinants influence key proteostasis pathways, acting as upstream modulators of disease-relevant molecular cascades. It further discusses the emerging concept that SP-derived fragments may participate in intercellular communication, adding an additional layer of regulatory complexity.},
}

@article {pmid42642835,
year = {2026},
author = {Aldaghi, FS and Siahpoosh, Z and Salehi, Z and Mashayekhi, F and Sohrabnezhad, S},
title = {Unraveling Neurodegeneration: Common Molecular Mechanisms and Novel Therapeutic Concepts in Major Neurodegenerative Disorders.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71615},
pmid = {42642835},
issn = {2162-3279},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy ; Oxidative Stress/physiology ; Animals ; *Neuroinflammatory Diseases/metabolism ; Mitochondria/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Alzheimer Disease/metabolism ; Multiple Sclerosis/metabolism ; Parkinson Disease/metabolism ; Huntington Disease/metabolism ; Inflammasomes/metabolism ; },
abstract = {PURPOSE: Although Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD) present with markedly different clinical phenotypes, these neurodegenerative diseases (NDDs) appear to converge on a shared set of underlying molecular disturbances. This review sought to integrate disease-specific causative triggers with shared pathogenic pathways, focusing on neuroinflammatory signaling, oxidative imbalance, mitochondrial impairment, and disrupted protein homeostasis, in order to support multi-target, disease-modifying therapeutic strategies.

METHOD: Relevant classical and contemporary literature, encompassing original research and review articles on the molecular basis of AD, PD, ALS, MS, and HD, was reviewed and synthesized narratively, with attention to how neuroinflammatory and oxidative stress pathways intersect, reinforce one another through mitochondrial and inflammasome-driven feedback, and recur across the five conditions.

FINDING: In each disorder, persistently activated microglia and astrocytes secreted inflammatory mediators and reactive oxygen species, engaged the NLRP3 inflammasome, and progressively destabilized cellular homeostasis through a self-perpetuating cycle linking neuroinflammation and oxidative stress. Disease-specific lesions nonetheless persisted: amyloid-β and tau pathology in AD; α-synuclein aggregation with iron-driven mitochondrial damage in PD; RNA-binding protein dysfunction, proteostatic collapse, and excitotoxicity in ALS; inflammatory demyelination and axonal bioenergetic failure in MS; and mutant huntingtin-driven transcriptional and mitochondrial disruption in HD. These distinct triggers ultimately converged on shared downstream cascades.

CONCLUSION: Recognizing this shared pathogenic foundation supports multi-target therapies-such as Nrf2 activation, NLRP3 inhibition, mitochondria-targeted antioxidants, and gene-based interventions-that extend across diagnostic boundaries, though challenges in intervention timing, patient stratification, and clinical translation remain unresolved.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy
Oxidative Stress/physiology
Animals
*Neuroinflammatory Diseases/metabolism
Mitochondria/metabolism
Amyotrophic Lateral Sclerosis/metabolism
Alzheimer Disease/metabolism
Multiple Sclerosis/metabolism
Parkinson Disease/metabolism
Huntington Disease/metabolism
Inflammasomes/metabolism

@article {pmid42643197,
year = {2026},
author = {Sigala, N and Cobandag, M and Leppard, L and Medford, N},
title = {Insight and executive functions in acquired brain injury: empirical evidence and theoretical frameworks.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1884495},
pmid = {42643197},
issn = {1664-2295},
mesh = {Humans ; *Brain Injuries/physiopathology/psychology/complications ; *Executive Function/physiology ; *Awareness/physiology ; *Prefrontal Cortex/physiopathology ; Cognitive Flexibility ; },
abstract = {Impaired self-awareness affects 30-50% of patients with moderate to severe acquired brain injury (ABI) and represents one of the most clinically consequential obstacles to effective rehabilitation. Despite substantial evidence that self-awareness and executive functions share neural substrates in prefrontal cortex, the mechanisms linking these two functions remain incompletely specified. This paper reviews the empirical evidence for the relationship between executive functions and insight in ABI, and evaluates four theoretical frameworks: the Cognitive Awareness Model, the Dynamic Comprehensive Model of Awareness, Mograbi et al.'s predictive coding framework, and Duncan's adaptive coding model. It then proposes a novel integration of the latter two as a mechanistically grounded account of why executive dysfunction and impaired self-awareness co-occur following prefrontal damage. We argue that adaptive coding describes the representational flexibility of prefrontal neurons in coding self-relevant information, whilst predictive coding provides the computational logic, driven by precision-weighted prediction errors, through which this adaptive selection is updated. We conclude by discussing assessment and rehabilitation implications in ABI.},
}

Humans
*Brain Injuries/physiopathology/psychology/complications
*Executive Function/physiology
*Awareness/physiology
*Prefrontal Cortex/physiopathology
Cognitive Flexibility

@article {pmid42645160,
year = {2026},
author = {Leggett, S and Sanghai, N and Ru, C and Marcogliese, PC and Tranmer, GK},
title = {Drosophila: An Emerging New Approach Method (NAM) for Studying Amyotrophic Lateral Sclerosis (ALS).},
journal = {Cells},
volume = {15},
number = {16},
pages = {},
pmid = {42645160},
issn = {2073-4409},
support = {202210PJT-495295/CAPMC/CIHR/Canada ; RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/drug therapy/metabolism ; *Drosophila melanogaster/genetics/metabolism ; Humans ; Disease Models, Animal ; DNA-Binding Proteins/metabolism/genetics ; Superoxide Dismutase-1/metabolism/genetics ; Drug Evaluation, Preclinical ; },
abstract = {Drosophila melanogaster (D. melanogaster), or fruit flies, are a commonly used model organism in the study of neurodegenerative diseases (NDs). Their short lifespan, low cost, genetic tractability, and conserved signaling and developmental pathways make them ideal for studying NDs and associated biochemical pathways. Further, flies offer the advantage of high-throughput exploratory drug and genetic screening without stringent ethical constraints. Therefore, D. melanogaster serves as an ideal organism for preliminary drug screening before transitioning to toxicity and efficacy studies in vertebrate models. Following the recent plan by the United States FDA (US FDA) and the National Institutes of Health (NIH) to progressively phase out preclinical drug testing in vertebrate animals and introduce New Approach Methodologies (NAMs), D. melanogaster has the potential to become part of the conventional drug testing pipeline in the future. This literature review focuses on the use of D. melanogaster models as a powerful, low-cost model organism to study superoxide dismutase 1 (SOD1)- and TAR DNA-binding protein 43 (TDP-43)-linked Amyotrophic Lateral Sclerosis (ALS), as well as previous efforts to screen drugs in SOD1- and TDP-43-expressing Drosophila models.},
}

Animals
*Amyotrophic Lateral Sclerosis/genetics/pathology/drug therapy/metabolism
*Drosophila melanogaster/genetics/metabolism
Humans
Disease Models, Animal
DNA-Binding Proteins/metabolism/genetics
Superoxide Dismutase-1/metabolism/genetics
Drug Evaluation, Preclinical

@article {pmid42646366,
year = {2026},
author = {Anwar, AI and Hegazi, AA and Bhuchakra, HP and Nelson, JR and Birdsong, TL and Fontenot, CJ and Zeibo, M and Fazal-Ur-Rehman, MM and Bieber, HP and Spring, CJ and Smith, JL and Hachem, IA and Singh, T and Sawaya, MF and Murnane, KS and Kaye, AD},
title = {Pridopidine Mediated Sigma-1 Receptor Activation and Therapeutic Implications in Neurodegenerative Diseases.},
journal = {Neurology international},
volume = {18},
number = {8},
pages = {},
pmid = {42646366},
issn = {2035-8385},
abstract = {Neurodegenerative diseases are targets for pridopidine therapy, which aims to improve quality of life through neuroprotective mechanisms that involve sigma-1 receptor (S1R) activation. Neurodegenerative motor and cognitive diseases are influenced by dopamine imbalance, where disruptions in pathways contribute to states that are hyperkinetic or hypokinetic, while current dopaminergic treatments are symptomatic rather than disease-modifying, especially for Huntington's disease and Amyotrophic lateral sclerosis. This review summarizes the mechanisms underlying pridopidine-mediated neuroprotection and examines the current evidence supporting its therapeutic potential. The S1R is an endoplasmic reticulum-mitochondria-associated chaperone involved in homeostasis of calcium, stress regulation, and mitochondrial function. Pridopidine is a small lipophilic molecule that crosses the blood-brain barrier and acts as an S1R agonist, with minimal dopamine D2 receptor occupancy. Activation of S1R by pridopidine modulates calcium signaling and enhances anti-apoptotic activity. Collectively, available evidence suggests that pridopidine may improve motor outcomes and slow disease progression in Huntington's disease and amyotrophic lateral sclerosis, supporting its promise as a disease-modifying therapeutic strategy.},
}

@article {pmid42646579,
year = {2026},
author = {Calabrò, RS and Calderone, A and Ravi, D and Galipò, C and Crupi, MF and Quartarone, A},
title = {Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
pmid = {42646579},
issn = {2076-3271},
mesh = {Humans ; *Nervous System Diseases/therapy ; *Transitional Care ; Multiple Sclerosis ; Hospitalization ; Chronic Disease ; Amyotrophic Lateral Sclerosis ; },
abstract = {BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.

RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.

CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.},
}

Humans
*Nervous System Diseases/therapy
*Transitional Care
Multiple Sclerosis
Hospitalization
Chronic Disease
Amyotrophic Lateral Sclerosis

@article {pmid42647236,
year = {2026},
author = {Sanchis-Sanchis, E and de la Rubia Ortí, JE and Sancho-Cantus, D and Cunha-Pérez, C and Casaña-Mohedo, J},
title = {The Microbiota-Gut-Brain Axis and Nutritional Interventions in Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms, Neuroinflammation, and Non-Motor Manifestations-Scoping Review.},
journal = {Pathophysiology : the official journal of the International Society for Pathophysiology},
volume = {33},
number = {3},
pages = {},
pmid = {42647236},
issn = {1873-149X},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder in which systemic pathophysiological alterations significantly contribute to disease progression and non-motor manifestations, such as depression and anxiety. The microbiota-gut-brain axis represents a critical bidirectional pathway in which intestinal dysbiosis and epithelial barrier disruption catalyze central neuroinflammation. This scoping review synthesizes evidence from 43 empirical and analytical studies across 28 countries and maps the findings under the WHO International Classification of Functioning (ICF) framework. Pathophysiological data reveal a profound taxonomic shift in patients with ALS, characterized by severe depletion of neuroprotective, butyrate-producing genera (Akkermansia and Prevotella) and enrichment of pro-inflammatory Enterobacteriaceae. This dysbiotic state leads to structural damage to the intestinal mucosa, alteration of Paneth cells, and downregulation of tight junction proteins (zonulin), triggering a "leaky gut" phenomenon. Subsequent systemic translocation of lipopolysaccharides (LPS) induces TLR4-mediated endotoxemia, microglial hyperactivation, and accelerated motor neuron apoptosis. Conversely, therapeutic modulation via Fecal Microbiota Transplantation (FMT), psychobiotics, and metabolic interventions (ketogenic or Mediterranean diets) has demonstrated significant efficacy in restoring epithelial integrity, mitigating mitochondrial hypermetabolism, and reducing emotional distress. This review identifies a critical research gap in the microstructural characterization of the enteric nervous system in ALS. Incorporating microbiome-targeted biomarkers into clinical protocols is crucial for implementing a stratified, multi-systemic therapeutic strategy aimed at enhancing patient prognosis and psychological well-being.},
}

@article {pmid42650212,
year = {2026},
author = {Varrassi, G and Tran, YV and Farì, G and Narvaez Encinas, M and Corriero, A and Puntillo, F and Pham, PV and Leoni, MLG},
title = {The Eye as a Window to Neurodegeneration: Oxidative Stress, Optic Nerve Vulnerability, and Retinal Biomarkers-A Scoping Review.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/antiox15080948},
pmid = {42650212},
issn = {2076-3921},
support = {//Tam Anh General Hospital, Ha Noi/ ; },
abstract = {Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection.},
}

@article {pmid42650794,
year = {2026},
author = {Mitsumoto, H and Blasco, H and Corcia, P and Silani, V},
title = {ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?.},
journal = {Biomolecules},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/biom16081126},
pmid = {42650794},
issn = {2218-273X},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Mitochondria/metabolism/pathology ; *Energy Metabolism ; Animals ; Oxidative Stress ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.},
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics
Humans
*Mitochondria/metabolism/pathology
*Energy Metabolism
Animals
Oxidative Stress

@article {pmid42650874,
year = {2026},
author = {Wang, Z and Fu, Y and Li, S and Zhang, Y and Sun, T and Miao, N},
title = {The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.},
journal = {Biomolecules},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/biom16081208},
pmid = {42650874},
issn = {2218-273X},
mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; RNA, Competitive Endogenous ; Animals ; *Gene Regulatory Networks ; *Motor Neuron Disease/genetics/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Muscular Atrophy, Spinal/genetics/pathology/metabolism ; },
abstract = {Motor neurons form a highly specialized network composed of α-, β-, and γ-subtypes that coordinate skeletal muscle activity. Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are characterized by the progressive degeneration of this network, resulting in motor dysfunction. Emerging evidence underscores the significant roles of long non-coding RNAs (lncRNAs) in motor neuron development and disease. However, only a few have been experimentally confirmed as true ceRNA regulators, highlighting the need to differentiate validated mechanisms from mere associations or predictions. This review summarizes the regulatory roles of lncRNA-associated ceRNA networks in motor neuron development, evaluates the evidence for their involvement in MNDs, and explores their potential impact on disease progression. It also addresses current challenges, knowledge gaps, and future research directions for understanding ceRNA-mediated mechanisms and developing therapeutic strategies for MNDs.},
}

Humans
*RNA, Long Noncoding/genetics/metabolism
*Motor Neurons/metabolism/pathology
RNA, Competitive Endogenous
Animals
*Gene Regulatory Networks
*Motor Neuron Disease/genetics/pathology/metabolism
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*Muscular Atrophy, Spinal/genetics/pathology/metabolism

@article {pmid42651103,
year = {2026},
author = {Costa, IM and Kanashiro, A and Barros, GSF and Monteiro, AJ and Bonilha, CS and Galdino, G and Veras, FP},
title = {Targeting Neutrophil Extracellular Traps in Neuroinflammation: A Therapeutic Perspective on Neurodegenerative Diseases.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080792},
pmid = {42651103},
issn = {2076-3425},
abstract = {Neuroinflammation is a complex process involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Neutrophils, although traditionally considered peripheral immune cells, have emerged as active participants in the immunopathology of the central nervous system (CNS) through the release of neutrophil extracellular traps (NETs), structures composed of decondensed chromatin embedded with pro-inflammatory proteins. Evidence suggests that NETs play a dual role: they are protective against pathogens but can also induce tissue damage when produced in excess. Several pathways are involved in their formation, including vesicle-mediated release (vital NETs), the lytic NADPH oxidase (NOX)-dependent pathway, and the mitochondrial pathway. Targeting NETs therapeutically, through the use of NETosis inhibitors, NET-degrading strategies, or blockade of neutrophil migration, has shown promise in reducing neuroinflammation/neurodegeneration and improving neurological outcomes in experimental models. This review aims to investigate both the protective and deleterious roles of NETs and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity, offering valuable insights for potential applications in clinical practice.},
}

@article {pmid42651138,
year = {2026},
author = {Lu, S and Chen, Z and Wang, Y and Bian, H and Yu, S and Huang, L},
title = {Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080828},
pmid = {42651138},
issn = {2076-3425},
support = {LH2019H106//Natural Science Foundation of Heilongjiang Province/ ; YQJH2023152//Excellent Young Teachers Basic Research Support Program" for Provincial Undergraduate Colleges in Heilongjiang Province/ ; ZHY2025-009//Heilongjiang Province Traditional Chinese Medicine Research Project/ ; },
abstract = {O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.},
}

@article {pmid42651198,
year = {2026},
author = {Harris, KE and Lascaratos, G and Chau, KY},
title = {Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080890},
pmid = {42651198},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders.

METHODS: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue.

RESULTS: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction.

CONCLUSIONS: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.},
}

@article {pmid42177450,
year = {2026},
author = {Ghasemi, F and Khoshnam Rad, N and Rashidinejad, B and Nasrollahzadeh, M},
title = {Pulmonary toxocariasis presenting as migratory pulmonary infiltrates and mediastinal lymphadenopathy: a case report and literature review.},
journal = {BMC pulmonary medicine},
volume = {26},
number = {1},
pages = {},
pmid = {42177450},
issn = {1471-2466},
mesh = {Humans ; Female ; Middle Aged ; *Toxocariasis/diagnosis/drug therapy/complications ; *Lymphadenopathy/parasitology ; Albendazole/therapeutic use ; Animals ; Tomography, X-Ray Computed ; Toxocara canis/isolation & purification ; Anthelmintics/therapeutic use ; *Lung Diseases, Parasitic/diagnosis/drug therapy ; *Pulmonary Eosinophilia/parasitology/diagnosis ; },
abstract = {BACKGROUND: Pulmonary toxocariasis, caused by the nematode Toxocara canis or T. cati, is an underdiagnosed cause of eosinophilic lung disease with highly variable radiological presentation that often mimics malignancy or other eosinophilic conditions.

CASE PRESENTATION: A 53-year-old female smoker presented with progressive dyspnea and cough. Initial chest CT revealed right lower lobe consolidation with mediastinal lymphadenopathy (station 4R with short-axis diameters 12 mm), raising concern for lung cancer. Bronchoscopy with EBUS-TBNA was non-diagnostic. The patient was empirically started on dexamethasone (8 mg daily, tapered over 3 months) for suspected organizing pneumonia. During steroid taper, her symptoms recurred with delayed emergence of peripheral eosinophilia (670/µL; initial absolute eosinophil count on presentation was 90/µL), elevated IgE (456 IU/mL), and serial CT scans demonstrating migratory pulmonary infiltrates involving the right lower, right middle, and left lower lobes. A history of raw beef liver consumption prompted serological testing, which confirmed Toxocara canis infection. Treatment with albendazole alone (400 mg twice daily for 14 days, without corticosteroids) resulted in complete clinical and radiological resolution.

LITERATURE REVIEW: We searched PubMed and Scopus (January 2014 - February 2026) for English- and French-language case reports of pulmonary toxocariasis. Fourteen new cases were identified and analyzed alongside the 12 cases from Ranasuriya et al.'s [1] review. These 26 cases demonstrate marked radiologic heterogeneity: multiple bilateral nodules (50%), consolidations (23%), pleural effusion (27%), and migratory infiltrates (8%). Pleural effusion has emerged as a distinct manifestation in seven recent cases. Delayed eosinophilia occurred in 12% of cases. Immunocompromised states (including primary ciliary dyskinesia, hematologic malignancies, and immunosuppressive therapy) were present in 23% of cases and may predispose to atypical presentations.

CONCLUSION: Pulmonary toxocariasis should be considered in patients with migratory infiltrates, unexplained eosinophilic pleural effusion, or lung nodules with eosinophilia. A meticulous dietary and exposure history is essential. Diagnosis is confirmed by serology, and patients respond well to albendazole therapy.},
}

Humans
Female
Middle Aged
*Toxocariasis/diagnosis/drug therapy/complications
*Lymphadenopathy/parasitology
Albendazole/therapeutic use
Animals
Tomography, X-Ray Computed
Toxocara canis/isolation & purification
Anthelmintics/therapeutic use
*Lung Diseases, Parasitic/diagnosis/drug therapy
*Pulmonary Eosinophilia/parasitology/diagnosis

@article {pmid42629129,
year = {2026},
author = {Sha, L and Jha, S},
title = {Microglia extracellular traps (MiETs) in Neurodegeneration: Mechanisms, Evidence Gaps, and Untapped Therapeutic Promise.},
journal = {Advances in immunology},
volume = {171},
number = {},
pages = {307-341},
doi = {10.1016/bs.ai.2026.04.008},
pmid = {42629129},
issn = {1557-8445},
mesh = {Humans ; *Extracellular Traps/immunology/metabolism ; *Microglia/immunology/metabolism ; Animals ; *Neurodegenerative Diseases/immunology/therapy/metabolism/pathology ; Histones/metabolism ; Signal Transduction ; Neuroinflammatory Diseases/immunology ; },
abstract = {Microglia are the resident myeloid cells of the central nervous system, they play essential roles in neural tissue homeostasis, including synaptic pruning, clearance of debris and protein aggregates, and regulation of neuroinflammatory processes. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, microglial activation and chronic glial-driven inflammation contribute substantially to neuronal dysfunction and loss. Beyond these well-characterised functions, recent evidence indicates that microglia can release chromatin-based extracellular traps (microglia extracellular traps, or MiETs), similar to the neutrophil extracellular traps (NETs) observed in peripheral immunity. Microglia ETs are induced by stimuli such as dopamine and microbial infection, dependent or independent of NADPH oxidase/ROS pathways and histone citrullination. This chapter provides a detailed examination of MiET formation, triggers, intracellular signalling, and structural components, as well as contribution to neurodegenerative pathology. Potential mechanisms include amplification of neuroinflammation via extracellular histones and proteases, disruption of the blood-brain barrier and extracellular matrix, synaptic damage, and possible facilitation of spread of misfolded protein aggregates. We situate MiET formation within the broader microglial functional repertoire (phagocytosis, cytokine production, synaptic stripping) and focus on how ET-dominant responses may compromise homeostatic or neuroprotective roles. The chapter reviews evidence from disease models, highlights key gaps and discusses translational implications. Targeting MiET formation or promoting the clearance of MiETs represents promising, yet unexplored, therapeutic avenues in neurodegenerative disease. By focusing on MiETs, this work expands the conceptual framework for microglial pathogenicity and invites future mechanistic and translational research.},
}

Humans
*Extracellular Traps/immunology/metabolism
*Microglia/immunology/metabolism
Animals
*Neurodegenerative Diseases/immunology/therapy/metabolism/pathology
Histones/metabolism
Signal Transduction
Neuroinflammatory Diseases/immunology

@article {pmid42631129,
year = {2026},
author = {Nuñez, E and Muguruza-Montero, A and Arrizabalaga-Iriondo, A and Zayas-Arrabal, J and M-Alicante, S and Urrutia, J and Revuelta, M},
title = {KV3.1 channel modulation: a systematic review of pharmacological intervention strategies.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1821275},
pmid = {42631129},
issn = {1663-9812},
abstract = {INTRODUCTION: Voltage-gated potassium channels of the KV3 subfamily, particularly KV3.1 (encoded by KCNC1), are essential regulators of fast-spiking inhibitory interneuron activity and high-frequency neuronal firing, enabling precise control of neuronal excitability and network synchrony. Growing evidence links KV3.1 dysfunction to epilepsy, schizophrenia, tinnitus, fragile X syndrome, amyotrophic lateral sclerosis, and KCNC1 related developmental and epileptic encephalopathies, positioning this channel as a promising therapeutic target.

METHODS: This systematic review, conducted in accordance with PRISMA guidelines, evaluates original studies published between 2016 and January 2026 that investigated pharmacological modulation of KV3.1 using in vitro, in vivo, structural, and translational approaches.

RESULTS: A total of thirty-two studies met the predefined PICOS criteria. The literature reveals two pharmacological strategies: positive allosteric modulation aimed at enhancing fast-spiking inhibitory interneuron function and restoring excitation inhibition balance, and state-dependent channel inhibition, particularly relevant for pathogenic gain of function KCNC1 variants.

DISCUSSION: While early positive allosteric modulators demonstrated proof of mechanism with limited clinical success, second-generation compounds exhibit improved translational potential, including evidence that they modulate functional brain networks in humans. In parallel, clinically approved antidepressants have been identified as open-channel blockers of KV3.1, enabling mutation-specific therapeutic repurposing.

CONCLUSIONS: Collectively, these findings highlight KV3.1 modulation as a context-dependent and increasingly precise pharmacological strategy for neurological and neurodevelopmental disorders.},
}

@article {pmid42632975,
year = {2026},
author = {Saeed, Y and Fatima, M and Rehman, MU and Aslam, MH},
title = {Diagnostic Delay in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis Comparing Time From Symptom Onset to Diagnosis in Bulbar-Onset Versus Limb-Onset Disease.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e113188},
pmid = {42632975},
issn = {2168-8184},
abstract = {Diagnostic delay is a recognized challenge in amyotrophic lateral sclerosis (ALS), depriving patients of timely access to disease-modifying therapy and multidisciplinary care. Although several individual cohorts have reported diagnostic delay separately for bulbar-onset and limb-onset ALS, few studies have directly compared the two, and their estimates have not been pooled. We aimed to compare time from symptom onset to diagnosis in bulbar-onset versus limb-onset ALS. We searched PubMed and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) from inception through April 2026 for studies reporting diagnostic delay separately for the two onset types. Where upper- and lower-limb onset were reported separately, these were combined into a single limb-onset group using standard formulae; medians with interquartile ranges were converted to means and standard deviations using the method of Wan et al. A random-effects meta-analysis (DerSimonian-Laird) pooled studies reporting a usable measure of dispersion by onset group, with the remaining studies summarized narratively. The outcome was the mean difference (MD) in diagnostic delay in months, where a negative value indicates faster diagnosis in bulbar onset; heterogeneity was quantified with I[2] and risk of bias with the Newcastle-Ottawa Scale. In total, 13 studies (898 bulbar-onset and 2,438 limb-onset patients from eight countries) met the inclusion criteria; nine contributed to the meta-analysis, as four reported no usable measure of dispersion and were summarized narratively. Bulbar-onset patients were diagnosed significantly faster than limb-onset patients (MD = -4.42 months; 95% confidence interval -5.73 to -3.11; p < 0.001), with moderate heterogeneity (I[2] = 56%). The direction of effect was consistent across all studies, and the pooled estimate was stable on leave-one-out analysis. The four non-pooled studies were each directionally consistent. Bulbar-onset ALS is diagnosed approximately 4 months faster than limb-onset ALS, likely because distinctive bulbar symptoms prompt earlier specialist referral whereas limb weakness is attributed to more common musculoskeletal or orthopedic conditions. Strategies raising awareness of limb-onset ALS among primary care and orthopedic physicians are warranted.},
}

@article {pmid42636890,
year = {2026},
author = {Guha, L and Malik, JA and Bose, B},
title = {Living drug carriers: Microbial and bioengineered platforms redefining precision therapeutic and immunomodulatory delivery.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {115274},
doi = {10.1016/j.jconrel.2026.115274},
pmid = {42636890},
issn = {1873-4995},
abstract = {Microbial living therapeutics are a new class of drug-delivery materials that combine synthetic biology, immunomodulation, and advanced formulations to achieve controllable therapeutic effects in space and time. In the broad field of living drug-delivery systems, therapeutic platforms include engineered microorganisms, mammalian immune cells, stem cells, viral vectors, extracellular-vesicle-producing cells, and hybrid bioengineered living materials. This review focuses on engineered microbial living drug carriers, including genetically modified bacteria and probiotic platforms, because these systems uniquely integrate programmable biosensing, in situ therapeutic synthesis, adaptive immunomodulation, and controllable drug delivery within a single living chassis. Designed microbes and consortia possess other unique functions, such as microenvironment sensing, programmed control of gene expression, and long-lasting in situ manufacturing of therapeutic payloads not available with small-molecule or biologic drugs. Recent progress in microbial chassis engineering, genetic circuit design, and biocontainment has enabled fine-tuning of immune responses, metabolic pathways, and tissue-specific signaling in a wide range of diseases from cancer to autoimmune and inflammatory diseases, to metabolic and endocrine disorders, neuro-immunological conditions (e.g., amyotrophic lateral sclerosis), infectious diseases including infectious threats without existing approved vaccines (Zika virus) as well as rare genetic disorders. Advances in formulation science, including encapsulation technologies, biomaterial-microbe hybrids, and stimuli-responsive release platforms, have enabled overcoming key translation challenges concerning microbial viability, biodistribution, safety, and controlled activation in complex physiological milieus like the gut (for enteric pathogens), tumor microenvironment (for oncolytic organisms), or injured tissues (for tissue-targeting organisms). Increasing numbers of clinical-stage LBP studies are now conducted under good manufacturing practice, standardized QC, and clinical conditions, ranging from emerging PK, biodistribution, and biomarker-driven studies to those adapted to living entities. The addition of host microbiome profiling, multi-omics analysis, and computational modeling is anticipated to increase therapeutic predictability and patient stratification. Taken together, these advances position live microbial therapeutics as programmable biological medicines with the potential for adaptive, context-specific administration and warrant further clinical development and increased integration within precision medicine-informed therapeutic approaches.},
}

@article {pmid42638120,
year = {2026},
author = {Tang, L and Fan, D},
title = {Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42638120},
issn = {2047-9158},
support = {CX25YZ13//the Chinese Institutes for Medical Research, Beijing/ ; 2022YFA1303003//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/therapy ; *Precision Medicine/methods/trends ; *Neuroinflammatory Diseases/immunology/therapy ; Animals ; Immunotherapy/methods ; },
abstract = {Neuroinflammation is no longer a secondary feature of amyotrophic lateral sclerosis (ALS), but rather a disease-modifying process that actively shapes the motor neuron vulnerability from the earliest stages of pathology. Central and peripheral immune cells, including microglia, astrocytes, and infiltrating T lymphocytes, adopt context-dependent states that can be neuroprotective or neurotoxic depending on disease stage and genetic background. These states are driven by discrete molecular programs, such as cGAS-STING-mediated innate immune sensing, NLRP3 inflammasome activation, and RIPK1-dependent necroptotic signaling, which represent tractable therapeutic targets. The repeated failure of broad-spectrum immunosuppressive trials reflects a fundamental mismatch between the non-selective interventions and the mechanistically distinct immune states of diseases. Converging transcriptomic, genetic, and immunophenotypic evidence supports the existence of putative neuroimmune endotypes in ALS, though this framework remains a working hypothesis pending prospective validation in biomarker-stratified cohorts. Advances in the following three domains are needed for realizing precision immunotherapy: standardized biomarker panels (including cerebrospinal fluid chitinases and TSPO-PET) to stratify patients by inflammatory subtype; pharmacodynamic readouts to confirm target engagement before interpreting clinical outcomes; and adaptive platform trial designs capable of evaluating mechanism-matching interventions in defined subgroups. This review integrates ALS-associated neuroinflammation with emerging precision medicine strategies, arguing that the central translational question is no longer whether or not to target neuroinflammation, but how, when, and in whom neuroinflammation should be targeted.},
}

Humans
*Amyotrophic Lateral Sclerosis/immunology/therapy
*Precision Medicine/methods/trends
*Neuroinflammatory Diseases/immunology/therapy
Animals
Immunotherapy/methods

@article {pmid42640367,
year = {2026},
author = {Iacono, D and Feltis, GC},
title = {Beyond the Ribosome: The Expanding Role of the Nucleolus in Neurodegenerative Pathways.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42640367},
issn = {1559-1182},
mesh = {*Cell Nucleolus/metabolism/pathology ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Ribosomes/metabolism ; Signal Transduction ; Aging/metabolism/pathology ; },
abstract = {The nucleolus, long defined by its canonical role in ribosome biogenesis, has emerged as a critical nexus for cellular homeostasis, stress sensing, and disease pathogenesis. This article synthesizes a broad range of evidence to construct a comprehensive model of the nucleolus in the context of aging and neurodegeneration. We begin by detailing its fundamental architecture and the intricate process of ribosome production, before exploring the paradigm-shifting discovery of its vast, non-canonical proteome, which implicates it in DNA repair, cell cycle control, and genome stability. A central theme is the nucleolus's function as a primary cellular stress sensor, which, upon disruption by genetic, metabolic, or proteotoxic insults, initiates the nucleolar stress response. We provide a detailed examination of the downstream signaling cascades, focusing on the canonical p53-MDM2 axis and the interconnected mTOR pathway, which together translate nucleolar status into decisions of cell fate, including apoptosis and cell cycle arrest. We then focus on the brain, presenting the neuropathological and morphological alterations of the nucleolus-such as atrophy, fragmentation, and changes in volume-that serve as hallmarks of normal aging and neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and C9orf72-linked ALS/FTD. We explore the deep regulatory layers of epigenetics, where DNA methylation and histone modifications of ribosomal DNA genes are dysregulated in disease, and discuss how multi-omics approaches are unraveling the complex molecular landscape of nucleolar function. Finally, we introduce the emerging concept of a gut-brain-nucleolus axis, proposing how systemic factors like the gut microbiome may influence neuronal health by triggering nucleolar stress through inflammatory and metabolic mediators. Overall, by highlighting the nucleolus as a convergence point for diverse pathogenic pathways, we frame it as a promising and druggable target for novel therapeutic strategies aimed at promoting neuronal resilience and combating neurodegenerative diseases.},
}

*Cell Nucleolus/metabolism/pathology
Humans
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Ribosomes/metabolism
Signal Transduction
Aging/metabolism/pathology

@article {pmid42621238,
year = {2026},
author = {Palakkot, S and Banik, A},
title = {Auditory Biomarkers in Neurodegenerative Disorders: A Literature Review.},
journal = {Journal of otology},
volume = {21},
number = {3},
pages = {160-166},
pmid = {42621238},
issn = {2524-1753},
abstract = {The prevalence of neurodegenerative diseases is escalating globally. However, the conventional diagnostic framework fails to identify the pathology until substantial neuronal damage occurs. The evidence from the recent literature indicates that auditory dysfunction commonly precedes motor and cognitive symptoms across multiple neurodegenerative diseases. The pathophysiology involves both the peripheral and cortical auditory structures, which produce distinctive patterns reflects systemic neurodegeneration. Hence, this suggests auditory assessment as a valuable tool for early identification of neural degeneration. This review synthesises the contemporary literature on auditory dysfunctions and underlying pathophysiology in Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, Amyotrophic lateral sclerosis, etc. The analysis included the temporal trajectories of auditory impairment, subjective-objective measurements, and evaluated the importance of early identification and longitudinal tracking. Objective measures of central auditory processing, including Auditory Brainstem Responses, P300, Mismatch Negativity, and speech-in-noise testing, provide objective, non-invasive diagnostic tools and its sensitivity comparable to established biomarkers. Integration of standardised auditory assessment batteries into clinical protocols could enable the early identification of pathology, differential diagnosis and the development of novel therapeutic strategies for both auditory and cognitive deficits. Current review suggests that future longitudinal studies with neurodegenerative conditions should focus on the clinical utility of auditory, cognitive, and neuroimaging biomarkers and facilitate clinical translation of these findings.},
}

@article {pmid42625715,
year = {2026},
author = {Chen, D and Shen, T and Ren, H and Qiu, P},
title = {Amyotrophic lateral sclerosis and degenerative cervical myelopathy: phenotype-based diagnostic pitfalls, investigative mismatch, and practical clinical reasoning.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1901811},
pmid = {42625715},
issn = {1664-2295},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/diagnostic imaging ; Diagnosis, Differential ; Phenotype ; Magnetic Resonance Imaging ; *Spinal Cord Diseases/diagnosis/physiopathology ; *Spinal Cord Compression/diagnosis/physiopathology ; },
abstract = {Differentiating amyotrophic lateral sclerosis (ALS) from degenerative cervical myelopathy (DCM) remains difficult because the two disorders can converge clinically while diverging biologically. ALS is a progressive motor neuron disease, whereas DCM is a potentially treatable compressive myelopathy; however, both may present with upper-limb weakness, hand wasting, hyperreflexia, gait disturbance, and cervical MRI abnormalities. This narrative review examines ALS-DCM overlap through the concept of explanatory sufficiency: whether the available clinical, imaging, and electrophysiological evidence adequately explains the whole syndrome rather than a single visible abnormality. We synthesize evidence on phenotype-specific overlap, MRI-clinical mismatch, EMG/NCS distribution, somatosensory and motor evoked potentials, Gold Coast diagnostic criteria, primary lateral sclerosis, and coexistence of motor neuron disease with structural cervical pathology. The review emphasizes that MRI is indispensable but not self-interpreting, EMG/NCS is most useful when interpreted by distribution rather than positivity alone, and SEPs/MEPs can add a functional cord-conduction layer when MRI and examination are discordant. We also provide action-oriented clinical warning signs for common overlap scenarios. Rather than offering a rigid algorithm, this review proposes a clinically driven reasoning framework that helps distinguish ALS, DCM, radiculopathy, and coexistence while reducing premature diagnostic closure in neuro-spine practice.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/diagnostic imaging
Diagnosis, Differential
Phenotype
Magnetic Resonance Imaging
*Spinal Cord Diseases/diagnosis/physiopathology
*Spinal Cord Compression/diagnosis/physiopathology

@article {pmid42619255,
year = {2026},
author = {Gadhave, DG and Jadhav, AB and Waghamode, NB and Khot, S and Khan, R and Hole, R and Dhobale, SM and Aswar, M and Paudel, KR},
title = {Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e71594},
doi = {10.1002/adhm.71594},
pmid = {42619255},
issn = {2192-2659},
abstract = {Aging is a significant risk factor of neurodegenerative disorders (NDs) such as Huntington's, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Although several clinical, neuroimaging, and biomarker-based diagnostic approaches are available for NDs, their limited sensitivity for early-stage detection, disease specificity, and prediction of disease progression continue to present significant clinical challenges, often resulting in delayed diagnosis and therapeutic intervention. According to previously published works, the preliminary pathological feature of such disorders is mitochondrial dysfunction. This may lead to elevated oxidative stress, impaired mitophagy, unbalanced mitochondrial function, and bioenergetic failure. This review examines how mitochondria-targeted nanotherapeutic approaches can overcome these pathological barriers and improve therapeutic outcomes in aging-associated neurodegeneration. Targeted delivery of drug-loaded nanocarriers, such as gene-delivery, lipid-based, metallic, and polymeric nanoparticles, has emerged as a potential platform to deliver medication directly to defective mitochondria. It may increase mitochondrial biogenesis, maintain redox balance, and protect against neuronal degeneration. This work incorporates disease-specific mitochondrial pathology with current progress in targeted nanotherapeutics, age-associated delivery barriers, clinical revolution, and emerging artificial intelligence (AI)-enabled precision therapeutic approaches. Mitochondria-targeted nanotherapeutics depict a potential disease-modifying strategy for aging-related NDs. However, further advancements in targeting efficacy, scalable production, long-term safety, and clinical validation can facilitate a successful clinical revolution.},
}

@article {pmid42552132,
year = {2026},
author = {Labrèche, F and Prud'homme, P and Gagnon, M and Dupré, N and Gravel, S},
title = {Occupational exposure to pesticides increases the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Occupational and environmental medicine},
volume = {83},
number = {5},
pages = {291-300},
doi = {10.1136/oemed-2025-110662},
pmid = {42552132},
issn = {1470-7926},
mesh = {Humans ; *Occupational Exposure/adverse effects ; *Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; *Pesticides/adverse effects/toxicity ; Risk Factors ; *Occupational Diseases/chemically induced ; Female ; },
abstract = {OBJECTIVE: To systematically review the evidence on the association between occupational exposure to pesticides and the risk of amyotrophic lateral sclerosis (ALS).

METHODS: A systematic search, conducted in eight bibliographic databases for publications between 1990 and 2025, identified observational studies estimating the risk of ALS after occupational pesticide exposure. Study quality was assessed using the WHO Risk of Bias (RoB) assessment instrument for systematic reviews, with the ROBINS-E (RoB in non-randomised studies of exposure) tool domains of bias. Pooled risk estimates were produced using random-effects models with restricted maximum likelihood, heterogeneity was assessed with I² statistics, and meta-regressions and publication bias explored with funnel plots and Egger's test.

RESULTS: Eight case-control studies (1734 cases) were retained for meta-analysis from 767 initially screened articles. 'Ever' occupational exposure to pesticides was associated with an increased risk of ALS (n=6 studies, pooled OR (pOR)=1.6; 95% CI 1.1, 2.2; I²=57%), for combined sexes. The risk for exposure to herbicides was slightly greater (pOR=1.7, I[2]=0.0%) than for exposure to insecticides or fungicides (pORs=1.6, I[2]=0.0%). Based on three studies, ever exposure to high levels of pesticides was associated with a higher risk (pOR=2.7; 95% CI=1.4, 5.0) than exposure to low levels (pOR=1.9; 95% CI=1.0, 3.7). Self-reported exposure assessment methods and older publication dates (<2015) were statistically significant predictors of the effect size.

CONCLUSION: Despite the small number of studies and some heterogeneity, our results add to the evidence suggesting that occupational exposure to pesticides may increase the risk of ALS.},
}

Humans
*Occupational Exposure/adverse effects
*Amyotrophic Lateral Sclerosis/chemically induced/epidemiology
*Pesticides/adverse effects/toxicity
Risk Factors
*Occupational Diseases/chemically induced
Female

@article {pmid42618940,
year = {2026},
author = {Saka, AK and Godhwani, K and Ramasamy, V and Soh, BL and Lingam, M and Lofters, A and Gerstle, D and Selby, P and LeBlanc, A and Pritlove, C and Sayani, A},
title = {The use of deliberative dialogue in health services research: a scoping review.},
journal = {Research involvement and engagement},
volume = {12},
number = {1},
pages = {},
pmid = {42618940},
issn = {2056-7529},
support = {TLP - 185094/CAPMC/CIHR/Canada ; },
abstract = {INTRODUCTION: Deliberative Dialogue (DD) is a structured participatory approach that brings together research evidence, professional expertise, and lived/living experience to support informed discussion and decision-making in health research. DD is increasingly used in the co-design, co-implementation, and co-evaluation of health-promoting interventions, where decisions must be both evidence-informed and responsive to local contexts, priorities, and needs. However, published studies vary considerably in how DD is described and reported, particularly in relation to facilitation, evidence use, participant preparation, power dynamics, and follow-up. This scoping review examined the application of DD in health services research, focusing on its methodological processes, reported outcomes and challenges, engagement of different interest-holders, and the rationales underlying its use.

METHODS: A scoping review was conducted following Arksey and O'Malley's framework and reported in accordance with PRISMA-ScR guidelines. Searches of OVID Medline, PsycINFO, PubMed, CINAHL, and Scopus identified 1,793 records. After screening and consolidating duplicate reports, 15 unique studies met the inclusion criteria. Data were extracted using a template informed by the Guidance for Reporting Involvement of Patients and the Public (GRIPP2), the Consolidated Standards of Reporting Trials (CONSORT), and Boyko et al.'s model of DD. The review was conducted using a critical Patient-Oriented Research (cPOR) approach, which centres lived/living experience, promotes shared decision-making between patient partners and researchers, and attends to the influence of power and structural contexts on knowledge production. The interdisciplinary team, including patient partners, researchers, clinicians, policymakers, and decision-makers, co-developed the study, contributed to data interpretation, and collaboratively refined the findings through iterative and reflexive discussion.

FINDINGS: The 15 included studies were published between 2012 and 2024 and represented diverse geographic and health-system contexts. DD was used to support intervention co-design, implementation planning, evaluation, priority-setting, guideline development, and service improvement. Studies consistently reported the involvement of multiple interest-holder groups and the development of practical outputs, including curricula, decision aids, care models, action plans, guidelines, and priority-setting frameworks. However, reporting of methodological processes was inconsistent. Only a minority of studies described facilitation protocols, participant preparation, strategies to address power dynamics, accessibility supports, or follow-up activities. While DD was associated with enhanced trust, mutual understanding, contextual relevance, and collaborative decision-making, evidence of longer-term impacts was limited. The synthesis also revealed substantial variation in how studies reported participant engagement, evidence use, consensus-building processes, and the translation of deliberative outputs into intervention-related decisions.

This review highlights DD as a valuable approach for collaborative, evidence-informed, and context-sensitive health services research. Across the included studies, DD was used to bring together diverse forms of knowledge and generate practical outputs to support intervention development and improvement. However, methodological details related to facilitation, accessibility, participant support, management of power dynamics, decision-making processes, and longer-term impacts were often underreported. These gaps point to the need for more transparent and equity-oriented reporting of DD, particularly in relation to how people with lived/living experience are engaged and how their contributions influence intervention-related decisions. Strengthening reporting in these areas may improve the transparency, reproducibility, and accountability of DD in the co-design, co-implementation, and co-evaluation of health interventions.},
}

@article {pmid42618698,
year = {2026},
author = {Shrestha, N and Munn, Z and Calma, A and Pavey, N and Tsuji, Y and Menon, P and Padovani, A and Risi, B and Ferullo, L and Filosto, M and Jewett, G and Shibuya, K and Otani, R and Shimizu, T and Kuwabara, S and Noto, YI and Kitaoji, T and Johnsen, B and Shen, D and Cui, L and van den Berg, LH and van Eijk, RPA and van Damme, P and Kiernan, MC and Giles, L and Vucic, S},
title = {Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.},
journal = {Journal of neurology},
volume = {273},
number = {9},
pages = {},
pmid = {42618698},
issn = {1432-1459},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Sensitivity and Specificity ; },
abstract = {BACKGROUND: To evaluate the diagnostic accuracy of the Gold Coast criteria (GCC) and compare their performance with the revised El Escorial (rEEC) and Awaji criteria in patients with suspected amyotrophic lateral sclerosis (ALS).

METHODS: Embase, MEDLINE, and Scopus were searched for English-language studies published between January 1, 2020, and August 11, 2025. Eligible studies assessed the diagnostic accuracy of GCC compared with rEEC and Awaji criteria in suspected ALS. Authors were invited to contribute individual participant data. Data were checked, harmonised, and recoded. A one-stage individual-participant data meta-analysis, adjusted for age and sex, was performed. Diagnostic performance was assessed using pooled sensitivity, specificity, and area under the receiver operating characteristic curve. Risk of bias was assessed using QUADAS-2 and QUADAS-C, and certainty of evidence using GRADE for diagnostic test accuracy. The study was registered with PROSPERO, CRD420251123597.

RESULTS: Individual participant data were available for 3007 participants from five international studies. GCC demonstrated higher sensitivity than rEEC and Awaji criteria: 0.96 (95% confidence interval [CI] 0.93-0.98) versus 0.87 (95% CI 0.78-0.92) and 0.87 (95% CI 0.78-0.93), respectively. Certainty of evidence for sensitivity was moderate at pre-test probabilities of 50% and 75%, and low at 25%. Specificity was numerically lower for GCC at 0.68 (95% CI 0.53-0.81) compared with rEEC at 0.73 (95% CI 0.59-0.83) and the Awaji criteria at 0.72 (95% CI 0.57-0.83). The certainty of evidence for specificity was rated as very low across all assessed pre-test probabilities (25%, 50%, and 75%).

CONCLUSIONS: GCC provide a sensitive framework for suspected ALS and may support earlier diagnosis in specialist settings. Specificity was imprecise and heterogeneous, supporting use with mimic exclusion and longitudinal reassessment.},
}

*Amyotrophic Lateral Sclerosis/diagnosis
Humans
Sensitivity and Specificity

@article {pmid42149647,
year = {2026},
author = {Hui, LM and Yu, E and Chung, A and Kwan, BYM},
title = {Artificial intelligence for assessment in competency-based medical education: current practices and future directions.},
journal = {Postgraduate medical journal},
volume = {102},
number = {1211},
pages = {806-816},
doi = {10.1093/postmj/qgaf195},
pmid = {42149647},
issn = {1469-0756},
mesh = {*Competency-Based Education/methods/trends ; Humans ; *Artificial Intelligence ; *Clinical Competence/standards ; *Educational Measurement/methods ; },
abstract = {BACKGROUND: Competency-Based Medical Education (CBME) relies on frequent, competency-focused assessments, which can be challenging to implement consistently. Artificial Intelligence (AI) holds promise to improve assessment efficiency, objectivity, and feedback in CBME, but its use remains in early stages with limited understanding of current practices and evaluation methods. This study aims to map existing AI applications in CBME assessments to guide future work.

METHODS: A comprehensive search was performed in MEDLINE (Ovid), EMBASE (Ovid), PsycINFO, and Scopus using tailored keywords and MeSH terms. Included studies focused on the deployment of AI for assessment within CBME, covering applications in generating, analyzing, or interpreting evaluation data across undergraduate, graduate, and continuing professional education. The PRISMA-ScR guidelines were used to ensure transparent reporting, and findings were synthesized following Levac et al.'s approach.

RESULTS: Of the 1002 search results, 32 studies met the inclusion criteria. Key findings indicate a wide application of AI from surgical or procedural skill assessment, to clinical note assessment, communication assessment, feedback generation, projected trainee performance, and analysis of narrative feedback from supervisors.

CONCLUSION: This review highlights potential advantages, such as timely evaluations, and challenges, such as lack of granularity, of AI integration. In conclusion, thoughtful integration of AI into competency-based medical education can complement traditional assessment methods and enhance learner outcomes, provided it is supported by robust infrastructure, ethical oversight, and collaborative policy development.},
}

*Competency-Based Education/methods/trends
Humans
*Artificial Intelligence
*Clinical Competence/standards
*Educational Measurement/methods

@article {pmid42614249,
year = {2026},
author = {Sheppard, B and Durnell, L and Haufler, AJ},
title = {From emergence to amplification: an analysis of lifecycle models to address health mis-disinformation in the digital environment.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1814102},
pmid = {42614249},
issn = {2296-858X},
abstract = {Health misinformation and disinformation (mis-disinformation) on social media presents a growing threat to individual and population health, societal resilience, and national security. While social media enables the rapid dissemination of health information, it also facilitates the spread of health mis-disinformation, a challenge further compounded by foreign influence campaigns, AI-generated content, and divergent regulatory environments. Effective interventions require tailoring to local socio-cultural and geo-political contexts. This article proposes a lifecycle model for health professionals that conceptualizes how content creation, dissemination, exposure, belief formation, and behavioral outcomes interact and can be targeted through strategic interventions to improve health outcomes and mitigate adverse behavioral effects. To achieve this, the article characterizes the challenges posed by the current and emerging health information environment; identifies and evaluates mis-disinformation lifecycle models in order to strengthen the existing knowledge base; and assesses the current state of knowledge and gaps on comparing intervention strategies to elicit desired behavioral responses, with an emphasis on individual approaches (e.g., debunking, media literacy, fact checking). A review of literature (2020-2025) identified 13 cross-comparative intervention studies which focused on key findings. Four lifecycle models were identified and assessed against six criteria derived from the lifecycle literature to identify the most suitable framework for adaptation in the public health domain. Kruijver et al.'s C5 Interaction Model emerged as the framework that satisfied the greatest number of criteria and was selected for adaptation. The model was extended to account for diverse socio-political and information environments, emerging technological interventions, and the distinct challenges posed by both mis-disinformation. Adaptation involved integrating concepts from risk perception, the Social Amplification of Risk Framework, and Social Judgment Theory, alongside health-specific examples to enhance relevance and practical applicability. To help translate the insights gained to strategy, we also convey the information in an Integrated Framework for Managing Health Mis-disinformation. By linking the evolution of health mis-disinformation to targeted interventions, the model and framework provide a foundation for promoting healthier behaviors and mitigating the adverse effects of misleading health information across diverse socio-demographic and cultural settings to improve health outcomes.},
}

@article {pmid42617572,
year = {2026},
author = {Tang, WX and Yang, C and Zhang, M and Kushida, CA and de Lecea, L and Li, SB},
title = {Sleep-wake control with age and neurodegenerative diseases.},
journal = {Sleep medicine reviews},
volume = {90},
number = {},
pages = {102352},
doi = {10.1016/j.smrv.2026.102352},
pmid = {42617572},
issn = {1532-2955},
abstract = {Aging causes dramatic alterations in bodily functions. Among them, sleep quality declines with age, particularly in individuals with neurodegenerative diseases. In this review, we first describe alterations in sleep-wake architecture and discuss potential mechanisms underlying sleep disorders that arise with age. We discuss evidence linking sleep disorders with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) syndrome. Even though the causes of AD, PD, PSP, and HD are diverse, several shared symptoms including difficulty falling asleep, fragmented sleep, and disrupted circadian rhythm collectively suggest their pathologies disrupt sleep-wake control. Hyperexcitability of implicated neurons is commonly observed prior to neurodegeneration. Upregulated neuronal excitability in the early phase of these diseases appears as a potential shared mechanism among neurodegenerative diseases. Abnormal protein accumulation and aggregation in these diseases exacerbate neuronal circuit hyperactivity by increasing neurons' intrinsic excitability or dampening inhibitory inputs to neurons controlling sleep-wake cycles. A better understanding of the mechanisms underlying sleep disorders that emerge with age may greatly benefit the development of novel preventative and therapeutic strategies for neurodegenerative diseases, and therefore improve the life quality of older adults.},
}

@article {pmid42612795,
year = {2026},
author = {Li, J and Duan, H and Hao, P and Zhao, W and Gao, Y and Yang, Z and Li, X},
title = {Regenerative medicine for neurodegenerative diseases:History, Strategies, and Clinical Advances.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.trsl.2026.08.005},
pmid = {42612795},
issn = {1878-1810},
abstract = {In the context of global ageing, the prevalence of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is rapidly increasing. However, current symptomatic treatments have achieved limited benefits in clinical settings and fundamentally fail to reverse the progressive loss of specific neuronal populations. Halting neurodegeneration and restoring impaired cognitive, motor or visual functions through nerve regeneration and circuit reconstruction represent the clinically meaningful goals for treatments of NDDs. Regenerative medicine has emerged as a promising paradigm to address this unmet need. In this review, we trace the historical evolution of regenerative therapies for NDDs - from early exploratory cell transplantation to modern approaches involving pluripotent stem cells (PSCs) and in vivo direct reprogramming. Furthermore, we elucidate the core strategies of regenerative medicine within an integrated framework encompassing "Replacement", "Regeneration", and "Rejuvenation". Finally, we highlight recent advances in clinical research, particularly milestone trials in cell replacement therapy for PD, as well as the application of mesenchymal stem cells (MSCs) in AD and ALS.},
}

@article {pmid42613144,
year = {2026},
author = {Valverde, A and Blasco, H and Corcia, P and Herault, O and Magistretti, P and Herault, L and Cali, C and Bartesaghi, L and Stone, J and Mitrofanis, J},
title = {Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.},
journal = {International review of neurobiology},
volume = {189},
number = {},
pages = {205-236},
doi = {10.1016/bs.irn.2026.01.013},
pmid = {42613144},
issn = {2162-5514},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/radiotherapy ; Animals ; *Infrared Rays/therapeutic use ; Red Light ; *Neurodegenerative Diseases/therapy ; },
abstract = {All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/radiotherapy
Animals
*Infrared Rays/therapeutic use
Red Light
*Neurodegenerative Diseases/therapy

@article {pmid42613627,
year = {2026},
author = {Jamali, MC and Shafie, A and Alqahtani, AJ and Al-Samawi, RI and Alyami, HM and Ashour, AA and Felemban, MF and Mansuri, N and Tayeb, FJ and Ahmad, I and Mudhafar, M and Sheweita, SA},
title = {Advances in the clinical application of mesenchymal stem cells for neurological disorders.},
journal = {Stem cell research & therapy},
volume = {17},
number = {1},
pages = {},
pmid = {42613627},
issn = {1757-6512},
mesh = {Humans ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/cytology/metabolism ; *Nervous System Diseases/therapy/pathology ; Animals ; Amyotrophic Lateral Sclerosis/therapy/pathology ; Alzheimer Disease/therapy/pathology ; },
abstract = {Therapeutic approaches employing mesenchymal stem cells (MSCs) have emerged as a promising avenue for investigating treatments for neurological disorders. This strategy aims to capitalize on the biological properties of MSCs to support the repair of damaged neural tissue and modulate pathological processes. This review provides a comprehensive overview of the current clinical evidence regarding MSC applications in major neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other pertinent disorders. Across clinical studies, MSC administration has generally demonstrated a favorable safety profile and procedural feasibility. However, therapeutic efficacy remains variable and inconsistent across trials. Importantly, differences in MSC sources, manufacturing procedures, delivery routes, dosing strategies, and patient selection contribute substantially to the heterogeneity of reported outcomes. Therefore, the current body of evidence supports the safety of MSC-based interventions, but their clinical effectiveness has not yet been consistently demonstrated. Future progress will depend largely on the standardization of cell preparation and treatment protocols, improved biomarker-driven patient stratification, and rigorously designed large-scale randomized trials.},
}

Humans
*Mesenchymal Stem Cell Transplantation/methods
*Mesenchymal Stem Cells/cytology/metabolism
*Nervous System Diseases/therapy/pathology
Animals
Amyotrophic Lateral Sclerosis/therapy/pathology
Alzheimer Disease/therapy/pathology

@article {pmid42613642,
year = {2026},
author = {Wang, JDJ and Teo, AYT and Xiao, B and Chao, Y and Zhou, ZD and Tan, BJ and Chan, LL and Rosalie, E and Tan, EK},
title = {PCSK9 inhibitors in neurodegenerative disorders: mechanisms, therapeutic potential, and clinical implications.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42613642},
issn = {2047-9158},
support = {LCG//National Medical Research Council/ ; STaR//National Medical Research Council/ ; },
mesh = {Humans ; *PCSK9 Inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Proprotein Convertase 9/metabolism/genetics ; Animals ; },
abstract = {Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in hepatic cholesterol metabolism via low density lipoprotein receptor degradation. PCSK9 inhibitors have revolutionized lipid-lowering therapy, providing robust reduction of cardiovascular risk. Large-scale randomized controlled trials and long-term extensions (e.g., FOURIER and EBBINGHAUS trials) have shown no significant adverse effects of PCSK9 inhibitors on neuropsychological testing or patient-reported cognitive outcomes, even with prolonged and intensive lowering of low-density lipoproteins. Pre-clinical studies also suggest PCSK9 as a key regulator of neurobiological processes, including synaptic plasticity, amyloid-beta clearance, neuroinflammation, and blood-brain barrier integrity. Human genetic studies revealed complex, sometimes conflicting associations between PCSK9 variants and risk of Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. In this review, we highlight the pathophysiologic mechanisms, emerging experimental therapeutics and clinical implications of PCSK9 inhibition in neurodegenerative disorders. Long-term adequately powered trials with robust neuropsychological, biomarker, and imaging endpoints, as well as mechanistic studies in human-derived models are needed to establish the cardiovascular and neurocognitive implications of PCSK9 inhibition and guide precision medicine strategies for those at elevated risk of neurodegeneration.},
}

Humans
*PCSK9 Inhibitors
*Neurodegenerative Diseases/drug therapy/metabolism
*Proprotein Convertase 9/metabolism/genetics
Animals