@article {pmid42924853,
year = {2026},
author = {Regazzetti, M and Kiper, P and Merico, A and Rossi, S and Bulcão Visco, D and Luque Moreno, C and Baba, A},
title = {Feasibility and apparent safety of functional electrical stimulation-assisted cycling in amyotrophic lateral sclerosis and primary lateral sclerosis: a single-arm longitudinal pilot feasibility study.},
journal = {European journal of translational myology},
volume = {},
number = {},
pages = {},
doi = {10.4081/ejtm.2026.16025},
pmid = {42924853},
issn = {2037-7452},
abstract = {Functional electrical stimulation-assisted cycling may be relevant in motor neuron disease, but its feasibility and safety in amyotrophic lateral sclerosis and primary lateral sclerosis remain unclear. The authors aimed to assess feasibility, apparent safety, and exploratory pre-post clinical changes of a three-week functional electrical stimulation-assisted cycling protocol in ambulatory inpatients with amyotrophic lateral sclerosis or primary lateral sclerosis. Fifteen patients were assessed; 11 were enrolled (5 ALS, 6 PLS) and received 15 supervised 30-minute FES-cycling sessions over three weeks in addition to conventional neuromotor rehabilitation. Bilateral eight-channel stimulation targeted quadriceps, tibialis anterior, hamstrings, and gastrocnemius during active or active-assisted cycling. Feasibility outcomes were enrollment, completion, tolerance, adverse events, and pre-post data availability. Clinical outcomes were analyzed descriptively. Eleven of 15 assessed patients were enrolled (73.3%; 5 ALS, 6 PLS). All enrolled participants completed the protocol, no adverse events were documented, and complete pre-post data were available. Exploratory outcomes showed favorable short-term changes in mobility, walking, strength, and spasticity. This protocol appears feasible and apparently safe in selected ambulatory inpatients. Findings are hypothesis-generating and support a prospective controlled feasibility trial before efficacy is tested.},
}

@article {pmid42925434,
year = {2026},
author = {Shah, A and Godad, A and Bagwe Parab, S},
title = {Unlocking therapeutic potential of Wnt signaling pathway in neurodegenerative diseases.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42925434},
issn = {1573-7365},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Wnt Signaling Pathway/drug effects/physiology ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The Wnt Signaling pathway is a regulatory network that is highly conserved in the central nervous system and is essential for the survival of neurons, synaptic plasticity, and the blood-brain barrier's integrity. The pathophysiology of major neurodegenerative and neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), is highly influenced by canonical and non-canonical Wnt Signaling dysregulation, according to increasingly compelling evidence. In addition to emphasising common molecular events such as GSK-3β overactivation, β-catenin destabilisation, neuroinflammation, synaptic dysfunction, and BBB disruption, this study offers a comparative and mechanistic overview of Wnt pathway changes across various illnesses. This article identifies overlapping treatment targets, such as GSK-3β, DKK1, LRP5/6, and Wnt ligands, by integrating common and disease-specific Wnt-associated pathways, in contrast to traditional disease-specific reviews. Furthermore, new translational approaches involving natural substances, Wnt modulators, and pathway-targeted treatments are critically examined. All things considered, this study presents Wnt Signaling as a potential neuroprotective and regenerative target for upcoming precision-based treatments in neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Wnt Signaling Pathway/drug effects/physiology
Animals
Blood-Brain Barrier/metabolism/drug effects

@article {pmid42925563,
year = {2026},
author = {Niu, Y and Zhang, D and Gong, T and Guo, G and Zhang, H and Gao, C and Yang, J},
title = {Constructing functional neural circuits to model amyotrophic lateral sclerosis with induced pluripotent stem cell-derived brain organoids.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRRONLINE-D-26-00781},
pmid = {42925563},
issn = {1673-5374},
abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Recent advances in human-induced pluripotent stem cell-derived brain organoids offer an innovative platform to model amyotrophic lateral sclerosis in a human-specific context. These three-dimensional organoid systems allow for the study of neuronal circuit-level dysfunction, which is central to amyotrophic lateral sclerosis pathogenesis, by incorporating multiple neuronal subtypes and supporting glial populations. In particular, the integration of region-specific brain organoids into assembloid models has enabled the reconstruction of functional long-range projections and cortico-motor circuits, closely resembling human neural connectivity. This review summarizes the generation and application of human induced pluripotent stem cell-derived brain organoids for amyotrophic lateral sclerosis research, with a focus on the reconstruction of neural circuits, multi-omics profiling, and functional assays. We also discuss how organoid systems can be leveraged for drug discovery and personalized medicine in amyotrophic lateral sclerosis, highlighting their potential to unveil human-specific disease mechanisms. Lastly, we address the current challenges and future directions for improving the physiological relevance of organoid models in amyotrophic lateral sclerosis research.},
}

@article {pmid42925619,
year = {2026},
author = {Moreira, JVA and Pinheiro, CVA and de Souza, RF and Chiappa, GR and Ramos, SC and da Silva de Magalhães, MJ and de Aguiar, DR and Dos Santos, DF},
title = {The clinical spectrum of suicide-related outcomes in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {General hospital psychiatry},
volume = {103},
number = {},
pages = {204-212},
doi = {10.1016/j.genhosppsych.2026.10.002},
pmid = {42925619},
issn = {1873-7714},
abstract = {OBJECTIVE: To synthesize clinically distinct suicide-related outcomes in amyotrophic lateral sclerosis (ALS) and comparative suicide risk without pooling non-equivalent constructs.

METHODS: We searched MEDLINE, Embase, Scopus, PsycINFO, the Virtual Health Library, and SciELO through March 17, 2026, and updated all searches for March 18 through October 9, 2026. We included observational reports of predefined suicide-related outcomes. Outcomes with at least 3 independent studies were pooled using random-effects generalized linear mixed models for proportions and a Hartung-Knapp model for comparative estimates. We used Joanna Briggs Institute tools and adapted GRADE.

RESULTS: Twenty-eight reports representing 26 independent cohorts were included; 21 cohorts contributed quantitative data. Active suicidal ideation was 43% (23/53; 95% CI, 30%-58%) in an end-stage cohort and 14% (10/71; 95% CI, 7%-24%) in a general clinic cohort; these estimates were not pooled. Hypothetical consideration of assisted dying was 50% (95% CI, 41%-59%; I[2] = 49%; 95% prediction interval, 21%-79%; 4 studies). Crude suicide mortality rates were 0.16 and 0.36 per 100 person-years in 2 cohorts. Three registry or administrative cohorts yielded a relative suicide-risk estimate of 4.6 (95% CI, 2.5-8.5; 95% prediction interval, 0.4-53.6). Certainty was low or very low.

CONCLUSIONS: Suicide-related experiences in ALS are clinically distinct. Clinicians should clarify meaning, assess intent and immediacy, evaluate decision-making capacity and treatable psychiatric symptoms, and address palliative and psychosocial needs. A death wish or assisted-dying preference should not be assumed to indicate active suicidal intent.},
}

@article {pmid42925692,
year = {2026},
author = {Ocampo, DEM and Martínez, SS},
title = {Dynamic UV-Vis monitoring of ternary pharmaceutical photodegradation using multivariate curve resolution and predictive modeling.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {367},
number = {Pt 2},
pages = {129014},
doi = {10.1016/j.saa.2026.129014},
pmid = {42925692},
issn = {1873-3557},
abstract = {Ultraviolet (UV) photodegradation of multicomponent pharmaceutical systems generates complex spectral signals due to overlapping absorption bands and transient intermediates, limiting conventional quantitative approaches. To address this challenge, an integrated chemometric strategy was developed to predict concentration profiles in dynamic ternary mixtures of paracetamol (PAR), naproxen sodium (NPX), and diclofenac sodium (DIC) in spiked river water using Ultraviolet-visible (UV-Vis) spectroscopy. UV-Vis spectra from individual photolysis experiments were analyzed by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to estimate concentration profiles of the parent pharmaceuticals. These profiles were associated with ternary mixture spectra reconstructed by linear combination of the spectral data obtained from the individual photolysis experiments. The combined spectral data, together with experimentally acquired calibration data, served as input to develop a linear Partial Least Squares (PLS) and non-linear Artificial Neural Network (ANN) models, enabling simultaneous prediction of component concentrations. The degree of nonlinearity in the calibration datasets was first assessed using the Non-Linearity Degree (NLD), yielding values of 0.248, 0.398, and 0.214 for PAR, NPX, and DIC, respectively. These results exceeded the 0.05 threshold, indicating significant non-linear behavior in the calibration datasets. Accordingly, the linear PLS model showed limited predictive performance, particularly for DIC. In contrast, the non-linear ANN model achieved higher predictive accuracy, demonstrating its superior suitability for the dynamically evolving multicomponent systems.},
}

@article {pmid42926444,
year = {2026},
author = {Bennett, A and Johnson, EK and Benjamin, KJM},
title = {IsoGraph resolves coordinated transcript choice and gene abundance in the aging human brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.04.756439},
pmid = {42926444},
issn = {2692-8205},
abstract = {Relative transcript usage can change without a corresponding change in total gene expression, but resolving coordinated transcript choice across genes while separating it from abundance remains challenging. We present IsoGraph, a gene-centered framework that represents isoform usage and abundance as paired network channels, identifies gene modules, and quantifies their channel-specific contributions. In synthetic benchmarks, IsoGraph preferentially recovered network structure when coordinated transcript usage carried the planted signal, whereas abundance-based representations were more informative in abundance-dominated and RNA-degradation settings. Applied to BrainSEQ and GTEx adult brain transcriptomes, IsoGraph identified age-associated transcript-usage signals that persisted after conditioning on gene abundance and, in a region-dependent manner, after adjustment for estimated cellular composition. Modules were stable across donor subsets, and frozen module axes retained age associations across cohorts even when exact gene partitions differed. IsoGraph module context captured predictive information about held-out differential transcript usage beyond gene-wise evidence and conventional co-expression. Convergent evidence from structural annotation, short-read junction usage, independent long-read sequencing, and within-donor allelic analyses supported constituent transcript events. Disease colocalization further prioritized candidate isoform events at neurological and psychiatric disease loci, including an alternative terminal-exon event at PRDM2 associated with amyotrophic lateral sclerosis. Together, these results establish coordinated transcript usage as a reproducible component of transcriptomic organization and provide a framework for resolving its contribution alongside gene abundance and for tracing network-level signals to candidate transcript events.},
}

@article {pmid42926625,
year = {2026},
author = {Bhandary, P and Wang, Y and Omar, M and Moore, JH and Wang, ZP},
title = {CCT2 expression marks a translation-activated state in sporadic ALS motor neurons and is associated with functional decline.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.06.757033},
pmid = {42926625},
issn = {2692-8205},
abstract = {Sporadic disease accounts for about 90% of amyotrophic lateral sclerosis (ALS) cases, and its biological heterogeneity is a major contributor to the failure of trials that enroll patients under a single diagnosis. Because sporadic ALS lacks a shared genetic anchor, identifying biological signals is critical for effective patient stratification. We analyzed induced pluripotent stem cell-derived motor neurons from 619 AnswerALS participants using transcriptomics, proteomics, and whole-genome sequencing and identified CCT2 as the first single-gene marker of a molecular state within sporadic ALS, providing a measurable basis for trial enrollment according to biology. We first anchored the analysis in known ALS genotypes. C9orf72 and SOD1 motor neurons did not converge on a common signature but retained genotype-specific differences that bulk postmortem tissue compresses. Scoring 391 sporadic patients along three transcriptomic axes (bioenergetic stress, cell cycle, and inflammation) resolved three states. One state was marked by CCT2, a TRiC chaperonin subunit, which distinguished it from the quiescent state with an area under the curve of 0.892. CCT2 was also elevated at the protein level and associated with the rate of ALSFRS-R decline, although this association weakened after adjustment for culture composition. Upstream regulator analysis placed this state downstream of MYC and mTORC1 activation. No germline test across 360 whole genomes explained these states. Validation using Target ALS data showed that the relationship between CCT2 and the cell cycle program was also present in postmortem cortex enriched for layer 5b projection neurons.},
}

@article {pmid42907117,
year = {2026},
author = {Blinker, EJ and Amoh, GKA and Ankamah, S and Agyemang, C and Omech, B and Beune, E and Wekesah, FM and Azumah, M and Munneke, W},
title = {Implementation strategies, outcomes and determinants of integrated care for cardiometabolic conditions and mental, neurological and substance use disorders: protocol for a mixed-methods systematic review.},
journal = {BMJ open},
volume = {16},
number = {10},
pages = {e125828},
pmid = {42907117},
issn = {2044-6055},
abstract = {ΙNTRODUCTION: The co-occurrence of cardiometabolic diseases and mental, neurological and substance use disorders health conditions represents a growing global health burden, particularly in low- and middle-income countries. Although integrated, people-centred multimorbidity care is increasingly recognised as essential across settings, evidence remained limited on how these models are operationalised in routine practice and which implementation strategies are most effective to support their delivery. This protocol outlines the methods for a systematic review aiming to identify implementation strategies used to integrate care for cardiometabolic conditions and mental, neurological and substance use (MNS) disorders, examine associated implementation outcomes and explore contextual determinants influencing implementation across settings.

METHODS AND ANALYSIS: This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. A comprehensive search will be conducted in PubMed, CINAHL, APA PsycINFO, Scopus and Web of Science and relevant grey literature sources. Eligible studies include randomised controlled trials, quasi-experimental studies, mixed-methods studies, qualitative studies and implementation evaluations reporting on integrated care models addressing both cardiometabolic conditions and MNS disorders. To be included in this Systematic Review, studies must detail strategies or models integrating care for at least one cardiometabolic condition and one MNS disorder and provide data on implementation outcomes or contextual determinants. Title/abstract screening, full-text screening, data extraction and data synthesis will be conducted independently by at least two researchers following pilot testing. A formal risk of bias assessment will be performed using the Mixed Methods Appraisal Tool. A mixed-method, framework-based synthesis will be undertaken. Implementation strategies will be coded using the Expert Recommendations for Implementing Change taxonomy, implementation outcomes using Proctor et al’s taxonomy, and contextual determinants using the Consolidated Framework for Implementation Research. Quantitative data will be summarised descriptively using frequencies, proportions and summary tables, with findings stratified by country income level, setting and type of integrated care model where possible. Qualitative data will be analysed using inductive coding and deductive mapping to implementation science frameworks.

ETHICS AND DISSEMINATION: Ethical approval is not required as no primary data will be collected. The findings of this study will be disseminated through peer-reviewed publications, conference presentations, and stakeholders’ engagement in the field.

REGISTRATION DETAILS: The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 6 April 2026 (registration number CRD420261321825).},
}

@article {pmid42918614,
year = {2026},
author = {Speranza, J and Gale-Rogers, C and Stretch, AC and West, RJH},
title = {Drosophila Models of Human Neurodegenerative Diseases.},
journal = {Current opinion in insect science},
volume = {},
number = {},
pages = {101639},
doi = {10.1016/j.cois.2026.101639},
pmid = {42918614},
issn = {2214-5753},
abstract = {In his book Insects and the Life of Man: Collected Essays on Pure Science and Applied Biology, Sir V. B. Wigglesworth examined how a fundamental understanding of insect physiology and biology can be applied to some of society's greatest challenges, including human health. Here we reflect on how, in the 50 years since his book's publication, Drosophila melanogaster have played a critical role in advancing our understanding of human neurodegenerative diseases. Focusing on Parkinson's disease, Huntington's disease, and the frontotemporal dementia / amyotrophic lateral sclerosis spectrum, we examine the role Drosophila have played in elucidating fundamental mechanisms of neurodegeneration, identifying therapeutic targets, and dissecting the complex interplay that exists between genetics and environmental factors. Together these studies highlight how Drosophila models continue to provide critical insight into the molecular mechanisms underpinning neurodegeneration and provide a fundamental pre-clinical model in which we can accelerate research into human neurodegenerative conditions.},
}

@article {pmid42918778,
year = {2026},
author = {Abu-Rumeileh, S and Großkopf, H and Guthknecht, A and Mensch, A and Osterloh, D and Ratti, A and Conrad, J and Stapf, C and Krippner, J and Oeckl, P and Stoltenburg-Didinger, G and Maranzano, A and Steinacker, P and Weise, CM and Barba, L and D'Anna, L and Klafki, HW and Wiltfang, J and Silani, V and Froelich, L and Ticozzi, N and Hausner, L and Thal, DR and Weishaupt, JH and Lachmann, I and Verde, F and Otto, M},
title = {Tau isoform mapping across tissues and biofluids reveals a signature distinguishing Alzheimer's disease from amyotrophic lateral sclerosis.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42918778},
issn = {2041-1723},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism ; *tau Proteins/blood/metabolism ; *Alzheimer Disease/diagnosis/blood/metabolism ; Female ; Protein Isoforms/metabolism/blood ; Male ; Biomarkers/blood/metabolism ; Brain/metabolism ; Aged ; Phosphorylation ; Spinal Cord/metabolism ; Mass Spectrometry ; Middle Aged ; Diagnosis, Differential ; Aged, 80 and over ; Immunoprecipitation ; Case-Control Studies ; },
abstract = {Blood phosphorylated tau 217 (p-tau217) accurately detects Alzheimer's disease (AD) pathology but is also elevated in amyotrophic lateral sclerosis (ALS), likely reflecting peripheral (big) tau released from muscle. Assays selectively measuring brain-derived (BD-) tau and BD-p-tau217 are therefore needed. We analysed serum BD-tau and p-tau217 in ALS (n = 139), AD (n = 101) and controls (n = 75) using direct immunoassays and after BD-Tau immunoprecipitation (BD-Tau-IP), and tau species in brain (n = 16), spinal cord (n = 11) and muscle (n = 10) by targeted mass spectrometry. With the direct immunoassays, BD-tau and p-tau217 were increased in AD and ALS versus controls. After BD-Tau-IP, BD-tau and BD-p-tau217 were elevated in AD only, improving diagnostic accuracy. Mass spectrometry revealed a central-to-peripheral shift from BD-tau to big tau predominance, with exclusively big p-tau217 detected in muscle. Selective detection of BD-tau species improves the specificity of blood AD biomarkers by reducing peripheral tau confounding.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism
*tau Proteins/blood/metabolism
*Alzheimer Disease/diagnosis/blood/metabolism
Female
Protein Isoforms/metabolism/blood
Male
Biomarkers/blood/metabolism
Brain/metabolism
Aged
Phosphorylation
Spinal Cord/metabolism
Mass Spectrometry
Middle Aged
Diagnosis, Differential
Aged, 80 and over
Immunoprecipitation
Case-Control Studies

@article {pmid42919527,
year = {2026},
author = {Jiang, M and Ning, J and Wang, J and Hu, W and Sun, P and Zhao, N and Cao, H and Liao, M},
title = {Metabolic nontarget-site mechanism confers dual resistance to cyhalofop-butyl and imazamox in Leptochloa chinensis from China.},
journal = {Pesticide biochemistry and physiology},
volume = {224},
number = {},
pages = {107324},
doi = {10.1016/j.pestbp.2026.107324},
pmid = {42919527},
issn = {1095-9939},
mesh = {*Herbicides/pharmacology/toxicity ; *Imidazoles/pharmacology/toxicity ; *Herbicide Resistance/genetics ; *Poaceae/drug effects/genetics/metabolism ; China ; *Nitriles/pharmacology/toxicity ; *Oximes/pharmacology ; *Butanes/pharmacology ; Plant Proteins/genetics/metabolism ; },
abstract = {Chinese sprangletop (Leptochloa chinensis (L.) Nees) has emerged as a dominant grass weed in rice fields, representing a serious risk to crop productivity because of its rapidly increasing resistance to herbicides. A putative resistant population, MASHS7 (R), was collected from an imidazolinone-tolerant rice field, where it had survived applications of cyhalofop-butyl (CYB) and imazamox (IMA) at the field-recommended rates. Dose-response assays indicated that compared with the susceptible (S) population, the R population developed resistance to CYB (26.29-fold) and IMA (5.50-fold). Additionally, both the cytochrome P450 (P450) inhibitor malathion and the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially reversed the resistance of the R population to CYB and IMA. Target-site resistance mechanism analysis revealed that the R plants carried a Trp-to-Cys mutation at codon 1999 of ACCase, with no mutations in the ALS gene, and exhibited no overexpression of any target gene. Compared with the S plants, the R plants metabolized CYB, cyhalofop acid (CYA) and IMA faster. RNA sequencing analysis and quantitative real-time PCR (qPCR) validation confirmed that two P450s (CYP709B2 and CYP81Q32b) and one GST (GST4) gene were constitutively upregulated in the R plants. Molecular docking results predicted favorable binding interactions of these enzymes with CYA and IMA.},
}

*Herbicides/pharmacology/toxicity
*Imidazoles/pharmacology/toxicity
*Herbicide Resistance/genetics
*Poaceae/drug effects/genetics/metabolism
China
*Nitriles/pharmacology/toxicity
*Oximes/pharmacology
*Butanes/pharmacology
Plant Proteins/genetics/metabolism

@article {pmid42919989,
year = {2026},
author = {Rossini, E and Garibaldi, M and Hanna, MG and Pitceathly, RDS and Pizzamiglio, C},
title = {Mitochondrial dysfunction in neurology: biomarkers and clinical implications.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42919989},
issn = {1759-4766},
abstract = {Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.},
}

@article {pmid42920457,
year = {2026},
author = {Malik, A and Ferdousi, M and Azmi, S and Malik, RA},
title = {Corneal Confocal Microscopy (CCM) in Patients With Central Neurodegenerative Disease.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e116756},
pmid = {42920457},
issn = {2168-8184},
abstract = {Corneal confocal microscopy (CCM) is a rapid, non-invasive ophthalmic imaging technique that enables detailed visualization and quantification of small corneal nerve fibres. Although initially developed for the assessment of diabetic neuropathy, its application has broadened substantially, with increasing evidence supporting its value in a range of central neurodegenerative diseases. This narrative review synthesizes current findings on the use of CCM in dementia, multiple sclerosis, stroke, burning mouth syndrome, amyotrophic lateral sclerosis, trigeminal neuralgia, migraine and Parkinson's disease. Across these conditions, CCM consistently identifies measurable alterations in corneal nerve fibre density, length, branching and morphology, as well as changes in corneal immune cell populations. These structural abnormalities frequently correlate with disease severity, functional decline and clinical progression. In some disorders, CCM demonstrates diagnostic performance comparable to or exceeding existing biomarkers, and offers distinct advantages as a non-invasive, repeatable and objective measure that can detect early or subclinical neurodegeneration. Corneal confocal microscopy also shows potential as a prognostic and monitoring tool, particularly in conditions with limited reliable biomarkers. It may help stratify risk, track therapeutic response, and provide surrogate endpoints for clinical trials. Despite these strengths, several limitations remain, including modest sample sizes in some studies, variability in image interpretation, and difficulties differentiating between neurodegenerative conditions with overlapping patterns of nerve loss. Emerging automated analysis methods and artificial intelligence-based algorithms may help address these challenges by improving accuracy, reproducibility, and scalability. Overall, CCM represents a promising technique that bridges ophthalmology and neurology. A growing body of literature supports its utility across multiple neurodegenerative diseases, and further large-scale, longitudinal studies may help establish its role within routine clinical assessment and research.},
}

@article {pmid42921272,
year = {2026},
author = {He, Z and Zeng, J and Wang, G and Li, Y and Zhang, F},
title = {Neurodegenerative Diseases: Epidemiology, Risk Factors, Classification, Pathophysiology, Clinical Features, Diagnosis, and Therapeutic Strategies.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71090},
doi = {10.1002/mco2.71090},
pmid = {42921272},
issn = {2688-2663},
abstract = {Neurodegenerative diseases are a growing cause of disability worldwide, particularly as populations age. Although these disorders differ in etiology and clinical presentation, advances in genetics, neuropathology, and biomarker research have identified shared disturbances in protein homeostasis, mitochondrial function, and immune regulation. These processes may contribute to selective neuronal vulnerability and neural circuit dysfunction. These findings are refining disease classification and diagnosis, yet effective disease-modifying therapies remain limited. Disease-specific abnormalities remain essential to clinical interpretation and treatment selection. Existing reviews often focus on individual disorders or isolated mechanisms, leaving the links between shared biology and disease-specific phenotypes insufficiently clear. We synthesize evidence on the epidemiology, risk factors, classification, and pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal dementia, Friedreich's ataxia, and multiple sclerosis. We compare their clinical manifestations and diagnostic approaches, including the evolving role of biomarkers, and critically assess established and emerging therapies. By distinguishing shared mechanisms from disease-specific abnormalities, we identify key translational gaps and explore how common biological disturbances may lead to distinct clinical trajectories. This cross-disease perspective may inform diagnostic reasoning, treatment development, and future comparative research.},
}

@article {pmid42922081,
year = {2026},
author = {Adorinni, S and Grieco, I and Morasso, S and Fornasier, M and Novello, G and Salmaso, V and Martínez-González, L and Cescon, E and Bassani, D and Bassan, GA and Gianferrara, T and Prencipe, F and Kost, V and Da Ros, T and Storici, P and Martinez, A and Spalluto, G and Moro, S and Federico, S},
title = {Riluzole-Derived Benzo[d]thiazoles as CK1δ Inhibitors for Amyotrophic Lateral Sclerosis-Related Neurodegeneration.},
journal = {ChemMedChem},
volume = {21},
number = {20},
pages = {},
pmid = {42922081},
issn = {1860-7187},
support = {PRIN 20227K7YJS//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Humans ; *Riluzole/chemistry/pharmacology ; Structure-Activity Relationship ; *Casein Kinase Idelta/antagonists & inhibitors/metabolism ; *Protein Kinase Inhibitors/chemistry/pharmacology/chemical synthesis ; Animals ; *Benzothiazoles/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; *Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; Molecular Structure ; },
abstract = {Riluzole-derived benzo[d]thiazoles were investigated as metabolite-inspired CK1δ inhibitors, a kinase involved in TDP-43 phosphorylation and therefore relevant to amyotrophic lateral sclerosis (ALS). Starting from the known CK1δ activity of riluzole, we examined whether its major hydroxylamine metabolite could preserve target recognition and provide a rational entry point for scaffold optimisation. The metabolite retained CK1δ inhibition, but its limited chemical stability and toxicity in neuronal cells identified the hydroxylamine group as a critical liability. Replacement of this functionality with a hydrazine converted the fragile metabolite-derived structure into a more potent and tractable CK1δ inhibitor series. Structure-activity relationship studies revealed that the hydrazine moiety accommodates broader substitution than the hydroxylamine counterparts, with branched alkyl and benzyl groups giving the most balanced profiles. Docking and molecular dynamics suggested that the improvement could be attributed to an additional hydrogen-bond with Gly86 in the hinge region. The best derivative combined submicromolar CK1δ inhibition with passive blood-brain barrier permeability, short-term cellular tolerance, ATP competitive inhibition, direct target engagement, and preliminary selectivity over GSK3β. Although this compound did not result neuroprotective in an oxidative stress model, it paves the way for a focused benzo[d]thiazole platform for probing CK1δ biology in ALS.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
Humans
*Riluzole/chemistry/pharmacology
Structure-Activity Relationship
*Casein Kinase Idelta/antagonists & inhibitors/metabolism
*Protein Kinase Inhibitors/chemistry/pharmacology/chemical synthesis
Animals
*Benzothiazoles/chemistry/pharmacology/chemical synthesis
Molecular Docking Simulation
*Neuroprotective Agents/chemistry/pharmacology/chemical synthesis
Molecular Structure

@article {pmid42922691,
year = {2026},
author = {Grycz, K and Jan, C and Zawistowski, P and Wasicki, B and Özkan, B and Aousji, O and Sirtori, R and Fallini, C and Caron, G and Danner, SM and Roselli, F and Zytnicki, D and Bączyk, M},
title = {Defective synapto-nuclear signaling contributes to motoneuron vulnerability in SOD1-ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.01.748568},
pmid = {42922691},
issn = {2692-8205},
abstract = {Glutamatergic excitatory synapses not only shape spiking activity and neuronal communication but also initiate activity-dependent signaling pathways that trigger transcriptional programs. Since glutamatergic excitatory synapses onto spinal motoneurons (MNs) are impaired presymptomatically in Amyotrophic Lateral Sclerosis, we investigated whether synapto-nuclear coupling is disrupted in MNs from mSOD1 mice and whether restoring it mitigates pathology. We developed an in vivo approach to selectively investigate the coupling between synaptic excitation and nuclear CREB phosphorylation in spinal MNs. Specific activation of Ia-MN synapses induces CREB phosphorylation in wild-type MNs but not in mSOD1 MNs at P50, indicating presymptomatic synapto-nuclear uncoupling. Enhancing cAMP/PKA signaling by pharmacological inhibition of cAMP degradation restored synapto-nuclear coupling, reduced misfolded SOD1, and slowed neuromuscular-junction denervation. Thus, activity-dependent synapto-nuclear signaling is impaired yet pharmacologically rescuable in mSOD1 MNs, supporting synapto-nuclear signaling as a determinant of MN resilience.},
}

@article {pmid42922848,
year = {2026},
author = {Gorenshtein, A and Omar, M and Jia, E and Adiniaev, Y and Daniel, O and Kruskal, J and Ahmed, M and Brook, O and Klang, E and Barash, Y},
title = {Limits of Trial-Adaptive Neural-Language Fusion Across Large Language Models in P300 Brain-Computer Interfaces.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.30.26361777},
pmid = {42922848},
abstract = {OBJECTIVE: Published P300-speller fusion schemes fix prior trust regardless of trial reliability; we tested whether a reliability estimate improves on it.

METHODS: We reanalyzed 3,373 archived P300-speller selections from 47 people with ALS (BigP3BCI). A fair, matched-search-space comparison, tuning both a fixed weight and an adaptive policy out-of-fold, was evaluated across 22 evaluable language-model priors up to 46.7B parameters. Two representative priors, GPT-2 and a classical 5-gram, additionally received detailed naive and mechanistic analyses.

RESULTS: No prior's 95% CI favored adaptive fusion under the fair comparison, despite unexploited oracle headroom at every scale. Under GPT-2, the naive comparison was significantly worse for adaptive fusion; both anchors converged to a degenerate or near-degenerate fair-comparison solution. For the representative anchors, three further controllers failed to convert that headroom into benefit; the fixed-fused posterior's output probability outperformed the best controller for flagging errors (2.8- to 3.8-fold enrichment).

CONCLUSION: A tuned fixed weight is a difficult-to-beat default across the tested scale range; reliability estimation gave no deployable adaptive advantage.

SIGNIFICANCE: Adaptive weighting should be validated against a fairly tuned baseline across model families and scales; in this dataset, the fused output's confidence identified high-risk selections better than the tested purpose-built ranker.},
}

@article {pmid42922986,
year = {2026},
author = {Yang, SH and Han, SK and Koo, Y},
title = {CRISPR/Cas9-mediated editing of SlALS1 enhances fruit sweetness in tomato.},
journal = {Frontiers in plant science},
volume = {17},
number = {},
pages = {1927332},
pmid = {42922986},
issn = {1664-462X},
abstract = {Fruit sweetness is a primary determinant of consumer preference and market value in tomato (Solanum lycopersicum), yet increasing sugar content without negatively affecting plant performance remains a major challenge in breeding programs. In this study, we targeted Acetolactate synthase 1 (SlALS1), a key enzyme in branched-chain amino acids (BCAAs) biosynthesis, to investigate whether modulation of primary metabolism could enhance fruit sugar accumulation. Tomato contains two ALS homologs, SlALS1 and SlALS2. Using CRISPR/Cas9-mediated genome editing, we generated SlALS1 knock-out lines in the Micro-Tom background. Loss of SlALS1 function led to a significant reduction in the levels of valine, leucine, and isoleucine in fruit tissues, confirming disruption of the BCAA biosynthetic pathway. Notably, soluble sugar content was markedly increased in the mutant lines, with glucose and fructose levels elevated by approximately 1.3-fold compared with wild-type fruits, resulting in a significantly higher Brix index. Metabolic profiling indicates that reduced BCAA biosynthesis may influence carbon allocation toward soluble sugar accumulation in fruit tissues, revealing an association between amino acid metabolism and carbohydrate accumulation during fruit development. Our findings demonstrate that precise editing of a central metabolic enzyme can enhance tomato fruit sweetness and suggest that SlALS1 may represent a promising target for genome editing aimed at improving fruit quality traits. However, further evaluation of agronomic traits, including plant growth and fruit yield, will be necessary to assess its potential for practical breeding applications.},
}

@article {pmid42923269,
year = {2026},
author = {Shen, C and Wu, XT and Yin, H and Zuo, JL and Zhang, CH and Cao, F and Zhang, Y and Tian, ZY and Robinson, N and Liu, JP},
title = {Selected traditional Chinese medicines for treating amyotrophic lateral sclerosis: a Bayesian network meta-analysis based on randomised controlled trials.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1706211},
pmid = {42923269},
issn = {1663-9812},
abstract = {OBJECTIVE: To assess the effectiveness of specific Traditional Chinese Medicine (TCM) therapies for Amyotrophic Lateral Sclerosis (ALS) using Bayesian network meta-analysis.

METHODS: PubMed, the Cochrane Library, EMBASE, Web of Science, and four Chinese databases up to 15th December 2024 was searched, including RCTs on adult Amyotrophic Lateral Sclerosis patients treated with TCM therapies (Chinese herbal medicine, preparations, non-pharmacological treatments) alone or combined with conventional treatments. Controls included no intervention, placebo, conventional treatments, or combinations. Primary outcomes were functional status (ALSFRS, ALSFRS-R, AALSS, m-Norris scales). Bayesian network meta-analysis compared treatment effects and calculated SUCRA values.

RESULTS: Thirty-five RCTs involving 27 TCM therapies were included. No significant differences in functional status or quality of life were found among TCM therapies, ICT, Riluzole alone, and Riluzole plus placebo. For functional status, Shenmai injection + ICT (SUCRA 0.735 for ALSFRS, 0.870 for ALSFRS-R), Jiweiling injection + placebo (SUCRA 0.868 for ALSFRS), Jiawei Sijunzi decoction alone (SUCRA 0.739 for ALSFRS-R), Acupuncture + rehabilitation exercises + Riluzole (SUCRA 0.928 for AALSS, 0.863 for m-Norris) and Shenzhe Jiangqi powder + placebo (SUCRA 0.860 for m-Norris) had the highest probabilities of being superior treatment. For quality of life, Thunder fire moxibustion + Riluzole and Jiweiling injection + placebo for ALSAQ-40 were favorable.

CONCLUSION: Despite no significant differences in functional status among TCM therapies, ICT, Riluzole alone, and Riluzole plus placebo, Jiweiling injection, Shenmai injection, Jiawei Sijunzi decoction, and Shenzhe Jiangqi powder may be regarded as candidate preparations for ALS patients. Future research should focus on real-world data to explore long-term effects and practical benefits.

https://inplasy.com/inplasy-2024-8-0050/, identifier INPLASY202480050.},
}

@article {pmid42924413,
year = {2026},
author = {Vornetti, G and Punzetti, F and Vacchiano, V and Rochat, MJ and Cantoni, E and Rizzo, G and D'Angeli, D and Morandi, L and Manners, DN and Liguori, R and Lodi, R and Tonon, C},
title = {Cerebellar involvement in sporadic amyotrophic lateral sclerosis: a magnetic resonance spectroscopy study.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag382},
pmid = {42924413},
issn = {2632-1297},
abstract = {Amyotrophic lateral sclerosis is increasingly recognized as a multisystem neurodegenerative disorder, and recent evidence suggests that the cerebellum may contribute to disease pathology, although cerebellar metabolic alterations have not previously been demonstrated in vivo. This study investigated cerebellar metabolic and structural changes using proton magnetic resonance spectroscopy ([1]H-MRS) and volumetric imaging. Thirty patients with amyotrophic lateral sclerosis (21 M, mean age 59.7 ± 7.6 years), 22 healthy controls (HC, 10 M, mean age 59.8 ± 9.6 years) and 16 individuals with hereditary spastic paraplegia type 4 (8 M, mean age 50.8 ± 12.5 years), a potential clinical mimic, underwent 3T MRI and [1]H-MRS with a single-voxel positioned in the left cerebellar hemisphere. Patients with amyotrophic lateral sclerosis showed significant reductions in myo-inositol/creatinine (P = 0.01) and glutathione/creatinine (P = 0.005), compared with HC, together with selective volume loss in cerebellar lobules I-IV, V, VI, and Crus I. Among metabolites, glutathione/creatinine had the highest discriminative accuracy for amyotrophic lateral sclerosis versus both HC and spastic paraplegia type 4, with areas under the curve of 0.80 and 0.71, respectively. These findings reveal distinct cerebellar metabolic alterations in amyotrophic lateral sclerosis, providing further evidence for cerebellar involvement in disease pathology and highlighting cerebellar [1]H-MRS as a potential adjunct to diagnostic evaluation.},
}

@article {pmid42906263,
year = {2026},
author = {Hawas, Y and Abo-Elnour, DE and Al-Hawari, NEM and Gahlan, S and Winkelman, JW},
title = {Restless legs syndrome and other neurological disorders: A systematic-narrative hybrid literature review with exploratory meta-analysis.},
journal = {Sleep medicine reviews},
volume = {90},
number = {},
pages = {102390},
doi = {10.1016/j.smrv.2026.102390},
pmid = {42906263},
issn = {1532-2955},
abstract = {Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder affecting approximately 3% of adults worldwide. This review aims to synthesize current evidence on associations between RLS and major neurological conditions, provide an exploratory quantitative synthesis summarizing association patterns and heterogeneity, and identify priority mechanistic and clinical research gaps. Databases were searched from inception until August 2026. In our exploratory synthesis of 119 unique studies, RLS was significantly associated with Parkinson's disease (case-control OR 3.22, 95% CI 2.35-4.41; cohort RR 1.74, 95% CI 1.02-2.95), multiple sclerosis (OR 4.04, 95% CI 3.26-5.00), neuromyelitis optica spectrum disorder (OR 2.91, 95% CI 1.45-5.84), migraine or headache disorders (forward OR 2.72, 95% CI 2.19-3.38; reverse adjusted OR 1.53, 95% CI 1.36-1.73), peripheral neuropathy (OR 3.82, 95% CI 2.49-5.83), epilepsy (OR 2.11, 95% CI 1.58-2.82), and amyotrophic lateral sclerosis (OR 7.69, 95% CI 2.74-21.59). This work is an evidence-mapping review with exploratory pooling and is not intended as a definitive evidence synthesis. RLS is likely associated with neurodegenerative and other specific neurological conditions. Recognition of these associations may support earlier identification of comorbid conditions and targeted management strategies. However, the current evidence remains observational and heterogeneous.},
}

@article {pmid42907506,
year = {2026},
author = {Lee, HJ and Doğan, C and Koyuncu, S and Wehrmann, M and Artan, M and Petrovic, D and Loureiro, R and Sahu, AK and Schnubel, J and Grobushkin, P and Prymidis, D and Georgomanolis, T and Sokol, A and Yang, M and Hoppe, T and Frezza, C and Vilchez, D},
title = {Cold activates a BH2 metabolic network promoting longevity and proteostasis.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42907506},
issn = {1476-4687},
abstract = {Moderately cold temperatures extend lifespan and promote health across species[1-3], yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans. Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4). BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2-BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal tissues, even at normal or elevated temperatures. In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington's disease, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.},
}

@article {pmid42908777,
year = {2026},
author = {Wang, M and Mak, C and Li, X and Li, S and Cui, C and Cai, D and Liang, Z and Lu, T and Jia, Q and Shao, X and Ma, Y and Fan, G and Li, K and Mai, W and Mak, C and Liu, N},
title = {Case Report: Herbal nutritional intervention in a critically ill ALS patient with multidrug-resistant infection.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1912856},
pmid = {42908777},
issn = {2296-858X},
abstract = {We report a retrospective single case of a female patient with a 9-year history of amyotrophic lateral sclerosis (ALS) who presented with respiratory failure due to a multidrug-resistant organism (MDRO) infection, predominantly Klebsiella pneumoniae (KP), and who showed significant clinical improvement during a comprehensive treatment regimen that included an adjunctive herbal nutritional intervention. The objective of this retrospective single-case report was to describe the clinical course of this patient following a nutritional intervention with two herbal beverages: Sang Shen Pu Gong Ying (SSPGY) and Wu Zhi Mao Tao Hong Zao (WZMTHZ). The patient was admitted in critical condition and managed in three phases: initial antibiotics with occasional herbal beverages, daily herbal beverages, and a combination of herbal beverages with intermittent antibiotics. Retrospective analysis of clinical data revealed significant improvements post-intervention. Body weight increased from 26 kg to 35.5 kg at discharge and 39 kg at the 6-week follow-up. Vital signs normalized, with no detectable KP in the final hospital phase. Inflammatory markers, including C-reactive protein and white blood cell count, decreased markedly. Neurological status, as indicated by neurofilament light chain (NfL) levels, improved, and the patient showed respiratory autonomy and positional changes. Nutritional markers, total protein and creatinine, also improved. This case documents clinical improvements, including extended ventilator-free breathing periods, in an ALS patient with MDRO infection following a combined therapeutic approach. Although concurrent medical interventions were administered in real-world clinical practice, these findings suggest the potential value of this adjunctive intervention, warranting further systematic investigation. Clinical Trial Registration: identifier ITMCTR2024000322.},
}

@article {pmid42913489,
year = {2026},
author = {Huang, J and Zhang, S and Zhang, D and Yang, T and Li, C and He, M and Wang, J and Song, T and Wang, X and Lu, Y and Kong, Q and Tan, J and Zhang, J},
title = {Liquid-liquid phase separation in neurodegenerative diseases: Mechanisms, pathological transitions, and therapeutic opportunities.},
journal = {Science progress},
volume = {109},
number = {4},
pages = {368504261499190},
doi = {10.1177/00368504261499190},
pmid = {42913489},
issn = {2047-7163},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/genetics/therapy ; Phase Separation ; Animals ; Protein Aggregation, Pathological/metabolism ; Amyloid beta-Peptides/metabolism/chemistry/genetics ; DNA-Binding Proteins/metabolism/genetics ; Huntingtin Protein/genetics/metabolism ; tau Proteins/metabolism/genetics/chemistry ; alpha-Synuclein/metabolism/genetics/chemistry ; RNA-Binding Protein FUS/metabolism/genetics ; Biomolecular Condensates/metabolism ; },
abstract = {Liquid-liquid phase separation (LLPS) provides a biophysical framework for understanding biomolecular organization, yet its pathological relevance in neurodegeneration remains incompletely resolved. In this narrative review, we critically synthesize current evidence on LLPS in Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, focusing on mutant huntingtin, α-synuclein, amyloid-β, tau, TDP-43, and FUS. We first outline the molecular principles-including intrinsic disorder, multivalent interactions, and environmental sensitivity-that govern their phase behavior. We then examine how dynamic condensates may, under specific cellular contexts, transition toward less reversible oligomeric, gel-like, or solid assemblies, integrating evidence from in vitro, cellular, and in vivo studies. Importantly, current evidence does not support LLPS as a universal or obligatory precursor of pathological aggregation; rather, its biological consequences appear to depend on condensate composition, material properties, subcellular localization, and proteostasis capacity, while direct demonstration of disease-relevant condensates in vivo remains limited. We further discuss whether aberrant LLPS represents a cause, consequence, or context-dependent component of neurodegeneration and highlight emerging strategies that modulate condensate formation, maturation, or clearance while preserving physiological functions. Overall, this review defines both the mechanistic potential and current limitations of the LLPS framework and identifies key questions that must be addressed before pathological phase-state modulation can become a clinically actionable therapeutic strategy.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology/genetics/therapy
Phase Separation
Animals
Protein Aggregation, Pathological/metabolism
Amyloid beta-Peptides/metabolism/chemistry/genetics
DNA-Binding Proteins/metabolism/genetics
Huntingtin Protein/genetics/metabolism
tau Proteins/metabolism/genetics/chemistry
alpha-Synuclein/metabolism/genetics/chemistry
RNA-Binding Protein FUS/metabolism/genetics
Biomolecular Condensates/metabolism

@article {pmid42913510,
year = {2026},
author = {},
title = {Proceedings of the 25[th] Annual Meeting of the Northeast ALS Consortium.},
journal = {Muscle & nerve},
volume = {74 Suppl 2},
number = {},
pages = {S1-S112},
doi = {10.1002/mus.70436},
pmid = {42913510},
issn = {1097-4598},
}

@article {pmid42915077,
year = {2026},
author = {Ritchie, LM and Lester, MB and Sharma, AK and Patterson, JD},
title = {Quantified Interfacial Affinity of Hydrogen Sulfate and Sulfate Speciation in Model Marine Aerosol Particles.},
journal = {The journal of physical chemistry. A},
volume = {130},
number = {37},
pages = {7460-7468},
doi = {10.1021/acs.jpca.6c04034},
pmid = {42915077},
issn = {1520-5215},
support = {CHE-1708635//National Science Foundation/ ; CHE-2404123//National Science Foundation/ ; CHE-2404124//National Science Foundation/ ; },
abstract = {Heterogeneous reactions occurring in atmospheric aerosols are crucial components of multiple chemical reaction cycles. Sulfate species exert substantial influence on many heterogeneous reaction mechanisms due to their abundance and speciation. Despite the importance of sulfate species on heterogeneous reactions, quantitative descriptions of interfacial affinity and sulfate species partitioning at interfaces remain incomplete. Here, we quantify the interfacial properties of HSO4-, using cetyltrimethylammonium hydrogen sulfate (CTAHS) reverse micelles (RMs), as model marine aerosol particles. Infrared spectra (IR) of CTAHS RMs were collected and analyzed using multivariate curve resolution-alternating least-squares (MCR-ALS). MCR-ALS analysis reveals that four distinct species contribute to the observed IR spectra, which we assign as CTA+-HSO4- contact pairs (CPs), interfacial HSO4-, core HSO4-, and core SO42-. Computational studies reveal that the CTA+-HSO4- CPs exist in two distinct orientations at the interface. Spectral contributions from each chemical species are used to determine the quantitative interfacial affinity (χInt.) of HSO4-. Our observations indicate that the cationic charge of the interface alters the ionic distribution of sulfate species compared to air-water interfaces, placing H3O+ below HSO4-.},
}

@article {pmid42916114,
year = {2026},
author = {Milardi, D and Han, J and Lee, HJ and Ding, F and Miller, Y and Faller, P and Bush, AI and Crouch, PJ and Finkelstein, DI and Double, KL and Jeremic, A and Lim, MH and Ramamoorthy, A},
title = {Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies.},
journal = {Chemical reviews},
volume = {126},
number = {18},
pages = {10249-10333},
doi = {10.1021/acs.chemrev.5c00420},
pmid = {42916114},
issn = {1520-6890},
support = {R01AG048934/AG/NIA NIH HHS/United States ; R35GM13973/GM/NIGMS NIH HHS/United States ; R35GM145409/GM/NIGMS NIH HHS/United States ; R01DK132214/DK/NIDDK NIH HHS/United States ; NA//Florida State University/ ; NA//National High Magnetic Field Laboratory/ ; 2022PAAYZE//NextGenerationEU/ ; CUP: B53D23016440006//NextGenerationEU/ ; DP230101031//Australian Research Council/ ; GNT1194028//National Health and Medical Research Council/ ; GNT2019931//National Health and Medical Research Council/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2022-NR073879//National Research Foundation of Korea/ ; RS-2024-00353015//National Research Foundation of Korea/ ; RS-2024-00411134//National Research Foundation of Korea/ ; MRF2007656//Medical Research Future Fund/ ; },
mesh = {Humans ; *Protein Aggregation, Pathological/metabolism/drug therapy ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Metals/chemistry/metabolism ; Animals ; Protein Aggregates ; },
abstract = {Protein aggregation is a pathological process associated with several human diseases termed proteinopathies, including neurodegenerative and metabolic disorders such as Alzheimer's disease, Parkinson's disease, type II diabetes, amyotrophic lateral sclerosis, and Huntington's disease. In these conditions, specific proteins misfold and accumulate into insoluble aggregates, disrupting normal cellular function and contributing to disease progression. Many studies have investigated the molecular mechanisms that underlie the aggregation pathways, the structure of aggregates, such as oligomeric intermediates and fibrils, and their cellular toxicity. Studies have also investigated the effects of cofactors like metals, lipids, other amyloid proteins, and small molecules. Recent research has increasingly emphasized the critical roles of metal ions such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) in amyloid aggregation and toxicity. Alterations in metal ion transport, binding, or redox activity have been linked to the onset and progression of several amyloid-associated diseases. These metal ions can interact directly with amyloidogenic proteins, influencing their structural conformation, aggregation kinetics, and propensity to form toxic oligomers. This review aims to advance our understanding of how the regulation of metal ions within cells and their dysfunction contribute to the accumulation of harmful proteins, which is a key factor in proteinopathies. By examining the interactions between metal ions and key amyloidogenic proteins─including amyloid-β (Aβ), α-synuclein, tau, superoxide dismutase 1 (SOD1), human islet amyloid polypeptide (hIAPP), and insulin─we highlight both common and unique pathways through which metal ions influence protein aggregation. Additionally, this review explores the impact of metal ions on protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, as well as emerging theranostic strategies. These include metal chelation therapies, metal-based imaging agents, and multifunctional compounds designed to restore metal balance while preventing aggregation and toxicity. By integrating biochemical, cellular, and therapeutic insights, this review contributes to a deeper understanding of the metallobiology of proteinopathies and supports the development of novel diagnostic and treatment approaches targeting metal-protein interactions.},
}

Humans
*Protein Aggregation, Pathological/metabolism/drug therapy
*Neurodegenerative Diseases/metabolism/drug therapy
*Metals/chemistry/metabolism
Animals
Protein Aggregates

@article {pmid42918320,
year = {2026},
author = {Nasb, M and Yang, D and Malik, TH and Xu, D and Dayoub, L and Zhou, J and Zhao, Y},
title = {State transitions in amyotrophic lateral sclerosis: mechanistic convergence and biomarker-guided stratification.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.036},
pmid = {42918320},
issn = {1873-7544},
abstract = {BACKGROUND: Biological heterogeneity is a major obstacle to therapeutic development in amyotrophic lateral sclerosis (ALS). Cross-sectional pathway labels do not show whether a mechanism is active or treatment-relevant in an individual patient.

METHODS: We conducted a structured critical narrative review informed by the Scale for the Assessment of Narrative Review Articles. MEDLINE, Embase, PubMed, and CENTRAL were searched for English-language literature published from 1 January 2015 to 7 August 2026; seminal earlier studies were identified by citation tracking. Human genetic, pathological, longitudinal biomarker, multi-omic, imaging, neurophysiological, and interventional evidence was prioritized. Evidence was appraised by human proximity, temporality, replication, mechanistic specificity, and treatment relevance.

RESULTS: Evidence supports interacting RNA/proteostasis, nucleocytoplasmic-transport, glial-inflammatory, and energetic-metabolic processes, but current evidence does not yet support the use of any candidate state for individual treatment assignment. The most mature temporal example is loss of TDP-43 splicing repression before neurofilament elevation in genetically at-risk individuals. Nucleocytoplasmic-transport evidence is strongest in C9orf72 disease; inflammatory and metabolic signals are confounded by disease burden and systemic illness; and the gut-brain axis remains a context-dependent amplifier. We propose prespecified transition rules, evidence grades, and biomarker-by-treatment interaction tests.

CONCLUSIONS: A state-transition model becomes clinically useful when longitudinal measurements add value beyond clinical predictors and injury markers and prospectively identify differential treatment benefit.},
}

@article {pmid42918387,
year = {2026},
author = {Verma, A and Goyal, A and Agrawal, N and Yadav, HN},
title = {Cellular senescence in ageing and neurodegenerative disorders: Molecular mechanisms, biomarkers, and therapeutic strategies.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111985},
doi = {10.1016/j.pnpbp.2026.111985},
pmid = {42918387},
issn = {1878-4216},
abstract = {Cellular senescence has been increasingly associated with neurodegenerative disorders, potentially linking ageing-related cellular impairment with mitochondrial dysfunction, chronic inflammation, and disrupted intercellular signalling. The present study aims to explore the increasing relevance of cellular senescence among key cell types, including neurons, astrocytes, neural progenitor cells, microglia and oligodendrocyte-lineage cells across neurodegenerative ailments such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. This review discusses the findings of pre-clinical and clinical studies which suggest that senescence-associated features may contribute to neurodegeneration. Further, it provides an overview of the biomarkers used in the identification of senescence in the CNS. Also, the review examines senotherapeutic treatment approaches, highlighting their actions on different CNS cell types and the growing clinical evidence. It also points out the challenges in translating these approaches to clinical application, such as targeting specific cell types and the lack of suitable biomarkers. Collectively, present findings suggest that senescence-associated alterations may contribute to neurodegeneration, although their effects appear to vary across cell types and diseases.},
}

@article {pmid42918426,
year = {2026},
author = {Kipanyula, MJ},
title = {Neurodegeneration in Sub-Saharan Africa: Intersections of Biological Ageing, Genomic Diversity and the Lifetime Exposome.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103429},
doi = {10.1016/j.arr.2026.103429},
pmid = {42918426},
issn = {1872-9649},
abstract = {Neurodegenerative diseases are emerging as an important consequence of population ageing in sub-Saharan Africa (SSA), but their scientific relevance extends beyond a projected rise in case numbers. SSA combines exceptional human genomic diversity with marked heterogeneity in vascular and metabolic risk, infection, nutrition, occupational exposures, air pollution, and access to health care. This combination creates an underused setting in which to study why biological ageing produces neurodegeneration in some individuals but relative resilience in others. This review critically synthesises evidence on Alzheimer's disease and related dementias, Parkinson's disease, amyotrophic lateral sclerosis/frontotemporal degeneration, Huntington's disease and related disorders, focusing on the intersection between hallmarks of ageing, disease-specific proteinopathies, ancestry and the lifetime exposome. Age-associated loss of proteostasis, mitochondrial dysfunction, impaired autophagy, chronic inflammation, neurovascular injury and genomic/epigenomic instability provide a mechanistic scaffold on which genetic susceptibility and cumulative exposures may act. Yet African evidence remains dominated by cross-sectional clinical phenotyping; neuropathology, longitudinal biomarkers, multi-omics and measured environmental exposures remain sparse. Recent African-ancestry Parkinson's disease genomics and emerging plasma biomarker studies demonstrate that ancestry-inclusive molecular neuroscience is feasible and can generate findings not predictable from European-ancestry datasets. The next phase should therefore move beyond documenting underdiagnosis toward longitudinal, biologically anchored cohorts that integrate phenotype, genomics, blood biomarkers, neuroimaging, exposomics, digital measures and health-system outcomes. This review proposes a research framework centred on biological ageing, gene-environment interaction and resilience. Such work would improve the validity of prevention, diagnosis and therapeutic translation in African populations while contributing globally to a more complete biology of neurodegenerative ageing.},
}

@article {pmid42902402,
year = {2026},
author = {Ufer, F and Rössling, R and Spottke, A and Németh, R and Schaprian, T and Coninck, NK and Gamez, A and Sterl, R and Naumann, P and Behr, N and Maier, A and Meyer, T and Weydt, P and Prüss, H},
title = {ABCD-Trial: study protocol for a randomized, double-blind, placebo-controlled study in patients with Amyotrophic lateral sclerosis for the evaluation of efficacy and safety of B-Cell Depletion with rituximab (ABCD).},
journal = {Trials},
volume = {27},
number = {1},
pages = {},
pmid = {42902402},
issn = {1745-6215},
mesh = {Humans ; *Rituximab/therapeutic use/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology/diagnosis ; Double-Blind Method ; *B-Lymphocytes/drug effects/immunology ; Male ; Treatment Outcome ; Female ; Randomized Controlled Trials as Topic ; Disease Progression ; *Lymphocyte Depletion/methods/adverse effects ; *Immunologic Factors/adverse effects/therapeutic use ; Time Factors ; Middle Aged ; },
abstract = {BACKGROUND: The exact disease-causing mechanisms in ALS remain incompletely understood. A possible cause is inflammation of neurons. Compared to other neurodegenerative diseases, neuroinflammation is pronounced in ALS, presumably leading to disease progression and neuronal death. Patients with ALS can have neuronal autoantibodies and most notably antibody-producing cells in the cerebrospinal fluid. The CD20-binding therapeutic antibody rituximab targets these antibody-producing B-cells. Rituximab is a medication commonly used in neurology. Single patients with ALS have already been treated with rituximab, which was well tolerated. We therefore want to evaluate safety and efficacy of a treatment with rituximab in ALS patients in a double-blind placebo-controlled trial. With this trial we aim for slower disease progression and unveiling disease-causing mechanisms in ALS.

METHODS: A total of 52 male and female patients older than 18 years with active sporadic ALS and disease duration of less than 24 months who are on a stable dose of riluzole (50 mg BID) should be included. Patients requiring assisted ventilation of any kind or have a known intolerance to the study medication rituximab are excluded. The study medication rituximab or placebo should be administered over a period of 52 weeks at 4 distinct time points, followed by a follow-up period of 79 weeks with 4 visits. Treatment efficacy should be evaluated using the ALS functioning scale ALSFRS-R-SE at every study visit (except safety visits). Safety will be assessed through regular laboratory analyses, adverse event (AE) and serious adverse event (SAE) monitoring, and CD20+ B-cell kinetics. The primary endpoint is the change in the ALS Functional Rating Scale-Revised (ALSFRS-R-SE) from baseline to week 79. Trial sites will be at Charité/DZNE Berlin and DZNE Bonn.

DISCUSSION: ALS is a rapidly progressive neurodegenerative disease with limited treatment options. Recent preclinical in vivo studies suggest that B-cell-mediated autoimmunity contributes to disease progression. This trial will evaluate whether rituximab, which specifically depletes CD20+ B-cells, can slow ALS progression and provide insights into disease mechanisms.

TRIAL REGISTRATION: The trial was registered in the German WHO-recognized primary register Deutsches Register Klinische Studien DRKS (German Clinical Trials Register) on 3/07/2023 under registration number DRKS00030948.},
}

Humans
*Rituximab/therapeutic use/adverse effects
*Amyotrophic Lateral Sclerosis/drug therapy/immunology/diagnosis
Double-Blind Method
*B-Lymphocytes/drug effects/immunology
Male
Treatment Outcome
Female
Randomized Controlled Trials as Topic
Disease Progression
*Lymphocyte Depletion/methods/adverse effects
*Immunologic Factors/adverse effects/therapeutic use
Time Factors
Middle Aged

@article {pmid42902541,
year = {2026},
author = {Purvis, C and Patterson, EL and Burns, EE},
title = {Characterizing geographic diversity of acetolactate synthase resistance in US johnsongrass (Sorghum halepense) biotypes.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71430},
pmid = {42902541},
issn = {1526-4998},
support = {//United Soybean Board/ ; },
abstract = {BACKGROUND: Acetolactate synthase (ALS)-inhibiting herbicides are widely used for Sorghum halepense weed control across agroecosystems. However, little is known about variation in resistance phenotypes and mechanisms among geographically diverse biotypes. This study surveyed S. halepense biotypes collected across the USA to quantify resistance to ALS inhibitors, identify target and non-target site mechanisms, and evaluate alternative herbicide options.

RESULTS: Dose response assays identified nicosulfuron resistance in 24% of evaluated biotypes, with resistant biotypes ED50 ranging from 66 to >4160 g ha[-1]. Among nicosulfuron resistant biotypes, 56% and 44% were also resistant to imazethapyr and thiencarbazone, respectively, demonstrating variability in resistance patterns among ALS herbicides of different chemical families. A novel primer set enabled simultaneous screening of all reported ALS resistance mutations across both ALS homeologs. Molecular screening identified the Trp574 substitution as the sole target-site resistance mechanism in 64% of resistant biotypes. Further, Trp574 mutation frequency varied among resistant biotypes, ranging from 21% to 91%, and was positively correlated with nicosulfuron resistance level. Resistant biotypes lacking target-site mutations exhibited over eightfold reductions in nicosulfuron ED50 following malathion pretreatment, suggesting involvement of cytochrome P450 non-target site resistance mechanisms. Despite the identification of these mechanisms, glyphosate and clethodim remained effective for S. halepense control in all but one biotype.

CONCLUSION: Overall, we demonstrated that ALS resistance in S. halepense varies across geographically diverse biotypes from the USA. Together, these findings provide important insight for resistance evolution and support development of management strategies for ALS resistant S. halepense biotypes. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid42904191,
year = {2026},
author = {Quy, K and Doan, AT and Vu, TM and Nguyen, TM and Nguyen, D},
title = {Lower Motor Neuron Disease Misclassified As Inflammatory Myopathy in a Young Woman With Myositis-Specific Antibodies.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e116583},
pmid = {42904191},
issn = {2168-8184},
abstract = {A 30-year-old woman presented with slowly progressive neck and proximal limb weakness over three years. Initial evaluation showed moderate creatine kinase elevation, anti-Mi-2β and anti-glycyl-tRNA synthetase (EJ) positivity, and electrophysiological and muscle biopsy findings interpreted as inflammatory myopathy. She was diagnosed with polymyositis and received multiple immunosuppressive therapies without clinical improvement. Despite normalization of creatine kinase, weakness and muscle wasting progressed. Re-evaluation revealed profound generalized atrophy, hyporeflexia, widespread limb and tongue fasciculations, and preserved sensation. Nerve conduction studies showed markedly reduced motor amplitudes with relative preservation of sensory responses, while repeat muscle biopsy demonstrated severe chronic neurogenic atrophy. Genetic testing identified a heterozygous FIG4 p.Arg197Cys variant of uncertain significance. Lower motor neuron dysfunction was demonstrated in multiple anatomical regions, and the overall clinical and electrophysiological findings were consistent with the Gold Coast diagnostic framework for amyotrophic lateral sclerosis with a lower-motor-neuron-predominant phenotype. Immunosuppression was withdrawn, weakness continued to progress, and mechanical ventilation was required approximately six months later. This case highlights the need to reconsider the diagnosis when presumed inflammatory myopathy progresses despite biochemical improvement and adequate immunosuppressive therapy, particularly when neurogenic features emerge.},
}

@article {pmid42904327,
year = {2026},
author = {Paquet, A and Touzel-Deschênes, L and Roy, V and Brisson, JD and Mathieu, J and Dupré, N and Saikali, S and Gros-Louis, F},
title = {Cytoplasmic TDP-43 Accumulation in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-7},
doi = {10.1017/cjn.2026.10695},
pmid = {42904327},
issn = {0317-1671},
abstract = {BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare, early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity and peripheral neuropathy. It is caused by biallelic mutations in the SACS gene, which encodes sacsin, a large protein involved in cytoskeletal organization and mitochondrial homeostasis, and protein quality control. Despite advances in understanding sacsin biology, the molecular mechanisms underlying neurodegeneration in ARSACS remain incompletely understood. Here, we report the first neuropathological evidence of pathological TAR DNA-binding protein 43 (TDP-43) accumulation in ARSACS.

METHODS: Available postmortem brain tissue from a genetically confirmed ARSACS patient homozygous for the Quebec founder mutation (SACS c.8844delT) was analyzed by immunohistochemistry, immunofluorescence and biochemical fractionation.

RESULTS: Neurons in the prefrontal cortex, motor cortex and cerebellum exhibited cytoplasmic phosphorylated dot-like TDP-43 (pTDP-43) aggregates with reduced nuclear localization. Biochemical fractionation further identified detergent-insoluble TDP-43 species in ARSACS tissue. Additional pathological features included increased neurofilament accumulation, vacuole-like neuronal changes, Purkinje cell loss and p62-positive cytoplasmic inclusions. Similar dot-like cytoplasmic pTDP-43 aggregates were observed in a second ARSACS case.

CONCLUSION: These findings identify pTDP-43 as a previously unrecognized pathological feature of ARSACS. While the patient exhibited no clinical or histopathological signs of amyotrophic lateral sclerosis, the presence of atypical pTDP-43 aggregates observed in ARSACS may represent a rare, secondary, early-stage or potentially underrecognized manifestation of TDP-43 pathology rather than a defining hallmark of the disease. Further studies in additional patients and experimental ARSACS models will be required to determine the prevalence and mechanistic basis of TDP-43 abnormalities in this disorder.},
}

@article {pmid42904407,
year = {2026},
author = {Dalkvist, M and Ersson, K and Bergström, S and Ekström, M and Emilsson, ÖI and Grote, L and Ingre, C and Kläppe, U and Lundström, S and Nygren, I and Sundh, J and Palm, A},
title = {End-of-life care of patients with amyotrophic lateral sclerosis and home mechanical ventilation: the national population-based DISCOVERY study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2026.2747563},
pmid = {42904407},
issn = {2167-9223},
abstract = {Background: Home mechanical ventilation (HMV), including noninvasive ventilation (NIV) and invasive ventilation (IV), is increasingly used in people with amyotrophic lateral sclerosis (pwALS), but its impact on end-of-life care remains unclear. Objective: To examine whether ventilation pathway (NIV or IV) influences symptom prevalence and relief during the final week of life in pwALS. Secondary objectives were to assess end-of-life discussions, place and cause of death, and anticipated death. Methods: This national, population-based retrospective cohort study included pwALS using HMV in the Swedish National Quality Registry for Respiratory Failure (Swedevox), cross-linked with the Swedish Register of Palliative Care, which contains staff-reported end-of-life data, and other national registries. Results: Among 652 pwALS, 609 received NIV (mean age 66 years, 42% female) and 43 IV (mean age 60 years, 42% female). Anxiety and breathlessness were more common in the NIV group (76% vs 48% and 72% vs 31%, both p < 0.001), while prevalence and relief of other symptoms were similar between groups. Most patients had end-of-life discussions (NIV 87%, IV 92%). NIV patients more often died in specialized palliative wards (22% vs 7%, p = 0.023). Most deaths were due to ALS (96%) and were anticipated (NIV 94%, IV 88%). Conclusions: In pwALS with HVM, NIV was associated with higher rates of anxiety and breathlessness in the final week of life, but the ventilation pathway did not influence overall symptom relief. End-of-life communications and cause of death were similar; place of death differed by ventilation pathway; however, most deaths were anticipated.},
}

@article {pmid42904859,
year = {2026},
author = {Zhang, L and Zhang, L and Zheng, Y and Zhuang, Z and Tang, L and Zheng, W and Xia, K and Ye, S and Yin, T and Huang, T and Fan, D},
title = {Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {5},
pages = {e70410},
doi = {10.1002/jcsm.70410},
pmid = {42904859},
issn = {2190-6009},
support = {82101490//National Natural Science Foundation of China/ ; 81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; //National Clinical Key Specialty Construction Program of China (2024)/ ; //Peking University Clinical Scientist Training Program/ ; 20250824//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; *Adiposity/genetics ; Female ; *Lipidomics/methods ; Genetic Risk Score ; Male ; Middle Aged ; Genetic Predisposition to Disease ; *Lipids/blood ; Lipid Metabolism ; Aged ; Risk Factors ; Biomarkers ; *Multifactorial Inheritance ; },
abstract = {OBJECTIVE: Although both pre-symptomatic adiposity and dysregulated lipid metabolism are implicated in amyotrophic lateral sclerosis (ALS), the mechanistic pathways linking adiposity to disease remain unclear. This study aimed to investigate how genetic predisposition to adiposity might influence ALS through specific lipid metabolic pathways.

METHODS: We conducted mass spectrometry-based quantitative lipidomics on plasma from 104 ALS patients and 78 age- and sex-matched controls. Life-course adiposity polygenic risk scores (PRS) for birth weight, body fat percentage, appendicular lean mass and whole-body fat-free mass were constructed. Associations and PRS-by-disease interaction effects on the lipidome were evaluated.

RESULTS: Compared to controls, ALS patients exhibited widespread lipid dysregulation. Seventy-eight lipid species were significantly altered (FDR  < 0.05, |Cohen's d| > 1.0), characterized by a predominant decrease in acylcarnitines (75% of species) and distinct shifts within sphingolipid and glycerophospholipid subclasses. A three-acylcarnitine candidate panel (C10:0, C12:0 and C18:2) using fivefold analysis with feature selection repeated within each training fold yielded an overall out-of-fold AUC of 0.958. Exploratory PRS-by-disease-status analyses identified 16 nominal interaction signals, including 13 acylcarnitines; no significant mediation effect of lipids between PRS and ALS risk was detected.

CONCLUSION: These findings identify robust ALS-associated plasma lipid alterations, and our exploratory findings suggest that genetic predisposition to adiposity may shape the pattern of lipid metabolic disruption in ALS, offering new insights into the disease's metabolic pathophysiology.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood/genetics
*Adiposity/genetics
Female
*Lipidomics/methods
Genetic Risk Score
Male
Middle Aged
Genetic Predisposition to Disease
*Lipids/blood
Lipid Metabolism
Aged
Risk Factors
Biomarkers
*Multifactorial Inheritance

@article {pmid42905162,
year = {2026},
author = {Stapf, CD and Uzelac, Z and Iterbeke, L and Guthknecht, A and Barba, L and Strube, D and Kölsch, A and Kleeberg, K and Kendzierski, T and Roos, A and Steinacker, P and Abu-Rumeileh, S and Claeys, KG and Weishaupt, J and Mensch, A and Otto, M},
title = {Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42905162},
issn = {1432-1459},
support = {Clinician Scientist Programme n. CS25/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS22/06//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS26/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; FTLDc 01GI1007A//German Federal Ministry of Education and Research/ ; D.3830//foundation of the state Baden-Württemberg/ ; },
mesh = {Humans ; Female ; *tau Proteins/blood ; Male ; Adolescent ; Biomarkers/blood ; Retrospective Studies ; Adult ; *Muscular Atrophy, Spinal/blood/drug therapy/physiopathology ; Middle Aged ; Phosphorylation ; Young Adult ; Amyotrophic Lateral Sclerosis/blood ; Alzheimer Disease/blood ; *Spinal Muscular Atrophies of Childhood/blood ; Aged ; Longitudinal Studies ; },
abstract = {BACKGROUND: Reliable blood biomarkers for longitudinal monitoring in adolescent and adult 5q spinal muscular atrophy (SMA) are lacking. Phosphorylated tau (p-tau) species are elevated in serum in amyotrophic lateral sclerosis (ALS), where they may reflect peripheral nerve and muscle pathology. We aimed to investigate serum p-tau181 and p-tau217 as longitudinal biomarkers in adolescent and adult SMA and assessed associations with clinical parameters.

METHODS: In this retrospective multi-centre study, we assessed serum p-tau181 and p-tau217 levels in adults with 5q SMA under treatment with nusinersen or risdiplam, comparing levels with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and non-neurodegenerative disease controls. Associations with motor function, respiratory capacity, creatine kinase (CK), and neurofilament light chain (NfL) were assessed using linear mixed-effects models adjusted for age and sex.

RESULTS: Serum p-tau181 was higher in SMA than in disease controls (β = -0.48, 95%-CI -0.81 to -0.15), but lower than in ALS (β = 0.99, 95%-CI 0.58 to 1.39) and AD (β = 0.56, 95%-CI 0.11 to 1.00). P-tau181 declined from baseline to FUP2 (Δ median -1.80 pg/mL, IQR -5.90 to 2.10); p-tau217 showed no longitudinal change. P-tau181 and p-tau217 were positively associated with motor function, functional status, respiratory capacity, and CK, with no association with NfL. In exploratory analyses, higher baseline p-tau181 was associated with greater HFMSE decline (β = 1.79, 95%-CI 0.59 to 2.99).

CONCLUSIONS: Serum p-tau181 and p-tau217 appear to reflect ongoing muscle turnover in adult SMA, declining as muscle mass decreases. Higher baseline p-tau181 was associated with subsequent functional deterioration, suggesting potential utility as a biomarker of active denervation and disease monitoring.},
}

Humans
Female
*tau Proteins/blood
Male
Adolescent
Biomarkers/blood
Retrospective Studies
Adult
*Muscular Atrophy, Spinal/blood/drug therapy/physiopathology
Middle Aged
Phosphorylation
Young Adult
Amyotrophic Lateral Sclerosis/blood
Alzheimer Disease/blood
*Spinal Muscular Atrophies of Childhood/blood
Aged
Longitudinal Studies

@article {pmid42905245,
year = {2026},
author = {Nowell, WB and McGale, N and Levy, O and Przydzial, K and Patel, N and Cleanthous, S and Andrews, JA and Rofail, D},
title = {Understanding Holistic Patient-Relevant Measurement in Amyotrophic Lateral Sclerosis: A Mixed-Methods Content Validity and Exploratory Rasch Analysis of Selected Clinical Outcome Assessments.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42905245},
issn = {2193-8253},
abstract = {INTRODUCTION: Living with amyotrophic lateral sclerosis (ALS) has a profound impact on function and health-related quality of life (HRQoL). This mixed-methods study aimed to cognitively debrief selected ALS outcome measures to investigate their relevance and conduct exploratory Rasch Measurement Theory (RMT) analyses to assess targeting.

METHODS: Semi-structured interviews were conducted (January-September 2024) with people living with ALS (PLwALS) and clinicians to cognitively debrief selected patient- and clinician-reported outcome (PRO and ClinRO) measures. The PRO measures debriefed with PLwALS were Rasch Overall ALS Disability Scale (ROADS), 5-item ALS Assessment Questionnaire (ALSAQ-5), and Neurological Fatigue Index for Motor Neurone Disease (NFI-MND). ROADS and ClinRO ALS Functional Rating Scale-Revised (ALSFRS-R) were debriefed with clinicians. Interview transcripts were qualitatively analyzed; structured codes were used to compile data on item relevance and comprehensiveness. Exploratory RMT analysis was conducted using quantitative data from PLwALS responses to evaluate selected PRO psychometric properties.

RESULTS: Qualitative analysis of interviews with 31 PLwALS found that PROs were meaningful and relevant, and identified the relevance of individual items. Clinicians (n = 10) endorsed ALSFRS-R as a relevant and meaningful measure, and supported ROADS' conceptual coverage and response category. RMT analysis indicated evidence of good targeting, reliability, and item fit for the PROs, with some exceptions for ALSAQ-5.

CONCLUSION: This study supports the use of ALSFRS-R, ROADS, ALSAQ-5, and NFI-MND to measure meaningful aspects of ALS, with support for ALSAQ-5 qualified by its limited measurement precision. Scores from these measures can provide important insights into the lived experience of PLwALS, characterizing disease progression and HRQoL.},
}

@article {pmid42905272,
year = {2026},
author = {Tahedl, M and Toomey, A and Mandal, N and Mangan, S and Siah, WF and Tan, EL and Hardiman, O and Kleinerova, J and McKenna, MC and Hutchinson, S and Lope, J and Bede, P},
title = {Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD).},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42905272},
issn = {1432-1459},
support = {HRB JPND-Cofund-2025-3/HRBI_/Health Research Board/Ireland ; JPND - 2025 "Qual-Bulb-MND"//EU Joint Programme - Neurodegenerative Disease Research/ ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; },
mesh = {Humans ; Female ; *Neurotransmitter Agents/metabolism ; Male ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/metabolism ; Middle Aged ; Aged ; Magnetic Resonance Imaging ; Atrophy ; Prospective Studies ; *Brain/diagnostic imaging/metabolism/pathology ; },
abstract = {BACKGROUND: Frontotemporal dementia syndromes encompass a genetically, clinically and radiologically heterogeneous set of conditions with distinctive clinical and imaging characteristics. The main FTD phenotypes exhibit strikingly different disease burden patterns with a predilection to specific brain regions and relative sparing of others. The apparent selectivity of cerebral involvement in FTD has not been fully elucidated.

METHODS: A prospective neuroimaging study has been undertaken with a uniform imaging protocol to characterise atrophy patterns in ALS-FTD, behavioural variant FTD, nonfluent variant primary progressive aphasia, and semantic variant primary progressive aphasia and evaluate associations with physiological neurotransmitter receptor expression maps. Anatomical correlations between focal volume loss and a large panel of neurotransmitters were systematically evaluated and associations ranked.

RESULTS: Associations were noted with GABAergic, opioid, cannabinoid, microglial and acetylcholine systems in ALSFTD-C9NEG. Correlations were observed with opioid, glutaminergic, and synaptic vesicle glycoprotein 2A receptor populations in ALSFTD-C9POS. Atrophy in bvFTD showed predilection to serotonergic, glutaminergic, opioid, GABAergic and cannabinoid circuits. Volume loss in nfvPPA colocalised with GABAergic, opioid, microglial, serotonergic, cannabinoid, acetylcholine, glutaminergic and dopaminergic networks. A multitude of neurotransmitter populations are implicated in svPPA including opioid, serotonergic, GABAergic, dopaminergic, and microglial systems.

DISCUSSION: The distinctive neuroimaging signatures of FTD phenotypes exhibit spatial associations with physiological neurotransmitter receptor density maps. The propensity of atrophy to specific brain regions in FTD subtypes may be defined by neurotransmitter populations. Our findings indirectly support the notion of neurotransmitter-system defined connectivity-based disease propagation in FTD.},
}

Humans
Female
*Neurotransmitter Agents/metabolism
Male
*Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/metabolism
Middle Aged
Aged
Magnetic Resonance Imaging
Atrophy
Prospective Studies
*Brain/diagnostic imaging/metabolism/pathology

@article {pmid42905535,
year = {2026},
author = {Cheung, SW and Fogarty, MJ},
title = {Molecular signatures of selective motor neuron vulnerability in old age.},
journal = {Experimental physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/EP094279},
pmid = {42905535},
issn = {1469-445X},
support = {R01 AG086136/NH/NIH HHS/United States ; },
abstract = {Motor neuron (MN) death and impairment of fast-fatigable motor units is widely recognized in elderly humans and rats. However, the molecular signatures identifying vulnerable MNs remains underexplored. In murine models of amyotrophic lateral sclerosis, matrix metalloproteinase 9 (MMP-9) and chondrolectin (Chodl) decline with disease progression and have been considered molecular markers of fast-fatigable MNs. However, their expression in brainstem and lumbar MNs, in accordance with the 'size principle' (in which motor units are recruited in a size-dependent manner, with MNs of lower capacitance activated before those of greater capacitance) and their expression throughout the lifespan remain unclear. Here, we evaluated MMP-9 and Chodl in lumbar and hypoglossal MNs in young (6 months) and old (24 months) Fischer 344 (F344) rats. Longitudinal lumbar spinal cord transverse brainstem sections (the orientations providing maximal MN somal sizes for each pool) were immunolabelled for choline acetyltransferase, MMP-9 and Chodl. Expression was quantified using confocal microscopy in young and old rats (n = 5 females, n = 5 males per age). Overall, MMP-9 demonstrated a positive association with lumbar MN somal surface area in young rats. Paired within-animal analysis showed that in larger MNs, MMP-9 positivity was ∼70% greater than smaller MNs. The size-dependence of MMP-9 expression was absent in old lumbar MNs, suggesting either selective loss or downregulation of MMP-9 MN expression in ageing. No size-dependent change in Chodl was observed in lumbar or hypoglossal MNs, nor was MMP-9 associated with MN size in hypoglossal MNs. Collectively, these findings identify MMP-9 as a marker enriched within large lumbar MNs in young rats and suggest that age-related alterations in MMP-9 expression may reflect the selective vulnerability of the lumbar MNs.},
}

@article {pmid42901819,
year = {2026},
author = {Obara, K and Janelidze, S and Ito, D and Karlsson, L and Yamamoto, M and Mastrangelo, A and Tran, S and Tsujikawa, K and Nishio, Y and Ogi, T and Vacchiano, V and Liguori, R and Nakamura, R and Atsuta, N and Sobue, G and Nilsson, C and Parchi, P and Katsuno, M and Mattsson-Carlgren, N},
title = {Cerebrospinal fluid amyloid and neurodegeneration biomarkers in the diagnosis and prognosis of amyotrophic lateral sclerosis: a multicohort observational study.},
journal = {EBioMedicine},
volume = {},
number = {},
pages = {106511},
doi = {10.1016/j.ebiom.2026.106511},
pmid = {42901819},
issn = {2352-3964},
abstract = {BACKGROUND: Neurofilament light chain (NfL) is an established biomarker for amyotrophic lateral sclerosis (ALS). However, it remains unclear whether biomarkers reflecting amyloid-β metabolism (Aβ), tau (phosphorylated tau, pTau), and astrogliosis (glial fibrillary acidic protein, GFAP) can complement NfL in clinical applications. It is also unclear how Alzheimer's disease (AD) co-pathology affects disease progression in ALS.

METHODS: We studied 264 patients with ALS and 164 disease-control participants, analysing baseline cerebrospinal fluid (CSF) NfL, Aβ peptides, pTau181, pTau217, and GFAP. A two-step diagnostic strategy was examined in individuals with intermediate NfL values, using machine-learning models. Prognostic associations were evaluated using linear mixed-effects and Cox models adjusted for established predictors; survival was additionally examined in pooled analyses including an external ALS cohort (n = 153).

FINDINGS: Patients with ALS exhibited higher CSF NfL, Aβ38, Aβ40, Aβ42, pTau181, and pTau217 than controls, even within Aβ-negative subgroups. NfL discriminated ALS from controls with an AUC of 0.85 (0.82-0.88), which increased to 0.90 (0.88-0.92) in machine-learning models incorporating additional biomarkers. The machine-learning models maintained a high positive predictive value (0.90) for classifying cases with intermediate NfL values. Significant Aβ × NfL interactions were observed for longitudinal functional decline, and pooled survival analyses showed stronger associations between NfL and survival in the Aβ-positive ALS subgroup (14%) than in the Aβ-negative ALS subgroup (HR 4.02 [2.17-7.45] vs 1.62 [1.36-1.92]).

INTERPRETATION: Multiple biomarker assessments can reduce misclassification of individuals with intermediate NfL values. CSF Aβ positivity modified the association between baseline NfL and disease progression. Personalised diagnosis and prognosis based on fine-grained co-pathology evaluation may enhance clinical management of ALS.

FUNDING: This study was primarily supported by JST SPRING (JPMJSP2125). A complete list of funding organisations is provided in Acknowledgements.},
}

@article {pmid42901869,
year = {2026},
author = {Su, WM and Duan, QQ and Zhang, N and He, SY and Liu, RY and Wen, XJ and Gu, XJ and Wang, Y and Cao, B and Chen, YP},
title = {Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by C9orf72 Expansion.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {5},
pages = {e70405},
pmid = {42901869},
issn = {2190-6009},
support = {82371422//the National Natural Science Fund of China/ ; 2026NSFSC0510//the Science and Technology Bureau Fund of Sichuan Province/ ; 2022YFC2703101//the National Key Research and Development Program of China/ ; 2023HXFH032//the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology/diagnosis ; *C9orf72 Protein/genetics ; Prospective Studies ; *Proteomics/methods ; Male ; Female ; Biomarkers/blood ; Middle Aged ; Aged ; Incidence ; DNA Repeat Expansion ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder for which reliable preclinical biomarkers to predict disease onset are currently lacking. Plasma proteomics offers a promising avenue for early detection. The identification of plasma proteins and pathways associated with incident ALS holds potential to improve early diagnosis, enable risk stratification and provide insights into disease mechanisms.

METHODS: Employing the Olink Explore platform, we quantified 2920 plasma proteins within a prospective cohort of UK Biobank participants. Multivariate Cox proportional hazards regression was utilized to identify proteins associated with incident generalized ALS, C9-ALS (C9orf72-associated ALS) and non-C9-ALS. Enrichment analysis was conducted to delineate the biological pathways implicated by the identified proteins. Associations between plasma protein levels and the age at onset (AAO) of ALS were assessed via linear regression, while a multivariate Cox model was employed to evaluate the relationships between protein levels and ALS survival. We subsequently assessed potential causal relationships using Mendelian randomization (MR) and colocalization and analysed protein cross-sectional temporal patterns in ALS.

RESULTS: In this prospective cohort study, we followed 52 584 participants from the UK Biobank for a mean of 11.8 years. During this period, 291 (0.55%) incident cases of ALS were identified, among whom 34 individuals carried the C9orf72 hexanucleotide repeat expansion mutation. Nine proteins demonstrated associations with all-type ALS risk (FDR < 0.05): NEFL (HR: 2.897), CSRP3 (HR: 1.233), MYBPC1 (HR: 1.352), MEGF10 (HR: 1.744), MYOM3 (HR: 1.289) and THBS4 (HR: 1.570) were identified as risk factors, whereas EGFLAM (HR: 0.402), ITGAV (HR: 0.284) and CD248 (HR: 0.573) exhibited protective effects. NEFL (HR: 2.742) and three additional proteins were primarily associated with non-C9-ALS, while only NEFL (HR: 4.403) and COL5A1 (HR: 3.072) showed significant associations with C9-ALS. When combined with age and sex, these proteins yielded area under the curve (AUC) values exceeding 0.750 for predicting ALS at 3, 5 and 10 years. Furthermore, elevated NEFL levels were correlated with an earlier onset of non-C9-ALS and began to increase approximately 9.27 years prior to diagnosis, reaching a peak 1-2 years before clinical presentation in non-C9ALS cases via cross-sectional temporal analysis. Pathway analysis implicated muscle-related, extracellular matrix, energy metabolism and inflammatory pathways.

CONCLUSIONS: This investigation uncovers extensive alterations in plasma proteins associated with ALS risk, revealing potential novel biomarkers for both sporadic and C9orf72-linked forms of the disease. These results enhance our comprehension of early ALS pathogenesis and provide a foundation for subsequent biomarker identification and the development of targeted therapeutic strategies.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology/diagnosis
*C9orf72 Protein/genetics
Prospective Studies
*Proteomics/methods
Male
Female
Biomarkers/blood
Middle Aged
Aged
Incidence
DNA Repeat Expansion

@article {pmid42896458,
year = {2026},
author = {Ozawa, M and Yoshimaru, D and Ishii, K and Okano, HJ and , },
title = {Data-driven progression trajectories across clinical subtypes of amyotrophic lateral sclerosis.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126224},
doi = {10.1016/j.jns.2026.126224},
pmid = {42896458},
issn = {1878-5883},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) exhibits substantial clinical heterogeneity; however, conventional classifications based on the predominant site of involvement may not fully capture patterns of disease progression. This study aimed to identify data-driven subtypes of ALS and reconstruct their temporal progression using item-level scores from the ALS Functional Rating Scale-Revised (ALSFRS-R).

METHODS: Baseline data from 3067 participants in the Pooled Resource Open-Access ALS Clinical Trials database were analyzed. Subtype and Stage Inference (SuStaIn) was applied to ALSFRS-R item scores to identify subtypes and infer their progression trajectories. Internal consistency was evaluated using complexity and sensitivity analyses. Longitudinal stability was assessed at 180 and 365 days. Associations with functional decline and survival were examined using adjusted statistical models.

RESULTS: Three clinically interpretable subtypes were identified, characterized by predominant upper-limb, lower-limb, or bulbar involvement. These subtypes exhibited distinct, consistent progression patterns across the analyses. Subtype stability was moderate short-term but limited longer-term; stage progression was largely monotonic. The bulbar subtype showed more rapid functional decline at both 180 and 365 days. Higher SuStaIn stage was associated with increased mortality. In an exploratory stage-stratified analysis, poorer survival was observed in the bulbar subtype than in the upper-limb subtype within the lower-stage group.

CONCLUSIONS: This study reconstructed ALS subtype-specific functional progression trajectories and inferred disease stage using a widely accessible clinical scale. SuStaIn-derived subtypes characterized patterns of functional heterogeneity, and higher stage was associated with increased mortality. Further prospective comparative validation is needed to establish the prognostic and clinical utility of this framework.},
}

@article {pmid42896567,
year = {2026},
author = {Gorenshtein, A and Adiniaev, Y and Liba, T and Barash, Y and Klang, E and Daniel, O},
title = {The calibration-to-accuracy mapping in P300 spellers does not transport across cohorts and was not restored by tested alignment or local recalibration.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/aeb62c},
pmid = {42896567},
issn = {1741-2552},
abstract = {Objective A calibration-derived score has been related to online P300-speller accuracy in the same session, always within the cohort measured. We evaluated whether a mapping from that score to expected accuracy transports to withheld cohorts. Approach Retrospective secondary analysis of BigP3BCI 1.0.0, the largest evaluation of this relationship to date: 18 of 20 studies contributed 271 participants, 739 session-condition records, and 19,611 character selections. The predictor was a decoder's cross-validated discriminability on calibration epochs, one study withheld from development. Between-cohort variation was summarised by the random-effects standard deviation tau. Main Results The association was positive in all 18 cohorts but varied widely (r 0.190 to 0.928; participant-level r = 0.714, p < 0.001), with 12 CIs excluding zero. Pooled estimation error was 0.098 (95% CI 0.091 to 0.107) against a benchmark of 0.146. Calibration did not transport: intercept tau 0.87 (unrepresented-cohort interval -1.97 to 1.85, log-odds); cohort-specific slopes varied more than tenfold (tau 0.43, interval 0.111 to 2.005). Neither alignment (signal- or score-space) nor either nonlinear boundary meaningfully reduced this heterogeneity. Local recalibration with up to 16 participants did not reliably improve on transporting; refitting both intercept and slope was significantly worse than transporting at the smallest sizes. Median time per selection, a stopping-rule proxy, accounted for 66% of between-cohort slope variance in meta-regression. The four ALS cohorts gave an uncorrected slope spread of 0.223, against 0.560 overall. Significance The evaluated score is a classifier's cross-validated discriminability on each session's calibration data rather than the source studies' undocumented online decoder. That score reproducibly signals within-session accuracy, but its mapping to accuracy is cohort-specific and supports ranking sessions after local validation rather than reporting accuracy elsewhere. The four-cohort ALS subgroup appeared more homogeneous than the full archive, illustrating how conclusions about transportability from a small cohort set can be fragile. .},
}

@article {pmid42898978,
year = {2026},
author = {Peng, S and Wang, L and Ouyang, J and Liu, R},
title = {The Role of Astrocytes in the Inflammatory Response in Neurodiseases.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71069},
pmid = {42898978},
issn = {2688-2663},
abstract = {Astrocytes have emerged as central regulators of neuroinflammation, extending far beyond their traditional roles as structural and metabolic support cells. In neurological disorders, astrocytes undergo reactive remodeling that encompasses morphological, transcriptional, metabolic, and functional changes. Rather than fitting into a fixed A1/A2 dichotomy, reactive astrocytes exist along a disease-, region-, and stage-dependent continuum shaped by local pathology and intercellular crosstalk. This review summarizes how astrocytes contribute to neuroinflammatory processes in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, central nervous system injury, infection, multiple sclerosis, epilepsy, and autism spectrum disorder. We highlight convergent mechanisms, including cytokine and chemokine release, complement activation, glutamate and ion homeostasis disruption, oxidative stress, metabolic reprogramming, and blood-brain barrier regulation, while emphasizing disease-specific astrocytic programs. We further discuss astrocyte interactions with microglia, neurons, oligodendrocytes, endothelial cells, and peripheral immune cells, as well as key regulatory pathways, epigenetic remodeling, and lipid-dependent metabolic signaling. Finally, we evaluate current and emerging astrocyte-targeted therapeutic strategies, including metabolic modulation, receptor targeting, gene editing, nanodelivery, and gut-brain axis interventions. Defining functionally validated astrocyte states and developing biomarker-guided, stage-adaptive therapies may enable more precise intervention in neuroinflammatory and neurodegenerative diseases.},
}

@article {pmid42899523,
year = {2026},
author = {Campanella, B and Birindelli, L and Legnaioli, S and Lorenzetti, G and Consani, C and Ales, V and Benedetti, E and Bertozzi, MA and Bramanti, E},
title = {Task-Dependent Synergy between FTIR and Raman Spectroscopy for Sperm Quality Prediction.},
journal = {Analytical chemistry},
volume = {98},
number = {41},
pages = {29684-29699},
doi = {10.1021/acs.analchem.6c04960},
pmid = {42899523},
issn = {1520-6882},
mesh = {Humans ; Male ; *Spectrum Analysis, Raman/methods ; Spectroscopy, Fourier Transform Infrared/methods ; *Spermatozoa/cytology ; Sperm Motility ; Semen/chemistry ; Biomarkers/analysis ; *Semen Analysis/methods ; },
abstract = {Male infertility affects approximately 15% of couples worldwide, contributing to 40-50% of infertility cases in Western countries. Standard semen analysis remains the cornerstone of fertility assessment, yet conventional parameters (concentration, motility, morphology) have limited predictive value for fertilization success. Vibrational spectroscopy, particularly Fourier transform infrared (FTIR) and Raman spectroscopy, offers rapid, nondestructive chemical fingerprinting of biological samples. However, optimal strategies for integrating multimodal spectroscopic data remain unclear, and the value of fusion may depend on the biological end point. This study systematically compares FTIR and Raman spectroscopy, both independently and through multiple fusion strategies, for predicting rectilinear progressive sperm motility (binary classification) and normal morphology (continuous regression) in human seminal plasma. We determine whether complementary information exists, when fusion provides value, and which strategy optimally leverages multimodal data. Building on Raman-derived Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) concentration profiles, we further develop a clinical classifier based on four seminal plasma biomarkers (human serum albumin, glutathione S-transferase, transferrin, lysophosphatidylcholine), validated by leave-one-patient-out cross-validation and Firth's penalized logistic regression to address near-complete separation in this small-sample setting (n = 30). Our findings reveal technique-specific advantages: Raman spectroscopy substantially outperforms FTIR for binary motility classification, with feature-level fusion matching but not exceeding Raman's performance, indicating limited complementarity. Conversely, FTIR alone achieves superior predictive accuracy for continuous morphological outcomes. The clinical classifier based on MCR-ALS-derived biomarkers achieved AUC (Area Under the ROC Curve) = 0.855, accuracy = 86.7%, and BER (Balanced Error Rate) = 0.136, with model significance confirmed by permutation testing. Elevated human serum albumin and lysophosphatidylcholine emerged as the strongest negative predictors of high motility, consistent with seminal tract inflammation and sperm-cytotoxic phospholipid accumulation, while transferrin showed a positive association in line with its role in iron availability for sperm function. These results demonstrate that optimal spectroscopic approaches depend on the biological end point, with Raman's structural sensitivity favoring motility assessment and FTIR's compositional profiling better capturing morphological variation. The biomarker-based classifier is easier to interpret and complements whole-spectrum models by bridging chemometric analysis and biological interpretation.},
}

Humans
Male
*Spectrum Analysis, Raman/methods
Spectroscopy, Fourier Transform Infrared/methods
*Spermatozoa/cytology
Sperm Motility
Semen/chemistry
Biomarkers/analysis
*Semen Analysis/methods

@article {pmid42892382,
year = {2026},
author = {Fleshner, L and Chan, R and Klufas, T and Grant-Kels, JM and Zhou, AE},
title = {Reply to Botto et al's "Applicant interview metrics and preference signaling in dermatology: A serial cross-sectional study".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.09.134},
pmid = {42892382},
issn = {1097-6787},
}

@article {pmid42892517,
year = {2026},
author = {Xu, Z and Chen, X and Yi, W},
title = {Cryo-EM advances in TDP-43 amyloid fibrils structure determination.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107659},
doi = {10.1016/j.nbd.2026.107659},
pmid = {42892517},
issn = {1095-953X},
abstract = {TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.},
}

@article {pmid42894325,
year = {2026},
author = {Shadfar, S and Parakh, S and Perri, E and Jagaraj, CJ and Assar Kashani, S and Beyers, K and Ragagnin, AMG and Laird, AS and Atkin, JD},
title = {Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.},
journal = {Redox report : communications in free radical research},
volume = {31},
number = {1},
pages = {2732775},
doi = {10.1080/13510002.2026.2732775},
pmid = {42894325},
issn = {1743-2928},
mesh = {Animals ; Zebrafish/metabolism ; *Protein Disulfide-Isomerases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Cyclins/metabolism/genetics ; Humans ; *Frontotemporal Dementia/metabolism/genetics ; Phenotype ; Mutation ; Animals, Genetically Modified ; Apoptosis ; Endoplasmic Reticulum Stress ; },
abstract = {BACKGROUND: Mutations in CCNF, encoding cyclin F, cause a small proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Mutant cyclin F mislocalises from the nucleus to the cytoplasm, impairs the ubiquitin proteasome system, disrupts endoplasmic reticulum (ER) to Golgi transport, and triggers ER stress and apoptosis. Protein disulphide isomerase (PDI), a redox-active ER chaperone of the thioredoxin superfamily, protects against ALS phenotypes induced by mutant SOD1, TDP-43, and FUS, but its activity against mutant cyclin F has not been examined.

OBJECTIVES: To test whether PDI overexpression prevents the cellular and behavioural phenotypes induced by the ALS/FTD-associated cyclin F[S621G] mutation.

METHODS: Neuro-2a cells were co-transfected with mCherry-tagged wild-type or mutant cyclin F[S621G] and V5-tagged PDI or empty vector. Subcellular localisation, XBP-1 and CHOP activation, proteasome reporter (GFPu) accumulation, nuclear morphology, and cleaved caspase-3 immunoreactivity were assessed by confocal microscopy. Transient transgenic zebrafish larvae generated by mRNA co-injection of cyclin F and PDI were assessed by photomotor response at 48 h post-fertilisation.

RESULTS: Mutant cyclin F[S621G] induced cytoplasmic mislocalisation, ER stress (assessed by XBP-1 and CHOP activation), proteasome dysfunction (indicated by GFPu accumulation), and apoptosis (assessed by nuclear condensation and caspase-3 activation), all of which were significantly attenuated by PDI co-expression. Zebrafish larvae expressing cyclin F[S621G] swam significantly shorter distances than uninjected or wildtype controls, and co-expression of PDI restored motor function to near-wildtype levels.

CONCLUSION: PDI protects against ALS/FTD-associated mutant cyclin F in both cellular and in vivo zebrafish models, identifying PDI as a redox-based therapeutic target for CCNF-linked ALS/FTD.},
}

Animals
Zebrafish/metabolism
*Protein Disulfide-Isomerases/metabolism/genetics
*Amyotrophic Lateral Sclerosis/metabolism/genetics
*Cyclins/metabolism/genetics
Humans
*Frontotemporal Dementia/metabolism/genetics
Phenotype
Mutation
Animals, Genetically Modified
Apoptosis
Endoplasmic Reticulum Stress

@article {pmid42894599,
year = {2026},
author = {Naseer, A and Iqbal, N and Bibi, I and Shah, SAR and Khalid, M and Khalid, A},
title = {Molecular recognition of axonal injury-associated candidate hub genes and predicted inhibitors across Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.},
journal = {In silico pharmacology},
volume = {14},
number = {3},
pages = {259},
pmid = {42894599},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have converging molecular pathologies such as neuroinflammation, mitochondrial dysfunction, and axonal degeneration, but do not have broadly effective disease-modifying therapies. A novel computational strategy was used in this study with an integrated in-silico pipeline to determine common candidate hub genes across AD, PD, and ALS and to computationally screen candidate inhibitors. The gene expression datasets were retrieved from the Gene Expression Omnibus database and analyzed with limma R package for blood-derived gene expression datasets for AD (GSE63060), PD (GSE99039) and ALS (GSE112680). A multi-dataset intersection analysis revealed 138 genes commonly upregulated and 0 commonly downregulated genes, which were functionally enriched in immune regulation, apoptotic signaling and mitochondrial instability pathways. Protein-protein interaction network analysis identified three key genes (MMP9, PTPN6 and TNFRSF1A) as high-confidence candidate hub genes for AD, PD, and ALS. The ZINC library of 34,853 compounds was screened for drug-like properties using QikProp to yield 16,466 drug-like compounds. Based on the comparative screening results, the structure of MMP9 (PDB ID: 8K5Y) was chosen for further analysis and two of the selected compounds ZINC04582833, ZINC00047690 were identified as the two highest ranked compounds with docking scores of - 10.4 and - 9.7 kcal/mol respectively. Both complexes were further evaluated by 100 ns MD simulations, showing RMSD profile stability, maintained secondary structure for both complexes. The results in this study make ZINC04582833 and ZINC00047690 computationally prioritized candidates for shared neurodegenerative targets for experimental validation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00774-6.},
}

@article {pmid42894639,
year = {2026},
author = {Wang, Y and Fournier, L and Wymann, B and Talbot, K and Luisier, R and Patani, R},
title = {OGT regulates RNA-binding protein nucleocytoplasmic partitioning, but this fails in amyotrophic lateral sclerosis.},
journal = {iScience},
volume = {29},
number = {11},
pages = {117807},
pmid = {42894639},
issn = {2589-0042},
abstract = {O-linked N-acetylglucosamine transferase (OGT) catalyzes the O-linked β-N-acetylglucosamine (O-GlcNAc) modification to proteins and has been implicated in a range of diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and currently incurable neurodegenerative disorder. However, the precise mechanisms by which OGT influences ALS pathogenesis remain largely unresolved. In this study, we used human-induced pluripotent stem cell (hiPSC)-derived spinal motor neurons (hiPSC-MNs), the principal cell type that undergoes degeneration in ALS, to systematically reveal that OGT-related mechanisms regulate RNA-binding protein (RBP) nucleocytoplasmic compartmentalization. Using a combination of antisense oligonucleotide (ASO) technology and small molecular pharmacology, we reveal two distinct regulatory mechanisms of RBP compartmentalization, including by intron-retaining transcript-mediated sequestration and O-linked N-acetylglucosaminylation (O-GlcNAcylation)-mediated nuclear transport. We finally examine the tractability of manipulating OGT activity in the ALS context but demonstrate that the OGT-related mechanisms governing RBP localization in healthy hiPSC-MNs are impaired in the context of ALS-causing VCP and TARDBP mutations.},
}

@article {pmid42895147,
year = {2026},
author = {Chaudhary, S and Dhankhar, S and Saini, M and Singh, TG and Chauhan, S and Kumar, V},
title = {Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273491538261009064612},
pmid = {42895147},
issn = {1996-3181},
abstract = {More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little effect on changing the course of the disease and are largely symptomatic. Psilocybin, a naturally occurring tryptamine alkaloid from psilocybin mushrooms, has become a promising medicinal agent because of its hallucinogenic, neuroprotective, and neuroplastic properties. After being metabolically transformed into its active form, psilocin, it primarily activates serotonin 5-HT2A receptors. This modulates glutamatergic neurotransmission and neurotrophic signaling pathways such as BDNF/TrkB and mTOR, which regulate synaptic remodeling, dendritic complexity, neurogenesis, neuroinflammatory response, and default mode network connectivity, all of which are linked to depression and dementia. Preclinical research studies demonstrate that psilocybin increases hippocampal plasticity, restores dendritic complexity, lowers proinflammatory cytokine levels, and promotes fear extinction in experimental models of stress, ischemic stroke, and neurodegeneration. Emerging clinical studies also indicate that individuals with moderate cognitive impairment, early-onset Alzheimer's disease, and Parkinson's disease may see long-term decreases in anxiety and depression as well as improvements in cognitive function, frequently after a single dose administration. Additionally, psilocybin has demonstrated promise in treating mental comorbidities that often accompany neurodegenerative illness, such as treatment-resistant depression, drug use disorders, and obsessive-compulsive disorder. However, there are still significant obstacles to overcome, such as optimizing dosing schedules, assessing safety issues such as temporary perceptual abnormalities and cardiovascular consequences, and translating preclinical results into extensive phase -III clinical studies. This review incorporates the most recent data on psilocybin's chemistry, pharmacology, metabolism, and mechanistic actions; it highlights the drug's therapeutic potential across a variety of neurodegenerative diseases and emphasizes the necessity of carefully planned randomized controlled trials to determine clinical efficacy, long-term safety, and its place in multimodal treatment approaches.},
}

@article {pmid42895434,
year = {2026},
author = {Maccabeo, A and Cabras, S and Callegaro, S and Pateri, MI and Pili, F and Canosa, A and Manera, U and Palumbo, F and Matteoni, E and Pellegrino, G and Minerva, E and Ciravegna, A and Gianferrari, G and Puligheddu, M and Moglia, C and De Marchi, F and Mazzini, L and Mandrioli, J and Borghero, G and Chiò, A and Calvo, A and Vasta, R},
title = {Factors associated with post-tracheostomy survival in Amyotrophic Lateral Sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2742815},
pmid = {42895434},
issn = {2167-9223},
abstract = {OBJECTIVE: To identify demographic and clinical factors associated with post-tracheostomy survival using three well-characterized cohorts of patients with Amyotrophic Lateral Sclerosis (ALS).

METHODS: ALS patients from the Piemonte and Valle d'Aosta ALS Register (PARALS) diagnosed between 1995-2019 interval who underwent tracheostomy were included. A multivariable Cox proportional hazards model was used to identify factors associated with post-tracheostomy survival. Significant findings were tested in two independent cohorts, the Emilia-Romagna Region ALS Register (ERRALS) and an incident ALS cohort from South Sardinia.

RESULTS: A total of 449 patients from PARALS underwent tracheostomy during the study period, with a median post-tracheostomy survival of 16.3 months (IQR 4.0-45.0). Younger age at tracheostomy was associated with longer survival (HR 1.03 per one-year increase, 95%CI1.01-1.05, p = 0.001), as being married/cohabiting (HR 0.78, 95%CI0.61-0.98, p = 0.033), a longer diagnosis-to-tracheostomy interval (HR 0.84 per one-year increase, 95%CI0.79-0.90, p < 0.001) and a lower ALS Functional Rating Scale slope from onset to tracheostomy (HR 1.13 per one-unit increase, 95%CI1.03-1.25, p = 0.012). These associations were replicated in the independent cohorts, when data were available. Additionally, discharge to nursing homes was associated with poorer survival in the Sardinian cohort (HR 4.23, 95%CI2.49-7.19; p < 0.001), whereas a more recent year of tracheostomy was associated with longer survival in the ERRALS cohort (HR 0.95, 95%CI0.90-0.99; p = 0.019).

DISCUSSION: We identified multiple factors associated with post-tracheostomy survival in ALS patients, encompassing clinical and demographic characteristics at tracheostomy as well as local factors influencing peri- and post-operative care. These findings may support decision-making and clinician-patient communication in the advanced stages of ALS.},
}

@article {pmid42895667,
year = {2026},
author = {Abu-Omar, K and Tcymbal, A and Messing, S and Gelius, P},
title = {[Physical activity and physical activity promotion among people with a migration background in Germany].},
journal = {Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz},
volume = {},
number = {},
pages = {},
pmid = {42895667},
issn = {1437-1588},
abstract = {Health equity has gained increasing importance in physical activity and health promotion and is firmly established as an important goal both internationally and in Germany. As social inequalities and multiple disadvantages influence physical activity behavior, population groups facing particular barriers to access-including people with a migration background-should receive greater consideration in physical activity promotion. This article provides an overview of the current state of research on physical activity and physical activity promotion among people with a migration background in Germany.Representative data indicate that people with a migration background are less physically active than people without a migration background. Key barriers reported include limited financial resources, language barriers, restricted opportunities for physical activity, and cultural factors. Different forms of social disadvantage, for example those related to gender, socioeconomic status, and migration background, may intersect and reinforce barriers to access. Using the project "Bewegung als Investition in Gesundheit" (BIG; "Physical Activity as an Investment in Health") as an example, this article illustrates how participatory and target-group-specific interventions can be used to reach, in particular, women with a migration background.In addition to participatory and target-group-specific interventions, equitable physical activity promotion requires structural conditions that facilitate access to opportunities for physical activity. The sustainable implementation and scaling-up of such interventions can contribute to reducing barriers to access and promoting health equity.},
}

@article {pmid42886553,
year = {2026},
author = {Gastaldo, D and Vito, S and Black, HH and Foreman, O and Yang, Z and Pham, V and Zhu, Y and Choi, M and Jovičić, A},
title = {Ataxin-2 downregulation rewires neuronal and astrocytic metabolism to protect against TDP-43 toxicity.},
journal = {Cell reports},
volume = {45},
number = {10},
pages = {118053},
doi = {10.1016/j.celrep.2026.118053},
pmid = {42886553},
issn = {2211-1247},
abstract = {Ataxin-2 (ATXN2) is a genetic modifier of TDP-43 toxicity and a promising therapeutic target in amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying its neuroprotective effects remain poorly understood. Using global proteomic profiling in yeast and mouse TDP-43 models, we establish that pbp1/ataxin-2 (pbp1 is the yeast ataxin-2 ortholog) reduction confers neuroprotection by activating orthogonal stress-adaptive pathways in neurons and glia, rather than simply reversing TDP-43-induced damage. In neurons, ataxin-2 downregulation activates glycolysis and reductive glutamine carboxylation driven by IDH1, restoring ATP production independently of impaired mitochondria. In astrocytes, it upregulates cholesterol biosynthesis via HMGCS1, enhancing trophic support to neurons. Full neuroprotection requires both mechanisms: neuronal survival is only completely rescued when ataxin-2 is reduced in neuron-astrocyte co-cultures. Importantly, ataxin-2 downregulation protects against both TDP-43 gain- and loss-of-function toxicity, broadening its therapeutic relevance. Collectively, these findings establish ataxin-2 as a regulator of stress-adaptive metabolic resilience.},
}

@article {pmid42891488,
year = {2026},
author = {Boyce, D and Premasiri, A and Sullivan, S and Levine, B and Vieira, FG},
title = {Registry Forge: an open-source end-to-end pipeline for patient-directed SMART on FHIR registries.},
journal = {JAMIA open},
volume = {9},
number = {5},
pages = {ooag200},
pmid = {42891488},
issn = {2574-2531},
abstract = {OBJECTIVES: Patient-directed SMART on FHIR lets registries acquire longitudinal electronic health record data, but the payload requires substantial engineering before use. We present Registry Forge, an open-source pipeline that converts it into curation-ready outputs.

MATERIALS AND METHODS: Registry Forge parses C-CDA, HTML, RTF, PDF, and FHIR inputs, joins records to a canonical identifier, and emits a browser dashboard, an OMOP CDM v5.4 data set, GA4GH Phenopackets v2, a code inventory, and disease-specific narrative extractions.

RESULTS: Applied to the ALS Research Collaborative Study (94 participants, 56 US health systems), it processed 22 686 files and 1791 FHIR Bundles (109 599 resources); only 15.0% of files were full C-CDA XML; HTML (48.4%) and RTF (34.3%) predominated.

DISCUSSION: Payloads are far more heterogeneous than often assumed; the architecture is designed for extension, though generalizability remains to be demonstrated.

CONCLUSION: Registry Forge closes the gap between acquisition and curation-ready data with no server infrastructure and is openly available.},
}

@article {pmid42891860,
year = {2026},
author = {Wełnicka-Wesołowska, A and Łuczkowska, K and Nowacki, P and Paczkowska, E and Meller, A and Machowska-Sempruch, K and Machaliński, B and Gołąb-Janowska, M},
title = {Peripheral and cerebrospinal fluid inflammatory markers in sporadic amyotrophic lateral sclerosis an exploratory cross-sectional association study.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42891860},
issn = {1590-3478},
support = {STRATEGMED1/234261/2NCBR/2014//Narodowe Centrum Badań i Rozwoju/ ; },
mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood ; Male ; Cross-Sectional Studies ; *Receptors, Tumor Necrosis Factor, Type I/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; Middle Aged ; Tumor Necrosis Factor-alpha/cerebrospinal fluid/blood ; Aged ; C-Reactive Protein/metabolism/cerebrospinal fluid ; Fibrinogen/metabolism ; Inflammation/cerebrospinal fluid/blood ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with an ambiguous etiology, whose onset may be linked to innate immune system activation outside the central nervous system (CNS). We investigated the association between peripheral blood and CNS inflammatory parameters in 45 sporadic ALS patients compared to 30 controls, analyzing peripheral blood tests (C-reactive protein [CRP], blood count, fibrinogen) and cerebrospinal fluid (CSF) immunological measures (Tumor Necrosis Factor alpha [TNF-α], TNF receptor type 1 [TNFR-1], CRP) alongside clinical characteristics. Results revealed significantly higher concentrations of TNFR-1 in the CSF of ALS patients compared to the control group (1,029.5 ± 176.0 vs. 846.1 ± 167.5 pg/ml; p < 0.0001). This difference remained significant in multivariable logistic regression adjusting for age and sex (OR 1.82 per 100 pg/ml increment, 95% CI 1.26-2.63; p = 0.0015). In an exploratory ROC analysis, CSF TNFR-1 discriminated patients from controls with an AUC of 0.78 (95% CI 0.67-0.88). TNFR-1 correlated with age (R = 0.32, p = 0.038), associations with disease severity and a lower concentration in bulbar-onset disease were exploratory and not robustly significant. Plasma and CSF CRP concentrations did not differ significantly between groups, but strongly correlated with each other in both ALS (R = 0.83) and control (R = 0.82) cohorts, indicating a disease-non-specific relationship. CSF TNFR-1 is independently associated with sporadic ALS and warrants further investigation as a candidate disease-associated inflammatory biomarker. Given the limitations, our findings do not prove diagnostic accuracy or causality. Longitudinal studies with disease controls and blood-CSF barrier integrity measures are needed.},
}

Humans
Female
*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood
Male
Cross-Sectional Studies
*Receptors, Tumor Necrosis Factor, Type I/cerebrospinal fluid/blood
Biomarkers/cerebrospinal fluid/blood
Middle Aged
Tumor Necrosis Factor-alpha/cerebrospinal fluid/blood
Aged
C-Reactive Protein/metabolism/cerebrospinal fluid
Fibrinogen/metabolism
Inflammation/cerebrospinal fluid/blood

@article {pmid42885660,
year = {2026},
author = {Bombaci, A and Iadarola, A and Giraudo, A and Fattori, E and Sinagra, S and Magnino, A and Falbo, M and De Marco, G and Calvo, A and Chiò, A and Cicolin, A},
title = {Salivary Dim-Light Melatonin Onset is Associated with Functional Decline, Respiratory Symptom Emergence, and Survival in Early Amyotrophic Lateral Sclerosis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78398},
pmid = {42885660},
issn = {1531-8249},
abstract = {OBJECTIVE: Sleep-wake and circadian disturbances are increasingly recognized in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information.

METHODS: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim-light conditions at 6 predefined time points around habitual sleep onset. Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined when the fitted curve first reached 3 pg/ml. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age- and sex-matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses.

RESULTS: A total of 50 plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 ± 1:18 vs 20:58 ± 0:50; p = 0.028) despite similar habitual sleep onset and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.11; p = 0.019), and poorer survival/tracheostomy-free outcome. In the resampled subgroup (n = 28), DLMO and melatonin-derived metrics did not change over ~6 months.

INTERPRETATION: Circadian phase alterations are detectable in early ALS. Baseline DLMO showed exploratory associations with functional, respiratory, and survival outcomes. Larger independent cohorts are required before DLMO can be considered a validated prognostic biomarker. ANN NEUROL 2026.},
}

@article {pmid42880848,
year = {2026},
author = {Martin, LJ},
title = {DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.},
journal = {Handbook of clinical neurology},
volume = {219},
number = {},
pages = {381-397},
doi = {10.1016/B978-0-443-19043-8.00014-1},
pmid = {42880848},
issn = {0072-9752},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Motor Neurons/metabolism/pathology/physiology ; *DNA Methylation/genetics/physiology ; Animals ; *Epigenesis, Genetic/genetics/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS), the 3rd most frequent neurodegenerative disease, is fatal. Skeletal muscles, neuromuscular junctions, and motor neurons in the cerebral cortex, brainstem, and spinal cord that control swallowing, breathing, and movement degenerate, causing paralysis, respiratory arrest, and death. Clinically meaningful disease mechanisms are unknown, and no effective therapies are available. ALS is a polygenic heterogeneous disease seen in 5%-10% of patients as inherited, but most patients have no inheritance pattern. ALS appears to manifest as a complex interplay between many genes in multiple tissues, individual lifestyle, the environment, and metabolism. Monozygotic twin and triplet studies of ALS suggest that epigenetic mechanisms could be involved in the pathogenesis because discordance is seen. Epigenetic anomalies involving DNA and RNA methylation occur in human ALS. Cell and animal models show that motor neuron development and degeneration can be regulated by DNA methylation. This chapter summarizes the DNA and RNA epigenetic anomalies that are prominent in human ALS and models of ALS, concluding with the suggestion that they are promising therapeutic targets with small molecules.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*Motor Neurons/metabolism/pathology/physiology
*DNA Methylation/genetics/physiology
Animals
*Epigenesis, Genetic/genetics/physiology

@article {pmid42880988,
year = {2026},
author = {Jia, F and Zhang, B and Yu, W and Chen, Z and Xu, W and Zhao, W and Wang, Z},
title = {Corrigendum to "Exploring the cuproptosis-related molecular clusters in the peripheral blood of patients with amyotrophic lateral sclerosis" [Comput. Biol. Med. 168, (2024), 107776].},
journal = {Computers in biology and medicine},
volume = {},
number = {},
pages = {111997},
doi = {10.1016/j.compbiomed.2026.111997},
pmid = {42880988},
issn = {1879-0534},
}

@article {pmid42882466,
year = {2026},
author = {Burdman, G and Hanna, M and Arias, AY and Vashist, A and Lakshmana, MK},
title = {Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191768},
pmid = {42882466},
issn = {2073-4409},
support = {1R21DA060111, 1R61AG086971, R03AG08475//National Institute of Health (NIH)/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Brain/pathology/cytology ; *Organoids/pathology/cytology ; *Nervous System Diseases/pathology ; Animals ; Microphysiological Systems ; Neurons/pathology ; Models, Biological ; },
abstract = {Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.},
}

Humans
*Induced Pluripotent Stem Cells/cytology/metabolism
*Brain/pathology/cytology
*Organoids/pathology/cytology
*Nervous System Diseases/pathology
Animals
Microphysiological Systems
Neurons/pathology
Models, Biological

@article {pmid42882496,
year = {2026},
author = {Morrone, M and Valori, CF and Brambilla, L and Rossi, D},
title = {Motor Neuron Disease in a Dish: The Power of Human Induced Pluripotent Stem Cell-Derived Spinal Motor Neurons and Glial Cells.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191798},
pmid = {42882496},
issn = {2073-4409},
support = {JPND2022-DC4MND//Ministry of Health/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology/pathology ; *Motor Neurons/pathology/metabolism ; *Neuroglia/pathology/metabolism ; *Motor Neuron Disease/pathology ; *Amyotrophic Lateral Sclerosis/pathology ; Animals ; Cell Differentiation ; Astrocytes/pathology/metabolism ; },
abstract = {Induced pluripotent stem cells (iPSCs) have revolutionized disease modelling by providing unprecedented opportunities to investigate complex human disorders. Among others, Amyotrophic Lateral Sclerosis (ALS), the most common adult-onset motor neuron disease, clearly embodies this complexity. This disorder remains particularly challenging not only because of its marked clinical and molecular heterogeneity but also as a consequence of the composite interactions between motor neurons and the neighboring non-neuronal cells, especially astrocytes, which contribute to disease progression. The ability to generate patient-specific spinal motor neurons and astrocytes from human iPSCs has enabled the development of in vitro models that recapitulate key pathological features of ALS, offering valuable platforms to investigate disease mechanisms, to identify therapeutic targets, and to support personalized medicine approaches. In this review, we summarize current iPSC-based strategies for modelling ALS, highlighting their applications in studying disease physiopathology and drug development. In addition, advanced human iPSC-derived technologies, including organoids and organ-on-a-chip systems, are discussed highlighting their potential, current limitations, and future perspectives.},
}

Humans
*Induced Pluripotent Stem Cells/metabolism/cytology/pathology
*Motor Neurons/pathology/metabolism
*Neuroglia/pathology/metabolism
*Motor Neuron Disease/pathology
*Amyotrophic Lateral Sclerosis/pathology
Animals
Cell Differentiation
Astrocytes/pathology/metabolism

@article {pmid42883264,
year = {2026},
author = {Sun, L and Apweiler, M and Schulzki, R and Grathwol, CW and Normann, C and Bräse, S and Fiebich, BL},
title = {Anti-Neuroinflammatory Effects of Cardenolides in IL-1β-Activated SK-N-SH Cells.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193501},
pmid = {42883264},
issn = {1420-3049},
support = {284178167//Deutsche Forschungsgemeinschaft/ ; 266379491//Deutsche Forschungsgemeinschaft/ ; //Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg/ ; },
mesh = {Humans ; *Interleukin-1beta/metabolism/pharmacology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; NF-kappa B/metabolism ; *Cardenolides/pharmacology/chemistry ; Cyclooxygenase 2/metabolism ; Cell Line, Tumor ; Dinoprostone/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; Cell Survival/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Interleukin-6/metabolism ; Prostaglandin-E Synthases/metabolism ; },
abstract = {Neuroinflammation is a key feature of neurological disorders such as Alzheimer's or Parkinson's disease, depression or amyotrophic lateral sclerosis. This study investigates the anti-neuroinflammatory effects of three cardenolide derivatives, digitoxigenin, digitoxigenone, and coroglaucigenin (all at concentrations of 1, 5, 10, and 25 µM), in IL-1β-stimulated human neuroblastoma SK-N-SH cells. All compounds significantly reduced PGE2 production without affecting cell viability by downregulation of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthases (mPGES)-1 expression and synthesis. Among them, digitoxigenin notably inhibited phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) and suppressed interleukin (IL)-6 and IL-8 expression and release. These findings demonstrate that cardenolide derivatives exert potent anti-neuroinflammatory effects by at least partially targeting key enzymes of the arachidonic acid pathway and modulating MAPK/NF-κB signaling, highlighting their potential as novel therapeutic candidates for neuroinflammatory diseases. Future research should focus on effects of the cardenolides in mixed-cell cultures, organoids and in vivo experiments, to evaluate possible side effects and the potential in disease models.},
}

Humans
*Interleukin-1beta/metabolism/pharmacology
*Anti-Inflammatory Agents/pharmacology/chemistry
NF-kappa B/metabolism
*Cardenolides/pharmacology/chemistry
Cyclooxygenase 2/metabolism
Cell Line, Tumor
Dinoprostone/metabolism
p38 Mitogen-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
Cell Survival/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism
Interleukin-6/metabolism
Prostaglandin-E Synthases/metabolism

@article {pmid42883328,
year = {2026},
author = {Garbarek, J and Hys, O and Woźniak, A and Szewczyk-Golec, K and Nuszkiewicz, J},
title = {Bee-Derived Products in Neurodegenerative Diseases: Bioactive Constituents, Redox-Modulating Mechanisms, Evidence, and Translational Perspectives.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193564},
pmid = {42883328},
issn = {1420-3049},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidation-Reduction/drug effects ; Antioxidants/pharmacology/chemistry/therapeutic use ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Bees/chemistry ; Propolis/chemistry/therapeutic use ; Oxidative Stress/drug effects ; Royal Jelly ; *Bee Venoms/chemistry/therapeutic use/pharmacology ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Signal Transduction/drug effects ; Honey/analysis ; },
abstract = {Oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation are closely interconnected processes involved in the pathogenesis and progression of neurodegenerative diseases. Bee-derived products, including honey, propolis, royal jelly, bee pollen, bee bread, and bee venom, contain diverse bioactive constituents with antioxidant, anti-inflammatory, immunomodulatory, and redox-modulating properties. This narrative review summarizes the major bioactive compounds present in bee-derived products and evaluates their potential relevance to neuroprotection. Particular attention is given to mechanisms involving activation of the Nrf2/ARE antioxidant response, inhibition of NF-κB-dependent inflammatory signaling, modulation of the NLRP3 inflammasome, mitochondrial protection, regulation of apoptosis, and maintenance of proteostasis. Available evidence from cellular and animal models, together with the limited clinical data, is discussed primarily in the context of Alzheimer's and Parkinson's diseases, with additional consideration of amyotrophic lateral sclerosis and other neurodegenerative or neuroinflammatory conditions. Although several bee-derived products and isolated constituents show promising biological effects, their therapeutic translation remains limited by variable chemical composition, insufficient standardization, low or uncertain bioavailability, limited evidence of central nervous system exposure, and safety concerns. Further mechanistic, pharmacokinetic, and well-controlled clinical studies are therefore required before their potential neuroprotective applications can be reliably established.},
}

Humans
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
Oxidation-Reduction/drug effects
Antioxidants/pharmacology/chemistry/therapeutic use
*Neuroprotective Agents/pharmacology/chemistry/therapeutic use
Bees/chemistry
Propolis/chemistry/therapeutic use
Oxidative Stress/drug effects
Royal Jelly
*Bee Venoms/chemistry/therapeutic use/pharmacology
Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use
Signal Transduction/drug effects
Honey/analysis

@article {pmid42883433,
year = {2026},
author = {Li, P and Qi, ZM and Wu, JZ and Liu, J and Yu, P},
title = {Targeting Ferroptosis in Neurodegenerative Diseases: Therapeutic Potential and Mechanistic Insights of Traditional Chinese Medicine.},
journal = {Biology},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/biology15191760},
pmid = {42883433},
issn = {2079-7737},
support = {NO.20250204060YY//Jilin Province Science and Technology Department/ ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by progressive and irreversible neuronal loss, whereas current treatments remain largely symptomatic. Ferroptosis is an iron-dependent form of regulated cell death whose execution is defined by iron-enabled phospholipid peroxidation and failure of cellular ferroptosis-defense systems. Mitochondrial metabolism can modify ferroptosis susceptibility, but its contribution varies with cell type and initiating stimulus. Converging evidence implicates ferroptosis in multiple NDs, in which affected regions commonly show iron accumulation, glutathione depletion, and increased lipid peroxidation. With their multi-component and multi-target properties, traditional Chinese medicine (TCM) interventions may modulate several nodes in this network. This review summarizes the core execution and defense mechanisms of ferroptosis, evaluates their roles in major NDs, and critically appraises bioactive herbal compounds, compound formulas, acupuncture, electroacupuncture, and moxibustion. The reported interventions mainly engage the Nrf2/GPX4 antioxidant axis, TFR1/FPN1/FTH1/NCOA4-mediated iron handling, ACSL4-dependent lipid peroxidation, and GPX4-independent defense systems. Because most studies are preclinical and many infer ferroptosis from non-specific markers, the evidence is graded here as direct, supportive, indirect, mixed, or complementary. Translation will require standardized formulations, causal ferroptosis validation, pharmacokinetic and brain-exposure data, validated human biomarkers, and rigorously designed clinical trials.},
}

@article {pmid42883851,
year = {2026},
author = {Martynova, E and Mukhamedyarov, M and Kabwe, E and Khaiboullina, S and Simwalangana, O and Markelova, M and Rizvanov, A and Arkhipova, S and Salafutdinov, I},
title = {Phenotypic Profiling of SOD1-G93A Mice: Integrating Sciatic Nerve Histopathology with Systemic Chemokine Dynamics During ALS Progression.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198604},
pmid = {42883851},
issn = {1422-0067},
support = {25 25 01147//Russian Science Foundation/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Sciatic Nerve/pathology/metabolism/ultrastructure ; Mice ; Mice, Transgenic ; *Chemokines/metabolism/blood ; Disease Models, Animal ; Disease Progression ; *Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/pathology/metabolism ; Motor Neurons/metabolism/pathology ; Phenotype ; Cytokines/metabolism ; Superoxide Dismutase ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, leading to muscle atrophy and fatal respiratory failure. While neuroinflammation is a hallmark of ALS, the temporal and spatial relationship between systemic inflammation and peripheral nerve degeneration remains poorly understood. In the present study, the transgenic SOD1-G93A mouse model was employed to conduct a longitudinal analysis of amyotrophic lateral sclerosis (ALS) progression. We integrated morphometric and ultrastructural examinations of the sciatic nerve with immunofluorescent profiling of the spinal cord (GFAP, IBA1, NG2). In addition, cytokine and chemokine dynamics were analyzed using 33-plex multiplex assay in the serum at various stages of the disease. Histological analysis revealed a progressive decline in myelin fiber density within the sciatic nerve and axonal death. As the disease progressed, Schwann cells exhibited morphological features consistent with a pro-fibrotic shift, as suggested by collagen accumulation observed on TEM. However, direct confirmation of a fibrotic phenotype requires additional markers (e.g., Col I/III, α-SMA, TGF-β) and was not assessed in this study. Significant motor neuron loss and robust glial activation were demonstrated in the spinal cord. Blood plasma analysis identified a coordinated systemic up-regulation of MCP-3, Eotaxin, CTACK, and TECK. There was lack of inflammatory cell infiltration in the peripheral nerve tissues. Our results indicate that ALS-associated peripheral nerve degeneration in the SOD1-G93A mice model is primarily a degenerative process characterized by early demyelination and without leukocyte infiltration. However, increased levels of MCP-3, Eotaxin, CTACK, and TECK are associated with disease progression and may reflect ongoing central neuroinflammation. While these changes are temporally consistent with blood-spinal cord barrier dysfunction reported in SOD1 mice, direct assessment of barrier integrity was not performed in this study. These data highlight the potential of blood chemokines as step biomarkers and highlight the compartmental nature of inflammation in ALS, where systemic immune changes do not necessarily equate to local inflammation in the peripheral nerve.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics
*Sciatic Nerve/pathology/metabolism/ultrastructure
Mice
Mice, Transgenic
*Chemokines/metabolism/blood
Disease Models, Animal
Disease Progression
*Superoxide Dismutase-1/genetics/metabolism
Spinal Cord/pathology/metabolism
Motor Neurons/metabolism/pathology
Phenotype
Cytokines/metabolism
Superoxide Dismutase

@article {pmid42874698,
year = {2026},
author = {Ta, V and Ju, J and Kurata, K and Van, M and Wong, E and Ohgi, K and Magaña, Y and Castle, M and Wang, S},
title = {Intravenous administration of a PHP.eB vector overexpressing neuronal Caveolin-1 delays motor neuron and neuromuscular degeneration in a TDP-43 mouse model of ALS.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116069},
doi = {10.1016/j.expneurol.2026.116069},
pmid = {42874698},
issn = {1090-2430},
abstract = {TDP-43 proteinopathy is observed in over 95% of ALS cases, yet effective disease-modifying therapies remain elusive. We previously showed that neuron-specific overexpression of caveolin-1 via SynCav1 extended survival and delayed neurodegeneration in an SOD1 mouse model of ALS. Here, we further assessed the effect of systemic delivery of AAV-PHP.eB-SynCav1 in TDP-43[A315T] mice. At 24 weeks, SynCav1-treated mice showed preserved motor neuron (MN) morphology, maintained neuromuscular junction (NMJ) innervation, and normalized pathologically driven neurotrophic transcription in the spinal cord. Immunoblotting revealed that SynCav1 increased calcium-impermeable GluA2 in membrane lipid rafts of lumbar SC. However, these effects diminished with disease progression: by 32 weeks, lumbar MN loss and NMJ denervation were no longer significantly different between TDP-43-SynNull and TDP-43-SynCav1 mice, although partial protection was observed in the cervical spinal cord. These findings establish SynCav1 as an effective early-phase neuroprotective strategy and highlight the need for combinatorial approaches to achieve sustained protection.},
}

@article {pmid42875203,
year = {2026},
author = {Kawama, K and Bokuda, K and Kimura, H and Hayashi, K and Kawazoe, T and Totani, K and Matsuki, Y and Ishizawa, K and Sawada, J and Itagaki, Y and Haraguchi, M and Matsuda, C and Nakayama, Y and Yabuki, M and Takahashi, K and Shimizu, T},
title = {Bullous Pemphigoid in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Study of 1,067 Cases.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.7919-26},
pmid = {42875203},
issn = {1349-7235},
abstract = {Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurons. Bullous pemphigoid (BP) is an autoimmune blistering disease associated with autoantibodies against BP180 and BP230. Previous studies have suggested an increased incidence of BP in patients with ALS. However, the neurological status and disease severity of patients with ALS at the time of BP onset remain insufficiently characterized. This study aimed to investigate the frequency and clinical characteristics of BP in patients with ALS.Methods In this retrospective study, we reviewed the medical records of 1,067 patients with ALS who were admitted to our institution between April 2010 and May 2025. Patients who developed BP after the onset of ALS were identified. BP was diagnosed by dermatologists based on clinical findings and, when available, by immunological or histopathological examinations. Disease severity at BP onset was assessed based on the ambulatory status and ventilatory support requirements.Results Seven of the 1,067 patients (0.66%) developed BP after ALS onset. The median interval between ALS and BP onset was 8.0 years (IQR 5.0-16.5). At BP onset, four patients (57.1%) were bedridden, four (57.1%) required tracheostomy and invasive ventilation, and two (28.6%) required non-invasive ventilation. Five patients (71.4%) required enteral feeding. The median age at BP onset was 68.0 years (IQR, 64.0-72.5). BP180 antibody testing was positive in three of the six patients. The lesions most commonly involved both the extremities and the trunk.Conclusion BP may occur more frequently in ALS patients than in the general population. Clinicians should consider BP when evaluating cutaneous lesions in patients with ALS.},
}

@article {pmid42875680,
year = {2026},
author = {Gupta, R and Kumar, R and K S, BS and Modi, DK and Kumari, S and Kumar, N and Singh, P and Ravi, K and Abomughaid, MM},
title = {Restoring Neural Homeostasis via Class II HDAC Modulation: Mechanistic Insights and Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42875680},
issn = {1559-1182},
mesh = {Humans ; *Histone Deacetylases/metabolism ; Animals ; *Homeostasis/drug effects/physiology ; Neurodegenerative Diseases ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; *Neurons/metabolism/drug effects ; Signal Transduction ; },
abstract = {Class II histone deacetylases (HDACs) comprise class IIa enzymes HDAC4, HDAC5, HDAC7, and HDAC9 and class IIb enzymes HDAC6 and HDAC10, which differ substantially in structure, catalytic activity, subcellular localization, and neural function. Class IIa HDACs exhibit weak intrinsic deacetylase activity and function predominantly as signal-responsive scaffolds that couple calcium and kinase signaling to transcription through nucleocytoplasmic shuttling, recruitment of HDAC3-containing NCoR/SMRT corepressor complexes, and interactions with MEF2, CREB, and FOXO. Conversely, HDAC6 is a predominantly cytoplasmic deacetylase that regulates α-tubulin acetylation, cytoskeletal dynamics, axonal transport, autophagy, and proteostasis. Dysregulated class II HDAC signaling contributes to neurodegenerative diseases through convergent mechanisms involving synaptic dysfunction, maladaptive transcriptional repression, mitochondrial impairment, oxidative stress, neuroinflammation, blood-brain barrier disruption, and defective clearance of pathological proteins. Disease-associated substrates include amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and TDP-43/SOD1 in amyotrophic lateral sclerosis. Emerging evidence additionally links aberrant HDAC4/5 signaling to neurodevelopmental disorders through altered synaptic maturation, excitation-inhibition balance, and circuit development. This review integrates the structural and mechanistic biology of class II HDACs with their disease-specific roles and evaluates therapeutic approaches to restore neural homeostasis. Particular emphasis is placed on selective HDAC6 inhibitors, modulation of class IIa protein-protein interactions and subcellular trafficking, natural compounds, and RNA-based strategies. Finally, we discuss major translational challenges, including isoform specificity, brain penetration, context-dependent functions, and the need to distinguish catalytic from non-enzymic mechanisms when developing disease-modifying interventions for neurological disorders while preserving normal essential HDAC functions and minimizing off-target toxicity.},
}

Humans
*Histone Deacetylases/metabolism
Animals
*Homeostasis/drug effects/physiology
Neurodegenerative Diseases
Histone Deacetylase Inhibitors/pharmacology/therapeutic use
*Neurons/metabolism/drug effects
Signal Transduction

@article {pmid42875948,
year = {2026},
author = {Li, M and White, A and Canales, K and Fotopoulos, N},
title = {Ethical Dilemmas in Predictive Testing for Monozygotic Twins With Hereditary ALS: A Clinical Case Report.},
journal = {Journal of genetic counseling},
volume = {35},
number = {5},
pages = {e70307},
doi = {10.1002/jgc4.70307},
pmid = {42875948},
issn = {1573-3599},
mesh = {Humans ; *Twins, Monozygotic/genetics ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Female ; Ethical Dilemmas ; *Genetic Testing/ethics ; Adolescent ; Superoxide Dismutase-1/genetics ; Genetic Counseling/ethics ; Male ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder typically presenting in midlife and leading to death within 2-5 years of onset. Pathogenic SOD1 variants, inherited in an autosomal dominant manner, account for approximately 20% of hereditary ALS cases. Predictive genetic testing in SOD1-related ALS presents unique ethical challenges, particularly in monozygotic twins who share identical genetic information but hold differing views about testing. We describe an 18-year-old monozygotic twin who requested predictive testing for the familial SOD1 pathogenic variant identified in her father, who died from ALS at age 40. This conferred a 50% a priori risk to both twins. One twin had long expressed the desire to know her genetic status, while the other preferred not to pursue testing. Because a positive result in one twin would automatically reveal the status of the other, the case raised ethical tensions surrounding autonomy, beneficence, non-maleficence, and justice. Institutional ethics consultation and peer supervision were used to navigate these competing ethical imperatives and provided initial recommendations and direction. Additional valuable insights were gained through a peer-supervision framework that brought together genetic counselors across varying levels of experience and specialties. These discussions informed our ethical assessment and supported the decision to proceed with predictive testing, as the benefits were ultimately deemed to outweigh the potential risks. Testing identified the familial SOD1 pathogenic variant, which was disclosed to the patient and her family. Her twin subsequently elected to undergo confirmatory testing and received comprehensive genetic counseling and psychosocial support. Ethical complexities surrounding predictive genetic testing in monozygotic twins with hereditary neurodegenerative diseases, such as ALS, require careful balancing of autonomy, beneficence, non-maleficence, and justice. Structured peer supervision is essential for working through ethical uncertainty, guiding sound clinical decisions, and supporting patient-centered care.},
}

Humans
*Twins, Monozygotic/genetics
*Amyotrophic Lateral Sclerosis/genetics/diagnosis
Female
Ethical Dilemmas
*Genetic Testing/ethics
Adolescent
Superoxide Dismutase-1/genetics
Genetic Counseling/ethics
Male

@article {pmid42875960,
year = {2026},
author = {Zhang, W and Sun, Y and Liao, ZY and Xue, B and Ju, SY and Wan, YJ and Wang, YJ},
title = {Recent Advances in Engineering Ammonia Lyase for Biosynthesis of Aromatic Noncanonical Amino Acids.},
journal = {Biotechnology journal},
volume = {21},
number = {10},
pages = {e70321},
doi = {10.1002/biot.70321},
pmid = {42875960},
issn = {1860-7314},
support = {LQN26B060007//Zhejiang Provincial Natural Science Foundation of China/ ; 2025C01097//"Pioneer" and "Leading Goose" Key R&D Program of Zhejiang/ ; 22178318//National Natural Science Foundation of China/ ; 22608515//National Natural Science Foundation of China/ ; 2025M771186//China Postdoctoral Science Foundation/ ; },
mesh = {*Ammonia-Lyases/metabolism/genetics/chemistry ; *Protein Engineering/methods ; *Amino Acids, Aromatic/biosynthesis/chemistry/metabolism ; Biocatalysis ; },
abstract = {Aromatic noncanonical amino acids (aromatic ncAAs) are valuable building blocks for pharmaceuticals, agrochemicals, food additives, and specialty chemicals, yet their sustainable and stereoselective synthesis remains challenging. Ammonia-lyases (ALs) have emerged as powerful biocatalysts for the one-step asymmetric hydroamination of arylacrylic acids, and recent advances in protein engineering have substantially enhanced their catalytic performance including efficiency, selectivity, promiscuity, and productivity. This review integrates catalytic mechanisms with the deployment of engineering strategies to illustrate how aromatic amino acid ammonia-lyases (AALs) have evolved into versatile biocatalysts for aromatic ncAAs synthesis. Particular attention is devoted to the engineering of AALs (including phenylalanine, tyrosine, histidine ammonia lyase) and (methyl)aspartate ammonia lyases, highlighting progress in substrate scope expansion, catalytic promiscuity, selectivity modulation, and hybrid catalytic systems. Current limitations and emerging opportunities are further assessed to delineate future directions for next-generation ALs engineering. The engineering strategies and current states of ALs summarized herein provide a conceptual basis for the efficient development of ALs for sustainable aromatic ncAAs biomanufacturing.},
}

*Ammonia-Lyases/metabolism/genetics/chemistry
*Protein Engineering/methods
*Amino Acids, Aromatic/biosynthesis/chemistry/metabolism
Biocatalysis

@article {pmid42876567,
year = {2026},
author = {Liu, C and Tang, Q and Yu, L and Yu, Z},
title = {Handling missed dose of riluzole by population pharmacokinetic model informed remedial regimen.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1890355},
pmid = {42876567},
issn = {1663-9812},
abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) frequently exhibit nonadherence characterized by delayed or missed doses while taking riluzole. This study aimed to provide a population pharmacokinetic (PPK) model informed individualized remedial regimens for patients who experience delayed or missed doses of riluzole.

METHODS: A PPK model for riluzole was developed via a nonlinear mixed-effect modeling approach based on 3,024 concentration-time points from 72 subjects. The final model was validated by multiple methods. Six remedial regimens for missed doses were simulated for concentration-time profiles under different scenarios, and the optimal remedial regimen was selected based on the least time of concentration beyond the normal range.

RESULTS: The PPK model of riluzole was best described with a two-compartment model with body weight as a covariate of peripheral distribution volume. The typical values of CL/F, Vc/F, Vp/F and Q were 67 L/h, 242 L, 376 L and 33.1 L/h, respectively. The model was showed acceptable performance by goodness-of-fit, visual predictive check, bootstrap analysis and normalized distribution prediction errors. Model-based remedial regimens for different missed scenarios were proposed.

CONCLUSION: A riluzole PPK model was developed and internally evaluated using multiple diagnostic approaches. Model-based remedial dosing strategies for different missed-dose scenarios were identified based on predefined PK criteria and Monte Carlo simulations. These exploratory strategies provide quantitative insights into riluzole exposure during nonadherent dosing conditions.},
}

@article {pmid42877417,
year = {2026},
author = {Shu, H and He, R and Zhu, Z and Zhang, W and Xu, P},
title = {Exploring potential genetic correlation and causality between cathepsins and neurodegenerative diseases: Insight from Mendelian randomization analyses.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261437791},
pmid = {42877417},
issn = {2542-4823},
abstract = {BACKGROUND: Previous research has exhibited a potential association between cathepsins and neurodegenerative diseases (NDDs). Nevertheless, the causal relationships between cathepsins and different types of NDDs remain inadequately clear.

OBJECTIVE: We aim to explore the genetically correlation and causality between 4 NDDs and 9 cathepsins based on genome-wide association study platform.

METHODS: Cathepsin B, E, F, G, H, L2, O, S, and Z and four NDDs types, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and dementia with Lewy bodies, were obtained from large-scale genome-wide summary data. To explore potential interactive roles of these cathepsins in the pathogenesis of NDDs, we applied two-sample bidirectional univariable Mendelian randomization (MR) and multivariable MR, with inverse variance weighting as the primary statistical approach.

RESULTS: The univariable MR analysis revealed one positive and two negative causal effects between genetic liability in nine cathepsins and four NDDs. Reverse univariable MR analysis identified one negative causal link. Furthermore, the multivariable MR analysis not only confirmed two significant associations observed in the univariable analysis but also revealed a new positive effect.

CONCLUSIONS: Our findings demonstrate that several cathepsins are causally associated with different NDDs, offering new insights into the underlying mechanisms of neurodegeneration. These results may contribute to the development of novel diagnostic and therapeutic strategies for managing neurodegeneration.},
}

@article {pmid42877731,
year = {2026},
author = {Ayenew, AA and Mol, B and Fekadu, GA and Bradford, B},
title = {Lived experiences and impacts of female genital mutilation/cutting (FGM/C): a meta-ethnographic synthesis.},
journal = {BMJ public health},
volume = {4},
number = {1},
pages = {e001907},
pmid = {42877731},
issn = {2753-4294},
abstract = {BACKGROUND: This meta-ethnographic review synthesised qualitative evidence on the lived experiences and impacts of female genital mutilation/cutting (FGM/C). By incorporating insights from individuals who have undergone FGM/C, men and healthcare providers caring for affected populations, the study enriches understanding of the practice and its multifaceted consequences.

METHODS: Using Noblit and Hare's seven-stage meta-ethnographic framework, an inductive and interpretive synthesis was conducted. A comprehensive search of electronic databases, including PubMed/Medline, ScienceDirect, Google Scholar, ResearchGate, African Journals Online (AJOL) and the WHO website, identified qualitative and mixed-method studies that captured in-depth perspectives on FGM/C. The Critical Appraisal Skills Programme tool was used to assess the methodological quality of the included studies, and Ames et al's 5-point scale was applied to evaluate the conceptual richness of each study.

RESULTS: Fifty-three qualitative studies spanning diverse geographical and cultural contexts, both in traditionally practising regions and migrant communities, were included. Through rigorous analysis of first-order constructs (participant quotes) and second-order constructs (study authors' themes), five overarching themes were developed: (1) the onset: inherited tradition and gendered expectations; (2) ramifications on health and well-being; (3) inadequate health-seeking behaviours and lack of comprehensive healthcare services; (4) the psychosocial toll and (5) the perceived benefits of FGM/C. Each overarching theme comprises second-order constructs, along with participants' quotes.

CONCLUSION: This synthesis demonstrates how FGM/C is deeply intertwined with sociocultural norms and functions as a bidirectional bridge, presenting a complex dilemma for the health of women and girls, healthcare systems and broader society. On one hand, it serves as a pivotal gateway to sociocultural belonging and a source of social capital, shaping women's and girls' lives long after the practice itself. On the other hand, it inflicts immediate, short-term and long-term health impacts and poses considerable challenges for healthcare systems due to its diverse and interconnected consequences. This complexity makes it challenging to address all related issues within a single setting or with a single specialist, often leaving affected individuals behind in accessing the highest attainable quality of care and support, while simultaneously complicating elimination efforts.

PROSPERO REGISTRATION NUMBER: CRD42023387750.},
}

@article {pmid42878739,
year = {2026},
author = {Sanghai, N and Tranmer, GK},
title = {Diagnostic evolution of carbonic anhydrase 3 (CA3) in Amyotrophic Lateral Sclerosis (ALS): an emerging prognostic biomarker.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/14737175.2026.2748281},
pmid = {42878739},
issn = {1744-8360},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease traditionally viewed as a motor neuron disorder in which muscle atrophy occurs secondary to neuronal loss. However, recent clinical proteomic advances have highlighted carbonic anhydrase 3 (CA3), a muscle-enriched enzyme, as a promising biomarker associated with ALS disease progression. Therefore, considering ALS a neurocentric disease is not untenable.

AREAS COVERED: In this review, the authors examined the emergence of CA3 as an ALS biomarker and evaluated evidence from recent large-scale clinical consortium studies supporting its diagnostic and prognostic utility. They also compare CA3 with established biomarkers, neurofilament light chain (NEFL), a surrogate endpoint approved by the FDA.

EXPERT OPINION: Discoveries of CA3 biomarker in ALS highlight that peripheral skeletal muscle is not merely a passive bystander, but an integral participant in ALS disease progression. Unlike NEFL, which primarily reflects neuroaxonal injury, CA3 may capture early neuromuscular dysfunction preceding motor neuron degeneration. CA3's emergence as an ALS biomarker supports a more integrated neuromuscular model of ALS and provides a compelling rationale for incorporating CA3 into multimodal diagnostic, prognostic, and pharmacodynamic biomarker panels to accelerate ALS drug discovery, therapeutic evaluation, and precision clinical trial development, highlighting their complementary roles in early diagnosis, patient stratification, and therapeutic clinical trial design.},
}

@article {pmid42879383,
year = {2026},
author = {Bianchi, E and Beghi, E and Carlino, A and Cerri, F and Lunetta, C and Vitelli, E and Al-Chalabi, A and Leone, MA and Pupillo, E},
title = {Needs and Expectations of ALS Patients and Caregivers: An Integrated Perspective.},
journal = {European neurology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ene/acsag005},
pmid = {42879383},
issn = {1421-9913},
abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease requiring complex multidisciplinary care. As disability advances, patients' and caregivers' needs may diverge.

OBJECTIVES: to assess needs, priorities and satisfaction with care among people with ALS (pALS) and their caregivers; to examine the association between satisfaction and Quality of life (QoL); to explore differences according to clinical characteristics; to understand the Italian ALS community's willingness to engage in research.

METHODS: In this cross-sectional multicentre study, 154 pALS and 211 caregivers were recruited (July 2021-November 2022). Structured interviews explored information received, care priorities, research expectations and satisfaction. Answers to the interview were compared between patients and caregivers and between different patients' subgroups with the chi-square or the Fisher's exact test. The scores of QoL questionnaires were compared between satisfied vs. unsatisfied with the Wilcoxon-Mann-Whitney test in patients (ALSAQ-40) and caregivers (SF-36).

RESULTS: Patients prioritized finding a cure (95%) and overcoming disease-related limitations (72%) over safe and tolerable drugs (55%), similarly to caregivers. Research on psychological and emotional support was rated more important by caregivers (70%) than patients (49%). QoL was higher among satisfied patients, with better ALSAQ-40 scores in mobility, daily activities, communication and emotional domains. Caregivers needing urgent psychological support were fewer among the satisfied (35%) than the not satisfied (50%), and SF-36 mental health scores were also higher in satisfied caregivers.

CONCLUSIONS: Incorporating both pALS and caregiver perspectives into clinical practice and research planning may enhance patient- and family-centered care, improve QoL, and better align healthcare research and resources with societal needs.},
}

@article {pmid42879493,
year = {2026},
author = {Grima-Terrén, M and Rommelfanger, M and Campanario, S and Calls-Cobos, A and Cisneros, A and Ramírez-Pardo, I and Chou, G and Zheng, Y and Hah, N and Serrano, AL and Perdiguero, E and Isern, J and Muñoz-Cánoves, P},
title = {An integrative transcriptomic atlas of ALS and aging skeletal muscle defines shared and distinct molecular programs of degeneration.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {42},
pages = {e2613546123},
doi = {10.1073/pnas.2613546123},
pmid = {42879493},
issn = {1091-6490},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Muscle, Skeletal/metabolism/pathology ; *Aging/genetics/pathology/metabolism ; Mice ; *Transcriptome ; Sarcopenia/genetics/pathology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Neuromuscular Junction/metabolism/pathology ; Muscular Atrophy/genetics/pathology/metabolism ; Superoxide Dismutase-1/genetics ; },
abstract = {Skeletal muscle atrophy and weakness resulting from loss of motor neuron innervation are shared hallmarks of amyotrophic lateral sclerosis (ALS) and age-associated sarcopenia. However, muscle wasting in ALS is rapid and severe, whereas sarcopenia progresses gradually over decades, peaking at an advanced age. The molecular mechanisms underlying muscle wasting in these conditions remain incompletely defined. Here, we used the SOD1[G93A] ALS mouse model and wild-type mice across the lifespan to generate an integrated single-nucleus transcriptomic atlas of skeletal muscle, mapping changes associated with ALS and aging. This atlas is complemented by structural and functional analyses. Our results identify transcriptionally distinct condition-specific myonuclear states, including disease-responsive programs within synaptic myonuclei at the neuromuscular junction, that are shared or distinct between the two conditions. Notably, at early stages, muscle from ALS mice exhibits molecular hallmarks of aged muscle at the myofiber level, indicating premature aging and reinforcing aging as a risk factor in ALS. At advanced disease stages and in old age, myonuclear subpopulations follow similar degenerative pathways in fast glycolytic fibers, consistent with their loss in both conditions. However, a distinct ALS-enriched myonuclei subpopulation displays uniquely regulated genes not observed in aged muscle, potentially underlying the more rapid and severe pathology observed in ALS. This atlas maps shared and divergent mechanisms of muscle degeneration in ALS and sarcopenia and provides a resource for identifying therapeutic targets tailored to each condition.},
}

Animals
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*Muscle, Skeletal/metabolism/pathology
*Aging/genetics/pathology/metabolism
Mice
*Transcriptome
Sarcopenia/genetics/pathology/metabolism
Mice, Transgenic
Disease Models, Animal
Neuromuscular Junction/metabolism/pathology
Muscular Atrophy/genetics/pathology/metabolism
Superoxide Dismutase-1/genetics

@article {pmid42879998,
year = {2026},
author = {Calma, AD and Pavey, N and Tsuji, Y and Ghapar, AA and Orden, B and Lee, G and Mekhael, L and Ryder, J and Silva, CS and Menon, P and Vucic, S},
title = {Serum neurofilament and measures of lower motor neuron dysfunction in amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {193},
number = {},
pages = {2112428},
doi = {10.1016/j.clinph.2026.2112428},
pmid = {42879998},
issn = {1872-8952},
abstract = {OBJECTIVE: Serum neurofilament light chain (NfL) is an emerging diagnostic and prognostic biomarker in amyotrophic lateral sclerosis (ALS). Ulnar far-field potentials (FFP) have also been proposed as a reliable neurophysiological biomarker in ALS. This study examined the relationship between serum NfL levels and neurophysiological biomarkers of lower motor neuron dysfunction in ALS.

METHODS: This study included 96 ALS participants and 53 participants with ALS-mimicking disorders. All participants underwent serum NfL measurement using a single-molecule array (Simoa) assay, together with peripheral neurophysiological assessment, including ulnar nerve FFP, compound muscle action potential (CMAP), near-field potential (NFP), split-hand index (SI), and neurophysiological index (NI).

RESULTS: FFP amplitude was reduced in ALS (5.0 ± 3.0 mV) compared with non-ALS participants (7.9 ± 3.2 mV; p < 0.001). Similar reductions were observed for NFP and CMAP amplitudes (p < 0.001). Serum NfL was higher in ALS participants (72.5 pg/mL, IQR 46.5-113.5) compared to ALS-mimicking controls (14 pg/mL, IQR 9-19; p < 0.001). Serum NfL showed weak negative correlations with CMAP (ρ = - 0.23, p = 0.03) and NFP amplitudes (ρ = -0.28, p = 0.01), but no significant correlation with FFP amplitude, SI or NI. After adjusting for disease duration and functional impairment on multiple linear regression, neither CMAP nor NFP amplitudes independently predicted serum NfL levels.

CONCLUSION: Serum NfL is elevated in ALS and weakly associated with CMAP and NFP amplitudes. The absence of a statistically significant correlation with FFP suggests that these biomarkers may capture distinct aspects of disease biology.

SIGNIFICANCE: Serum NfL and FFP amplitude may provide complementary diagnostic information in ALS.},
}

@article {pmid42880056,
year = {2026},
author = {Wang, M and Li, J and Wang, X and Chai, X and Luo, J and Zhang, Y and Chang, X and Sun, Y and Wang, H},
title = {Harnessing cGAS-STING in neurodegeneration: From mitochondrial DNA leakage and microglial reactivity to species-specific translational barriers.},
journal = {Cytokine & growth factor reviews},
volume = {92},
number = {},
pages = {101537},
doi = {10.1016/j.cytogfr.2026.101537},
pmid = {42880056},
issn = {1879-0305},
abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of innate immunity, has emerged as a critical driver of sterile neuroinflammation in the aging brain. Age-related decline in mitochondrial quality control, coupled with nuclear and lysosomal erosion, fosters the aberrant accumulation of cytosolic self-DNA, establishing a permissive environment for chronic cGAS-STING activation. This review synthesizes recent breakthroughs elucidating how major neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-converge on this pathway through distinct, disease-specific triggers, ranging from PINK1/Parkin deficiency-driven mitochondrial DNA leakage to TDP-43 proteinopathy-associated retrotransposon de-repression. Critically, we evaluate the translational landscape, highlighting the profound challenge posed by species-specific pharmacology, as exemplified by the failure of the covalent inhibitor H-151 to engage human STING. We argue that the future of therapeutic intervention lies not in wholesale pathway ablation, but in nuanced, context-dependent fine-tuning that disentangles its detrimental chronic effects from its indispensable homeostatic functions. This review positions the cGAS-STING axis as a promising yet delicate frontier for combating age-related neurodegeneration.},
}

@article {pmid42880226,
year = {2026},
author = {DeAngelo, JD and Silverstein, AM and Shechter, D},
title = {Protein arginine methylation rewires molecular interactions.},
journal = {Cell chemical biology},
volume = {33},
number = {10},
pages = {1404-1421},
doi = {10.1016/j.chembiol.2026.09.011},
pmid = {42880226},
issn = {2451-9448},
mesh = {*Arginine/metabolism/chemistry ; Methylation ; *Protein-Arginine N-Methyltransferases/metabolism/chemistry ; Humans ; Protein Binding ; *Intrinsically Disordered Proteins/metabolism/chemistry ; },
abstract = {Protein arginine methyltransferases (PRMT1-9) catalyze monomethylation and dimethylation of arginine residues in RNA- and DNA-associated proteins. Protein arginine methylation can weaken or strengthen nucleic acid binding, recruit or exclude protein partners, and promote or suppress higher-order assembly, making its molecular consequences highly context dependent. Methylation preserves the cationic character of the guanidinium group, while altering hydrogen-bond donor topology, steric accessibility, and interaction geometry. These effects are particularly consequential in intrinsically disordered regions (IDRs), where arginine-rich motifs mediate multivalent protein-protein and protein-nucleic acid interactions. Here, we propose an interaction-equilibrium framework in which arginine methylation redistributes binding capacity among the competing protein, nucleic acid, and assembly states. This framework integrates reader-dependent and reader-independent effects of methylarginine and provides a chemical basis for understanding how a charge-preserving modification can reweight molecular interactions across diverse cellular contexts.},
}

*Arginine/metabolism/chemistry
Methylation
*Protein-Arginine N-Methyltransferases/metabolism/chemistry
Humans
Protein Binding
*Intrinsically Disordered Proteins/metabolism/chemistry

@article {pmid42880349,
year = {2026},
author = {Juhl, A and Jüngert, J and Hebert, S and Siebenlist, G and Mulzer, LM and Morhart, P and Woelfle, J and Knieling, F and Reutter, H and Hanslik, G},
title = {Postnatal Dynamics of Choroid Plexus Cysts in Newborns and Infants: A Retrospective Single-Center Cohort Study.},
journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2982-3894},
pmid = {42880349},
issn = {1438-8782},
abstract = {Purpose Choroid plexus cysts (CPC) are frequently detected prenatally and are generally considered benign. However, data on their postnatal course, growth dynamics, and clinical relevance are limited. This study investigates the long-term development, growth patterns, and resolution of CPC in newborns and infants. Materials and Methods We retrospectively analysed 251 CPC in 164 patients admitted to a neonatal intensive care unit between 2014 and 2024. CPC were assessed using serial cranial ultrasonography. Growth dynamics were evaluated using Kaplan-Meier survival analysis and chi-square testing. Results CPC were identified in both preterm and term infants, with a mean CPC size of 4.1 mm at diagnosis. Of 177 CPC with serial imaging data, 40% were not present on initial scans and appeared postnatally. The median time to resolution was 108 days. Many CPC initially increased in size before decreasing or resolving completely. A chi-square analysis showed a significant shift in growth behaviour between the 6- and 12-week follow-up groups (p = 0.006). No infant required intervention related to CPC. Conclusion Postnatal CPC often follow a benign, self-limiting course, meaning they tend to resolve naturally over time, with dynamic growth patterns. Routine monitoring of isolated CPC in asymptomatic infants may not be needed in all cases. Ziel Choroidplexuszysten (CPC) werden häufig pränatal festgestellt und gelten im Allgemeinen als gutartig. Allerdings liegen nur begrenzte Daten zu ihrem postnatalen Verlauf, ihrer Wachstumsdynamik und ihrer klinischen Relevanz vor. Diese Studie untersucht die langfristige Entwicklung, die Wachstumsmuster und die Rückbildung von CPC bei Neugeborenen und Säuglingen. Materialien und Methoden Wir analysierten retrospektiv 251 CPC bei 164 Patienten, die zwischen 2014 und 2024 auf eine neonatologische Intensivstation aufgenommen wurden. Die CPC wurden mittels serieller kranialer Sonographie beurteilt. Die Wachstumsdynamik wurde mittels Kaplan-Meier-Überlebensanalyse und Chi-Quadrat-Test ausgewertet. Ergebnisse CPC wurden sowohl bei Frühgeborenen als auch bei termingeborenen Säuglingen festgestellt, wobei die durchschnittliche CPC-Größe bei der Diagnose 4,1 mm betrug. Von 177 CPC mit seriellen Bildgebungsdaten waren 40 % bei den ersten Untersuchungen nicht nachweisbar und traten postnatal auf. Die mediane Zeit bis zur Rückbildung betrug 108 Tage. Viele CPC nahmen zunächst an Größe zu, bevor sie sich verkleinerten oder vollständig zurückbildeten. Eine Chi-Quadrat-Analyse zeigte eine signifikante Verschiebung im Wachstumsverhalten zwischen den 6- und 12-Wochen-Nachbeobachtungsgruppen (p = 0,006). Bei keinem Säugling war eine interventionelle Behandlung im Zusammenhang mit dem CPC erforderlich. Schlussfolgerung Postnatale CPC zeigen in der Regel einen gutartigen und selbstlimitierenden Verlauf mit dynamischen Wachstumsmustern und spontaner Rückbildung. Eine routinemäßige Verlaufskontrolle isolierter CPC bei asymptomatischen Säuglingen ist möglicherweise nicht in allen Fällen erforderlich.},
}

@article {pmid42869255,
year = {2026},
author = {Zhang, ZY and Qin, BQ and Wu, SZ and Zhang, H},
title = {Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118545},
doi = {10.1016/j.bcp.2026.118545},
pmid = {42869255},
issn = {1873-2968},
abstract = {Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.},
}

@article {pmid42869714,
year = {2026},
author = {Zhang, X and Xu, B and Peng, C and Li, H and Yang, K and Shen, A and Wang, J and Yang, X and Xia, Y and Hu, J and Aris, IM},
title = {Life-course associations of early-life risk factors, modifiable adult lifestyles, and transitions of cardiometabolic disease and multimorbidity: A prospective cohort study.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101486},
doi = {10.1016/j.ajcnut.2026.101486},
pmid = {42869714},
issn = {1938-3207},
abstract = {BACKGROUND: Whether associations of early-life risk factors with cardiometabolic disease (CMD) transitions vary by adult lifestyles remains unclear.

OBJECTIVES: We aimed to examine the associations between early-life risk factors and CMD transitions, and to assess whether adult lifestyles can modify these associations.

METHODS: We analyzed data from 174,718 adults participating in the United Kingdom Biobank prospective cohort study. We defined 5 CMD transitions using a multistate model: from CMD-free to first CMD (FCMD; including stroke, ischemic heart disease, and type 2 diabetes), from FCMD to cardiometabolic multimorbidity (CMM), and from CMD-free, FCMD, and CMM to death. An early-life risk score (ERS; 0-3) summed low birth weight, maternal smoking around birth, and absence of human milk feeding in infancy. Adult lifestyle was quantified using an adult lifestyle score (ALS) adapted from 4 behavioral metrics of the Life's Essential 8 framework, and data were collected at study enrollment when participants had a median age of 55 y.

RESULTS: During a median follow-up of 14.6 y, individuals with both high early-life risk (ERS ≥2) and an unhealthy adult lifestyle (ALS: 0-49) had the highest risks for most adverse transitions, including CMD-free to FCMD [hazard ratio (HR): 2.04; 95% confidence interval (CI): 1.89, 2.21], FCMD to CMM (HR: 1.46; 95% CI: 1.27, 1.69), CMD-free to death (HR: 2.31; 95% CI: 1.95, 2.72), and FCMD to death (HR: 1.64; 95% CI: 1.34, 2.01). The associations of ERS with the risk of most CMD transitions were less pronounced among participants with a healthy adult lifestyle than among those with an unhealthy adult lifestyle.

CONCLUSIONS: Joint exposure to adverse early-life experiences and an unhealthy adult lifestyle was associated with elevated risks of CMD progression and mortality. Notably, the detrimental associations of early-life risk factors with specific CMD transitions were less pronounced among individuals with healthier adult lifestyles.},
}

@article {pmid42869990,
year = {2026},
author = {Castro, J and de Carvalho, M and Swash, M},
title = {Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.},
journal = {Pflugers Archiv : European journal of physiology},
volume = {478},
number = {11},
pages = {},
pmid = {42869990},
issn = {1432-2013},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; Animals ; *Muscle Spindles/physiopathology/physiology ; *Motor Neurons/physiology ; Motor Neurons, Gamma/physiology ; *Spinal Cord/physiopathology ; Interneurons/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha-gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.},
}

*Amyotrophic Lateral Sclerosis/physiopathology/pathology
Humans
Animals
*Muscle Spindles/physiopathology/physiology
*Motor Neurons/physiology
Motor Neurons, Gamma/physiology
*Spinal Cord/physiopathology
Interneurons/physiology

@article {pmid42870990,
year = {2026},
author = {Nazir, A and Hanan, NP and Roberts, T},
title = {GEDI canopy cover assessment using airborne LiDAR across eco-climate regions of the United States.},
journal = {Frontiers in plant science},
volume = {17},
number = {},
pages = {1951245},
pmid = {42870990},
issn = {1664-462X},
abstract = {Information about woody plant density and canopy cover is central to our definition of terrestrial ecosystem types and crucial for understanding ecosystem state, dynamics, biogeochemical processes, and biodiversity. The Global Ecosystem Dynamics Investigation (GEDI) LiDAR on the International Space Station (ISS) samples 3-D structural information on woody vegetation structure, including an estimate of canopy cover in each 25 m diameter footprint. This study presents an evaluation of the GEDI fractional canopy cover estimates by comparing GEDI retrievals to high-resolution airborne laser scanning (ALS) data at 20 study sites with ~460,000 GEDI footprints across the United States. Based on the statistical assessment, we observed high correlations (R[2] = 0.84 without geolocation correction; R[2] = 0.96 with geolocation correction) with a Root Mean Square Error (RMSE) of 14.1% (without geolocation correction) and 7.2% (with geolocation correction). However, error in GEDI L2B canopy cover in some eco-climate regions is still significant, particularly in drylands (mean relative error (MRE) = 69.8%) and shrublands (MRE = 84.1%). The analysis also determined that the GEDI fractional cover retrievals are most effective when actual canopy cover is low (<20%) or high (>70%), with errors typically inflated in areas where canopy cover is in the 20-70% range. This study provides a baseline evaluation of GEDI canopy cover accuracy across eco-climate regions of CONUS, supporting improved interpretation and future refinement of the GEDI canopy cover product.},
}

@article {pmid42871488,
year = {2026},
author = {Monfared Jahromi, N and Maleki, A},
title = {Short-term Classification of Neurodegenerative Diseases using Time-series Features Based on Analysis of Gait Dynamics.},
journal = {Journal of biomedical physics & engineering},
volume = {16},
number = {5},
pages = {395-406},
pmid = {42871488},
issn = {2251-7200},
abstract = {BACKGROUND: Neurodegenerative Diseases (NDDs) refer to disorders, leading to the gradual degeneration of neurons in the human nervous system and profoundly affecting individuals' motor and cognitive functions. Early diagnosis and monitoring of the progression of NDDs are of critical importance.

OBJECTIVE: The primary aim of this study is to present an automatic diagnostic method using time-domain analysis of short-term gait signals of two consecutive steps, for the classification of Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and a Healthy Control Group (HC).

MATERIAL AND METHODS: This analytical study used datasets from PhysioNet, including 64 five-minute recordings from 13 individuals with ALS, 15 with Parkinson's, 20 with Huntington's, and 16 healthy individuals. To reduce noise and enhance signal quality, a median filter was applied. The preprocessed gait signals were then systematically segmented into consecutive two-step windows, which were used to construct the feature vectors. Finally, the constructed feature vectors were used as inputs for both linear and nonlinear classifiers. The proposed method was evaluated by calculating the accuracy index.

RESULTS: The quaternary classification of ALS vs. PD vs. HD vs. HC using the bag-tree classifier achieved an accuracy of 82.8%. Furthermore, for the binary classifications of HC vs. HD, HC vs. ALS, HC vs. PD and NDD vs. HC, the accuracies were 88.4%, 97.6%, 90% and 89.1%, respectively.

CONCLUSION: Gait dynamics analysis has a high potential for the rapid diagnosis of neurodegenerative diseases. Short term analysis in two consecutive stages enables the use of the Kinect sensor for gait analysis.},
}

@article {pmid42871744,
year = {2026},
author = {Castells-Ballester, J and Shcherbik, N},
title = {Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae.},
journal = {Microbial cell (Graz, Austria)},
volume = {13},
number = {},
pages = {358-377},
pmid = {42871744},
issn = {2311-2638},
abstract = {Protein misfolding and aberrant protein aggregation are central features of neurodegenerative disorders, including amyotrophic lateral sclerosis, where the RNA-binding protein TDP-43 accumulates in abnormal intracellular assemblies. Although yeast models have identified multiple modifiers of TDP-43 toxicity, the cellular factors that determine how aggregation-prone proteins are organized remain incompletely understood. Here, we investigated whether the ribosome- and mRNP-associated proteins Scp160 and Bfr1 influence TDP-43 proteotoxicity and aggregate formation. We report that deletion of SCP160 or BFR1 improves growth during TDP43-GFP induction without reducing steady-state reporter abundance and decreases formation of prominent TDP43-GFP foci. Deletion of BFR1 produced an intermediate TDP-43 phenotype, with a weaker effect than SCP160 deletion on severe foci formation and toxicity. Importantly, the effect of SCP160 or BFR1 deletion on visible protein aggregation was not specific to TDP-43: severe Htt103Q-GFP aggregation was strongly reduced, and formation of VHL-GFP foci was suppressed, including under conditions of proteasome inhibition. Despite these shared effects, the two mutants were not phenotypically identical. Deletion of SCP160 produced a distinct spatial phenotype in which residual TDP43-GFP foci showed markedly increased association with Sec63-positive ER structures and reduced distance to these regions, whereas bfr1 Δ cells did not show the same Sec63-associated shift. Together, these findings uncouple TDP43-GFP abundance from toxicity and prominent foci formation and identify Scp160 and Bfr1 as factors that influence the intracellular partitioning of aggregation-prone and misfolded proteins, with an additional role for Scp160 in the spatial organization of TDP43 relative to the ER.},
}

@article {pmid42872064,
year = {2026},
author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H},
title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1928641},
pmid = {42872064},
issn = {1664-3224},
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; },
abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Neurodegenerative Diseases/metabolism
Animals
Translational Research, Biomedical
Signal Transduction
Alarmins/metabolism
Biomarkers

@article {pmid42872742,
year = {2026},
author = {Onoichenco, A and Morris, SL and Aloe, S and McCay, K and Song, Y and Brady, ST},
title = {Isolated Axoplasm from Squid and Pathogenic Mechanisms in Amyotrophic Lateral Sclerosis.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/72560},
pmid = {42872742},
issn = {1940-087X},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Decapodiformes ; *Axons/pathology/metabolism ; Kinesins/metabolism ; },
abstract = {The squid giant axon is an experimental model that has been instrumental in providing answers to many fundamental questions in cell biology, including the discovery of the motor protein kinesin and probing molecular mechanisms of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). The giant axon offers scale and ease of access that is not possible in mammalian models. The power of this model stems from the fact that one can introduce reagents and proteins that would not cross a plasma membrane at defined concentrations in a buffer environment that is closely modeled on normal components of the axoplasm. By leveraging the unique biology of the squid axon, early studies were able to define the channels and ion specificities of the action potential. Subsequent studies using video-enhanced contrast- differential Interference contrast microscopy (VEC-DIC) and the isolated axoplasm led to the identification of kinesins, a class of motor proteins responsible for intracellular vesicle trafficking toward the plus end of microtubules. This combination of isolated axoplasm and advanced imaging continues to provide insights into pathogenic mechanisms for adult-onset neurodegeneration, including ALS, and regulation of fast axonal transport, a process disrupted in motor neuron disease. Here, procedures for dissecting the giant axon, isolating axoplasm, and perfusing defined amounts of proteins and/or reagents into the axoplasm are detailed, as well as methods for visualizing and interactively analyzing vesicle traffic in real time. This model represents a singular avenue to understand the critical function of neurons, shedding light on the mechanisms driving ALS pathology and other neurodegenerative diseases. This system also offers a tractable platform for drug testing, where candidate therapeutic compounds can be introduced directly into the axoplasm, and their effects on vesicle trafficking can be assessed in real time, providing a rapid and physiologically relevant means of identifying potential ALS therapeutic targets.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/metabolism
*Decapodiformes
*Axons/pathology/metabolism
Kinesins/metabolism

@article {pmid42873357,
year = {2026},
author = {Gündoğdu, AA and Özkan, NG and Adapınar, DÖ},
title = {The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42873357},
issn = {1573-7365},
mesh = {Humans ; *Microtubules/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Axonal Transport/physiology ; },
abstract = {Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.},
}

Humans
*Microtubules/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
Animals
tau Proteins/metabolism
Axonal Transport/physiology

@article {pmid42873683,
year = {2026},
author = {Wei, Z and Yanlin, G and Jing, L and Shazhen, A and Zhihan, Z and Zhuo, Z and Jiajia, Y and Xia, G and Xue, L and Shiyi, Y and Fei, X},
title = {Body composition characteristics in patients with inflammatory myopathy based on bioelectrical impedance analysis.},
journal = {Clinical and experimental rheumatology},
volume = {},
number = {},
pages = {},
doi = {10.55563/clinexprheumatol/fhq0ug},
pmid = {42873683},
issn = {0392-856X},
abstract = {OBJECTIVES: To investigate body composition features in idiopathic inflammatory myopathy (IIM) using bioelectrical impedance analysis (BIA) and evaluate their clinical, diagnostic and follow-up value.

METHODS: This study included 103 patients with inflammatory myopathy over a 6-year period, excluding 15 cases, resulting in a final cohort of 88 IIM patients. Clinical assessments and BIA were performed. Healthy controls and patients with amyotrophic lateral sclerosis (ALS) were independently recruited as separate comparison groups.

RESULTS: IIM patients showed reduced muscle mass (SMM: 20.9±4.4 vs. 23.4±4.8, p=0.001), elevated ECW/TBW ratio (ECW/TBW total (ETT): 0.398±0.015 vs. 0.381±0.007, p<0.001), and decreased phase angle (PhARA: 3.50 [2.92, 4.50]° vs. 5.15 [4.50, 5.62]°, p<0.001; PhALA: 3.55 [2.84, 4.43]° vs. 5.03 [4.48, 5.42]°, p<0.001). These features correlated with disease severity, inflammation, and nutritional status. Compared to ALS, IIM patients had more marked ECW retention (ETT: 0.397±0.0145 vs. 0.389±0.0110, p=0.001) and impaired membrane integrity (PhARA: 3.450±0.99° vs. 4.295±1.44°, p=0.014; PhALA: 3.500 [2.850, 4.400]° vs. 4.400 [3.875, 4.925]°, p=0.003). Body composition demonstrated substantial potential for diagnostic application (XGBoost model: specificity 85.00%, sensitivity 88.46%), and more importantly, may serve as a valuable tool for disease management.

CONCLUSIONS: BIA technology provides important novel disease characteristics for IIM patients, which are closely related to traditional clinical features and demonstrate significant diagnostic and management potential.},
}

@article {pmid42586272,
year = {2026},
author = {Chen, RF and Chen, SC},
title = {Response to Tognaccini et al, "Comment on Chen et al's 'Disparities of itch severity in outpatient clinics as measured by the ItchyQuant'".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.08.022},
pmid = {42586272},
issn = {1097-6787},
}

@article {pmid42762993,
year = {2026},
author = {Lei, L and Tan, R and Xu, F and Chen, J and Ma, F and Wang, W and Liu, Y},
title = {Response to Rodríguez-Conde et al's "Prognostic determinants of early and late relapse in cutaneous squamous cell carcinoma: A multicenter retrospective cohort study".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.08.124},
pmid = {42762993},
issn = {1097-6787},
}

@article {pmid42863380,
year = {2026},
author = {Mustafayev, B and Mustafayeva, A and Bakhtiyarov, A and Nikatov, K and Satylkhan, B and Mustafayev, A},
title = {Expanded Longitudinal Validation of Adaptive Learning Stability in AI-Assisted Neurosurgical Residency Training.},
journal = {Journal of surgical education},
volume = {83},
number = {11},
pages = {104210},
doi = {10.1016/j.jsurg.2026.104210},
pmid = {42863380},
issn = {1878-7452},
abstract = {OBJECTIVE: To evaluate the longitudinal stability, reproducibility, and robustness of Adaptive Learning Stability (ALS) within an expanded AI-assisted neurosurgical residency cohort during a 12-month observation cycle.

DESIGN: This was a prospective controlled educational study. Residents completed 4 consecutive quarterly checkpoints integrating cognitive, technical, and decision-making assessments over 12 months. The RCKaS-AI framework incorporated predictive analytics, individualized adaptive remediation, and mentor-validated feedback pathways. Primary analysis evaluated longitudinal entrustment trajectory stability across checkpoints. Secondary analyses included inter-resident variance dynamics, remediation frequency, faculty workload, and predictive agreement between forecasted and observed competency progression.

SETTING: Two accredited neurosurgical residency programs in Kazakhstan, from January 2025 to January 2026.

PARTICIPANTS: Sixty-four neurosurgical residents randomized into standard RCKaS (n = 32) and AI-enhanced RCKaS-AI (n = 32) cohorts.

RESULTS: Both cohorts demonstrated progressive improvement in entrustment scores across sequential checkpoints. In the RCKaS-AI cohort, mean entrustment scores increased from 59.1 ± 12.8 at CP1 to 94.3 ± 6.9 at CP4, compared with 58.4 ± 13.1 to 85.7 ± 10.4 under standard RCKaS conditions (p = 0.001). Inter-resident variance decreased by 41% in the AI-assisted cohort versus 18% in the standard cohort. Residents within the RCKaS-AI framework achieved entrustment level 4 significantly earlier than controls (38 ± 7 weeks vs 50 ± 9 weeks, p = 0.003). Mean remediation frequency decreased from 3.4 ± 1.1 to 1.9 ± 0.7 sessions per resident, while faculty workload declined by 34%. Predictive analytics demonstrated strong agreement between forecasted and observed competency trajectories (r = 0.84; 95% CI, 0.77-0.89).

CONCLUSIONS: Expanded longitudinal implementation of the RCKaS-AI framework demonstrated reproducible stabilization of competency trajectories during neurosurgical residency training. These findings support the robustness of adaptive AI-assisted feedback systems as a practical mechanism for longitudinal competency regulation within structured surgical education programs. Further multicenter validation is required to evaluate external reproducibility across broader residency environments.},
}

@article {pmid42864293,
year = {2026},
author = {Wang, S and Wang, M and Sun, Y and Liu, G and Li, Y and Zhang, W and Yao, J},
title = {[Effect of electroacupuncture at Jiaji (EX-B2) on disease progression in mice with amyotrophic lateral sclerosis based on NLRP3/Caspase-1/ASC signaling pathway].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {10},
pages = {1677-1684},
doi = {10.13703/j.0255-2930.20250518-k0001},
pmid = {42864293},
issn = {0255-2930},
mesh = {Animals ; *Electroacupuncture ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Mice ; Signal Transduction ; Humans ; Male ; *Caspase 1/metabolism/genetics ; Disease Progression ; *Acupuncture Points ; CARD Signaling Adaptor Proteins/metabolism/genetics ; Female ; Mice, Inbred C57BL ; Disease Models, Animal ; Spinal Cord/metabolism ; *Carrier Proteins/metabolism/genetics ; },
abstract = {OBJECTIVE: To explore the underlying mechanism of electroacupuncture (EA) at "Jiaji" (EX-B2) on the disease progression through modulating NOD-like receptor family pyrin domain containing 3 (NLRP3)/cysteine-aspartic acid protease 1 (Caspase-1)/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) signaling pathway in mice with amyotrophic lateral sclerosis.

METHODS: Forty-five mice carrying the human superoxide dismutase 1 G93A (hSOD1[G93A]) gene were randomly divided into a model group, a Jiaji EA group, and an inhibitor group, 15 mice per group. The other 15 mice without hSOD1[G93A] gene carried were collected as a wild group. When the mice were aged 60 days, in the Jiaji EA group, EA was operated at "Jiaji" (EX-B2) of L1/L2, L5/L6, with continuous wave, a frequency of 2 Hz and an intensity of 1 mA, retained for 20 min, twice a week; in the inhibitor group, the intraperitoneal injection with NLRP3 inhibitor (10 mg/kg) was administered, twice a week. The interventions lasted for 4 weeks in each group. When the mice were aged 120 days, 9 mice in each group were randomly selected for tissue collection from lumbar spinal cord, and the disease progression and limb function were observed for the remaining 6 mice. The neurological function score was employed to assess the disease progression of mice in each group, and the gait experiment was conducted to observe the gait and stride length; HE staining was used to observe the motor neuron morphology in the anterior horn of the lumbar spinal cord, immunohistochemistry was used to detect the expression of ionic calcium-binding adapter molecule 1 (Iba-1) in the anterior horn of the lumbar spinal cord, and Western blot was used to detect the protein expression of NLRP3, Caspase-1, ASC, interleukin (IL)-18 and IL-1β in lumbar spinal cord.

RESULTS: Compared with the wild group, in the model group, the disease was worsened progressively, on days 90 and 120 after birth, the stride length of mice was reduced (P<0.05, P<0.01), and the gait was unstable and dragging on 120 days after birth; the motor neurons in the anterior horn of the spinal cord exhibited obvious cellular edema and rupture, marked vacuolization and nuclear pyknosis, along with severe neuron loss; the expression of Iba-1 increased in the anterior horn of the lumbar spinal cord (P<0.01), colored dark brown and densely aggregated; and the protein expression of NLRP3, Caspase-1, ASC, IL-18, IL-1β in lumbar spinal cord was up-regulated (P<0.01). When compared with the model group, in the inhibitor group and the Jiaji EA group, the onset of paresis and the progression of paralysis were delayed and the survival rates increased (P<0.01); stride length was larger in the mice at the age of 120 d (P<0.01); more clear gait was presented, and the ages in days was significantly delayed for gait dragging; the improvements were exhibited in the degree of edema, vacuolization, and nuclear pyknosis observed in the motor neurons of the anterior horn of the lumbar spinal cord; the expression of Iba-1 was reduced in the anterior horn of the lumbar spinal cord (P<0.01), appearing gray-brown, and scattered clusters in small number; and the protein expression of NLRP3, Caspase-1, ASC, IL-18, and IL-1β in lumbar spinal cord was decreased (P<0.05, P<0.01). The protein expression of NLRP3, Caspase-1 and IL-18 in lumbar spinal cord in the Jiaji EA group was up-regulated in comparison with that in the inhibitor group (P<0.05).

CONCLUSION: Electroacupuncture at "Jiaji" (EX-B2) can delay the disease progression in mice with amyotrophic lateral sclerosis, which may be related to modulating NLRP3/Caspase-1/ASC signaling pathway and inhibiting the inflammatory response, thereby attenuating the inflammatory injury of lumbar spinal cord.},
}

Animals
*Electroacupuncture
*Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
Mice
Signal Transduction
Humans
Male
*Caspase 1/metabolism/genetics
Disease Progression
*Acupuncture Points
CARD Signaling Adaptor Proteins/metabolism/genetics
Female
Mice, Inbred C57BL
Disease Models, Animal
Spinal Cord/metabolism
*Carrier Proteins/metabolism/genetics

@article {pmid42864345,
year = {2026},
author = {Agarwal, T and Sneideris, T and Svara, F and Jermakovs, K and Coyle, H and Qamar, S and Kava, E and Scrutton, R and Pleschka, N and Peres, P and Cereghetti, G and Andrzejewska, E and Diaz-Barreiro, A and Palmer, G and Costa-Filho, AJ and Krainer, G and Knowles, TP and Nixon-Abell, J},
title = {Mapping high resolution, multidimensional phase diagrams of near-physiological protein condensates.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42864345},
issn = {2041-1723},
support = {227745/Z/23/Z//Wellcome Trust (Wellcome)/ ; },
mesh = {Humans ; *RNA-Binding Protein FUS/genetics/metabolism/chemistry ; *Biomolecular Condensates/chemistry/metabolism ; Cell Nucleolus/metabolism/chemistry ; *Stress Granules/metabolism/chemistry ; Animals ; Mutation ; Microfluidics/methods ; Phase Separation ; Machine Learning ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Aptamers, Nucleotide ; },
abstract = {Biomolecular condensates are membraneless compartments, crucial for organising and regulating diverse cellular processes. Current approaches to study condensate biology either use simplified recombinant protein systems with limited physiological relevance, or complex live-cell models with restricted experimental control and scalability. Here, we present ExVivo PhaseScan, a droplet microfluidics platform that couples mammalian lysate-based reconstitution with scalable analysis to generate high-resolution phase diagrams of compositionally complex protein condensates. We apply this approach to study two multicomponent condensate systems, stress granules and nucleoli, and dissect the physicochemical interactions that influence their stability. We further developed a machine learning pipeline to analyse condensate morphology which we use to reveal how mutations in the amyotrophic lateral sclerosis (ALS)-linked protein Fused in Sarcoma (FUS) remodels condensate properties. We identify liquid-to-solid transitions of mutant FUS within stress granules and nucleoli, and show that these transitions can be reversed by RNA aptamer-based interventions. Together, these findings establish ExVivo PhaseScan as a versatile tool for dissecting the physicochemical and pathological regulation of condensates, with potential to inform therapeutic strategies for diseases driven by aberrant phase transitions.},
}

Humans
*RNA-Binding Protein FUS/genetics/metabolism/chemistry
*Biomolecular Condensates/chemistry/metabolism
Cell Nucleolus/metabolism/chemistry
*Stress Granules/metabolism/chemistry
Animals
Mutation
Microfluidics/methods
Phase Separation
Machine Learning
Amyotrophic Lateral Sclerosis/genetics/metabolism
Aptamers, Nucleotide

@article {pmid42864501,
year = {2026},
author = {Saha, T and Mehan, S},
title = {Combined rituximab and magnesium acetyl taurate therapy attenuates neurodegeneration via ERK/c-JNK/P38MAPK signaling modulation in methylmercury-induced amyotrophic lateral sclerosis-like neurotoxicity.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42864501},
issn = {1432-1912},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, oxidative stress, neuroinflammation, mitochondrial dysfunction, and dysregulation of intracellular signaling pathways. The present study investigated the neuroprotective potential of rituximab (RTXMB), alone and in combination with magnesium acetyl taurate (MACT600), against methylmercury (MLMC5)-induced ALS-like pathology in adult Wistar rats through modulation of the ERK/c-JNK/P38MAPK signaling pathway. ALS was induced by oral administration of MLMC5 (5 mg/kg) for 21 days. RTXMB (50 and 100 mg/kg) and MACT600 (600 mg/kg) treatments were administered from day 22 to day 42. Behavioral assessments, neurochemical estimations, ELISA, Western blotting, hematological analysis, gross morphology, and histopathological evaluations were performed. MLMC5 exposure produced significant impairments in locomotion, muscular strength, cognition, and emotional behavior, accompanied by increased oxidative stress, inflammatory cytokines, glutamate excitotoxicity, apoptotic markers, methylmercury accumulation, and dysregulation of ERK/c-JNK/P38MAPK signaling. Moreover, MLMC5 caused marked demyelination, neuronal degeneration, neurotransmitter imbalance, skeletal muscle damage, and hematological dysfunction. RTXMB treatment significantly attenuated these pathological alterations in a dose-dependent manner, with RTXMB100 showing greater neuroprotective efficacy. Combined administration of RTXMB100 and MACT600 demonstrated the most pronounced therapeutic effects by restoring antioxidant defenses, suppressing neuroinflammation and apoptosis, normalizing neurotransmitter levels, preserving myelin integrity, and improving neuronal morphology. The findings suggest that RTXMB, particularly in combination with MACT600, exerts potent neuroprotective effects against ALS-like pathology via modulation of MAPK signaling pathways and may represent a promising therapeutic strategy for ALS management.},
}

@article {pmid42864601,
year = {2026},
author = {Li, M and Jiao, YG and Tao, R and Hu, Y and Fei, JY and Wang, CT and Yao, SH},
title = {Optimized gGBE enables robust G-to-Y conversion in mammalian cells and zebrafish embryos.},
journal = {Zoological research},
volume = {47},
number = {6},
pages = {1839-1850},
doi = {10.24272/j.issn.2095-8137.2025.361},
pmid = {42864601},
issn = {2095-8137},
mesh = {Animals ; *Zebrafish/genetics/embryology ; Humans ; *Gene Editing/methods ; Embryo, Nonmammalian ; CRISPR-Cas Systems ; Amyotrophic Lateral Sclerosis/genetics ; *Glycoside Hydrolases/genetics/metabolism ; },
abstract = {Base editing is a powerful and precise genome-editing tool capable of introducing single-base substitutions with high resolution. Depending on the base-modification domains employed, base editors can mediate both transition and transversion base editing in mammalian cells. While deaminase-derived base editors have enabled efficient transition editing in the zebrafish genome, glycosidase-derived transversion editing remains a significant challenge. In this study, guided by structural insights into the Cas9 complex, we engineered a series of glycosidase guanine base editor (gGBE) constructs by inlaying the N-methylpurine DNA glycosylase (MPG) domain into Cas9 protein. Among these variants, we identified a high-performance gGBE in which MPG was inserted between residues G1246 and S1247 of the PI domain in Streptococcus pyogenes Cas9, which we named gGBE-PIGS. This variant improved editing efficiency by up to 3.5-fold in mammalian cells and 13-fold in zebrafish embryos, without compromising editing precision. Furthermore, we developed a gGBE-editing-responsive GFP reporter to monitor editing efficiency and enrich for gGBE-edited cells and embryos. Using a combination of the optimized gGBE-PIGS and the GFP reporter, we successfully generated zebrafish models carrying mutations homologous to human amyotrophic lateral sclerosis (ALS)-associated variants. Together, these findings highlight the robustness and versatility of the gGBE platform for precise base editing and underscore its promising potential for in vivo disease modeling and therapeutic genome engineering.},
}

Animals
*Zebrafish/genetics/embryology
Humans
*Gene Editing/methods
Embryo, Nonmammalian
CRISPR-Cas Systems
Amyotrophic Lateral Sclerosis/genetics
*Glycoside Hydrolases/genetics/metabolism

@article {pmid42864685,
year = {2026},
author = {Liao, K and Lin, J and Zhou, Y and Lewandowski, SA},
title = {Vascular profiling of the spinal cord and cortex reveals region-specific endothelial dysfunction and fibroblast remodeling in human ALS.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42864685},
issn = {2051-5960},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics/physiopathology ; *Fibroblasts/pathology/metabolism ; *Spinal Cord/blood supply/pathology/metabolism ; *Endothelial Cells/pathology/metabolism ; *Cerebral Cortex/blood supply/pathology/metabolism ; Blood-Brain Barrier/metabolism/pathology ; Transcriptome ; Female ; Male ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Increasing evidence suggests that neurovascular dysfunction contributes to ALS pathogenesis, but a comprehensive understanding of vascular cell alterations in the human central nervous system remains lacking. Here, to systematically characterize neurovascular changes in ALS, we curated single-nucleus transcriptomic datasets from human spinal cord and cortical tissues with a specific focus on vascular cell populations. Comparative analyses revealed substantial vascular perturbations in the spinal cord compared to the cortex. Among vascular-associated cell populations, endothelial cells and fibroblasts exhibited the most pronounced transcriptional alterations. Endothelial cells from ALS spinal cords displayed reduced blood-brain barrier integrity signatures and increased expression of inflammatory and stress-response programs, with the greatest changes manifested in capillary endothelial cells. In parallel, we generated a refined cellular atlas of spinal cord fibroblasts and identified three major fibroblast populations, including a distinct LAMA1[low] perivascular fibroblast subtype. Fibroblast signatures were found to be consistently elevated in ALS across single-nucleus transcriptomic, bulk transcriptomic, and experimental validation datasets. Together, our findings establish a region-resolved view of neurovascular alternations in human ALS, which is characterized by endothelial barrier dysfunction and disease-associated remodeling of specialized perivascular fibroblasts. These findings broaden the cellular framework of ALS pathogenesis beyond neuronal and glial alterations and highlight the neurovascular niche as an integral component of human ALS disease biology.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics/physiopathology
*Fibroblasts/pathology/metabolism
*Spinal Cord/blood supply/pathology/metabolism
*Endothelial Cells/pathology/metabolism
*Cerebral Cortex/blood supply/pathology/metabolism
Blood-Brain Barrier/metabolism/pathology
Transcriptome
Female
Male

@article {pmid42864786,
year = {2026},
author = {Hokkoku, K},
title = {[Lumbar Spinal Disease or Peripheral Nerve Disorder? The Role of Neurological Examination in Differential Diagnosis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {10},
pages = {1089-1096},
doi = {10.11477/mf.188160960780101089},
pmid = {42864786},
issn = {1881-6096},
mesh = {Humans ; Diagnosis, Differential ; *Peripheral Nervous System Diseases/diagnosis ; *Neurologic Examination ; Nerve Conduction Studies ; *Spinal Diseases/diagnosis ; },
abstract = {Lower-limb numbness, pain, and weakness are common clinical complaints that require differentiation between cauda equina or radicular lesions associated with lumbar spinal disease and peripheral nerve disorders. Because degenerative findings on lumbar imaging are common, particularly among older adults, the responsible lesion should not be determined based on imaging findings alone. In this context, neurological examination contributes to anatomical localization and is central to the differential diagnosis. Particular emphasis is placed on interpreting muscle weakness and sensory disturbance according to myotomal, dermatomal, and peripheral nerve distributions. Other neurological findings, including gait disturbance, neurogenic claudication, bladder or bowel dysfunction, nerve stretch signs, and reflex changes, also provide important clues for localization. This review further addresses common diagnostic challenges encountered in daily practice, including differentiation of L5 radiculopathy from fibular neuropathy in patients with foot drop, distinction between cauda equina lesions and polyneuropathy, recognition of immune-mediated polyradiculoneuropathies, and identification of amyotrophic lateral sclerosis when it mimics lumbar spinal disease. Ancillary tests such as nerve conduction studies, needle electromyography, somatosensory evoked potentials, nerve ultrasound, and imaging should be interpreted in relation to the lesion localization suggested by neurological examination.},
}

Humans
Diagnosis, Differential
*Peripheral Nervous System Diseases/diagnosis
*Neurologic Examination
Nerve Conduction Studies
*Spinal Diseases/diagnosis