@article {pmid41044342,
year = {2025},
author = {Ionescu, A and Ankol, L and Ganapathy Subramaniam, A and Altman, T and Magen, I and Cohen, Y and Danino, Y and Gradus-Pery, T and Niv, Y and Bar Avi, O and Geller, D and Ibraheem, A and Cheng, R and Steinberg, N and Alfahel, L and Duc, P and Ergul-Ulger, Z and Arslan, D and Tan, E and Rage, F and Riva, N and Quattrini, A and Bekircan-Kurt, CE and Israelson, A and Dori, A and Hornstein, E and Perlson, E},
title = {Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41044342},
issn = {1546-1726},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1[G93A] mice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression.},
}

@article {pmid41043802,
year = {2025},
author = {Hardie, T and Oliver, A and McCarthy, PJ and McCann, B},
title = {Identifying Cognitive Processes in Male Rugby Union Place-Kickers Using a "Think Aloud" Protocol.},
journal = {Journal of sport & exercise psychology},
volume = {},
number = {},
pages = {1-11},
doi = {10.1123/jsep.2024-0358},
pmid = {41043802},
issn = {1543-2904},
abstract = {This study explored cognitive processes in elite rugby union place-kickers using a Think Aloud protocol. Five male kickers (Mage = 25.8 years) from Scotland's top domestic league wore microphones to verbalize thoughts during place-kicks from varied distances and angles. Recordings were transcribed verbatim and analyzed through abductive content analysis using Elliott et al.'s framework. Findings revealed planning as the dominant cognitive theme, with participants consistently using preperformance routines incorporating visualization techniques. External attributions of failure emerged as a novel coping strategy among four of five kickers. The results demonstrate how elite performers use metacognitive strategies, informed by dynamic self-regulation, and adaptive systems principles to regulate attention and adapt to task demands. These findings provide new insights into the cognitive architecture of specialized sports skills and highlight Think Aloud's value for capturing real-time thought processes. For applied practice, the study offers concrete recommendations for developing individualized routines that optimize attentional control and performance consistency in pressure situations.},
}

@article {pmid41043541,
year = {2025},
author = {Zhuang, J and Zhang, Z and Jin, H and Qi, J and Chen, Y and Ding, L and Fu, C and Cheng, W},
title = {C9orf72 related poly-Glycine-Alanine promotes tau phosphorylation and cell death via ERK1/2 interaction in cellular models.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.09.053},
pmid = {41043541},
issn = {1873-7544},
abstract = {Frontotemporal lobar degeneration (FTLD), particularly cases linked to the C9ORF72 GGGGCC repeat expansion (r(G4C2)exp), is closely associated with TAR DNA-binding protein 43 (TDP-43) pathology but also exhibits concurrent tau pathology characterized by hyperphosphorylation and neurofibrillary tangles (NFTs). Despite evidence suggesting heightened tau pathology severity in C9ORF72 mutation carriers compared to other FTLD subtypes, the mechanistic interplay between r(G4C2)exp and tau dysregulation remains poorly understood. Using a cellular model, we demonstrated that (GA)50 causes significant neuronal cell death. We found that (GA)50 was shown to specifically bind to extracellular-regulated kinase 1/2 (ERK1/2) protein, leading to its hyperphosphorylation. This activation of ERK1/2 was associated with increased tau phosphorylation and aggregation. Importantly, inhibiting ERK1/2 activity with U0126 significantly reduced tau phosphorylation, aggregation, and cell death in cells overexpressing (GA)50. These in vitro findings suggest that (GA)50-driven ERK1/2 hyperphosphorylation may represent potential driver of tau pathology in C9ORF72-related FTLD, highlighting the ERK1/2 signaling or its interaction with poly-glycine-alanine (GA) as a potential therapeutic target.},
}

@article {pmid41043460,
year = {2025},
author = {Rasheed, S and Bennett, J and Yoo, PE and Burkitt, AN and Grayden, DB},
title = {Decoding saccadic eye movements from brain signals using an endovascular neural interface.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae0f52},
pmid = {41043460},
issn = {1741-2552},
abstract = {An Oculomotor Brain-Computer Interface (BCI) records neural activity from brain regions involved in planning eye movements and translates this activity into control commands. While previous successful studies have relied on invasive implants in non-human primates or electrooculography (EOG) artefacts in human electroencephalogram (EEG) data, this study aimed to demonstrate the feasibility of an oculomotor BCI using a minimally invasive endovascular StentrodeTM device implanted near the supplementary motor area of a patient with Amyotrophic Lateral Sclerosis (ALS). Approach. One participant performed self-paced visually-guided and free-viewing saccade tasks in four directions (left, right, up, down) while endovascular EEG and eye gaze recordings were collected. Visually-guided saccades were cued with visual stimuli, whereas free-viewing saccades were self-directed without explicit cues. Brain signals were pre-processed to remove cardiac artefacts, downsampled, and classified using a Random Forest algorithm. For saccade onset classification (fixation vs. saccade), features in time and frequency domains were extracted after xDAWN denoising, while for saccade direction classification, the downsampled time series were classified directly without explicit feature extraction. Main results. The neural responses of visually-guided saccades overlapped with cue-evoked potentials, while free-viewing saccades exhibited saccade-related potentials that began shortly before eye movement, peaked approximately 50 ms after saccade onset, and persisted for around 200 ms. In the frequency domain, these responses appeared as a low-frequency synchronisation below 15 Hz. Saccade onset classification was robust, achieving mean area under the receiver operating characteristic curve (AUC) scores of 0.88 within sessions and 0.86 across sessions. Saccade direction decoding yielded within-session AUC scores of 0.67 for four-class decoding and up to 0.75 for the best performing binary comparisons (left vs. up and left vs. down). Significance. This proof-of-concept study demonstrates the feasibility of an endovascular oculomotor BCI in a patient with ALS, establishing a foundation for future oculomotor BCI studies in human subjects.},
}

@article {pmid41043426,
year = {2025},
author = {Ma, GM and Xia, CC and Lyu, BY and Liu, J and Luo, F and Guan, MF and Wang, JY and Sun, L and Zhang, L and Chen, Y and Mao, YW and Yu, GQ and Wang, WY},
title = {Integrated profiling of iPSC-derived motor neurons carrying C9orf72, FUS, TARDBP, or SOD1 mutations.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102649},
doi = {10.1016/j.stemcr.2025.102649},
pmid = {41043426},
issn = {2213-6711},
abstract = {Here, we conducted temporal RNA sequencing (RNA-seq) profiling of human induced pluripotent stem cells (hiPSCs) and induced pluripotent stem cell (iPSC)-derived motor neurons (iMNs) carrying C9orf72, FUS, TARDBP, or SOD1 mutations in both patients with amyotrophic lateral sclerosis (ALS) and healthy individuals. We discovered dysregulated gene expression and alternative splicing (AS) throughout iMN development and maturation, and iMNs with mutations in ALS-associated genes displayed enrichment of cytoskeletal defects and synaptic alterations from the premature stage to mature iMNs. Our findings indicate that synaptic gene dysfunction is a common molecular hallmark of familial ALS, which may result in neuronal susceptibility and progressive motor neuron degeneration. Analysis of upstream splicing factors revealed that differentially expressed RNA-binding proteins (RBPs) in iMNs from patients with ALS may cause abnormal AS events. Overall, our research provides a comprehensive and valuable resource for gaining insights into the shared mechanisms of familial ALS pathogenesis during motor neuron development and maturation in iMN models.},
}

@article {pmid41043388,
year = {2025},
author = {Deniz, AA},
title = {Spheres, worms, and packing problems in the nanoscale assembly of ALS-linked protein Matrin-3.},
journal = {Molecular cell},
volume = {85},
number = {19},
pages = {3549-3550},
doi = {10.1016/j.molcel.2025.09.013},
pmid = {41043388},
issn = {1097-4164},
mesh = {Humans ; *RNA-Binding Proteins/metabolism/chemistry/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Animals ; Nuclear Matrix-Associated Proteins ; },
abstract = {Matrin-3 (MATR3) is an RNA-binding protein that forms higher-order assemblies and pathological inclusions associated with neurodegenerative diseases. In this issue of Molecular Cell, Sprunger et al.[1] explore the assembly of MATR3 and find that it forms spherical and worm-like nanoscale assemblies distinct from condensates formed by macrophase separation.},
}

Humans
*RNA-Binding Proteins/metabolism/chemistry/genetics
*Amyotrophic Lateral Sclerosis/metabolism/genetics
Animals
Nuclear Matrix-Associated Proteins

@article {pmid41043093,
year = {2025},
author = {Crayle, JI and Crayle, JI and Rampersaud, E and Myers, JR and Wuu, J and Wu, G and Benatar, M and Bedlack, RS},
title = {Author Response: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.},
journal = {Neurology},
volume = {105},
number = {9},
pages = {e210166},
doi = {10.1212/WNL.0000000000210166},
pmid = {41043093},
issn = {1526-632X},
}

@article {pmid41043092,
year = {2025},
author = {Lewis, A and Galetta, SL},
title = {Editors' Note: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.},
journal = {Neurology},
volume = {105},
number = {9},
pages = {e214258},
doi = {10.1212/WNL.0000000000214258},
pmid = {41043092},
issn = {1526-632X},
}

@article {pmid40891271,
year = {2025},
author = {Genuis, SK and Luth, W and Johnston, WS},
title = {Asymmetry and Alignment: Physician Perspective on Patient-Based Evidence for Improving Health Communication.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-4},
doi = {10.1017/cjn.2025.10407},
pmid = {40891271},
issn = {0317-1671},
abstract = {We investigated the response of experienced amyotrophic lateral sclerosis physicians to patient-based evidence pertaining to health communication. Fifteen expert amyotrophic lateral sclerosis (ALS) physicians participated in an in-person focus group. Focusing on clinical feasibility and first-hand experience, participants discussed recommendations from people with ALS and caregivers for improving communication. Data were qualitatively analyzed using conventional content analysis. Findings demonstrated shared and differing perspectives, and communication challenges. Findings suggest a difference in perspective centered on how to achieve the shared goal of patient-centered communication. We discuss asymmetry between healthcare professional perspectives and patient-based evidence, and opportunities for alignment that will advance effective health communication.},
}

@article {pmid41043090,
year = {2025},
author = {van Rheenen, W and Harms, M and van Es, MA and Veldink, JH},
title = {Reader Response: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.},
journal = {Neurology},
volume = {105},
number = {9},
pages = {e210115},
doi = {10.1212/WNL.0000000000210115},
pmid = {41043090},
issn = {1526-632X},
}

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

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

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

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

@article {pmid41042380,
year = {2025},
author = {Wang, S and Jiang, H and Yao, T},
title = {Integrative genomics and functional immunology reveal Clostridia species as modulators of neuroinflammation in amyotrophic lateral sclerosis.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {74},
number = {1},
pages = {136},
pmid = {41042380},
issn = {1420-908X},
support = {2020B22//Doctoral Fund of the First Affiliated Hospital of Harbin Medical University/ ; 2023ZX07D06//The key research and development project of Heilongjiang Province/ ; 2022-KYYWF-0301//Innovative Scientific Research Funding Project of Harbin Medical University/ ; PL2024H140//Natural Science Foundation of Heilongjiang Province,China/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/microbiology/genetics ; *Gastrointestinal Microbiome ; Male ; Female ; Middle Aged ; Cytokines/immunology ; Genomics ; *Neuroinflammatory Diseases/immunology/microbiology/genetics ; Aged ; Myeloid-Derived Suppressor Cells/immunology ; Mendelian Randomization Analysis ; },
abstract = {OBJECTIVE: This multiomics study investigated causal relationships between the gut microbiota (GM), immune dysregulation, and amyotrophic lateral sclerosis (ALS) pathogenesis using Mendelian randomization (MR) with experimental validation.

MATERIALS: Analyses incorporated genome-wide data from 87,347 participants (GM: n = 7738; ALS: 20,806 patients, 59,804 controls; immune phenotypes: n = 3757), transcriptomic data from 71 subjects (56 ALS patients, 15 controls), and experimental validation in matched cohorts (n = 6 subjects per group).

METHODS: Two-sample bidirectional MR and mediation analysis were used to evaluate associations. Experimental validation employed flow cytometry for myeloid-derived suppressor cell quantification, enzyme-linked immunosorbent assay for cytokines, and real-time polymerase chain reaction for bacterial validation. Statistical analyses included inverse variance weighted methods with Cohen's d calculations.

RESULTS: Sixteen bacterial taxa, including p_Firmicutes.c_Clostridia, displayed protective associations with the risk of ALS, whereas sixteen showed harmful associations. Mediation analysis suggested that p_Firmicutes.c_Clostridia may confer protection through CD33+HLA-DR-myeloid-derived suppressor cell upregulation (23.8% mediation effect). Experimental validation confirmed fewer myeloid-derived suppressor cells in ALS patients (4.0 ± 0.8% vs. 7.5 ± 1.0%, p < 0.001, Cohen's d = 1.4) and lower levels of anti-inflammatory cytokines (TGF-β1: Cohen's d = 1.8, p < 0.001).

CONCLUSIONS: These findings support causal associations between gut microbial taxa and the ALS risk, which are mediated through immunoregulatory mechanisms, highlighting therapeutic targets within the gut‒immune‒brain axis.},
}

Humans
*Amyotrophic Lateral Sclerosis/immunology/microbiology/genetics
*Gastrointestinal Microbiome
Male
Female
Middle Aged
Cytokines/immunology
Genomics
*Neuroinflammatory Diseases/immunology/microbiology/genetics
Aged
Myeloid-Derived Suppressor Cells/immunology
Mendelian Randomization Analysis

@article {pmid41042334,
year = {2025},
author = {Zhang, J and Han, F and Wang, X and Wu, F and Song, X and Liu, Q and Wang, J and Grecucci, A and Zhang, Y and Yi, X and Chen, BT},
title = {Brain metabolic imaging with 18 F-PET-CT and machine-learning clustering analysis reveal divergent metabolic phenotypes in patients with amyotrophic lateral sclerosis.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {41042334},
issn = {1619-7089},
support = {No.2024PT5109//Scientific Research Program of FuRong Laboratory/ ; 2021YFA0805202//the National Key R&D Program of China/ ; STI2030-Major Projects: 2021ZD0201803//Science and Technology Innovation 2030/ ; Xiangya Hospital, Grant No. 2020LNJJ13 and 2022LNJJ09//Project Program of National Clinical Research Center for Geriatric Disorders/ ; No. 62402176//National Natural Science Foundation of China/ ; 2024JJ6191//Hunan Provincial Natural Science Foundation of China/ ; kq2402099//Changsha Municipal Natural Science Foundation/ ; 23B0626//Project Supported by Scientific Research Fund of Hunan Provincial Education Department/ ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant clinicopathologic heterogeneity. This study aimed to identify distinct ALS phenotypes by integrating brain 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (18 F-FDG PET-CT) metabolic imaging with consensus clustering data.

METHODS: This study prospectively enrolled 127 patients with ALS and 128 healthy controls. All participants underwent a brain 18 F-FDG-PET-CT metabolic imaging, psychological questionnaires, and functional screening. K-means consensus clustering was applied to define neuroimaging-based phenotypes. Survival analyses were also performed. Whole exome sequencing (WES) was utilized to detect ALS-related genetic mutations, followed by GO/KEGG pathway enrichment and imaging-transcriptome analysis based on the brain metabolic activity on the 18 F-FDG-PET-CT imaging.

RESULTS: Consensus clustering identified two metabolic phenotypes, i.e., the metabolic attenuation phenotype and the metabolic non-attenuation phenotype according to their glucose metabolic activity pattern. The metabolic attenuation phenotype was associated with worse survival (p = 0.022), poorer physical function (p = 0.005), more severe depression (p = 0.026) and greater anxiety level (p = 0.05). WES testing and neuroimaging-transcriptome analysis identified specific gene mutations and molecular pathways with each phenotype.

CONCLUSIONS: We identified two distinct ALS phenotypes with varying clinicopathologic features, indicating that the unsupervised machine learning applied to PET imaging may effectively classify metabolic subtypes of ALS. These findings contributed novel insights into the heterogeneous pathophysiology of ALS, which should inform personalized therapeutic strategies for patients with ALS.},
}

@article {pmid41042311,
year = {2025},
author = {Ouyang, C and Jin, X and Zhao, H and Chen, S and Zhao, G and Li, D and Liu, W and He, X and Wu, Y and Yang, J and An, B},
title = {Generating Broad-Spectrum Resistance to ALS-Inhibiting Herbicides in Rice by CRISPR/Cas9-Mediated NHEJ.},
journal = {Rice (New York, N.Y.)},
volume = {18},
number = {1},
pages = {86},
pmid = {41042311},
issn = {1939-8425},
support = {2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; 2020B1212060047//The Program of Guangdong Provincial Key Laboratory of New Technology in Rice Breeding/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; NO.ZDYF2024XDNY179//Hainan Province Science and Technology Special Fund/ ; },
abstract = {Herbicides are pivotal for modern agriculture, but challenges like weed resistance and crop rotation issues necessitate the development of herbicide-resistant genetic resources. This study focused on acetolactate synthase (ALS), a key enzyme targeted by numerous herbicides. Using CRISPR/Cas9-mediated non-homologous end joining (NHEJ) and combining with whole-stage selection, we induced mutations in the OsALS gene of indica rice and identified novel in-frame mutations at the P171 and S627 sites, respectively. Among them, one mutation at the P171 site, the triple mutation P171T/R172G/M174L (ALS-TM) conferred broad-spectrum resistance to Imidazolinones Pyrimidinylthiobenzoates Sulfonylaminocarbonyltriazolinones and Sulfonylureas herbicides. Compared to wild-type (WT) rice, ALS-TM showed 1153-fold higher resistance to imazethapyr (IMT) than WT based on GR50 values (The herbicide dose causing a 50% reduction in growth), with minimal growth inhibition at 10-fold IMT treatment. Enzymatic assays revealed that ALS-TM maintained catalytic efficiency while reducing herbicide binding, which validated the resistance at the protein level. Field trials showed that ALS-TM mutant retained normal agronomic traits even after IMT spraying, indicating no yield penalty. Additionally, ALS mutations were validated as effective transgenic selection markers, enabling efficient rice transformation under different selection systems. These results demonstrated that ALS-TM could also serve as a reliable tool in basic research, facilitating the selection and identification of transgenic materials in laboratory studies. This study provided a robust method for generating herbicide-resistant rice germplasm and highlighted the potential of CRISPR-mediated NHEJ for creating novel resistant mutations.},
}

@article {pmid41042072,
year = {2025},
author = {Trubshaw, M and Gohil, C and Edmond, E and Proudfoot, M and Yoganathan, K and Wuu, J and Northall, A and Kohl, O and Stagg, CJ and Nobre, AC and Talbot, K and Thompson, AG and Benatar, M and Woolrich, M and Turner, MR},
title = {Divergent Brain Network Activity in Asymptomatic C9orf72 and SOD1 Variant Carriers Compared With Established Amyotrophic Lateral Sclerosis.},
journal = {Human brain mapping},
volume = {46},
number = {14},
pages = {e70345},
doi = {10.1002/hbm.70345},
pmid = {41042072},
issn = {1097-0193},
support = {MR/K01014X/1/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 NS105479/NH/NIH HHS/United States ; 172123//Muscular Dystrophy Association/ ; 4365//Muscular Dystrophy Association/ ; 2015//ALS Association/ ; 203139/Z/16/Z//Wellcome Centre for Integrative Neuroimaging/ ; NIHR203316//National Institute of Health Research Oxford Health Biomedical Research Centre/ ; //National Institute of Health Research Oxford Cognitive Health Clinical Research Facility/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/diagnostic imaging ; *C9orf72 Protein/genetics ; Male ; *Superoxide Dismutase-1/genetics ; Female ; Magnetoencephalography ; Middle Aged ; Adult ; *Nerve Net/physiopathology/diagnostic imaging ; Heterozygote ; Aged ; *Connectome ; },
abstract = {Understanding the presymptomatic biology in those at high risk of developing amyotrophic lateral sclerosis (ALS) is essential for the development of preventative therapeutic interventions. Approximately 10% of ALS is associated with a C9orf72 expansion or pathogenic variants in SOD1. Magnetoencephalography (MEG), combined with machine learning algorithms, can model brain network dynamics in such at-risk populations to develop pathogenic biomarkers. Individuals with symptomatic ALS (symALS, n = 61), asymptomatic C9orf72 carriers (aC9, n = 16), or pathological SOD1 carriers (aSOD, n = 12), and healthy controls (n = 84) underwent resting-state MEG recordings. Extracted metrics included regional oscillatory power, connectivity, and spectral shape. 'DyNeMo' was trained to identify six functional dynamic brain networks. Metrics were compared between groups. A classifier was trained to distinguish asymptomatic gene carriers from controls. Compared to controls, beta frequency power was decreased in both symALS and aC9 groups. The aC9 group showed a marked slowing of frontal oscillatory activity, while the aSOD group showed a marked acceleration. Dynamic network coactivation was dramatically disrupted in aC9, more than in both symALS and aSOD. The classifier accurately distinguished genetically at-risk groups from controls (receiver-operator-characteristic area-under-curve 0.89). The cerebral network dynamics of aC9 are markedly different from both aSOD and symALS, supporting the concept of profoundly different upstream pathways in SOD1 ALS, sparing wider cortical pathology when compared to C9orf72 ALS. aC9 changes may reflect chronic adaptive changes relating to neurodevelopmental factors or underpin aspects of system vulnerability that define penetrance variability. MEG metrics might provide important biomarkers of prevention therapy efficacy and phenoconversion in at-risk populations.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/physiopathology/diagnostic imaging
*C9orf72 Protein/genetics
Male
*Superoxide Dismutase-1/genetics
Female
Magnetoencephalography
Middle Aged
Adult
*Nerve Net/physiopathology/diagnostic imaging
Heterozygote
Aged
*Connectome

@article {pmid41041552,
year = {2025},
author = {Scoles, D and Paul, S and Nguyen, H and Gandelman, M and Dansithong, W and Figueroa, K and Bonini, N and Pulst, S},
title = {A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7411941/v1},
pmid = {41041552},
issn = {2693-5015},
abstract = {RNA-binding proteins (RBPs) play an essential role in development, normal functioning and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (h STAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.},
}

@article {pmid41041029,
year = {2024},
author = {Zareei, A and Razeghinejad, R and Talebnejad, MR and Khalili, MR and Masoumpour, MS and Shayan, Z and Mahdaviazad, H and Keshtkar, M and Mohammadi, E and Tajbakhsh, Z and Shahmohammadi, M and Nowroozzadeh, MH},
title = {Macular Sublayer Thickness in Healthy Iranian Children: An Optical Coherence Tomography Study from the Population-Based Shiraz Pediatric Eye Study.},
journal = {Journal of current ophthalmology},
volume = {36},
number = {4},
pages = {393-399},
pmid = {41041029},
issn = {2452-2325},
abstract = {PURPOSE: To establish normative values for macular sublayer thickness in healthy Iranian children using optical coherence tomography (OCT) and to assess the effects of age and gender.

METHODS: This study was part of the population-based Shiraz pediatric eye study. Of 2400 children aged 6-12 years invited, 480 were randomly selected for optical biometry and macular spectral-domain OCT (SD-OCT) imaging. Finally, 431 OCT scans from children with medium axial length (AL; 21.5-26.5 mm) were analyzed. The OCT device automatically segmented seven retinal sublayers, and their thickness was measured across Early Treatment Diabetic Retinopathy Study (ETDRS) subfields. Thickness in the central 1-mm subfield was assessed by gender and age groups (6-9 vs. 10-12 years), adjusted for AL. Regression analysis examined the impact of age, sex, and AL on retinal sublayer thickness. Only data from the right eye were used.

RESULTS: The mean age of participants was 9.12 ± 1.59 years (range, 6-12), with 254 (58.9%) being girls. The mean AL was 22.91 ± 0.71 mm, and the mean foveal thickness was 258 ± 8 µm. A normative database was created for the total retinal thickness and the seven retinal sublayers across the nine ETDRS subfields. Boys had longer globes (by approximately 0.4 mm; P < 0.001) and thicker foveae (by about 5 µm; P = 0.001) compared to girls. Among the seven sublayers studied, boys had a thicker ganglion cell complex layer (P = 0.014) and outer nuclear layer (ONL; P = 0.012), while girls had a thicker retinal pigment epithelium (RPE; P = 0.029). The inner nuclear layer and outer plexiform layer showed no significant differences (P = 0.075 and P = 0.810, respectively). The mean AL was 22.78 ± 0.68 mm in the 6-9 age group and 23.10 ± 0.72 mm in the 10-12 age group (P < 0.001). The older age group (10-12 years) exhibited thicker ONL (P = 0.009) and RPE (P = 0.002) layers compared to the younger group.

CONCLUSIONS: This study provides normative data for macular sublayer thickness in Iranian children aged 6-12 years using Heidelberg SD-OCT. Boys had longer ALs and thicker maculae, while girls had a thicker RPE layer. Older children had longer globes and thicker retinas, mainly due to increased ONL and RPE thickness.},
}

@article {pmid41040969,
year = {2025},
author = {Lotesto, V and Voisine, C},
title = {Reduced insulin-like signaling restores motor and chemosensory neuron function in C. elegans expressing TDP-43, an ALS-associated protein.},
journal = {microPublication biology},
volume = {2025},
number = {},
pages = {},
pmid = {41040969},
issn = {2578-9430},
abstract = {TAR DNA-binding Protein 43 (TDP-43) is linked to the pathology of neurodegenerative diseases. We used the roundworm Caenorhabditis elegans to examine the neurotoxic impact of the pan-neuronal expression of wild-type human TDP-43 (hTDP-43) fused to a yellow fluorescent protein. Using the daf-2 (e1370) mutant allele, we sought to determine whether activating cellular stress responses in the insulin-like signaling (ILS) pathway could restore neuronal function in hTDP-43 expressing C. elegans . Using well characterized behavioral assays, our data show that manipulating the ILS pathway significantly improves functionality of motor and chemosensory neurons in animals expressing hTDP-43.},
}

@article {pmid41040692,
year = {2025},
author = {Schone, HR and Yoo, P and Fry, A and Chetty, N and Sawyer, A and Herbers, C and Liu, F and Moon, CH and Hill, K and Majidi, S and Harel, NY and Nogueira, RG and Levy, E and Putrino, DF and Lacomis, D and Oxley, TJ and Weber, DJ and Collinger, JL},
title = {Motor Cortex Coverage Predicts Signal Strength of a Stentrode Endovascular Brain-Computer Interface.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.19.25335875},
pmid = {41040692},
abstract = {Brain-computer interfaces (BCIs) are an emerging assistive technology for individuals with motor impairments, enabling the command of digital devices using neural signals. The Stentrode BCI is an implant, positioned within the brain's neurovasculature, that can record movement-related electrocortical activity. Over 5 years, 10 participants (8 amyotrophic lateral sclerosis, 1 primary lateral sclerosis, 1 brainstem stroke) have been implanted with a Stentrode BCI and significant inter-participant variability has been observed in the recorded motor signal strength. This variability warrants a critical investigation to characterize potential predictors of signal strength to promote more successful BCI control in future participants. Therefore, we investigated the relationship between Stentrode BCI motor signal strength and a variety of user-specific factors: (1) clinical status, (2) pre-implant functional activity, (3) peri-implant neuroanatomy, (4) peri-implant neurovasculature, and (5) Stentrode device integrity. Data from 10 implanted participants, including clinical demographics, pre- and post-implant neuroimaging and longitudinal Stentrode BCI motor signal assessments were acquired over a year. Across all potential predictors, the strongest predictor of Stentrode motor signal strength was the degree to which the Stentrode BCI's deployment position overlapped with primary motor cortex (M1). These findings highlight the importance of targeting M1 during device deployment and, more generally, provides a scientific framework for investigating the role of user-specific factors on BCI device outcomes.},
}

@article {pmid41040684,
year = {2025},
author = {Kwan, JY and Lantz, CI and Korobeynikov, VA and Snyder, A and Huang, X and Haselhuhn, T and Dore, KN and Madruga, A and Danielian, LE and Schindler, AB and Chia, R and Rasheed, M and Crook, J and Szabo, M and Portley, M and Sherer, CM and King, MC and Huang, TH and Kosa, P and Bielekova, B and Ward, ME and Grunseich, C and Shneider, NA and Traynor, BJ and Narendra, DP},
title = {Clinical, neuropathological, and biochemical characterization of ALS in a large CHCHD10 R15L family.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.22.25335938},
pmid = {41040684},
abstract = {Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluate five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo , in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 2-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.},
}

@article {pmid41040384,
year = {2025},
author = {Charalampopoulou, A and Taga, A and Rust, K and Luciani, E and Marshall, K and Montgomery, E and Mansinghka, A and Singh, R and Zhao, Y and O'Keefe, C and Wang, TH and Venkatesan, A and Habela, CW and Maragakis, NJ},
title = {Development of a Human iPSC-Derived "Corticospinal Tract-on-a-Chip" for Neurodegenerative Disease Research.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.24.678092},
pmid = {41040384},
issn = {2692-8205},
abstract = {UNLABELLED: Degeneration of the corticospinal tract is a central feature in a number of neurodegenerative disorders and leads to significant disability. However, modeling corticospinal neuron (CSN) pathology and corticospinal connectivity in neurological disorders is particularly challenging. While rodent models are important for understanding early degeneration of CSN, interspecies differences in corticospinal connectivity and challenges of in vivo study suggest that human in vitro models of corticospinal biology may be ripe for development. Human induced pluripotent stem cells (hiPSC) are promising tools for overcoming intrinsic limitations that arise from physiological differences between rodents and humans. We have developed an innovative hiPSC-based microfluidic platform for modeling human CSN and spinal motor neuron (SpMN) connectivity. The incorporation of regionally specific astrocyte subtypes (cortical and spinal) in addition to CSNs and SpMNs in this newly designed system allows for the modeling of both regional and neural cell-subtype interactions. Using this model, multielectrode array electrophysiology reveals the maturation of both cortical and spinal motor neurons over the time course of 12 weeks. Retrograde labeling methods demonstrate synaptic connectivity between corticospinal and spinal motor neurons. Optogenetic strategies to selectively activate excitatory CNs attenuated by glutamate receptor antagonism confirms the functional relevance of the model. Incorporating morphological, electrophysiological and physiological measures of corticospinal connectivity, this platform is a versatile model for use in neurodegenerative disease research and for the future development of targeted CSN therapies.

SIGNIFICANCE STATEMENT: Degeneration of the corticospinal tract is a key feature of numerous neurodegenerative diseases, yet current in vitro models lack the anatomical and functional fidelity to study this system. We developed a human iPSC-derived "Corticospinal Tract-on-a-Chip" using a multielectrode array platform that incorporates regionally patterned cortical and spinal neurons and astrocytes. This model demonstrates structural and functional synaptic connectivity and enables longitudinal electrophysiological recordings. Critically, it supports compartment-specific manipulation and real-time analysis of CST network dynamics, capabilities lacking in existing systems. By mimicking human corticospinal physiology in vitro , this platform offers a novel tool for mechanistic investigation and preclinical testing of CST-targeted therapies. It holds broad relevance for studying disorders such as ALS, hereditary spastic paraplegia, and primary lateral sclerosis.},
}

@article {pmid41040221,
year = {2025},
author = {Uyan, Ö and Sambare, S and Oomen, ME and Wightman, N and Schooley, A and Klim, JR and Belaghzal, H and Aydemir, Ö and Akgol-Oksuz, B and Uslu, ZSA and Eggan, K and Brown, RH and Dekker, J},
title = {Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.22.677835},
pmid = {41040221},
issn = {2692-8205},
abstract = {We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.},
}

@article {pmid41040165,
year = {2025},
author = {Horan-Portelance, L and Acri, DJ and Mann, A and Brooks, J and Bailey, HM and Gibbs, JR and DeCasien, AR and Cookson, MR},
title = {Integrative analysis reveals generalizable human neurodegenerative disease-associated glial states.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.25.678630},
pmid = {41040165},
issn = {2692-8205},
abstract = {Disease-associated glia represent plastic transcriptional cellular states observed across neurodegenerative diseases (NDDs). In particular, microglial states have been characterized in Alzheimer's disease and mouse models of amyloidosis. Although single-cell transcriptomic technologies have increased the dimensionality of information available across cell states, few studies have systematically tested for changes in glial transcription across brain regions and disease states. Here, we report a statistical framework for glial annotation, disease association, and transcriptional profiling, which facilitate identification of generalizable glial states that are present across a spectrum of NDDs (Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Frontotemporal dementia). We identify seven astrocyte substates, 14 microglia/myeloid substates, and five oligodendrocyte substates where transcriptional variability is attributable to region, disease, or batch effects. Regional heterogeneity of astrocytes masked disease associations, even within cortical astrocytes. We found only limited oligodendrocyte transcriptional heterogeneity, resulting in few substates for further interrogation. Notably, microglia showed the strongest evidence for disease association. We show, for the first time, that this association exists across the entire NDD spectrum. Using latent factor analysis, we created a consensus human neurodegenerative disease-associated microglia (hnDAM) signature, which we experimentally validated in 11 independent sample series. We demonstrate that the hnDAM signature is a statistically testable biomarker for conserved microglial activation in NDDs by: i) comparing to murine DAM-like signatures, ii) performing transcription factor analysis, and iii) modeling transcriptional reprogramming perturbations in iPSC-derived microglia. Taken together, this work broadens our understanding of glial activation across neuropathologies and reveals hnDAM as a putative therapeutic target that can be widely generalized to patients suffering from NDDs.},
}

@article {pmid41038449,
year = {2025},
author = {Elshehawy, M and Kadambi, M and Hughes, D and Clarke, D and Cooper, A and Inani, M and Goktas, P and Goddard, S and Diwakar, L},
title = {Emergency management of anaphylaxis and the impact of the new UK ALS guidelines.},
journal = {Clinical medicine (London, England)},
volume = {},
number = {},
pages = {100519},
doi = {10.1016/j.clinme.2025.100519},
pmid = {41038449},
issn = {1473-4893},
abstract = {BACKGROUND: Anaphylaxis is a severe, potentially life-threatening allergic reaction that requires urgent and effective management. The UK Resuscitation Council updated its Advanced Life Support (ALS) guidelines for anaphylaxis in 2021, emphasizing early and repeated adrenaline administration, IV fluid use, and reduced reliance on antihistamines and steroids.

METHODS: A retrospective audit was carried out to compare the management of anaphylaxis at two English NHS hospitals, namely the University Hospital of North Midlands (UHNM) and the Shrewsbury and Telford Hospital (SATH) before (2018) and after (2022/23) the ALS guideline implementation. Adherence to NICE anaphylaxis guidance was also assessed.

RESULTS: Data from 272 patients revealed significant improvements in recognition of anaphylaxis in 2022 compared with 2018 (70.8% vs. 50%; p=0.001). The use of adrenaline and IV fluids increased, whereas the use of antihistamines and steroids declined, aligning with the new guidance. Tryptase measurement (checked in 45% patients) and specialist referral rates (67% at UHNM vs. 3% at SATH; p=0.0001) remained suboptimal at both centers. A case example highlights the risks of misdiagnosis and adrenaline overuse in patients with recurrent urticarial presentations.

CONCLUSION: Anaphylaxis management in these centers has changed in keeping with the new ALS guidelines, although antihistamines and steroids were still used in the acute management of around 50% of the patients. Adrenaline overuse may be an unintended consequence of the guideline, which needs monitoring. There may have been some improvement in anaphylaxis recognition, but serum tryptase measurement and referral to allergy specialists remain poor.},
}

@article {pmid41037265,
year = {2025},
author = {Zhu, X and Russell, ER and Lyall, DM and Ho, F and Mackay, DF and Pell, JP and Stewart, W},
title = {Traumatic Brain Injury and Risk of Amyotrophic Lateral Sclerosis.},
journal = {JAMA network open},
volume = {8},
number = {10},
pages = {e2535119},
doi = {10.1001/jamanetworkopen.2025.35119},
pmid = {41037265},
issn = {2574-3805},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology ; Male ; Female ; *Brain Injuries, Traumatic/complications/epidemiology ; Middle Aged ; Retrospective Studies ; Adult ; Aged ; United Kingdom/epidemiology ; Risk Factors ; Proportional Hazards Models ; },
abstract = {IMPORTANCE: History of traumatic brain injury (TBI) or repetitive head impacts is associated with an increased risk of neurodegenerative disease. This association has attracted attention in recent years through the relationship between contact sports participation and the increased risk of a number of neurodegenerative diseases, including motor neuron disease or amyotrophic lateral sclerosis (ALS). However, to date, the association between TBI in the community and ALS risk remains uncertain.

OBJECTIVE: To leverage population-level health records to explore the association between a history of TBI and subsequent ALS risk.

This retrospective cohort study accessed UK-wide electronic health record (EHR) data from individuals 18 years or older with TBI history and age-, sex-, and area deprivation-matched general population comparators. EHR data were available from January 1, 2005, to December 31, 2020, with database interrogation performed on February 11, 2021, and data analysis conducted between June 1, 2023, and October 3, 2024.

EXPOSURE: Documented history of TBI.

MAIN OUTCOMES AND MEASURES: Outcomes were obtained by individual-level linkage to EHR data available via Clinical Practice Research Datalink. Risk of ALS was evaluated using Cox proportional hazards regression models to investigate its association with TBI.

RESULTS: Overall, 85 690 adults with a history of TBI and 257 070 matched adults with no history of TBI were included, for a total of 342 760 participants (50.1% male; mean [SD] age, 50.7 [17.6] years). During a median 5.72 (IQR, 3.07-8.82) years of follow-up, providing 2.13 million person-years of follow-up, 150 incident ALS cases were recorded, resulting in 7.05 cases per 100 000 person-years. Risk of ALS was higher among individuals with a history of TBI compared with individuals without a TBI history (hazard ratio [HR], 2.61; 95% CI, 1.88-3.63). However, this association was time dependent, with risk confined to the 2 years following TBI (HR, 6.18; 95% CI, 3.47-11.00), but not thereafter.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of 342 760 adults, an association between TBI and subsequent risk of ALS was identified. However, this association was confined to the 2 years immediately following injury. As such, the association between TBI and higher ALS risk may indicate reverse causality, with TBI in some individuals perhaps reflecting a consequence of early, subclinical ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/etiology
Male
Female
*Brain Injuries, Traumatic/complications/epidemiology
Middle Aged
Retrospective Studies
Adult
Aged
United Kingdom/epidemiology
Risk Factors
Proportional Hazards Models

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

@article {pmid41036176,
year = {2025},
author = {Toro, CA and Zhao, W and Garcia Silva, P and Retamal-Santibáñez, D and Rojas, F and Pan, J and Johnson, N and Duarte, Y and Cardozo, CP and Sáez, JC and van Zundert, B},
title = {Boldine as a neuroprotective agent against motor neuron degeneration in models of amyotrophic lateral sclerosis.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1640590},
pmid = {41036176},
issn = {1662-5102},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Current FDA-approved treatments offer only modest benefits. Connexins (Cx), proteins that mediate intercellular communication have emerged as potential therapeutic targets, with increased Cx hemichannel (HC) activity observed in ALS models, and blocking Cx HC activity prevents motor neuron loss in vitro. Boldine, a natural compound with both Cx HC-blocking and antioxidant properties, has shown neuroprotective potential. This study investigated boldine's effects in ALS models. In vitro, spinal cord cell cultures exposed to conditioned media from mutant SOD1[G93A] astrocytes showed a 50% reduction in motor neuron survival, elevated Cx HC activity, and increased reactive oxygen species (ROS). Boldine treatment significantly reduced Cx HC activity and ROS, and increased motor neuron viability. In vivo, oral boldine was well-tolerated in male mutant SOD1[G93A] mice starting at 7 weeks of age. Mice receiving 50 mg/kg/day showed a median survival increase of 9 days (132 vs. 123 days), though not statistically significant. Functional assessments revealed delayed disease progression: in the horizontal ladder rung walk test, boldine-treated mice exhibited a 36.8% reduction in crossing time and 21.2% fewer stepping errors. Improved scores were also observed on the Basso Mouse Scale at later stages, indicating preserved locomotor function. However, boldine had no significant effect in the rotarod test. These results support boldine's neuroprotective effects in ALS, particularly in fine motor coordination and locomotor performance. Its reduction of Cx HC activity and oxidative stress highlights boldine's promise as a potential therapeutic candidate for ALS.},
}

@article {pmid41035727,
year = {2025},
author = {Wanner, GK and Dworkin, M and Rosenbaum, RA},
title = {Statewide Prehospital Buprenorphine in Delaware: Two-Years of Paramedic-Initiated Medication for Opioid Use Disorder After Overdose.},
journal = {Delaware journal of public health},
volume = {11},
number = {3},
pages = {24-28},
pmid = {41035727},
issn = {2639-6378},
abstract = {The Delaware Division of Public Health, Office of Emergency Medical Services (EMS) implemented the first statewide program enabling paramedics throughout the state to initiate buprenorphine treatment for opioid use disorder (OUD) in the prehospital setting. Building on a model from Camden, New Jersey, this protocol was approved in 2022 in response to rising overdose deaths and was fully implemented across Delaware's advanced life support (ALS) EMS agencies in April 2023. Eligible patients-those 18 years or older, resuscitated with naloxone, and able to consent-received up to 24 mg of sublingual buprenorphine along with ondansetron for nausea. Between April 2023 and May 2025, paramedics administered 118 buprenorphine doses to 105 patients, with improvement in withdrawal symptoms reported after 63.6% of doses. Despite a rise in patient ineligibility due to altered mental status-likely linked to sedating adulterants,such as xylazine and medetomidine,in regional street drugs-paramedics increased the percentage of eligible patients accepting offered buprenorphine from 19.0% to 22.8% between the first and second year of the program. This protocol not only addresses acute overdose management in the field but also connects patients to ongoing care, aiming to reduce mortality and expand access to medications for opioid use disorder.},
}

@article {pmid41034919,
year = {2025},
author = {Liu, Y and Guo, R and Wang, N and Yang, Y and Li, J and Jing, D and Cui, R and Ma, R and Ma, J},
title = {Integrated molecular data analysis confirms PDK1 as a candidate risk factor in ALS pathophysiology.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {76},
pmid = {41034919},
issn = {1756-6606},
support = {H2023206266//the Natural Science Foundation of Hebei Province/ ; CYQD2023005//the Hebei Medical University Chunyu Project/ ; 241200073A//the Industry-University-Research Project of Universities Stationed in Hebei in collaboration with Shijiazhuang/ ; 25292401D//Hebei Province International Science and Technology Cooperation Key Project/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/enzymology ; Humans ; Animals ; Risk Factors ; *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism/genetics ; HEK293 Cells ; Mice, Transgenic ; *3-Phosphoinositide-Dependent Protein Kinases/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Gene Expression Profiling ; Mice ; *Genetic Predisposition to Disease ; Gene Ontology ; },
abstract = {Combining cellular, animal, and MR analyses from three independent cohorts, we identified PDK1 as a consistent risk factor for ALS development, highlighting its potential as a therapeutic target. To further elucidate PDK1's pathogenic mechanisms, we conducted transcriptomic profiling. Samples were stratified into PDK1 high- and low-expression groups. GO and KEGG analyses demonstrated that upregulated DEGs were enriched in pathways involving β-CATENIN, cell adhesion and Ribosome, suggesting a potential role for WNT/β-catenin signaling activation in ALS pathogenesis. To further validate the consistent risk association of PDK1 with ALS across multiple datasets, we utilized 4-month-old SOD1G93A transgenic mice, 4-month-old C9orf72 transgenic mice, and SOD1-overexpressing HEK293T cells. Significant upregulation of PDK1 mRNA was observed in all models, and a significant increase in protein abundance was found in SOD1G93A. This provides strong experimental evidence for the results of the MR study. These results indicate that PDK1 may affect the pathogenesis of amyotrophic lateral sclerosis through genetic variations and transcriptional dysregulation, and may play an important role in the occurrence and development of the disease.},
}

*Amyotrophic Lateral Sclerosis/genetics/physiopathology/enzymology
Humans
Animals
Risk Factors
*Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism/genetics
HEK293 Cells
Mice, Transgenic
*3-Phosphoinositide-Dependent Protein Kinases/genetics/metabolism
RNA, Messenger/genetics/metabolism
Gene Expression Profiling
Mice
*Genetic Predisposition to Disease
Gene Ontology

@article {pmid41034691,
year = {2025},
author = {Farrag, AMAS and Ota, K and Yoshimura, H and Takemoto, M and Mitarai, T and Kamikawa, T and Abo, M and Singh, VP and Cui, C and Zhou, L and Ishidate, F and Fujiwara, T and Sato, SI and Hori, Y and Ozawa, T and Kikuchi, K and Uesugi, M},
title = {Live-Cell Monitoring and Omics Analysis of Liquid-Solid Transitions of Biomolecular Condensates.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c07340},
pmid = {41034691},
issn = {1520-5126},
abstract = {Biomolecular condensates, or so-called membraneless organelles, transition from liquid into more solid-like states over time, contributing to the development of pathological conditions. The present study proposes a simple method using photoactive yellow protein (PYP) and its specific fluorescent covalent ligands to distinguish between the liquid and solid states of protein condensates in live cells. The method, compatible with fluorescence-activated cell sorting (FACS), correlates the stiffness of specific protein condensates with their accessibility to PYP ligands, enabling quantitative multicolor monitoring of condensate solidification. We applied this technique to 12 phase-separating proteins and their mutants, finding that TDP-43, particularly its A315T mutant linked to familial amyotrophic lateral sclerosis, most readily forms solid aggregates. Furthermore, this FACS-compatible strategy enabled the isolation of distinct cell populations based on condensate states, allowing for subsequent proteomic and transcriptomic analyses. Our findings demonstrate that condensate solidification is accompanied by the upregulated expression of extracellular matrix proteins, suggesting a previously unrecognized link between solid aggregate formation and extracellular matrix hardening.},
}

@article {pmid41034581,
year = {2025},
author = {Michaelis, T and Lindestam Arlehamn, CS and Johansson, E and Frazier, A and Berry, JD and Cudkowicz, M and Goyal, NA and Fournier, C and Snyder, A and Kwan, JY and Crook, J and Phillips, EJ and Mallal, SA and Ravits, J and Marder, KS and Sidney, J and Sulzer, D and Sette, A},
title = {Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41034581},
issn = {1476-4687},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons. Neuroinflammation is apparent in affected tissues, including increased T cell infiltration and activation of microglia, particularly in the spinal cord[1,2]. Autoimmune responses are thought to have a key role in ALS pathology, and it is hypothesized that T cells contribute to the rapid loss of neurons during disease progression[3,4]. However, until now there has been no reported target for such an autoimmune response. Here we show that ALS is associated with recognition of the C9orf72 antigen, and we map the specific epitopes that are recognized. We show that these responses are mediated by CD4[+] T cells that preferentially release IL-5 and IL-10, and that IL-10-mediated T cell responses are significantly greater in donors who have a longer predicted survival time. Our results reinforce the previous hypothesis that neuroinflammation has an important role in ALS disease progression, possibly because of a disrupted balance of inflammatory and counter-inflammatory T cell responses[4]. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells[5], and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.},
}

@article {pmid41034505,
year = {2025},
author = {Song, X and Wu, W and Varshney, M and Roman, A and Gustafsson, JÅ and Warner, M},
title = {Role of LXRβ in oligodendrocytes in neuronal survival.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41034505},
issn = {1476-5578},
abstract = {We have reported that mice in which the liver X receptor β (LXRβ) gene is inactivated lose dopaminergic neurons in the substantia nigra and motor neurons in the ventral horn of the spinal cord. These mice develop progressive hind limb paralysis starting at 6 months of age. Since LXRβ is not expressed in either dopaminergic neurons or motor neurons, we have focused on LXRβ-expressing cells whose function is essential for neuron survival. We now report defects in oligodendrocyte maturation in the absence of LXRβ. At 4 months of age, long before motor neuron loss occurs, there was reduction in expression of the four following genes in oligodendrocytes: The monocarboxylate transporter 1 (MCT1), which is essential for metabolic support of motor neurons; BDNF, a motor neuron trophic factor; 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis; glutamine synthetase (GS), an enzyme crucial for the elimination of neurotoxic glutamate from synapses. Differentiation of ES cells from WT and LXRβ[-/-] mice into motor neurons/oligodendrocytes revealed that LXRβ[-/-] cultures showed less arborization of motor neurons and a reduced proportion of mature oligodendrocytes. Our study suggests that defects in glial cells can have profound effects on neuronal survival and that early defective oligodendrocyte maturation can lead to motor neuron death. The expression of LXRβ in oligodendrocytes should be investigated as a target for preventing neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease.},
}

@article {pmid41034394,
year = {2025},
author = {Torres, P and Pradas, I and Fernàndez-Bernal, A and Povedano, M and Dominguez, R and Jové, M and Gonzalez-Mingot, C and Ayala, V and Ferrer, I and Pamplona, R and Portero-Otin, M},
title = {Exploring platelet metabolomics and fatty acid profiles for ALS prognosis and diagnosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {34236},
pmid = {41034394},
issn = {2045-2322},
support = {Margarita Salas//Spanish Ministry of Universities/ ; 2023 BP 00144//Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya/ ; PIRS Program//Diputació de Lleida/ ; 2017SGR696 and SLT002/16/00250//Generalitat de Catalunya/ ; RTI2018-099200-B-I00//Spanish Ministry of Science, Innovation and Universities/ ; PI20/0155//Instituto de Salud Carlos III/ ; PI23/00176//Instituto de Salud Carlos III/ ; Jack Van den Hoek Donation//Fundació Miquel Valls/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/blood ; *Metabolomics/methods ; *Fatty Acids/metabolism/blood ; Male ; Female ; Middle Aged ; Prognosis ; Biomarkers/blood/metabolism ; *Blood Platelets/metabolism ; Aged ; Disease Progression ; Adult ; *Metabolome ; Case-Control Studies ; ROC Curve ; Gas Chromatography-Mass Spectrometry ; Chromatography, Liquid ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with heterogeneous clinical progression, reflecting distinct underlying pathological mechanisms. Early and accurate diagnosis and prognosis require reliable biomarkers to improve clinical management and therapeutic stratification. The present study explores the potential of platelet global metabolomics and fatty acid (FA) profiling as potential sources of diagnostic and prognostic biomarkers for ALS. We analysed platelets from 15 recently diagnosed ALS patients and 21 healthy controls (CTLs) using liquid chromatography-mass spectrometry (LC-MS) for metabolomics and gas chromatography-flame ionization detection (GC-FID) for FA profiling. ALS patients were classified as fast or slow progressors based on the median ALS Functional Rating Scale-Revised (ALSFRS-R) slope. While global metabolomic and FA profiles have shown limited potential for distinguishing ALS from CTL, preliminary molecular annotation based on mass and retention times disclosed specific metabolites with potential diagnostic value. Importantly, both global metabolomic and FA analyses demonstrated a marked capacity to differentiate fast progressors from slow progressors (receiver operating characteristic (ROC) curves of approximately 1), revealing distinct metabolic signatures associated with disease progression. Our findings demonstrate that platelet global metabolomics and FA profiling hold promise as prognostic biomarkers in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/blood
*Metabolomics/methods
*Fatty Acids/metabolism/blood
Male
Female
Middle Aged
Prognosis
Biomarkers/blood/metabolism
*Blood Platelets/metabolism
Aged
Disease Progression
Adult
*Metabolome
Case-Control Studies
ROC Curve
Gas Chromatography-Mass Spectrometry
Chromatography, Liquid

@article {pmid41033144,
year = {2025},
author = {Bicaj, M and Oliveri, F and Rossi, C and Rosano, A and Uccelli, A and Caponnetto, C and Ferraro, PM},
title = {Development of cognitive/behavioral disturbances in motor neuron diseases with pure motor onset: can we predict it?.},
journal = {Journal of the neurological sciences},
volume = {478},
number = {},
pages = {123707},
doi = {10.1016/j.jns.2025.123707},
pmid = {41033144},
issn = {1878-5883},
abstract = {BACKGROUND: Approximately 50 % of motor neuron disease (MND) patients manifest cognitive and/or behavioral impairment (C/BI). Notably, while some patients exhibit those disturbances from disease onset, others develop them during disease course, but the determinants of such phenomenon are still largely unknown.

OBJECTIVES: This study aimed at identifying baseline predictors of subsequent C/BI development in MNDs.

METHODS: Pure motor MND cases with longitudinal Edinburgh Cognitive and Behavioral ALS screen (ECAS) exams were included (N = 80). Based on longitudinal data, patients were categorized as either remaining motor ("non-converters", N = 55) or developing C/BI ("converters", N = 25). Demographic, genetic, baseline motor and cognitive/behavioral features (with relative progression rates) were compared between groups using Mann-Whitney U and Chi-squared tests. Logistic regression models were used to identify significant predictors of C/BI development.

RESULTS: Relative to non-converters, converters cases exhibited older age at symptoms onset/first visit (p = 0.02, p = 0.01), lower frequency of right limbs onset (p = 0.02), lower ECAS alternation (p = 0.01), spelling (p = 0.02) and fluency letter S (p = 0.05) scores, as well as higher alternation (p = 0.004) and spelling (p = 0.006) progression rates, albeit those contrasts did not survive correction for multiple comparisons. All variables except for the spelling score and progression rates were predictive of C/BI development (p from 0.002 to 0.03).

DISCUSSION: While no firm conclusions can be drawn due to the lack of results surviving correction, our study suggests that specific clinical features significantly predict C/BI development in MNDs. These findings may facilitate an earlier identification of patients at risk for extra-motor symptoms development, enabling a more tailored clinical management.},
}

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

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

@article {pmid41032491,
year = {2025},
author = {Burkhill, L and Davies, TM},
title = {A case study exploring the management of dyspnoea in motor neurone disease.},
journal = {British journal of community nursing},
volume = {30},
number = {10},
pages = {488-492},
doi = {10.12968/bjcn.2025.0023},
pmid = {41032491},
issn = {1462-4753},
mesh = {Humans ; *Dyspnea/etiology/therapy/nursing ; Male ; *Amyotrophic Lateral Sclerosis/complications/nursing ; *Motor Neuron Disease/complications ; United Kingdom ; Quality of Life ; Analgesics, Opioid/therapeutic use ; Middle Aged ; Aged ; },
abstract = {Motor neurone disease affects around 5000 people in the UK at any given time. It is a progressive disease with a poor prognosis and carries a high symptom burden. Dyspnoea (breathlessness) is one of its most challenging yet common symptoms and occurs because of a weakening of the muscles that control breathing. This case study explores the management of a man diagnosed with amyotrophic lateral sclerosis in the community. His advance decision to refuse treatment directive to avoid non-invasive ventilation during the day was managed through a combination of opioid medication, breath stacking, positioning and other strategies recommended by the National Institute for Health and Care Excellence. Individualised care planning and maintaining quality of life was key in his management.},
}

Humans
*Dyspnea/etiology/therapy/nursing
Male
*Amyotrophic Lateral Sclerosis/complications/nursing
*Motor Neuron Disease/complications
United Kingdom
Quality of Life
Analgesics, Opioid/therapeutic use
Middle Aged
Aged

@article {pmid41030970,
year = {2025},
author = {Peethambaran Mallika, A and Yu, JG and Sitzman, O and Baghel, MS and Renganathan, S and Sinha, IR and Melnikova, T and Ling, JP and Wong, PC},
title = {Symptomatic treatment by a BBB-permeable AAV engineered to restore TDP-43 function slows motor neuron disease and prevents paralysis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.14.670400},
pmid = {41030970},
issn = {2692-8205},
abstract = {TAR DNA-binding protein 43kDa (TDP-43) dysfunction is an early pathogenic mechanism that underlies amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder that lacks disease modifying therapies. We previously developed a mouse model in which TDP-43 is selectively deleted from motor neurons (ChAT-Cre;Tardbp [f/f]) that mimics the early stages of ALS. Here, we demonstrate that intravenous delivery of a blood-brain-barrier (BBB) permeable AAV capsid expressing our rationally designed splicing repressor CTR (AAV-PHP.eB-CTR) in symptomatic ChAT-Cre;Tardbp [f/f] mice markedly slowed disease progression and prevented paralysis. Systemic delivery of AAV-PHP.eB-CTR led to transduction of ∼80% of spinal motor neurons, repression of TDP-43-associated cryptic exons within motor neurons expressing CTR, and attenuation of motor neuron loss. Notably, the addition of the TARDBP 3'UTR autoregulatory element to CTR maintained its expression within a physiological range. In control littermates that received AAV-PHP.eB-CTR and were monitored for >20 months, grip strength and body weight remained normal, and no histopathological abnormalities were observed, underscoring a favorable safety profile for this gene therapy. These results provide preclinical proof-of-concept that BBB-crossing AAV delivery of CTR can rescue motor neuron disease through the restoration of TDP-43 function, offering a promising mechanism-based therapeutic strategy for ALS.},
}

@article {pmid41030957,
year = {2025},
author = {Coneys, R and Cammack, AJ and Nair, RR and Thompson, D and Mechtersheimer, J and Carcolé, M and Gupta, Y and Rech, GE and Flower, M and O'Brien, N and Ruepp, MD and Mizielinska, S and Ducotterd, F and Tabrizi, SJ and Fisher, EMC and Cunningham, TJ and Ward, M and Skarnes, WC and Isaacs, AM},
title = {Generation of C9orf72 repeat knock-in iPSC lines for modelling ALS and FTD.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.02.10.637041},
pmid = {41030957},
issn = {2692-8205},
abstract = {Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the C9orf72 gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these C9orf72 knock-in lines differentiate efficiently into neurons and display characteristic C9orf72 -associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS/FTD research.},
}

@article {pmid41029500,
year = {2025},
author = {Aljaberi, HA and Rahmani, S and Naji, AM},
title = {Correlation between refractive errors and ocular biometric parameters at Al-Mustaqbal University, Iraq.},
journal = {BMC ophthalmology},
volume = {25},
number = {1},
pages = {517},
pmid = {41029500},
issn = {1471-2415},
mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; Adult ; Iraq/epidemiology ; Young Adult ; *Biometry/methods ; Adolescent ; *Cornea/pathology ; *Axial Length, Eye/pathology ; *Refractive Errors/epidemiology/physiopathology/diagnosis ; *Refraction, Ocular/physiology ; Universities ; Corneal Pachymetry ; },
abstract = {PURPOSE: To establish the relationship between ocular biometry and refractive errors in young adult Iraqis by analyzing three critical biometric ocular parameters, including axial length (AL), corneal radius (CR), and central corneal thickness (CCT).

METHODS: A cross-sectional study was conducted on individuals aged 18-33 years at Al-Mustaqbal University, Iraq, including 1841 participants (3682 eyes). Quantitative measurements of AL, CR, and CCT were obtained using an Auto Kerato-Refractometer, IOL Master, and pachymetry techniques. Statistical analyses included Pearson correlation, multiple linear regression, one-way ANOVA, and independent samples t-tests to compare biometric parameters between refractive error groups. Generalized Estimating Equations (GEE) were applied to account for the correlation between fellow eyes.

RESULTS: The overall mean AL was 24.45 ± 1.10 mm, mean CR was 7.37 ± 0.77 mm, and mean CCT was 555.83 ± 50.83 μm. Myopic participants had a significantly longer AL (25.11 ± 0.42 mm) compared to hyperopic participants (22.71 ± 0.65 mm; p < 0.001). Likewise, myopic eyes had significantly thicker corneas (CCT: 565.62 ± 12.68 μm) than hyperopic eyes (495.42 ± 18.74 μm; p < 0.001), as determined by independent samples t-tests. Females exhibited slightly longer ALs than males across both myopic and hyperopic groups (p < 0.0001). Regression analysis showed that AL was the strongest predictor of spherical equivalent (SE), followed by CR and CCT. The regression model including AL and CR explained 94.5% of the variance in SE (R² = 0.945).

CONCLUSIONS: The findings confirm that AL and CCT are strongly associated with refractive errors, with AL being a primary determinant. This study highlights the role of gender differences in biometric ocular parameters and provides valuable insights into the prevalence of refractive errors in young adults in Iraq. These results can inform future public health initiatives aimed at addressing refractive errors in this population.},
}

Humans
Male
Female
Cross-Sectional Studies
Adult
Iraq/epidemiology
Young Adult
*Biometry/methods
Adolescent
*Cornea/pathology
*Axial Length, Eye/pathology
*Refractive Errors/epidemiology/physiopathology/diagnosis
*Refraction, Ocular/physiology
Universities
Corneal Pachymetry

@article {pmid41028829,
year = {2025},
author = {Jiang, Q and Yang, D and Jiang, R and Wan, S and Wu, M and Xu, D and Zhou, J},
title = {Analysis of factors influencing sleep disorders in patients with amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {34104},
pmid = {41028829},
issn = {2045-2322},
support = {2025AFD532//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; 2024AFD279//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; 2023AFD128//Hubei Provincial Natural Science Foundation (Joint Fund)/ ; GZY-KJS-2025-008//Science and Technology Special Project of State Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Middle Aged ; *Sleep Wake Disorders/etiology/epidemiology/complications ; Cross-Sectional Studies ; Aged ; Fatigue/complications ; Adult ; Sleep Quality ; Anxiety/complications ; Disease Progression ; Pain ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease frequently accompanied by sleep disorders. Conventional insomnia interventions are often unsuitable for ALS patients due to cognitive and respiratory impairments. There is a lack of targeted studies addressing sleep-related issues using multifactorial analyses specific to this group. This cross-sectional study included 266 ALS patients at the Motor Neuron Disease Rehabilitation and Treatment Center of Hubei Provincial Hospital of Traditional Chinese Medicine. Participants were evaluated using tools like the Pittsburgh Sleep Quality Index (PSQI) and ALS Functional Rating Scale-Revised (ALSFRS-R). Regression models identified factors affecting sleep disorders and quality. Patients with sleep disorders were more likely to have non-motor symptoms like anxiety, depression, pain, and excessive daytime sleepiness compared to those without. Fatigue severity and anxiety levels were identified as independent influencing factors of sleep disorders. Additionally, fatigue, anxiety, pain intensity, and disease progression rate were significantly linked to sleep quality. This study is the first comprehensive analysis of sleep-related factors in Chinese ALS patients, highlighting the crucial roles of fatigue, anxiety, pain, and disease progression rate. It provides a basis for future personalized, non-pharmacological interventions tailored to the specific needs of ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/physiopathology
Male
Female
Middle Aged
*Sleep Wake Disorders/etiology/epidemiology/complications
Cross-Sectional Studies
Aged
Fatigue/complications
Adult
Sleep Quality
Anxiety/complications
Disease Progression
Pain

@article {pmid41028808,
year = {2025},
author = {Rawat, A and Khurana, S and Verma, S and Dhawan, U and Gourie-Devi, M and Ganguly, NK and Taneja, V},
title = {Insights from meta-analysis and experimental validation identify exosomal miR-146a-5p as a potential biomarker for sporadic amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {33846},
pmid = {41028808},
issn = {2045-2322},
support = {2020-2641/CMB/ADHOC-BMS//Indian Council of Medical Research/ ; 3/1/2/151/Neuro/2021-NCD-I//Indian Council of Medical Research/ ; 420804-07627//Research Development Program, Sir Ganga Ram Hospital/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood/mortality ; Humans ; *MicroRNAs/genetics/blood/metabolism ; Biomarkers/blood/metabolism ; *Exosomes/genetics/metabolism ; Male ; Female ; Gene Expression Profiling ; Middle Aged ; },
abstract = {MicroRNAs (miRNAs) have emerged as key regulators in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite growing evidence that miRNAs exhibit altered expression profiles in ALS, their utility as a biomarker remains limited. To address this, we conducted a meta-analysis using the Robust Rank Aggregation package, incorporating 20 differential miRNA profiling studies. Among these, miR-146a-5p emerged as the most dysregulated and significant miRNA in ALS (P = 0.0000142, P-adj = 0.0096), particularly in extracellular vesicle-derived studies. To evaluate its diagnostic accuracy, we validated miR-146a-5p expression in serum-derived exosomes and observed a significant increase in sporadic ALS (sALS) patients (n = 22) as compared to healthy controls (n = 18). Moreover, higher levels of miR-146a-5p were strongly associated with longer survival (≥ 5 years) (P = 0.0135), with a positive correlation between miR-146a-5p expression and survival duration (P = 0.0313) in sALS patients. Further, gene set enrichment analysis of miR-146a-5p target genes highlighted critical involvement of the Immune system and NF-kappa B signaling pathways in ALS pathophysiology. These findings highlight miR-146a-5p as a potential biomarker for ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood/mortality
Humans
*MicroRNAs/genetics/blood/metabolism
Biomarkers/blood/metabolism
*Exosomes/genetics/metabolism
Male
Female
Gene Expression Profiling
Middle Aged

@article {pmid41028508,
year = {2025},
author = {Tragesser, C and Sodhi, CP},
title = {Beyond aganglionosis: BCL-2 and Laminin signatures Elucidate Hirschsprung disease and Hirschsprung-Associated Enterocolitis pathogenesis.},
journal = {Pediatric research},
volume = {},
number = {},
pages = {},
pmid = {41028508},
issn = {1530-0447},
abstract = {This commentary offers a detailed analysis of Dede et al.'s research paper, "Expression of BCL-2 and Laminin in Rectosigmoid Hirschsprung Disease: Correlations with Hirschsprung-Associated Enterocolitis[1]."},
}

@article {pmid41028049,
year = {2025},
author = {Spiteri, AG and Steele, JR and Lee, HC and Zhang, H and Sun, J and Schittenhelm, RB and Yu, CH and McLean, C and Masters, CL and Goudey, B and Jin, L and Pan, Y},
title = {Proteomic analysis of brain and spinal cord tissue reveals distinct immune and mitochondrial processes between human and mouse ALS models.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {33959},
pmid = {41028049},
issn = {2045-2322},
support = {GNT2007912//National Health and Medical Research Council/ ; GNT2022203//NHMRC-AMED 2022 Dementia Collaborative Research/ ; AARF1020292//Alzheimer's Association grant/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/immunology/pathology/genetics ; *Spinal Cord/metabolism/pathology/immunology ; Humans ; Disease Models, Animal ; Mice ; *Proteomics/methods ; *Mitochondria/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; *Brain/metabolism/pathology/immunology ; *Proteome ; Motor Neurons/metabolism ; Male ; Female ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the progressive loss of motor neurons in the brain and spine. More than 95% of cases are pathologically characterized by the cytoplasmic accumulation of hyperphosphorylated and ubiquitinated transactive response DNA-binding protein 43 (TDP-43). Multiple mouse models with TDP-43 accumulation have been developed, however, whether they recapitulate molecular features of ALS pathology is unclear. Given the lack of curative treatment for ALS, there is an urgent need to identify the precise biological processes contributing to disease pathogenesis for the development of effective therapeutic treatments. Thus, in this study we employed label-based untargeted proteomics to characterize the ALS proteome and related biological processes in the spinal cord and brain of TDP-43[Q331K] mice, a transgenic mouse model of ALS and the motor cortex and the cervical, thoracic, and lumbar spinal cord regions from humans. In humans, we observed highly overlapping responses across the four tissues examined, primarily related to the upregulation of immune processes and the downregulation of mitochondrial function. In contrast, TDP-43[Q331K] mice demonstrate a lack of enrichment for immune activation and the opposite regulation of mitochondrial processes. A meta-analysis of previously published mouse datasets identified the Ubqln2 knock-out mouse model as showing stronger parallels with our late-stage human ALS. Overall, this study provides in-depth analysis of the site-specific dysregulated proteomes and their associated functional processes across species. Thereby, identifying potential therapeutic targets while emphasizing the limitations of specific mouse models at certain timepoints in recapitulating ALS-related processes for future model development.},
}

Animals
*Amyotrophic Lateral Sclerosis/metabolism/immunology/pathology/genetics
*Spinal Cord/metabolism/pathology/immunology
Humans
Disease Models, Animal
Mice
*Proteomics/methods
*Mitochondria/metabolism
DNA-Binding Proteins/genetics/metabolism
Mice, Transgenic
*Brain/metabolism/pathology/immunology
*Proteome
Motor Neurons/metabolism
Male
Female

@article {pmid41026994,
year = {2025},
author = {Nakken, O and Vaage, AM and Stigum, H and Bjornevik, K and Holmoy, T and Meyer, HE},
title = {Duration of Current Statin Use and Amyotrophic Lateral Sclerosis Risk: A Norwegian Population-Based Cohort Study.},
journal = {Neurology},
volume = {105},
number = {8},
pages = {e214221},
doi = {10.1212/WNL.0000000000214221},
pmid = {41026994},
issn = {1526-632X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Norway/epidemiology ; Male ; Female ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects/administration & dosage/therapeutic use ; Middle Aged ; Adult ; Aged ; Cohort Studies ; Risk Factors ; Time Factors ; Hypercholesterolemia/drug therapy ; },
abstract = {BACKGROUND AND OBJECTIVES: Although hypercholesterolemia may contribute to long-term amyotrophic lateral sclerosis (ALS) risk, it can also seem as a secondary effect during the early, prediagnostic phase of the disease. We aimed to investigate the relationship between short-term and long-term use of statins and subsequent ALS risk.

METHODS: We designed a cohort study where information on cardiovascular risk factors among Norwegian participants in large population-based health surveys was linked to nationwide administrative data on subsequent statin use and ALS diagnosis. Duration of statin use was calculated based on cumulative defined daily doses and analyzed as time-varying exposure with 3 levels: 0-1 year (short-term), 1-5 years, and 5-17 years (long-term). In Cox regression models adjusted for sex, age, health survey participation, triglyceride and cholesterol levels, body mass index, smoking, diabetes, and hypertension, we calculated hazard ratios (HRs) for ALS according to time-varying statin exposure. In a negative control analysis, we examined whether exposure to renin-angiotensin system (RAS)-acting agents was associated with ALS risk.

RESULTS: A total of 425,564 participants (54% women), aged 40-65 years in January 2005, were followed for a mean period of 16 years (SD 2.3) during which 493 ALS cases (44% women) were identified. Compared with no current statin use, the HR for ALS was 3.56 (95% CI 2.58-4.90) for those with 0-1 year, 0.85 (95% CI 0.59-1.23) for those with 1-5 years, and 0.67 (95% CI 0.45-1.00) for those with 5-17 years of current use. The associations between both short-term and long-term statin use and ALS risk were most evident in men, with HRs for ALS of 4.03 (95% CI 2.72-5.95) and 0.47 (95% CI 0.26-0.86), respectively. There was no clear association between either short-term or long-term use of RAS-acting agents and ALS risk.

DISCUSSION: The strong association between short-term current statin use and increased ALS risk is consistent with reverse causality, where statin initiation in the prediagnostic phase may occur when lipid levels rise and individuals seek medical attention due to emerging ALS symptoms. Long-term statin use was associated with reduced risk of ALS in men.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology
Norway/epidemiology
Male
Female
*Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects/administration & dosage/therapeutic use
Middle Aged
Adult
Aged
Cohort Studies
Risk Factors
Time Factors
Hypercholesterolemia/drug therapy

@article {pmid41026411,
year = {2025},
author = {Eraslan, A and Kose, O},
title = {Prevalence and patterns of adductor lesions on MRI in athletes with osteitis pubis.},
journal = {Journal of orthopaedics and traumatology : official journal of the Italian Society of Orthopaedics and Traumatology},
volume = {26},
number = {1},
pages = {65},
pmid = {41026411},
issn = {1590-9999},
mesh = {Humans ; Male ; Adult ; *Osteitis/diagnostic imaging/epidemiology ; Retrospective Studies ; Cross-Sectional Studies ; *Magnetic Resonance Imaging ; Adolescent ; Prevalence ; Young Adult ; Middle Aged ; *Athletic Injuries/diagnostic imaging/epidemiology ; Athletes ; Tendinopathy/diagnostic imaging/epidemiology ; *Tendon Injuries/diagnostic imaging/epidemiology ; },
abstract = {PURPOSE: Adductor lesions (ALs) frequently coexist with osteitis pubis (OP) in athletes, yet the prevalence and clinical impact of different AL types have not been comprehensively evaluated. This study aimed to determine the frequency of various AL types using magnetic resonance imaging (MRI) and to investigate their association with clinical outcomes in athletes with OP.

MATERIALS AND METHODS: This retrospective cross-sectional study included male athletes aged 18-45 years with MRI-confirmed OP. ALs were classified into four types on the basis of MRI: type 1 (strain), type 2 (tendon avulsion), type 3 (tendinopathy), and type 4 (secondary cleft sign). Types 1-2 were considered acute, and types 3-4 chronic lesions. The relationships between AL types, age, symptom side, return to sport (RTS), and hip outcome score (HOS) were analyzed.

RESULTS: Among 132 athletes with OP, 90% had concurrent AL, while 10% had isolated OP. Type 3 AL was the most frequent type (77.3%), followed by type 4 (23.5%), type 1 (15.9%), and type 2 (2.3%). Logistic regression revealed that type 3 was more likely to be found in younger athletes, while types 1 and 4 were found in older athletes. Although 95% of athletes had bilateral OP, 72% reported unilateral symptoms. The symptom side showed better consistency with the AL side than the OP side (Cohen's kappa = 0.489 versus 0.057). All athletes were treated conservatively, 50 chronic AL cases were applied also injection (31 corticosteroid-CS, 19 platelet reach plasma-PRP). Athletes with isolated OP achieved a higher RTS rate than those with AL (100% versus 75%, p = 0.033). RTS rates were higher in acute AL cases than in chronic cases (91% versus 72%) and in CS injections than in PRP injections (80% versus 63%), but without statistical significance. HOS scores were comparable across groups.

CONCLUSIONS: Adductor lesions, particularly chronic types, are highly prevalent in athletes with OP. While age influences the type of AL, the symptom side is compatible with the AL side, regardless of the type. RTS rates are more satisfactory in isolated OP and acute AL cases, but chronic AL cases were less successful in RTS outcomes despite injection treatments. These findings underscore the importance of identifying and classifying ALs for prognosis and treatment strategy in athletic groin pain.

LEVEL OF EVIDENCE: level IV, retrospective cohort study.},
}

Humans
Male
Adult
*Osteitis/diagnostic imaging/epidemiology
Retrospective Studies
Cross-Sectional Studies
*Magnetic Resonance Imaging
Adolescent
Prevalence
Young Adult
Middle Aged
*Athletic Injuries/diagnostic imaging/epidemiology
Athletes
Tendinopathy/diagnostic imaging/epidemiology
*Tendon Injuries/diagnostic imaging/epidemiology

@article {pmid41026230,
year = {2025},
author = {Zhang, P and Yuan, X and Liu, Y and Song, J and Liu, R and Wang, H},
title = {Deciphering the dual resistance pathways to mesosulfuron-methyl in Lolium multiflorum: target-site and non-target-site insights.},
journal = {Plant cell reports},
volume = {44},
number = {10},
pages = {228},
pmid = {41026230},
issn = {1432-203X},
support = {241111111700//Key Research and Development Project of Henan Province/ ; HN2022121//Postdoctoral research project of Henan Province/ ; 2018024//High-level Talent Introduction Project of Henan Institute of Science and Technology/ ; },
mesh = {*Sulfonylurea Compounds/pharmacology ; *Lolium/genetics/drug effects/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Acetolactate Synthase/genetics/metabolism ; Mutation/genetics ; Plant Proteins/genetics/metabolism ; China ; },
abstract = {Lolium multiflorum exhibits resistance to mesosulfuron-methyl through ALS mutations; HZ2 population also shows metabolic resistance through P450 pathways. Lolium multiflorum L., is a weed that frequently appears in wheat fields and is recognized for its strong competitive nature, where it can cause significant damage to grain production. The weeds of L. multiflorum in the wheat fields may have developed resistance to mesosulfuron-methyl. This study explored the response of L. multiflorum populations in certain areas of Henan Province, China, to mesosulfuron-methyl. The study found that, compared to the HX1 sensitive population, the HZ1 and HZ2 populations showed resistance to mesosulfuron-methyl in the full dose-response test, with resistance ratios of 12.38- and 24.19-fold, respectively. Genetic sequencing revealed novel mutations at the Pro-197-Thr and Asp-376-Glu residues of the ALS gene in both resistant populations. A critical finding was the divergent resistance mechanisms between the geographically close populations, with HZ1 resistance solely conferred by target-site mutations and HZ2 exhibiting multiple resistance driven by both target-site mutations and enhanced metabolism mediated by cytochrome P450 monooxygenases. This was conclusively demonstrated by applying the P450 inhibitors malathion and PBO, which reversed resistance in HZ2 by 66.77% and 70.53%, respectively. Furthermore, both resistant populations showed heightened sensitivity to isoproturon, suggesting a potential management strategy. Molecular docking simulations corroborated that the identified mutations reduce herbicide binding affinity. Our findings provide the first evidence of concurrent target-site and non-target-site resistance to mesosulfuron-methyl in Chinese L. multiflorum, offering crucial insights for diagnosing and managing herbicide resistance.},
}

*Sulfonylurea Compounds/pharmacology
*Lolium/genetics/drug effects/metabolism
*Herbicide Resistance/genetics
*Herbicides/pharmacology
Acetolactate Synthase/genetics/metabolism
Mutation/genetics
Plant Proteins/genetics/metabolism
China

@article {pmid41025901,
year = {2025},
author = {Merbaum, P and Zwamborn, R and Hop, P and Sequencing Consortium, PMA and van Rheenen, W and Veldink, J},
title = {Dissecting epigenetic age acceleration in amyotrophic lateral sclerosis.},
journal = {Epigenomics},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17501911.2025.2563502},
pmid = {41025901},
issn = {1750-192X},
abstract = {AIM: We compared signatures of epigenetic aging in amyotrophic lateral sclerosis (ALS) patients and healthy controls to investigate the role of potential confounders and genetic subgroups.

METHODS: We used whole-blood methylome profiles for 5,146 ALS patients and 2,156 controls available for Project MinE. We predicted biological age with three generations of epigenetic clocks and estimated age acceleration by regressing our model on control individuals to evaluate case/control differences. To investigate the contribution of C9orf72 expansions, we regressed the model on C9orf72-negative ALS patients. The predicted DunedinPACE pace of aging and telomere length additionally characterized aging dynamics.

RESULTS: We found that white blood cell type proportions confound the previously observed increase in the pace of biological aging in ALS. When correcting for cell counts, there is no evidence for accelerated epigenetic aging compared to controls, except for ALS patients with the C9orf72 repeat expansion. None of the epigenetic age acceleration scores contributed to survival.

CONCLUSION: Our study revealed no significant difference in the pace of biological agingbetween ALS patients and controls, except for ALS patients carrying the C9orf72 mutation. We emphasize the importance of altered white blood cell proportions in general ALS pathophysiology as opposed to accelerated aging per se.},
}

@article {pmid41024834,
year = {2025},
author = {Meena, BL and Sharma, D},
title = {Are we overestimating success of salvage hepatectomy in unresectable hepatocellular carcinoma?.},
journal = {World journal of clinical oncology},
volume = {16},
number = {9},
pages = {111537},
pmid = {41024834},
issn = {2218-4333},
abstract = {The Zhang et al's study addresses an important clinical question of timing and role of salvage surgery post-downstaging procedures in patients with advanced hepatocellular carcinoma wherein different modalities like trans arterial chemoembolization, tyrosine kinase inhibitors, and anti-programmed cell death 1 antibodies have been used as downstaging procedure. Although proper selection of patients is a pre-requisite for salvage related liver failure.},
}

@article {pmid41024438,
year = {2025},
author = {Ramesh, N and Evans, A and Wojta, K and Yang, Z and Boks, MP and Kahn, RS and de Boer, SCM and van der Lee, SJ and Pijnenburg, YAL and Reus, LM and Ophoff, RA},
title = {Accurate DNA Methylation Predictor for C9orf72 Repeat Expansion Alleles in the Pathogenic Range.},
journal = {HGG advances},
volume = {},
number = {},
pages = {100522},
doi = {10.1016/j.xhgg.2025.100522},
pmid = {41024438},
issn = {2666-2477},
abstract = {The hexanucleotide (G4C2) repeat expansion in the promoter region of C9orf72 is the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study, we conducted a genome-wide DNA methylation (DNAm) analysis using EPIC version 2 (EPICv2) arrays on an FTD cohort comprising 27 carriers and 250 non-carriers of the pathogenic C9orf72 repeat expansion from the Amsterdam Dementia Cohort. We identified differentially methylated CpGs probes associated with the pathogenic C9orf72 expansion and used these findings to create a DNAm Least Absolute Shrinkage and Selection Operator (LASSO) predictor to identify repeat expansion carriers. Eight CpG sites at the C9orf72 locus were significantly differentially hypermethylated in repeat expansion carriers compared to non-carriers. The LASSO model predicted repeat expansion status with an average accuracy of 98.6%. The LASSO predictor was further validated in a separate, independent validation cohort containing 1,589 bipolar disorder patients, 580 first degree relatives, and 289 independent controls with available EPICv2 data, identifying four C9orf72 repeat expansion carriers, subsequently confirmed by repeat-primed PCR. This result highlights the accuracy and generalizability of the DNAm predictor of C9orf72 repeat expansion carriers. The identification of a highly accurate DNAm biomarker for a repeat expansion locus associated with neurodegenerative disorders may provide great value for studying this locus. The approach holds significant promise for investigating this and other repeat expansion loci, particularly given the growing interest in epigenetic epidemiological studies involving large cohorts with available DNAm data.},
}

@article {pmid41024384,
year = {2025},
author = {Gautam, M and Laith, A and Gunel, A and Yilmaz, M and Basak, N and Idrisoglu, H and Ozdinler, PH},
title = {Exosome Proteomics of SOD1[D90A] Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70208},
pmid = {41024384},
issn = {2328-9503},
support = {//A Long Swim/ ; //Les Turner ALS Foundation/ ; //The Queen B Foundation/ ; },
abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss.

OBJECTIVE: Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations.

METHODS: Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1[D90A] mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay.

RESULTS: Father, Son, and Daughter are at different disease stages and carry the SOD1[D90A] mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1[D90A] mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA.

INTERPRETATION: Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.},
}

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

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

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

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

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

@article {pmid41023992,
year = {2025},
author = {Nehring, C and Kaifie, A and Reddy, A and Willis, M and Schlumberger, F and Chaudhuri, N and Fastenau, A},
title = {Barriers to seeking healthcare services and contributing factors to grade 2 disability among women affected by leprosy in Telangana, India - a qualitative study.},
journal = {International journal for equity in health},
volume = {24},
number = {1},
pages = {240},
pmid = {41023992},
issn = {1475-9276},
abstract = {BACKGROUND: Leprosy, a neglected tropical disease, remains a significant global health issue, with India accounting for nearly 60% of cases in 2022. Untreated Leprosy can result in irreversible disabilities and lead to social stigma, significantly affecting the lives of patients and their families. This study explores the barriers faced by women with leprosy in accessing healthcare and other factors that contributed to the development of Grade 2 disability in India.

METHODS: Qualitative data were gathered through 20 interviews with women affected by leprosy at the Sivananda Rehabilitation Home, a leprosy clinic in Hyderabad, India. An interview guide was developed to conduct semi-structured interviews, specifically regarding the time between the onset of symptoms, diagnosis, and treatment start. An inductive analysis followed by the application of Levesque et al.’s framework was undertaken to identify themes and patterns in the participants’ experiences with the disease and treatment.

RESULTS: Six key themes were identified. The social environment plays a pivotal role in disease progression, with participants often prioritising societal expectations over their own health, such as being good wives and mothers. Stigmatisation led to social isolation, as many women avoided contact outside their families to hide deformities. Most participants visited several healthcare facilities before receiving a diagnosis, facing financial and emotional burdens. Communication gaps were evident both within healthcare facilities - where companions were sometimes informed before the patient – and in their social environments. Finally, individual factors such as lack of knowledge, awareness, and trust in medical advice also contributed to care-seeking delays.

CONCLUSIONS: This study highlights significant gaps in healthcare access for women with leprosy in India. Family dynamics, societal roles, and stigma delay care, while physical and emotional burdens add to challenges. Communication gaps and limited awareness further reinforce neglect and mistrust. Addressing these barriers is crucial for effective policy and program implementation to reduce the burden of leprosy among women.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12939-025-02642-9.},
}

@article {pmid41022917,
year = {2025},
author = {Chandramouli, P and Jayaseelan, R and Pandulu, G and Yaswanth, KK},
title = {Experimental and statistical investigation on uniaxial compressive performance of hybrid double skin tubular slender columns.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {33368},
doi = {10.1038/s41598-025-17597-8},
pmid = {41022917},
issn = {2045-2322},
abstract = {Double-skin tubular columns have emerged as preferable in the construction sector because of their distinguished ease of benefits over traditional concrete columns. The uniaxial compression behaviour of the novel hybrid GFRP-concrete-steel double-skin tubular columns for different orientations is tested experimentally with various slenderness ratios. The experimental phase tested twenty-seven specimens by considering the three parameters such as fibre orientations (± 0°, 0°/90° and ± 45°), infill of the concrete (NSC, HSC and GPC) and void ratio (0.58, 0.6 and 0.68). The effect of these parameters was based on the ultimate load capacity, axial load-strain, and lateral deflection of DSTCs. The experimental tests revealed that as the column specimen's height increased, the confinement action became less effective. The test variables evaluated the effect of the slenderness ratio, the axial load-carrying capacity, ultimate axial strain, hoop strain, energy dissipation and ductility index. The fibre in 0/90° showed a higher energy dissipation and ductility index than the 0° and ± 45°. The load-carrying capacity of HSC infill revealed a 16% - 28% increase over the NSC and GPC. The axial strain showed a non-linear behaviour after 75% of the ultimate load. This study aims to develop a mathematical expression that predicts and optimises using a response surface methodology approach. The generated models were validated using Yu et al's model by introducing the slenderness ratio and proposed a new equation that closely agrees with the experimental results.},
}

@article {pmid41022842,
year = {2025},
author = {Sun, R and Zhuang, Y and Lin, Y and Hu, F},
title = {In situ secondary structure imaging of protein phase separation and aggregation by hyperspectral stimulated Raman scattering microscopy.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {8552},
pmid = {41022842},
issn = {2041-1723},
support = {22174085//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32350027//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {*Spectrum Analysis, Raman/methods ; Humans ; *Protein Aggregates ; Protein Structure, Secondary ; *Proteins/chemistry ; *Nonlinear Optical Microscopy/methods ; *Biomolecular Condensates/chemistry ; Phase Separation ; },
abstract = {Biomolecular condensates enable the coordination of cellular activities with high spatiotemporal selectivity. Many techniques have been developed to characterize protein condensate. However, direct visualization of protein structure in phase-separated condensate remains underexplored. Here we develop in situ quantitative imaging of secondary structure in protein condensates by stimulated Raman scattering (SRS) microscopy. Characteristic spectra of four secondary structures are obtained from protein amide I vibration analysis. Hyperspectral SRS imaging reveals significant enrichments and disordered to ordered structural changes during phase separation of ALS-related proteins. Time-lapse imaging of protein aging process directly visualizes heterogeneous β-sheet formation on the condensate surface. And secondary structures of mutant proteins are imaged to correlate amino acid sequence to phase separation property. Live-cell label-free imaging of protein structure is further demonstrated to exhibit pronounced heterogeneity in subcellular aggregates. Therefore, our technique provides crucial molecular-level information to investigate protein phase separation and its transition in pathological aggregation.},
}

*Spectrum Analysis, Raman/methods
Humans
*Protein Aggregates
Protein Structure, Secondary
*Proteins/chemistry
*Nonlinear Optical Microscopy/methods
*Biomolecular Condensates/chemistry
Phase Separation

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

@article {pmid41022144,
year = {2025},
author = {Guo, W and Cai, S and Li, Y and McGarry, BE and Caprio, TV and Temkin-Greener, H},
title = {End-of-Life Outcomes and Staff Visits for Hospice Recipients Residing in Assisted Living.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {105887},
doi = {10.1016/j.jamda.2025.105887},
pmid = {41022144},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine (1) whether hospice staff visits are associated with end-of-life (EOL) transitions, place of death (POD), and live discharges among assisted living (AL) residents, and (2) whether state AL regulations on staffing and medication administration influence these outcomes. We hypothesized that more frequent staff visits and specific regulatory provisions would be associated with improved EOL outcomes.

DESIGN: Retrospective cohort study using Medicare claims data from 2018-2019. Sensitivity analyses used logistic regression models to assess robustness.

SETTING AND PARTICIPANTS: National, population-based study of Medicare decedents residing in licensed AL communities across the United States. The main analytic sample included 42,466 AL residents who received hospice and died during enrollment. A separate sample of 61,851 was used to assess live discharges. Participants were identified by linking 9-digit ZIP codes of 10,452 licensed ALs to Medicare enrollment files. Individuals younger than 55 years, not enrolled in hospice, or enrolled in Medicare Advantage were excluded.

METHODS: Key exposures included the frequency of hospice staff visits (clinical vs nonclinical) and the presence of state AL regulations related to staffing and medication delegation. Outcomes included EOL transitions within the last 7 days of life, POD in AL vs other settings, and live discharges from hospice.

RESULTS: More frequent clinical staff visits were associated with lower rates of EOL transitions (-12 percentage points [pp]), reduced live discharges (-4 pp), and increased likelihood of dying in place (+4 pp; all P < .001). Nonclinical visits showed modest but consistent associations with improved outcomes. State regulations requiring on-site staffing and permitting medication delegation were associated with fewer transitions and higher rates of in-place death.

CONCLUSIONS AND IMPLICATIONS: Hospice staffing intensity, especially clinical visits, appears to be associated with EOL outcomes for AL residents. AL state regulations are also associated with hospice quality. These findings underscore the role of both organizational practices and regulatory policy in shaping hospice experiences in AL settings.},
}

@article {pmid41022136,
year = {2025},
author = {Jutkowitz, E and Gadkari, G and Hsu, EC and Tunalilar, O and Smith, L and Hua, CL and Bunker, JN and Thomas, KS},
title = {Trends in Assisted Living and Memory Care Supply From 2019 to 2023.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {105890},
doi = {10.1016/j.jamda.2025.105890},
pmid = {41022136},
issn = {1538-9375},
abstract = {OBJECTIVES: Describe geographic variation from 2019 to 2023 in assisted living (AL) and memory care supply, and its correlation with county-level characteristics.

DESIGN: Descriptive study of the supply of AL and memory care.

SETTING AND PARTICIPANTS: Licensed AL communities in the United States operating in 2019 and 2023.

METHODS: Data come from a national list of licensed ALs and the US Census Bureau's American Community Survey. The primary outcomes of interest were AL supply and memory care supply (beds per 1000 adults age 65+ at the county level). We descriptively evaluated county characteristics by AL supply in 2019 and the change in AL supply from 2019 to 2023.

RESULTS: In 2023, counties with the highest AL and memory care supply were more likely to have greater wealth, higher educational attainment, and were urban. Between 2019 and 2023, 43% of counties had a decrease in AL supply, 35% of counties had no change in AL supply, and 22% of counties had an increase in AL supply. Counties with a decrease or no change in AL supply compared with increase in AL supply had a larger proportion of the population 65+ years of age, lower median household income, and were more rural. Between 2019 and 2023, 29% of counties had a decrease in memory care supply, 37% had no change in memory care supply, and 34% had an increase in memory care supply. Counties with unchanged or a decrease in memory care supply had lower educational attainment, more poverty, lower home values, and were more rural.

CONCLUSIONS AND IMPLICATIONS: We found low overall availability of AL and memory care supply and decreases in their supply in rural and socioeconomically disadvantaged counties. It is important to incentivize ALs, including memory care, to operate in underserved areas to ensure equitable access to these important long-term care settings.},
}

@article {pmid41021520,
year = {2025},
author = {Yu, J and Du, H and Xue, E and Fu, Y and Chen, L and Shao, J},
title = {Effectiveness, ethics, and sustainability of nudge-based interventions for self-monitoring in patients with hypertension and type 2 diabetes: A systematic review.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {},
number = {},
pages = {},
doi = {10.1037/hea0001564},
pmid = {41021520},
issn = {1930-7810},
support = {//Zhejiang Provincial Natural Science Foundation/ ; //National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVE: This study aims to assess the effectiveness, ethics, and sustainability of nudge-based interventions in improving self-monitoring behaviors among patients with hypertension (HTN) and type 2 diabetes mellitus (T2DM).

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

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

CONCLUSIONS: This review highlights the potential of nudge-based interventions to improve self-monitoring adherence among patients with HTN and T2DM. However, balancing effectiveness, ethical considerations, and sustainability will be crucial for optimizing these interventions in real-world settings. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid41021147,
year = {2025},
author = {Xie, X and Wu, P and Wen, T and Jia, R and Zhang, R and Hu, F and Jin, J and Qin, X and Chen, QY},
title = {Iron and Ferritin Dyshomeostasis Intersect with Sex, Age, and Disease Severity in Amyotrophic Lateral Sclerosis.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {4},
pages = {127},
pmid = {41021147},
issn = {1559-1166},
support = {82302973//National Natural Science Foundation of China/ ; YX6J010//Xi'an Jiaotong University "Young Talent Support Plan"/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; Male ; Female ; Middle Aged ; *Iron/blood ; *Ferritins/blood ; Aged ; Adult ; Homeostasis ; Sex Factors ; Age Factors ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor neurons. Due to heterogeneity in both cause and clinical phenotype, accuracy of diagnosis and efficacy of treatment remain challenging. An evolving body of evidence point to the importance of the "gene-time-environment" hypothesis in ALS onset and progression. Despite extensive research, understanding of the complex environmental risk factors remains fragmented. In this study, we comprehensively analyzed the associations between trace elements, biochemical signatures, and modifiable risk factors among ALS patients stratified by age, sex, type of onset, disease severity, and progression. Specifically, we investigated blood concentrations of cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), and iron (Fe) levels in 121 participants. Moreover, we examined the associations between trace metals, biochemical indicators including serum ferritin (SF), blood glucose, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), cerebrospinal fluid (CSF) cell count, CSF total protein, as well as history of hypertension, hazardous chemical exposure, drinking, and smoking in ALS patients. Specifically, we report that high Fe levels were found in male and spinal-onset patients. Moreover, high serum ferritin was positively associated with age of onset, blood iron and glucose, as well as high disease severity. Results from this study highlight the complex characteristics of ALS and provide new insight for understanding the intricate relationship between disease phenotype, metal homeostasis, and modifiable risk factors.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood
Male
Female
Middle Aged
*Iron/blood
*Ferritins/blood
Aged
Adult
Homeostasis
Sex Factors
Age Factors

@article {pmid41020397,
year = {2025},
author = {Dergai, O and Wuu, J and Koziczak-Holbro, M and Malaspina, A and Granit, V and Hernandez, JP and Cooley, A and Sachdev, R and Yu, L and Bidinosti, M and Flotte, L and Nash, M and Jennings, LL and Berry, JD and Bruijn, LI and Brachat, S and Benatar, M},
title = {Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78046},
pmid = {41020397},
issn = {1531-8249},
abstract = {OBJECTIVE: Biomarkers with clear contexts of use are important tools for amyotrophic lateral sclerosis (ALS) therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large-scale proteomic study in well-phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression.

METHODS: Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. Slow off-rate modified aptamer (SOMAmer)-based relatively quantitative measurement of ~7,000 proteins was performed in plasma and cerebrospinal fluid (CSF), with immunoassay validation of candidates of interest.

RESULTS: We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted p-value <0.05), with 25 showing >40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log-fold elevation, whereas ANTXR2 and ART3 had the greatest log-fold reduction. A similar set of plasma proteins was found to increase (eg, PDLIM3, TNNT2, and MYL11) or decrease (eg, ANTXR2, ART3, and MSTN) with disease progression. CSF proteins with the greatest log-fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11, and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue-specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Plasma KCNIP3 was elevated by ~60% in those on riluzole. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.

INTERPRETATION: We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of disease. ANN NEUROL 2025.},
}

@article {pmid41019660,
year = {2025},
author = {Gómez Mendieta, MªA and Santiago Recuerda, A and Varela Cerdeira, M and Liebert Alvarez, B and Valdazo Alonso, M and Corpa Rodríguez, E},
title = {Non-Sedated Cannula Replacement in Home-Care Patients With Amyotrophic Lateral Sclerosis: Cost Reduction and Patient-Family Satisfaction Evaluation.},
journal = {Open respiratory archives},
volume = {7},
number = {4},
pages = {100480},
pmid = {41019660},
issn = {2659-6636},
abstract = {This study describes a home-based tracheostomy tube replacement protocol for individuals diagnosed with amyotrophic lateral sclerosis (ALS) requiring invasive mechanical ventilation. Implemented between May 2020 and July 2024, the protocol was offered to 16 eligible patients, with 14 opting for home-based care under the supervision of the Carlos III/La Paz Hospital. Procedures were conducted without sedation by a multidisciplinary team, with the aim of maintaining patient safety and continuity of care. A total of 120 home-based replacements were performed, most without major complications or the need for emergency hospitalization. In comparison to hospital-based procedures, the home protocol was associated with an estimated cost reduction of approximately €340 per case, potentially resulting in annual savings of €10,200. Patients reported high satisfaction, noting decreased caregiver burden and improved perceived quality of care. While limited by patient selection criteria, these preliminary findings suggest that home-based tracheostomy care may be a feasible, safe, and cost-effective alternative for long-term management in ALS.},
}

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

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

@article {pmid41018179,
year = {2025},
author = {Liu, M and Niu, T and Zhang, X and Zhang, Z and Zhao, L and Li, J and Fu, S and Han, M and Li, R and Dong, H and Liu, Y},
title = {Development and validation of a predictive model for depression risk in patients with amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1639895},
pmid = {41018179},
issn = {1664-2295},
abstract = {INTRODUCTION: Depression is a severe neuropsychiatric manifestation in patients with amyotrophic lateral sclerosis (ALS), substantially impacting their quality of life and exacerbating caregiver burden, due to the need for different approaches in clinical care. However, a predictive model for the risk of depression in patients with ALS is lacking. This study aimed to develop and validate a predictive model using routinely accessible clinical and laboratory indicators to identify patients at high risk of depression.

METHODS: Patients with ALS who were hospitalized in the Department of Neurology at the Second Hospital of Hebei Medical University between March 2017 and December 2024 were included. Basic clinical data, laboratory test results, and relevant questionnaire scores were collected, and patients were divided into depressed and non-depressed groups. The least absolute shrinkage and selection operator regression and multivariate logistic regression analyses were applied for variable selection and model construction. Model performance was evaluated using the area under the receiver operating characteristic curve, calibration curves, decision curve analysis, and clinical impact curves, with internal validation performed via bootstrap resampling.

RESULTS: Depression was observed in 33.9% of patients. Significant predictors included educational level, sleep disorders, anxiety, Revised Amyotrophic Lateral Sclerosis Functional Rating Scale total scores, C-reactive protein levels, and the Systemic Inflammation Response Index. The final model demonstrated good predictive accuracy and clinical applicability. A depression risk scoring table was further developed based on the coefficients of the logistic regression.

CONCLUSION: The nomogram and the scoring table offer a reliable and practical approach for clinicians to identify patients with ALS who are at high risk for depression and enable early psychological intervention in clinical settings.},
}

@article {pmid41018173,
year = {2025},
author = {Tanaka, S and Kobayashi, M and Ikeguchi, R and Iwasaki, N},
title = {A Case of Amyotrophic Lateral Sclerosis With Coexisting Maturity-onset Diabetes of the Young Type 5.},
journal = {JCEM case reports},
volume = {3},
number = {11},
pages = {luaf219},
pmid = {41018173},
issn = {2755-1520},
abstract = {We report the case of a 60-year-old Japanese woman with genetically confirmed maturity-onset diabetes of the young type 5 [MODY5; HNF1B (hepatocyte nuclear factor 1B)-MODY] who developed amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder. MODY is a rare monogenic form of diabetes mellitus, typically associated with urogenital anomalies and pancreatic hypoplasia. At the age of 25, she was diagnosed with diabetes mellitus. The clinical findings, including bilateral renal cysts, agenesis of the pancreatic body and tail, and impaired insulin secretion without β-cell-specific autoimmune autoantibodies, suggested HNF1B-MODY. A 1.4-Mb hemiallelic deletion on chromosome 17q12 encompassing HNF1B was confirmed, and she was subsequently diagnosed with HNF1B-MODY. At age 59, she developed symptoms of a common cold, followed by dysarthria and limb weakness. The neurological examination revealed tongue fasciculations, spasticity, and hyperreflexia. Electromyography indicated widespread motor neuron degeneration, consistent with a diagnosis of definite ALS. Whole-exome sequencing revealed no known ALS-related pathogenic variants, and no ALS candidate genes were detected in the deleted region of 17q12. To our knowledge, this is the first reported case of concurrent ALS and HNF1B-MODY. While a direct genetic link is unclear, this co-occurrence may provide insights into the shared molecular pathways and warrants further investigation.},
}

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

@article {pmid41017705,
year = {2025},
author = {Wang, H and Wei, Y and Wang, J and Liu, J and Ou, S and Wang, J},
title = {Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00354},
pmid = {41017705},
issn = {1673-5374},
abstract = {The voltage-gated sodium channel Nav1.6, encoded by the sodium voltage-gated channel alpha subunit 8 gene, is a crucial regulator of neuronal excitability, with widespread expression throughout the central and peripheral nervous systems. Recent breakthroughs in structural biology, particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm, have provided unprecedented insights into its molecular organization and functional modulation. As a key mediator of action potential initiation and propagation, Nav1.6 possesses unique biophysical properties, including persistent and resurgent sodium currents that critically influence neuronal firing patterns. This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions. Key findings include the following: (1) Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations, where gain-of-function variants lead to severe epileptic encephalopathies, while loss-of-function variants are associated with generalized epilepsy, highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967. (2) In Alzheimer's disease, Nav1.6 mediates amyloid-β oligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling, suggesting novel disease-modifying strategies. (3) Parkinson's disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization. (4) Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration, with riluzole showing partial efficacy through sodium current modulation. (5) Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons, which drives calcium-dependent axonal injury via reverse Na+/Ca2+ exchange. (6) Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons, regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-α signaling pathways. (7) Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability. Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches, including state-dependent pore blockers designed using structural insights; allosteric modulators targeting specific conformations; gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides; and miRNA-based regulation of channel expression. Current challenges include achieving sufficient subtype selectivity, optimizing blood-brain barrier penetration, and developing clinically relevant biomarkers for patient stratification. Future directions emphasize the integration of advanced technologies-such as singlecell multiomics to map neuronal subtype-specific expression patterns, patient-derived organoids for personalized drug testing, and machine learning-assisted drug design-to accelerate translation. Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.},
}

@article {pmid41018230,
year = {2025},
author = {Qin, JY and Zhou, ZL and Zhou, YQ and Chen, Y and Yang, XY and Zhang, HQ and Xu, ZC},
title = {Double gene mutations of LRSAM1 and REEP1 and a new REEP1 mutation site found in a patient with amyotrophic lateral sclerosis with subjective paresthesia: A case report.},
journal = {Ibrain},
volume = {11},
number = {3},
pages = {393-399},
pmid = {41018230},
issn = {2769-2795},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. Although dyskinesia is the most prominent clinical manifestation of ALS, with an in-depth understanding of disease pathogenesis and clinical detection, more and more ALS patients are found to have nonmotor symptoms, such as sensory impairment. Genetic testing technology has developed rapidly in recent years. New genes have been proven to be involved in the pathogenesis of ALS. However, according to the existing research evidence, no literature has reported that patients with ALS have leucine-rich repeats and sterility α mutations in motif 1 (LRSAM1) and receptor expression accessory protein 1 (REEP1). The mutation sites of REEP1 gene have not been reported, and the simultaneous mutations of two genes have not been reported. In the largest human gene mutation frequency database gnomad, the mutation sites of two genes are currently defined as new heterozygous variants with unclear clinical significance. Therefore, this article reports the clinical data of this case to further deepen the clinicians' understanding of the disease, and may provide evidence for further study of the new genotype-phenotype of LRSAM1 and REEP1.},
}

@article {pmid41017138,
year = {2025},
author = {Kobayashi, H and Suzuki-Masuyama, H and Tanabe, H and Kato, H and Endoh-Yamagami, S},
title = {Neuronal Damage Induced by Gradual Oxidative Stress in iPSC-Derived Neurons: Implications for Ferroptosis Involvement and ALS Drug Evaluation.},
journal = {Journal of neurochemistry},
volume = {169},
number = {10},
pages = {e70246},
doi = {10.1111/jnc.70246},
pmid = {41017138},
issn = {1471-4159},
support = {//internal funding from FUJIFILM Corporation/ ; },
mesh = {*Ferroptosis/drug effects/physiology ; *Oxidative Stress/drug effects/physiology ; *Induced Pluripotent Stem Cells/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Humans ; *Neurons/drug effects/pathology/metabolism ; Neuroprotective Agents/pharmacology ; Mice ; Edaravone/pharmacology ; Cells, Cultured ; *Motor Neurons/drug effects/metabolism/pathology ; },
abstract = {The molecular mechanisms underlying neurodegenerative diseases are not fully understood, but oxidative stress is known to play a central role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). In this study, we developed a method to induce gradual oxidative stress in induced pluripotent stem cell (iPSC)-derived motor neurons and cortical excitatory neurons by omitting antioxidants in the media, aiming to create a platform for studying oxidative stress-dependent neuronal damage in neurodegenerative diseases. Neuroprotective effects in this platform were observed with edaravone, an approved ALS medicine, in iPSC-derived motor neurons, suggesting its potential for ALS drug evaluation. The oxidative stress-induced neuronal damage was accompanied by increased lipid peroxidation, and it was suppressed by ferroptosis inhibitors and an iron-specific chelator, suggesting that neurons died through ferroptosis. Furthermore, through a compound screen, a cholesterol biosynthesis inhibitor, AY 9944, was identified as being capable of inhibiting neuronal damage induced by oxidative stress. Additionally, neuroprotective activity was observed with 7-dehydrocholesterol, an immediate precursor of cholesterol, while the efficacy of AY 9944 was compromised by knockout of the EBP gene, which encodes an enzyme involved in cholesterol biosynthesis. These findings suggest the involvement of ferroptosis in the progression of neurodegenerative diseases and the inhibition of ferroptosis by modulating the cholesterol biosynthesis pathway, providing potential insights for drug development.},
}

*Ferroptosis/drug effects/physiology
*Oxidative Stress/drug effects/physiology
*Induced Pluripotent Stem Cells/drug effects/metabolism/pathology
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
Animals
Humans
*Neurons/drug effects/pathology/metabolism
Neuroprotective Agents/pharmacology
Mice
Edaravone/pharmacology
Cells, Cultured
*Motor Neurons/drug effects/metabolism/pathology

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

@article {pmid41016645,
year = {2025},
author = {Thumbadoo, KM and Nementzik, LR and Swanson, MEV and Dieriks, BV and Dragunow, M and Faull, RLM and Curtis, MA and Blair, IP and Nicholson, GA and Williams, KL and Scotter, EL},
title = {A meta-analysis of genetic variant pathogenicity and sex differences in UBQLN2-linked amyotrophic lateral sclerosis and frontotemporal dementia.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107127},
doi = {10.1016/j.nbd.2025.107127},
pmid = {41016645},
issn = {1095-953X},
abstract = {Ubiquilin 2, encoded by the X-linked UBQLN2 gene, is a ubiquitin-binding quality control protein. Pathogenic UBQLN2 genetic variants cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS/FTD), however, clinical phenotypes from these variants show striking inter- and intra-familial heterogeneity. Further, there are many UBQLN2 variants whose significance to disease is uncertain. Here, we examine the pathogenic potential of UBQLN2 variants reported in individuals with ALS/FTD and their non-symptomatic relatives. Meta-analysis from 27 published studies identified 186 affected individuals and 51 asymptomatic carriers, each harbouring one of 43 unique UBQLN2 coding variants. Features of identified variants, including evolutionary conservation, minor allele frequencies, localisation to protein domains, and in silico predictions of pathogenicity were compiled. Per biological sex, clinical features were compared between UBQLN2 variants segregated by pathogenicity. Pathogenic UBQLN2 variants carriers, of which most are familial ALS cases, showed a sex-specific difference in age at onset wherein males developed disease on average 18.15 years prior to females (29.54 ± 11.9 versus 47.69 ± 13.4 years, p < 0.0001), with no change in disease duration (p = 0.2091). UBQLN2 variants of uncertain significance showed a bimodal distribution of onset age per sex suggesting a mixture of true benign and true pathogenic variants. In human brain tissue, two male UBQLN2 p.Thr487Ile (ALS-FTD and ALS) cases showed a greater burden of ubiquilin 2 aggregates than a related female case (ALS-FTD). These robust sex-specific differences in ALS/FTD presentation in carriers of pathogenic UBQLN2 variants may improve predictions of ALS/FTD risk in carriers, aiding in diagnosis and disease management.},
}

@article {pmid41016203,
year = {2025},
author = {Oka, S and Inoue, N and Takefuji, Y},
title = {Beyond predictive accuracy: Statistical validation of feature importance in biomedical machine learning.},
journal = {Computer methods and programs in biomedicine},
volume = {272},
number = {},
pages = {109085},
doi = {10.1016/j.cmpb.2025.109085},
pmid = {41016203},
issn = {1872-7565},
abstract = {In medical machine learning (ML), a fundamental methodological distinction exists between optimizing model performance for predictive tasks and pursuing causal inference for mechanistic interpretation. Achieving high predictive accuracy does not necessarily imply that a model can uncover the true physiological mechanisms underlying the data. This letter addresses a critical interpretational challenge in medical machine learning, building upon Yuyang Yan et al.'s valuable work on exacerbation classification in asthma and COPD. While their multi-feature fusion model, particularly comprising models such as K-Nearest Neighbors (KNN), Support Vector Machines (SVM), Random Forest (RF), and Bidirectional Long Short-Term Memory (BiLSTM) demonstrates high predictive accuracy for respiratory exacerbations, we highlight that such performance alone does not guarantee reliable insights into feature importance. Complex tree-based models like RF, when interpreted via methods like SHapley Additive exPlanations (SHAP), can exhibit inherent biases, overemphasizing features used in early splits and reflecting what is important for their specific prediction rather than the true underlying physiological drivers. Validating feature importance remains challenging without ground truth, as different models often yield varying rankings. We argue that solely relying on model-dependent interpretations risks misrepresenting the actual mechanisms of complex medical phenomena. Therefore, we advocate for a robust analytical strategy that transcends mere predictive metrics. This involves a synergistic approach combining the predictive power of ML with impartial, complementary statistical methodologies-such as non-parametric correlation and mutual information-to ensure genuinely trustworthy scientific insights into the true drivers of respiratory exacerbations.},
}

@article {pmid41013833,
year = {2025},
author = {Spittel, S and Meyer, T and Weyen, U and Grehl, T and Weydt, P and Steinbach, R and Petri, S and Baum, P and Metelmann, M and Sperfeld, AD and Kettemann, D and Norden, J and Rödiger, A and Ilse, B and Grosskreutz, J and Hildebrandt, B and Walter, B and Münch, C and Maier, A},
title = {Response to Fortin-Bédard et al. "User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study".},
journal = {Neurological research and practice},
volume = {7},
number = {1},
pages = {70},
doi = {10.1186/s42466-025-00405-z},
pmid = {41013833},
issn = {2524-3489},
}

@article {pmid41013664,
year = {2025},
author = {Fortin-Bédard, N and Gbètoho Atigossou, OL and Flamand, VH and Bouffard, J and Routhier, F},
title = {The use of robotic arms for individuals with severe upper-limb disabilities.},
journal = {Neurological research and practice},
volume = {7},
number = {1},
pages = {69},
pmid = {41013664},
issn = {2524-3489},
abstract = {This letter to the editor aims to comment on the article « User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study » recently published by Spittel et al. (Neurol Res Pract, 6(1), 42).},
}

@article {pmid41011086,
year = {2025},
author = {Moțățăianu, A and Andone, S and Maier, S and Chinezu, R and Roman, M and Dumitreasă, M and Bălașa, R and Ormenișan, I},
title = {Beyond Motor Decline in ALS: Patient-Centered Insights into Non-Motor Manifestations.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {9},
pages = {},
pmid = {41011086},
issn = {1648-9144},
support = {project number PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation, and Digitization, CNCS-UEFISCDI/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/psychology ; Male ; Female ; Middle Aged ; Aged ; Quality of Life/psychology ; Disease Progression ; Surveys and Questionnaires ; Sleep Wake Disorders/etiology ; Adult ; },
abstract = {Background and Objectives: Traditionally regarded as a purely motor disorder, amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. However, it is increasingly recognized as a condition with a broader clinical spectrum, encompassing a variety of non-motor symptoms (NMS) that significantly impact patients' quality of life and may influence disease progression and prognosis. Materials and Methods: The study included 44 patients diagnosed with probable or definite ALS and 35 healthy controls (HC). Functional neurological status, non-motor manifestations, and cognitive and affective domains were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R), the Non-Motor Symptoms Questionnaire (NMSQuest), the Frontal Assessment Battery (FAB), and the Beck Depression Inventory (BDI), respectively. Results: A majority of ALS patients exhibited non-motor symptoms (NMS). Significant associations were identified between specific NMS domains and ALSFRS-R subdomains: sleep disturbances were associated with lower fine motor, respiratory, and total scores; digestive symptoms with lower bulbar, respiratory, and total scores; cardiovascular symptoms with lower total scores; urinary symptoms with higher bulbar subscores and a significantly slower progression rate (ΔPR); and sensory symptoms with higher gross motor subscores. BDI scores were negatively correlated with respiratory and bulbar functions, whereas FAB scores showed positive correlations with both bulbar and total ALSFRS-R scores. Conclusions: Non-motor symptoms are highly prevalent in this ALS cohort. These symptoms do not consistently correlate with greater motor impairment, as urinary and somatosensory involvement may occur independently of functional decline. Cognitive, affective, and behavioral alterations co-exist with motor symptoms and are associated with poorer overall functional performance.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/physiopathology/psychology
Male
Female
Middle Aged
Aged
Quality of Life/psychology
Disease Progression
Surveys and Questionnaires
Sleep Wake Disorders/etiology
Adult

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

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

@article {pmid41009796,
year = {2025},
author = {Awai, A and Johnson, EL and Leng, T and Patrickson, J and Zody, MC and Lillard, JW and On Behalf Of The Nygc Als Consortium, },
title = {Stratifying ALS Patients by Mode of Inheritance Reveals Transcriptomic Signatures Specific to sALS and fALS.},
journal = {International journal of molecular sciences},
volume = {26},
number = {18},
pages = {},
pmid = {41009796},
issn = {1422-0067},
support = {R25GM058268.//NIH G-RISE/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Transcriptome/genetics ; Gene Expression Profiling ; Spinal Cord/metabolism/pathology ; Female ; Middle Aged ; Male ; Motor Cortex/metabolism ; Aged ; Gene Regulatory Networks ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease, marked by considerable clinical and molecular heterogeneity. While several genetic drivers have been linked to familial ALS (fALS), the biology of sporadic ALS (sALS)-which accounts for the majority of ALS cases-remains poorly defined. To address this gap, we analyzed 247 bulk mRNA-sequenced post-mortem tissue samples from the lumbar spinal cord and motor cortex and compared expression profiles between fALS, sALS, and controls. Variance-stabilized DEGs from DESeq2 analysis were used as inputs for weighted gene co-expression network analysis (WGCNA). Finally, gene ontology was used to identify transcriptomic signatures and biological pathways unique to sALS and fALS. In the spinal cord, sALS samples exhibited specific downregulation of mitochondrial complex I subunits (e.g., NDUFS8 and NDUFB7) and regulatory genes (e.g., AURKAIP1 and ATP5F1D), suggesting compromised metabolic resilience. In the motor cortex, a co-expression module associated with adaptive immune function and leukocyte infiltration was downregulated in sALS yet upregulated in fALS, indicating distinct inflammatory pathways between these two forms of ALS. Together, our findings highlight that while sALS and fALS are largely the same disease, they exhibit distinct transcriptomic signatures. By accounting for mode of inheritance in study designs-particularly sALS, which represents ~90% of ALS cases-researchers may reveal deeper insights into ALS pathology. This perspective could enable more targeted therapeutic strategies, ultimately improving outcomes for all ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/metabolism
*Transcriptome/genetics
Gene Expression Profiling
Spinal Cord/metabolism/pathology
Female
Middle Aged
Male
Motor Cortex/metabolism
Aged
Gene Regulatory Networks

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

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

@article {pmid41009467,
year = {2025},
author = {Bowser, R and An, J and Schwartz, K and Sucholeiki, RL and Sucholeiki, I},
title = {ALS Patients Exhibit Altered Levels of Total and Active MMP-9 and Several Other Biomarkers in Serum and CSF Compared to Healthy Controls and Other Neurologic Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {18},
pages = {},
pmid = {41009467},
issn = {1422-0067},
support = {W81XWH-21-ALSRP-DTA//Department of Defense (DOD) Amyotrophic Lateral Sclerosis Research Program (ALSRP) Therapeutic Development Award (TDA)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid ; *Matrix Metalloproteinase 9/blood/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; Male ; Female ; Middle Aged ; Aged ; Matrix Metalloproteinase 2/blood/cerebrospinal fluid ; Alzheimer Disease/blood/cerebrospinal fluid ; Case-Control Studies ; Cystatin C/blood/cerebrospinal fluid ; *Nervous System Diseases/blood/cerebrospinal fluid ; Adult ; Parkinson Disease/blood/cerebrospinal fluid ; Neurofilament Proteins/blood/cerebrospinal fluid ; Creatinine/blood/cerebrospinal fluid ; },
abstract = {Matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, their protein levels and correlation with other biomarkers are not well understood. We measured total and active MMP-2/-9 and additional biomarkers (creatinine, neurofilament light, cystatin C, and alkaline phosphatase) in the serum of people with ALS (ALS, n = 30) and compared their levels with age-matched healthy controls (HC, n = 20) and other neurological diseases (diabetic nephropathy, Alzheimer's disease, Parkinson's disease; n = 8 each). We also measured MMP-2/-9 in a set of CSF samples from ALS (n = 30) and age-matched other neurological diseases (OND, n = 14). Lastly, we measured the competitive binding behavior of a dual MMP-2/MMP-9 inhibitor, AQU-118, against active MMP-9 in situ within the serum of ALS. We found significantly elevated levels of both total MMP-9 protein (two studies, 7.5 and 9.5-fold; both p < 0.0001) and active MMP-9 (2.5-fold; p < 0.0001) in ALS serum compared to HC. Serum NfL was significantly elevated (6-fold, p < 0.0001) and serum creatinine was significantly decreased (40%, p < 0.0001) in ALS compared to HC. There were significantly decreased levels of MMP-2 (two studies, 26 and 33%; p < 0.001 and p = 0.0001, respectively) in the serum of ALS as compared to HC. ALS also had significantly higher active MMP-9 in serum than patients with Alzheimer's disease and higher than Parkinson's disease or diabetic nephropathy. We confirmed that active MMP-9 in ALS is fully available for proteolytic activity in both serum and CSF and can be inhibited using an MMP-2/-9 inhibitor. Active MMP-9 is systemically elevated in ALS and therefore a therapeutic target for ALS drug development.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid
*Matrix Metalloproteinase 9/blood/cerebrospinal fluid
*Biomarkers/blood/cerebrospinal fluid
Male
Female
Middle Aged
Aged
Matrix Metalloproteinase 2/blood/cerebrospinal fluid
Alzheimer Disease/blood/cerebrospinal fluid
Case-Control Studies
Cystatin C/blood/cerebrospinal fluid
*Nervous System Diseases/blood/cerebrospinal fluid
Adult
Parkinson Disease/blood/cerebrospinal fluid
Neurofilament Proteins/blood/cerebrospinal fluid
Creatinine/blood/cerebrospinal fluid

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

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

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

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

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

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

@article {pmid41008523,
year = {2025},
author = {Lin, H and Zhang, J and Hu, J and Ma, L and Lai, K and Zheng, C and Yang, Q and Zhang, L},
title = {Improvement of Soluble Expression, Stability, and Activity of Acetaldehyde Lyase by Elastin-like Polypeptides Fusion for Acetoin Production from Acetaldehyde.},
journal = {Biomolecules},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/biom15091216},
pmid = {41008523},
issn = {2218-273X},
mesh = {*Acetaldehyde/metabolism ; *Elastin/chemistry/metabolism/genetics ; Escherichia coli/genetics/metabolism ; *Recombinant Fusion Proteins/genetics/metabolism/chemistry ; *Acetoin/metabolism ; Enzyme Stability ; *Peptides/chemistry/metabolism/genetics ; Kinetics ; Solubility ; Elastin-Like Polypeptides ; },
abstract = {To achieve the large-scale, low-cost preparation of acetaldehyde lyase (ALS), elastin-like polypeptides (ELPs) as non-chromatographic purification tags were employed to develop an ELP-ALS fusion protein in Escherichia coli. Induction expression results demonstrated that the ELPs tag efficiently improved the soluble expression of the ALS enzyme. Through two rounds of inverse transition cycling (ITC), highly pure ELP-ALS was obtained with an enzyme recovery rate of 85.77%, outperforming Ni[2+]-affinity chromatography (66.80%). The comparative analysis of enzymatic properties revealed that ELP fusion markedly improved the stability and substrate tolerance of the ALS enzyme. Kinetic parameter analysis under identical conditions showed that ELP-ALS possessed a Vmax of 15.25 U/mg and a kcat/Km of 73.05 s[-1]·M[-1], representing 1.86-fold and 2.97-fold improvements over His-ALS, respectively. Fed-batch reaction using ELP-ALS and acetaldehyde as biocatalyst and substrate, respectively, yielded 95.92 g/L acetoin with 49.32% increase compared to His-ALS (64.24 g/L). These results demonstrated the application potential of ELP-ALS as a promising biocatalyst for acetoin production from acetaldehyde due to its lower preparation cost, higher biocatalytic efficiency, better stability, and substrate tolerance.},
}

*Acetaldehyde/metabolism
*Elastin/chemistry/metabolism/genetics
Escherichia coli/genetics/metabolism
*Recombinant Fusion Proteins/genetics/metabolism/chemistry
*Acetoin/metabolism
Enzyme Stability
*Peptides/chemistry/metabolism/genetics
Kinetics
Solubility
Elastin-Like Polypeptides

@article {pmid41008437,
year = {2025},
author = {Packer, R and Rumbach, A and Farrell, A and Hutchinson, N and Verner-Wren, S and Henderson, R and McCombe, P},
title = {Living with Dysphagia and Dysarthria: A Qualitative Exploration of the Perspectives of People with Motor Neuron Disease and Their Caregivers.},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {18},
pages = {},
doi = {10.3390/healthcare13182306},
pmid = {41008437},
issn = {2227-9032},
support = {Unknown//Health Practitioner Research Scheme Funding, Allied Health Professional Office of Queensland/ ; },
abstract = {Background/Objectives: Dysphagia and dysarthria are common and distressing symptoms of motor neuron disease (MND) progression. The medical complications of dysphagia and the influence of dysarthria on communication effectiveness have been documented. The aim of the current study was to describe the lived experience of dysphagia and dysarthria from the perspectives of both people with motor neuron disease (pwMND) and their caregivers. Methods: A qualitative descriptive study influenced by phenomenological principles was utilized in interviews with six pwMND and six caregivers. Results: Three themes were developed that captured participants' experiences of dysphagia and dysarthria: (1) "This is the way things are"; (2) Your whole life changes, but some things stay the same; (3) Juxtaposition to information and support. Conclusions: The findings advance our understanding of the lived experience of dysphagia and dysarthria in MND. Health professionals need to consider broader assessment practices across both mealtimes and communicative interactions and each individual's unique information and support needs when providing healthcare information.},
}

@article {pmid41008332,
year = {2025},
author = {Bernetti, C and Cea, L and Buoso, A and Greco, F and Rossi, M and Pilato, F and Calandrelli, R and Di Gennaro, G and Di Lazzaro, V and Zobel, BB and Mallio, CA},
title = {A Comprehensive Overview of Subacute Combined Degeneration: MRI Diagnostic Challenges and Treatment Pathways.},
journal = {Brain sciences},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/brainsci15090972},
pmid = {41008332},
issn = {2076-3425},
abstract = {Subacute combined degeneration (SCD) is a neurological disorder primarily caused by vitamin B12 deficiency. This condition leads to progressive demyelination and axonal damage, predominantly affecting the dorsal and lateral columns of the spinal cord. This review provides a comprehensive overview of SCD, detailing its complex etiology, pathophysiology, and clinical presentation. We highlight the critical role of magnetic resonance imaging (MRI) in the diagnostic process, discussing both the characteristic spinal cord findings and the more subtle intracranial abnormalities. Furthermore, we address the diagnostic challenges presented by conditions that mimic SCD in MRI, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). We conclude by outlining current treatment pathways and identifying key areas for future research, including the use of advanced neuroimaging techniques and the potential for new therapeutic approaches. This updated synthesis aims to provide a clear framework for clinicians and researchers to better understand and manage SCD.},
}

@article {pmid41007730,
year = {2025},
author = {Schreiner, TG and Menéndez-González, M and Schreiner, OD and Ciobanu, RC},
title = {Intrathecal Therapies for Neurodegenerative Diseases: A Review of Current Approaches and the Urgent Need for Advanced Delivery Systems.},
journal = {Biomedicines},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/biomedicines13092167},
pmid = {41007730},
issn = {2227-9059},
abstract = {Neurodegenerative diseases (NDDs) pose an immense global health burden, and developing effective treatments is hindered by the blood-brain barrier (BBB). Intrathecal (IT) administration of therapeutics directly into the cerebrospinal fluid (CSF) bypasses the BBB, offering a promising avenue for antisense oligonucleotides (ASOs), gene therapies, antibodies, and stem cells for these disorders. This review synthesizes the current landscape of IT therapies for Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis based on the current literature and ClinicalTrials.gov. We highlight key trials and approaches, including the success of ASOs in spinal muscular atrophy and recent progress in other NDDs. However, the efficacy of these novel treatments is often constrained by the limitations of first-generation IT delivery systems, which struggle with uneven distribution, systemic leakage, and the demands of modern biologics. Drawing from recent analyses, we underscore the critical shortcomings of current devices and point out the innovations needed in shaping next-generation systems: subcutaneous access ports, CSF flow platforms, AI-driven adaptive dosing, nanoporous membranes, intrathecal pseudodelivery, and hydrogel scaffolds. We conclude by emphasizing the urgent need for these advanced IT drug delivery systems, alongside rigorous comparative assessments, cost-benefit analyses, and clear regulatory pathways to fully realize the potential of emerging CNS therapies and transform NDD management.},
}

@article {pmid41007432,
year = {2025},
author = {Ramos-Velasco, B and Alcalde, J and Izquierdo, JM},
title = {Welander Distal Myopathy-Associated TIA1 E384K Mutation Disrupts Stress Granule Dynamics Under Distinct Stress Conditions.},
journal = {Biology},
volume = {14},
number = {9},
pages = {},
doi = {10.3390/biology14091288},
pmid = {41007432},
issn = {2079-7737},
support = {RTI2018-098517B-I00 and PID2021-126152OB-I00//Ministerio de Ciencia, Innovación y Universidades and Agencia Española de Investigación through FEDER funds (RTI2018-098517B-I00 and PID2021-126152OB-I00)/ ; },
abstract = {Cellular stress triggers the formation of diverse RNA-protein aggregates, which can be associated with physiological responses, pathological conditions, or even detrimental outcomes. Under stress-induced proteostasis disruption, these RNA-protein assemblies are known as stress granules (SGs). Targeting such condensates-while sparing functional RNAs and proteins-remains a major therapeutic challenge in protein aggregation disorders such as myopathies and neuropathies. In this study, we investigated the cellular response to various stress conditions in the context of the TIA1 E384K mutation, a founder variant implicated in both Welander distal myopathy (WDM) and amyotrophic lateral sclerosis (ALS). Cells were exposed to different stressors, including proteotoxic, proteostatic, chemotoxic, and osmotic insults, and the behavior of TIA1-related SGs was analyzed. Our findings reveal a distinct yet conserved pattern in the dynamics of TIA1-dependent SG formation and clearance, influenced by the specific type of stressor and modulated by eIF2α Ser35 phosphorylation. These results indicate that the WDM-associated TIA1 mutation leads to aberrant SG dynamics across different stress conditions. Collectively, these observations support the idea that TIA1 E384K-associated SG dysregulation plays a role in WDM and ALS pathogenesis and underscores the importance of multiple stress contexts in disease progression.},
}

@article {pmid41005925,
year = {2026},
author = {Marín-García, M and Gonzalez-Olmos, R and Gómez-Canela, C},
title = {Direct UV photolysis of cloperastine in aqueous solution: Kinetic model and degradation pathway.},
journal = {Journal of environmental sciences (China)},
volume = {159},
number = {},
pages = {670-682},
doi = {10.1016/j.jes.2025.03.025},
pmid = {41005925},
issn = {1001-0742},
mesh = {*Photolysis ; *Water Pollutants, Chemical/chemistry/radiation effects ; *Ultraviolet Rays ; Kinetics ; *Piperidines/chemistry/radiation effects ; Models, Chemical ; },
abstract = {The increasing production and release of synthetic organic chemicals, including pharmaceuticals, into our environment has allowed these substances to accumulate in our surface water systems. Current purification technologies have been unable to eliminate these pollutants, resulting in their ongoing release into aquatic ecosystems. This study focuses on cloperastine (CPS), a cough suppressant and antihistamine medication. The environmental impact of CPS usage has become a concern, mainly due to its increased detection during the COVID-19 pandemic. CPS has been found in wastewater treatment facilities, effluents from senior living residences, river waters, and sewage sludge. However, the photosensitivity of CPS and its photodegradation profile remain largely unknown. This study investigates the photodegradation process of CPS under simulated tertiary treatment conditions using UV photolysis, a method commonly applied in some wastewater treatment plants. Several transformation products were identified, evaluating their kinetic profiles using chemometric approaches (i.e., curve fitting and the hard-soft multivariate curve resolution-alternating least squares (HS-MCR-ALS) algorithm) and calculating the reaction quantum yield. As a result, three different transformation products have been detected and correctly identified. In addition, a comprehensive description of the kinetic pathway involved in the photodegradation process of the CPS drug has been provided, including observed kinetic rate constants.},
}

*Photolysis
*Water Pollutants, Chemical/chemistry/radiation effects
*Ultraviolet Rays
Kinetics
*Piperidines/chemistry/radiation effects
Models, Chemical

@article {pmid41005783,
year = {2025},
author = {Ofosu, NN and Luth, W and Genuis, SK and Tymkow, K and Budiyanto, I and McGuckin, T and Campbell-Scherer, D and Johnston, WS},
title = {Challenges and opportunities for expediting ALS diagnosis in Alberta, Canada: a human-centred design approach.},
journal = {BMJ open},
volume = {15},
number = {9},
pages = {e104139},
doi = {10.1136/bmjopen-2025-104139},
pmid = {41005783},
issn = {2044-6055},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Alberta ; Female ; Male ; Middle Aged ; Qualitative Research ; Referral and Consultation ; Aged ; *Delayed Diagnosis ; Interviews as Topic ; Adult ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal motor neuron disease. Diagnostic delay severely impairs patient access to ALS multidisciplinary clinics, available disease-modifying medications and therapies that may prolong survival.

OBJECTIVES: To investigate how patient and physician perspectives might be leveraged to promote timely ALS diagnosis, and how system-level barriers might be addressed to promote appropriate referral to ALS multidisciplinary care.

DESIGN AND SETTING: A qualitative study in Alberta, Canada, used human-centred design and interviews to map the diagnostic journeys of ALS patients and identify individual-level and system-level diagnostic barriers and opportunities.

PARTICIPANTS AND ANALYSIS: 30 semistructured interviews (10 patients; 20 physicians) were conducted. Data were inductively analysed with the aid of Miro board software. Patient and physician data were triangulated to identify key phases of the journey from symptom onset to confirmed ALS diagnosis and themes related to the diagnostic barriers and opportunities. Journey maps were created to visualise the diagnostic journey.

RESULTS: Patient journeys were comprised of five phases and commonly involved iterative cycles of referral and testing before an ALS diagnosis was confirmed. Four primary themes related to diagnostic barriers: difficulty recognising and responding effectively to early-stage ALS symptoms, absence of a single definitive diagnostic test, long wait times between referrals and clinical visits, and physician reluctance to pronounce an ALS diagnosis. Analysis indicated three approaches for improving diagnostic processes: increase ALS awareness; improve communication between referring physicians and physicians receiving referrals (consultants); and develop physician, diagnostic testing and multidisciplinary clinic referral forms that will guide symptom assessment and accurate referral.

CONCLUSIONS: Timely ALS diagnosis is challenging for patients navigating the frequently prolonged, circuitous diagnostic journey and physicians who struggle with referral pathways and the efficient diagnosis of this rare disease. Findings demonstrate the importance of increased ALS awareness and effective communication and response within referral pathways. Recommendations include strengthening the clinical approach of community-based physicians and supporting access and referral pathways. Current initiatives arising from this investigation seek to achieve meaningful change in timely referrals for progressive neurological diseases like ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis
Alberta
Female
Male
Middle Aged
Qualitative Research
Referral and Consultation
Aged
*Delayed Diagnosis
Interviews as Topic
Adult

@article {pmid41005713,
year = {2025},
author = {Didier, J and Landtsheer, S and Pacheco, MP and Kishk, A and Schneider, JG and Goldeck, D and Pawelec, G and Spira, D and Demuth, I and Sauter, T},
title = {Clinical Data-Driven Classification of Pre-Frailty Reveals Sex-Specific Patterns - Data from the Berlin Aging Study II (BASE-II).},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112114},
doi = {10.1016/j.mad.2025.112114},
pmid = {41005713},
issn = {1872-6216},
abstract = {Frailty is a geriatric condition with multidimensional consequences that strongly affect older adults' quality of life. The lack of a universal standard to describe, diagnose, and treat frailty further complicates this situation. Nowadays, multitudinous frailty assessment tools are applied depending on the regional and clinical context, adding complexity by increasing heterogeneity in the definition and characterization of frailty. Better insights into the causes and pathophysiology of frailty and its early stages are required to establish strong and accurately tailored treatment rationales for frail patients. We analysed participants aged 60 and above using cross-sectional biochemical and survey data from the Berlin Aging Study II (BASE-II, N=1512, pre-frail=470, frail=14), applying machine-learning techniques to investigate determinants of physical frailty measured by Fried et al.'s 5-item frailty phenotype. Our findings highlight new prognostic sex-specific biomarkers of pre-frailty (the early stage of frailty) with possible clinical applications, enriching the current sex-agnostic diagnostic scores with easy monitorable physical and physiological characteristics. Low appendicular lean mass and high fat composition in men, or vitamin D deficiency and high white blood cell counts in women, emerged as strong indicators of the respective pre-frailty profiles. Because the number of fully frail individuals was extremely small (n = 14, <1%), our findings should be interpreted as reflecting predictors of pre-frailty, not of frailty itself. We conclude that understanding the development of frailty remains a complex challenge, and that sex-specific differences must be considered by clinical geriatricians and researchers.},
}

@article {pmid41005573,
year = {2025},
author = {Marlow, TR and Bowden, KM and Collins, MO and Shaw, PJ},
title = {The potential role of misfolded wild-type SOD1 protein in sporadic amyotrophic lateral sclerosis (ALS): a review of the evidence.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107124},
doi = {10.1016/j.nbd.2025.107124},
pmid = {41005573},
issn = {1095-953X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective loss of motor neurons in the motor cortex, brainstem and spinal cord. In 1993, the first ALS-linked gene mutations were identified in the Cu,Zn superoxide dismutase (SOD1) gene, which account for approximately 20 % of familial ALS cases. The mechanism of toxicity in this subset of patients is thought to arise from a gain-of-toxic function from the protein's propensity to misfold and aggregate into cytoplasmic inclusions. Immunohistochemical studies have shown that misfolded wildtype SOD1 (wtSOD1) is also detected in the motor neurons and glial cells of ALS patients without SOD1 mutations. It is proposed that disrupted, or aberrant, posttranslational modifications cause wtSOD1 to adopt a toxic conformation similar to that of the mutant protein. Subsequent mechanistic studies have shown that this misfolded wtSOD1 can disrupt cellular function and lead to motor neuron death through pathways similar to those observed in mutant SOD1-ALS. Given the limited neuroprotective treatments currently available that can effectively slow or reverse disease progression, targeting a pathogenic mechanism that features in both familial and sporadic ALS cases represents a promising therapeutic approach for a broader patient population. This review examines the growing body of evidence that supports or challenges the role of misfolded wtSOD1 in the pathophysiology of sporadic ALS and explores the potential implications of this mechanism in disease progression. Understanding how misfolded wtSOD1 contributes to disease pathogenesis provides new opportunities for developing more widely available treatments for this devastating disease.},
}

@article {pmid41005474,
year = {2025},
author = {Li, Y and Liu, D and Li, S},
title = {IRE1/Xbp1 promotes the clearance of poly(GR) dipeptide repeats in Amyotrophic Lateral Sclerosis.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110764},
doi = {10.1016/j.jbc.2025.110764},
pmid = {41005474},
issn = {1083-351X},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by the expansion of GGGGCC (G4C2) repeats in the C9orf72 gene and progressive motor neuron degeneration. A key pathological hallmark of these diseases is the accumulation and cytoplasmic mislocalization of dipeptide repeat (DPR) proteins, particularly poly(GR), which are neurotoxic. Enhancing the clearance of poly(GR) represents a promising therapeutic strategy; however, the molecular mechanisms regulating poly(GR) turnover are not fully understood. Our previous work demonstrated that translationally stalled poly(GR) is targeted by the ribosome-associated quality control (RQC) pathway. In the present study, we identify the IRE1/Xbp1s signaling axis as an essential regulator of poly(GR) degradation. Ectopic expression of IRE1 or its downstream effector Xbp1s, as well as pharmacological activation of IRE1 using IXA4, significantly reduces poly(GR) protein levels in a Drosophila disease model, mammalian cell lines, fibroblasts derived from C9orf72-ALS patients, and a C9orf72 transgenic mouse model. Mechanistically, RNA-sequencing analysis reveals that IRE1/Xbp1s signaling upregulates heat shock protein Hsp70Ba, which plays a critical role in maintaining poly(GR) proteostasis. Additionally, we show that the Rictor/AKT/VCP pathway contributes to the translational regulation and turnover of poly(GR). Importantly, activation of IRE1, either through ectopic expression or IXA4 treatment, mitigates motor neuron loss in the C9orf72 mouse model. Collectively, our findings highlight the IRE1/Xbp1s axis as a key modulator of poly(GR) clearance and suggest its therapeutic potential in ALS/FTD.},
}

@article {pmid41004918,
year = {2025},
author = {Yanagawa, K and Ike, M and Aoyama, A and Yokoo, T and Terai, S and Hayashi, T and Onodera, O},
title = {Tongue shear wave elastography for bulbar dysfunction in amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {179},
number = {},
pages = {2111367},
doi = {10.1016/j.clinph.2025.2111367},
pmid = {41004918},
issn = {1872-8952},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) often manifests with tongue involvement, leading to dysarthria and dysphagia. While current diagnostic methods are invasive or qualitative, the development of non-invasive quantitative assessments of tongue function is essential.

METHODS: A prospective study (March 2022 - March 2024) included 38 ALS patients (categorized by bulbar or spinal onset) and 12 controls. Clinical symptoms were evaluated using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Tongue muscle elasticity was measured using shear wave elastography (LOGIQ® E9, 9 MHz).

RESULTS: Median shear modulus of the genioglossus (GG) muscle was significantly lower in bulbar-onset ALS (7.80 kPa, range 5.41-10.08) compared to spinal-onset ALS (12.48 kPa, range 8.50-21.42) and controls (14.16 kPa, range 11.37-20.21). The geniohyoid (GH) muscle showed similar patterns. Both muscles showed significantly reduced elasticity in bulbar-onset ALS compared to controls (p < 0.05). The GG muscle elasticity showed strong positive correlation with bulbar symptom severity on the ALSFRS-R.

CONCLUSIONS: Reduced tongue muscle elasticity in bulbar-onset ALS, along with its correlation with bulbar symptoms, suggests the potential utility of this technique for both diagnosis and prognosis.

SIGNATURE: These findings indicate that shear wave elastography is a promising noninvasive tool for the quantitative assessment of tongue dysfunction in ALS.},
}

@article {pmid41004427,
year = {2025},
author = {Fioretti, PV and Barbieri, A and Migazzi, A and Bressan, D and Grassano, M and Donini, L and Roccuzzo, M and Torrieri, MC and Conci, F and Ferracci, E and Invernizzi, S and Bowden, KM and Bacchetti, F and Cappelli, S and Peroni, D and Belli, R and Pancher, M and Mugoni, V and Scarduelli, G and Gianesello, M and Pasetto, L and Canarutto, G and Carra, S and Soldano, A and Bisio, A and Robbiati, S and Valentini, C and Nardella, C and Piazza, S and D'Agostino, VG and Quattrone, A and Sleiman, S and Whitfield, JR and Soucek, L and Vignoli, B and Viero, G and Tiberi, L and Zippo, A and Demichelis, F and Bonetto, V and Milanese, M and Buratti, E and Verde, F and Ticozzi, N and Calvo, A and Ratti, A and Shaw, PJ and Terenzio, M and Chiacchiera, F and Pennuto, M and Basso, M},
title = {MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf360},
pmid = {41004427},
issn = {1460-2156},
abstract = {Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice, and patient-derived cells modeling TDP-43, SOD1, and C9orf72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioral abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived EVs that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.},
}

@article {pmid41004400,
year = {2025},
author = {Hostetler, N and Zakutney, S and Pringle, CE and Zwicker, J and Breiner, A},
title = {Atypical features including acquired oculomotor apraxia in C9orf72-associated familial primary lateral sclerosis.},
journal = {Journal of neuromuscular diseases},
volume = {},
number = {},
pages = {22143602251380427},
doi = {10.1177/22143602251380427},
pmid = {41004400},
issn = {2214-3602},
abstract = {BACKGROUND: The phenotypic variability of C9orf72-associated disease is broadening, including atypical and non-motor presentations. C9orf72-associated neurodegeneration has only rarely been associated with primary lateral sclerosis (PLS), and even more rarely with ocular motor apraxia.

OBJECTIVES: Describe a family with C9orf72 mutation presenting with frontotemporal dementia (FTD) and atypical PLS phenotypes and discuss the implications regarding 1) where PLS lies on the ALS-FTD spectrum, and 2) how C9orf72 mutations influence PLS clinically.

METHODS: Chart review.

RESULTS: A 52-year-old male experiencing 4 months of progressive right lower leg spasticity with a family history of FTD was referred to us. Within 15 months, he was anarthric and required a powered wheelchair. He developed acquired ocular motor apraxia, consistent with supranuclear ophthalmoplegia. He later developed laryngeal dystonia which led to his death. Ten years later, his 67-year-old brother presented with 8 months of progressive spastic dysarthria, hyperreflexia, right foot drop, and right facial weakness. Genetic testing revealed heterozygous C9orf72 hexanucleotide repeat expansion.

CONCLUSIONS: This family's presentation expands on sparse reports of C9orf72-associated PLS. The proband showcases a severity of ocular motor deficits not yet reported in PLS, extending ocular motor findings in MND. These deficits also provide clinical evidence of degeneration outside the motor cortex/spinal cord in PLS. The symptomatology (laryngeal dystonia, rapid progression) clinically overlaps with ALS/FTD, suggesting PLS may lie on the ALS-FTD spectrum. The severity and atypicality of this case also support suggestions that C9orf72 mutations amplify the spectrum/severity of disease observed in TDP-43 proteinopathies.},
}

@article {pmid41004063,
year = {2025},
author = {Dellarole, IL and Lombardo, A and Ciullini, A and Cazzaniga, FA and Domina, R and Bacınoğlu, MB and Moda, F},
title = {Seed Amplification Assays as Powerful Tools for Detecting Peripheral Biomarkers in Prion-Like Diseases.},
journal = {Sub-cellular biochemistry},
volume = {112},
number = {},
pages = {293-320},
pmid = {41004063},
issn = {0306-0225},
mesh = {Humans ; *Biomarkers/metabolism/blood/cerebrospinal fluid ; *Prion Diseases/diagnosis/metabolism ; *Prions/metabolism ; *Nucleic Acid Amplification Techniques/methods ; Neurodegenerative Diseases/diagnosis ; },
abstract = {Seed amplification assays (SAAs) are highly sensitive and advanced techniques originally developed for the study and diagnosis of prion diseases. Thanks to their remarkably high sensitivity and specificity, SAAs are now widely employed in both research and clinical settings for prion detection, especially in peripheral tissues of patients with prion disorders. Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and amyotrophic lateral sclerosis, show prion-like mechanisms involving the misfolding and self-propagation of pathological proteins. As a result, SAAs are being adapted and refined for clinical use to improve the diagnosis of these conditions. This includes detecting traces of pathological proteins in cerebrospinal fluid as well as in minimally or noninvasively collected samples, such as blood, urine, skin, and olfactory mucosa. This chapter offers an overview of the role of SAAs in the clinical diagnosis of neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism/blood/cerebrospinal fluid
*Prion Diseases/diagnosis/metabolism
*Prions/metabolism
*Nucleic Acid Amplification Techniques/methods
Neurodegenerative Diseases/diagnosis

@article {pmid40999374,
year = {2025},
author = {Celebi, C and Cavdar, I and Urkan, M},
title = {Validation and reliability of the Turkish version of the surgical site infection assessment scale: a methodological study.},
journal = {BMC surgery},
volume = {25},
number = {1},
pages = {412},
pmid = {40999374},
issn = {1471-2482},
abstract = {BACKGROUND: Although the incidence of healthcare-associated infections has decreased over the past decade, surgical site infections (SSIs) have continued to constitute a significant proportion of these infections. Therefore, early identification and management of high-risk patients has been crucial in reducing the incidence of SSIs.

OBJECTIVES: In this study, we aimed to evaluate the validity and reliability of the Turkish version of the Surgical Site Infection Assessment Scale (SSIAS), which was developed to identify patients at risk of superficial incisional SSI.

METHODS: In this methodological study, we evaluated the Turkish validity and reliability of the SSIAS in a prospective cross-sectional sample of 170 patients who underwent elective abdominal surgery at a tertiary healthcare center. The scale was adapted in accordance with international guidelines through a forward-backward translation process performed by three professional translators and content validation by a panel of 20 experts. We assessed the psychometric properties using univariate logistic regression and ROC analysis for construct validity (AUC calculation). Diagnostic accuracy was evaluated based on sensitivity, specificity, and predictive values at the optimal cutoff point (> 14), determined using the Youden index.

RESULTS: The adaptation process was carried out based on Beaton et al.‘s guidelines, and the content validity ratio (CVR) was calculated between 0.78 and 1.00. ROC analysis revealed an AUC of 0.935 (95% CI: 0.897–0.972), and at the > 14 cutoff point, we observed 91.8% sensitivity and 79.3% specificity. The scale demonstrated superior predictive performance compared to previously developed tools. Surgical site infections occurred in 49 patients. The mean scale score of infected patients was 16.76 ± 1.85. For each one-point increase in the scale score, the risk of infection increased by 3.52 times. Smoking, comorbidities, abnormal laboratory findings, length of preoperative hospitalization, wound classification, body temperature, and prolonged presence of drains were identified as factors influencing the risk of infection.

CONCLUSION: The Turkish version of the Surgical Site Infection Assessment Scale (SSIAS), originally developed by Anwar et al., was found to be a valid and reliable tool for predicting SSI risk in Türkiye. Due to its high predictive power, it offers practical potential for early risk identification and preventive action in clinical settings.

TRIAL REGISTRATION: Not applicable.},
}

@article {pmid41003918,
year = {2025},
author = {Mansi, IA and Boktor, M},
title = {Authors' Response to Weng et al.'s Comment on "Association of GLP1-Receptor Agonists with Risk of Hepatocellular Carcinoma: A Retrospective Cohort Study".},
journal = {Drug safety},
volume = {},
number = {},
pages = {},
pmid = {41003918},
issn = {1179-1942},
}

@article {pmid41003894,
year = {2025},
author = {Weinfurt, KP and Reeve, BB},
title = {Artificial intelligence and the future of patient-centered outcomes.},
journal = {Journal of patient-reported outcomes},
volume = {9},
number = {1},
pages = {113},
pmid = {41003894},
issn = {2509-8020},
mesh = {*Artificial Intelligence ; Humans ; *Patient Reported Outcome Measures ; Patient-Centered Care ; },
abstract = {BACKGROUND: Terheyden et al. recently described a compelling vision for large language model-enabled patient-reported outcome measures (LLM-PROMs).

MAIN TEXT: We support Terheyden et al.'s vision and offer complementary observations about the potential for generative artificial intelligence (GenAI) in assessing patient-centered outcomes. GenAI has the potential to improve the quality and efficiency of developing traditional PROMs and collecting patient experience data. Traditional PROMs rely on standardized questions and responses, which may introduce ambiguity about the health concept being assessed. Yet, interviewers who are trained in the meaning of the concepts can tailor questions to the respondent's experience and conversation style and have a back-and-forth clarification of meaning to ensure that both the interviewer's and respondent's meanings are aligned. The shortcoming of this approach is that it cannot be done at scale with human interviewers. However, trained GenAI interviewers could make such an assessment a reality for large samples of patients. The technology is already available to train GenAI interviewers in interview technique, the intent of each item, and a consistent approach toward coding the respondent's answer based on the conversation.

CONCLUSION: The health outcomes research field should actively inquire into what patient experience data can be collected via GenAI and rigorously evaluate the quality of the assessments obtained.},
}

*Artificial Intelligence
Humans
*Patient Reported Outcome Measures
Patient-Centered Care

@article {pmid41003732,
year = {2025},
author = {Yang, X and Jia, Z and Lian, X and Zhang, R and Li, B and Tian, D and Gao, X and Guo, S and Wang, B and Liu, H and Long, Y and Wang, L and Zhang, J and Xue, Q and Liang, Z and Han, Y and Feng, H and Huang, L and Wang, P and Shao, N and Shi, FD and Zhang, C},
title = {Ofatumumab treatment in patients with neuromyelitis optica spectrum disorder: a retrospective multicenter cohort study.},
journal = {Journal of neurology},
volume = {272},
number = {10},
pages = {655},
pmid = {41003732},
issn = {1432-1459},
support = {82301469//National Natural Science Foundation of China/ ; 82171777//National Natural Science Foundation of China/ ; 20JCJQJC00280//Natural Science Foundation of Tianjin Municipal Science and Technology Commission/ ; 24ZXGZSY00030//Tianjin Public Health Science and Technology Major Project/ ; TJSQNYXXR-D2-120//Tianjin Health Research Project/ ; TJWJ2024RC001//Tianjin Health Research Project/ ; 2024CZLJ003//Leading Talent of Changzhou "The 14th Five-Year Plan" High-Level Health Talents Training Project/ ; },
mesh = {Humans ; Female ; Male ; *Neuromyelitis Optica/drug therapy ; Retrospective Studies ; Adult ; Middle Aged ; *Antibodies, Monoclonal, Humanized ; Aquaporin 4/immunology ; Treatment Outcome ; Cohort Studies ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Disability Evaluation ; },
abstract = {BACKGROUND: Ofatumumab is a fully human anti-CD20 monoclonal antibody that selectively and highly depletes B cells. However, limited data on ofatumumab treatment are available in patients with neuromyelitis optica spectrum disorders (NMOSD). In this study, we aimed to evaluate the efficacy and safety of subcutaneous ofatumumab in patients with NMOSD.

METHODS: We conducted a retrospective multicenter cohort study of patients with NMOSD who received ofatumumab treatment at 15 tertiary hospitals in China. The primary outcome was the annualized relapse rate (ARR). The secondary outcomes included disability measures (Expanded Disability Status Scale score, EDSS; the Aminoff-Logue Disability Scale, ALS), changes in aquaporin-4 IgG (AQP4-IgG) titers, and safety profiles during ofatumumab treatment.

RESULTS: A total of 112 patients (88% female, median age 44.0 years with interquartile range [IQR 29.5-57.5]) received ofatumumab treatment for a median of 1.7 years (IQR: 1.1-2.0). The median ARR decreased significantly from 2.0 (IQR 0.7-10.0) before ofatumumab to 0 (IQR 0.0-0.0; p < 0.001) after ofatumumab. Twenty-two patients (20%) experienced 25 relapses, with 20 (80%) occurring within the first year of initiating ofatumumab treatment and 19 (76%) classified as minor. The EDSS score from start to the last follow-up also improved significantly (median: pre-treatment 3.5, IQR 2.0-6.5, post-treatment: 2.0, IQR1.0-3.5, p < 0.001). Among 94 patients, 71 (76%) showed reduced AQP4-IgG titers at last follow-up. Injection-related reactions were reported in 13 (12%) of 112 patients. Twenty-four infections occurred in 20 patients (18%) during the ofatumumab treatment, with 92% (22/24) being grade 1 or 2 (CTCAE version 5.0). Only 2 patients (2%) experienced pneumonia requiring hospitalization and recovered after antibiotic treatment (grade 3). Hypogammaglobulinemia was recorded in 14% (13/95) of patients and was not associated with infection.

CONCLUSIONS: Subcutaneous ofatumumab treatment significantly reduces the relapse risk, limits worsening of disability, and reduces AQP4-IgG titers in NMOSD. Moreover, the safety profiles were generally acceptable. Further research is necessary to explore the sustained clinical response of ofatumumab in NMOSD.},
}

Humans
Female
Male
*Neuromyelitis Optica/drug therapy
Retrospective Studies
Adult
Middle Aged
*Antibodies, Monoclonal, Humanized
Aquaporin 4/immunology
Treatment Outcome
Cohort Studies
*Antibodies, Monoclonal/therapeutic use/adverse effects
Disability Evaluation