@article {pmid41513843,
year = {2026},
author = {Keritam, O and Kleinveld, VE and Klotz, S and Caliskan, H and Mayerhofer, M and Sener, M and Jäger, F and Weng, R and Bormann, D and Pugna, I and Gebert, J and Fedak, I and Renner, A and Antoniewicz, L and Rath, J and Zulehner, G and Krenn, M and Zimprich, F and Löscher, WN and Cetin, H},
title = {Demographic, clinical and genetic characteristics of patients with amyotrophic lateral sclerosis from two specialised centres in Austria.},
journal = {Journal of neurology},
volume = {273},
number = {1},
pages = {74},
pmid = {41513843},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/physiopathology/diagnosis ; Austria/epidemiology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Registries ; C9orf72 Protein/genetics ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness and ultimately death from respiratory failure. Heterogeneity in disease trajectories and outcomes among patients with ALS (pwALS) is influenced by healthcare access, rehabilitation, and palliative care, but real-world data on demographic and clinical characteristics remain scarce in many countries, including Austria.

OBJECTIVES: To characterise the demographic, clinical, and genetic landscape of pwALS in Austria.

METHODS: In this retrospective cohort study, we included pwALS diagnosed according to the Gold Coast criteria and treated at two large tertiary referral centres. Demographic, clinical, and genetic data were extracted from the local ALS registries, and survival was determined via linkage with Statistik Austria, censored in December 2023.

RESULTS: A total of 341 patients with motor neuron disease were included (44.9% female), of whom 5% were diagnosed with primary lateral sclerosis and 2.9% with progressive muscular atrophy. Among pwALS (n = 314), spinal onset was most common (67.2%), followed by bulbar onset (29.6%) and respiratory onset (2.5%). Median survival from symptom onset was 36.0 months (IQR 20.0-74.0), with age at onset (HR 1.04, 95% CI 1.02-1.05; p < 0.0001), diagnostic delay (HR 0.97, 95% CI 0.96-0.98; p < 0.0001), and PEG tube placement (HR 0.72, 95% CI 0.50-1.00; p = 0.0478) as the only independent predictors of survival. (Likely) pathogenic variants were identified in 5.5% of patients, including two in SOD1 and one each in C9orf72, OPTN, TARDBP, and FUS.

CONCLUSIONS: This study provides the first comprehensive description of the demographic, clinical, and genetic characteristics of pwALS in Austria, offering valuable real-world insight into disease presentation and genetic diversity.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/epidemiology/physiopathology/diagnosis
Austria/epidemiology
Female
Male
Middle Aged
Retrospective Studies
Aged
Adult
Registries
C9orf72 Protein/genetics

@article {pmid41513898,
year = {2026},
author = {Roos, AK and Forsberg, S and Stenvall, E and Andersen, PM and Zetterström, P and Nordin, A and Forsberg, KME},
title = {Heterogeneous phenotype and cardiovascular comorbidities in Swedish patients with spinobulbar muscular atrophy.},
journal = {Journal of neurology},
volume = {273},
number = {1},
pages = {75},
pmid = {41513898},
issn = {1432-1459},
support = {FO 2022-0309//Hjärnfonden/ ; FO2023-0088//Hjärnfonden/ ; 2012-3167//Vetenskapsrådet/ ; 2017-03100//Vetenskapsrådet/ ; . JLL-980693//Region Jämtland Härjedalen/ ; 2012.0091//Knut och Alice Wallenbergs Stiftelse/ ; 2014.0305//Knut och Alice Wallenbergs Stiftelse/ ; 2020.0232//Knut och Alice Wallenbergs Stiftelse/ ; F2021-0044//Neuroförbundet/ ; 2023.10//Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; 2023.16//Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; RV-993493//Västerbotten Läns Landsting/ ; RV-996140//Västerbotten Läns Landsting/ ; RV-939329//Västerbotten Läns Landsting/ ; RV56103-7002829//Västerbotten Läns Landsting/ ; RV-1014212//Västerbotten Läns Landsting/ ; RV-996234//Västerbotten Läns Landsting/ ; RV-941598//Västerbotten Läns Landsting/ ; },
mesh = {Humans ; Male ; Sweden/epidemiology ; Middle Aged ; Female ; Aged ; Comorbidity ; *Cardiovascular Diseases/epidemiology/genetics ; Adult ; Phenotype ; Cohort Studies ; Receptors, Androgen/genetics ; Bulbo-Spinal Atrophy, X-Linked/epidemiology ; },
abstract = {BACKGROUND: Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disorder characterized by adult-onset progressive muscle atrophy, flaccid paresis, and bulbar palsy. In addition, increasing evidence indicates that SBMA is a multisystem disorder with prominent non-motor symptoms, such as sensory neuropathy, androgen insensitivity, and glucose intolerance. This study aimed to further characterize the clinical manifestations and biomarker profile in a large Swedish SBMA cohort.

METHODS: 49 genetically confirmed SBMA patients were identified from a motor neuron disease database at Umeå University Hospital, Sweden. CAG repeat length in the androgen receptor (AR) gene was assessed by RP-PCR. Blood samples were analyzed for cardiovascular and muscle biomarkers. Clinical data were collected from medical records and interviews, with autopsy findings reviewed in two cases.

RESULTS: The mean CAG repeat length was 43.1, with a mean age at motor symptom onset of 58.6 years. Notably, 19% of patients initially presented with sensory symptoms. High prevalence of hypertonia (70%), diabetes mellitus (39%), and cardiac disease (38%) was observed. Elevated troponin levels were common, and pNfL (neurofilament light chain in plasma) was elevated in seven patients, likely reflecting combined cerebrovascular and cardiovascular comorbidity. Importantly, two of these seven patients exhibited rapid disease progression, and a concomitant diagnosis of ALS was confirmed histopathologically.

DISCUSSION: This cohort was characterized by a relatively low number of AR gene CAG repeats and a late onset of motor symptoms. Sensory symptoms frequently occurred before motor decline. Cardiovascular disease and diabetes were common comorbidities and, in some cases, preceded neurological symptoms. These findings underscore the need for improved clinical awareness of the heterogeneous presentation of SBMA and support routine cardiovascular monitoring to reduce diagnostic delays and prevent early mortality.},
}

Humans
Male
Sweden/epidemiology
Middle Aged
Female
Aged
Comorbidity
*Cardiovascular Diseases/epidemiology/genetics
Adult
Phenotype
Cohort Studies
Receptors, Androgen/genetics
Bulbo-Spinal Atrophy, X-Linked/epidemiology

@article {pmid41515048,
year = {2025},
author = {Ramírez-May, AG and Rivera-Cruz, MDC and Mendoza-López, MR and Acosta-Pech, RG and Trujillo-Narcía, A and Bautista-Muñoz, C},
title = {The Use of Rhizospheric Microorganisms of Crotalaria for the Determination of Toxicity and Phytoremediation to Certain Petroleum Compounds.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {1},
pages = {},
pmid = {41515048},
issn = {2223-7747},
abstract = {Microbial toxicity tests in the rhizosphere play an important role in the risk assessment and phytoremediation of chemical compounds in the environment. Tests for the inhibition of nodule number (NN), Rhizobia in the rhizosphere (RhR), Rhizobium in nodules (RhN) and arbuscular mycorrhizal fungi (AMFs) are important to evaluate the toxicity as well as the removal of total petroleum hydrocarbons (TPHs), 15 linear alkanes (LAs), and total linear alkanes (TLAs). The inhibition and removal was evaluated at 60 (vegetative stage, VS) and 154 days (reproductive stage, RS) of the life cycle of Crotalaria incana and Crotalaria pallida in soil with four doses of CRO (3, 15, 30, and 45 g/kg) plus a control (16 treatments). Results indicated that RhN and five structures of the AMFs present an index of toxicity (IT < 1), and the microbiological variable is inhibited by the CRO. RhR exhibits a hormesis index (IT > 1) that is stimulated by the CRO in the VS and RS for C. incana and C. pallida. The highest removal of TPHs (77%) was in the rhizosphere of C. incana in the RS with 45 g/kg of CRO. C. pallida removed the greatest amount of TLA (91%). There was a positive correlation between the RhR and the removal of TPHs, TLA, and LAs (higher molecular weight). It could be argued that symbiotic microorganisms are significant for use in toxicity testing, and the rhizosphere of C. incana and C. pallida can be used for the phytoremediation of HTPs and ALs in loamy-clay soil contaminated with CRO.},
}

@article {pmid41516158,
year = {2025},
author = {Lee, BC and Wang, CC and Chen, SP and Tsai, HJ},
title = {Multilevel Screening Platform Utilizing Cellular and Zebrafish Models to Identify Short Peptides with High Improvement of Motor Neuron Growth.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
pmid = {41516158},
issn = {1422-0067},
support = {NSTC-114-2313-B-030-001//National Science and Technology Council, Taiwan/ ; 9991F02-1120232 and A0113210//Fu Jen Catholic University, Taiwan/ ; CPL-202508003//Collaborative Research Project between Fu Jen Catholic University Hospital and Fu Jen Catholic University, Taiwan/ ; },
mesh = {Animals ; Zebrafish ; *Motor Neurons/drug effects/metabolism/cytology ; Disease Models, Animal ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Peptides/pharmacology ; Humans ; Drug Evaluation, Preclinical/methods ; Zebrafish Proteins/genetics/metabolism ; Neuronal Outgrowth/drug effects ; },
abstract = {Zebrafish is emerging as a model animal for phenotype-based drug screening. Drugs screened from the zebrafish platform have advanced into clinical trials, underscoring their translational potential. Amyotrophic lateral sclerosis is a progressive motor neurons (MN) degenerative disease with few approved drugs. Previously, supplementation with exogenous recombinant phosphoglycerate kinase 1 (Pgk1) was found to improve MN growth through its interaction with receptor Eno2. To bypass the high complexity and cost of full-length Pgk1 production, a short segment within Pgk1 (M08) was predicted as the key motif interacting with Eno2, and a zebrafish phenotypic screening platform was established to find the most neurotrophic compound(s) among M08 and its mutants. We first found that M08-injected zebrafish embryos significantly increased branched caudal primary MNs (CaPMNs). However, compared to M08 (59.20 ± 1.80%), M039, among 17 mutants further screened, showed even more improvement of branched CaPMNs, up to 74.54 ± 3.73%. Next, when we administered the M039 peptide to C9ORF72-knockdown ALS-like zebrafish embryos, it improved axonal growth and swimming ability. Then, we employed a cellular model as a secondary screen, and M039 exhibited improved neurite outgrowth of MN (NOMN) and reduced p-Cofilin in NSC34 neural cells grown in ALS-like condition. Therefore, by using a zebrafish MN phenotype as a primary screening platform, we identified a mutated short peptide M039 having the most pronounced positive effect on improving neurite growth among all 17 mutants in comparison to parental M08, demonstrating the feasibility of zebrafish screening as a cost-effective strategy for finding promising neuroprotective short peptides that serve as neurotherapeutic potentials.},
}

Animals
Zebrafish
*Motor Neurons/drug effects/metabolism/cytology
Disease Models, Animal
Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics
*Peptides/pharmacology
Humans
Drug Evaluation, Preclinical/methods
Zebrafish Proteins/genetics/metabolism
Neuronal Outgrowth/drug effects

@article {pmid41517507,
year = {2025},
author = {Koska, V and Teufel, S and Aytulun, A and Weise, M and Ringelstein, M and Guthoff, R and Meuth, SG and Albrecht, P},
title = {Evolution of Retinal Morphology Changes in Amyotrophic Lateral Sclerosis.},
journal = {Journal of clinical medicine},
volume = {15},
number = {1},
pages = {},
pmid = {41517507},
issn = {2077-0383},
abstract = {Background/Objectives: To compare changes in the thickness of retinal layers between patients with amyotrophic lateral sclerosis (ALS) and healthy controls using optical coherence tomography. Amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motoneurons with a rapidly progressive course, but non-motor symptoms such as decreased ocular motility and reduced visual acuity have also been reported. Specific biomarkers or surrogate parameters assessing neurodegeneration in ALS are of interest. Methods: In a retrospective, longitudinal study using optic coherence tomography of the retinal layers, we compared changes in the thickness of the layers between patients with ALS and healthy controls. Correlations to clinical scores, such as the modified ranking scale, were analyzed. Results: In our cohort of patients with early ALS (disease duration 5.15 ± 21.4 months at baseline), we neither observed differences in retinal layer thickness at baseline nor did the thickness changes in any retinal layer differ in comparison to healthy controls at baseline. Moreover, we observed no significant thickness changes over the course of the observational period in our patients with ALS. However, a correlation analysis revealed a negative association of the thickness change rates in the complex of ganglion cell and inner plexiform layer and the inner nuclear layer with a higher modified Rankin scale at follow-up. Conclusions: This study adds to the notion that OCT may not be a suitable tool to monitor atrophy and disease progression in ALS. However, further longitudinal studies with longer follow-up times and larger cohorts are warranted.},
}

@article {pmid41517538,
year = {2025},
author = {Dziadkowiak, E and Marschollek, K and Kwaśniak-Nowakowska, A and Zimny, A and Rałowska-Gmoch, W and Boroń, M and Koszewicz, M},
title = {Establishing Diagnostic and Differential Diagnostic Criteria for Amyotrophic Lateral Sclerosis.},
journal = {Journal of clinical medicine},
volume = {15},
number = {1},
pages = {},
pmid = {41517538},
issn = {2077-0383},
abstract = {Motor neuron disease (MND) represents a broad and heterogeneous group of disorders involving the upper or lower motor neurons, represented mainly by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and progressive bulbar palsy (PBP). Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Rare atypical variants of MND-ALS include flail arm syndrome (FA), flail leg syndrome (FL), facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus motor neuron disease (FEWDON-MND) and long-standing and juvenile MND-ALS. In this article, we present a review of diagnostic criteria and the differential diagnosis for MND, focusing on ALS.},
}

@article {pmid41517697,
year = {2026},
author = {Wang, Z and Yao, L and Tu, M},
title = {Evaluating the causal connections between sleep duration and disease prevalence: A comprehensive systematic review and meta-analysis of Mendelian randomization studies.},
journal = {Medicine},
volume = {105},
number = {2},
pages = {e45225},
pmid = {41517697},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Sleep/genetics/physiology ; Prevalence ; Genetic Predisposition to Disease ; Sleep Duration ; },
abstract = {BACKGROUND: The causal link between sleep duration and diverse health conditions remains unconfirmed. This meta-analysis aimed to clarify these relationships by synthesizing Mendelian randomization (MR) study evidence.

METHODS: PubMed was systematically searched up to February 15, 2024, for MR studies exploring genetic predispositions to sleep duration/insomnia (short/long/overall sleep duration, insomnia) and associations with circulatory, digestive, neurodegenerative, metabolic diseases, and cancers. Eligible effect estimates were meta-analyzed.

RESULTS: Fifty-one MR studies were included. Genetic variations in sleep traits were strongly linked to elevated risk of 12 cardiovascular diseases, obesity-related metrics (Type 2 diabetes, fasting glucose/insulin, HbA1c), neurological disorders (Alzheimer, amyotrophic lateral sclerosis, Parkinson disease), mental health conditions (attention-deficit/hyperactivity disorder, autism, bipolar disorder, major depressive disorder, schizophrenia), inflammatory bowel disease, and lung cancer.

CONCLUSION: Genetic evidence confirms causal associations between sleep characteristics and multiple diseases, emphasizing sleep's key role in health promotion and supporting personalized sleep management to reduce disease risk.},
}

Humans
Mendelian Randomization Analysis
*Sleep/genetics/physiology
Prevalence
Genetic Predisposition to Disease
Sleep Duration

@article {pmid41517814,
year = {2026},
author = {Jacob, SM and Son, B and Bagheri, S and Lee, S and Leckie, J and Chohan, B and Belway, C and Mascarenhas, J and Mobach, T and Korngut, LW and Sharkey, KA and Park, J and Nguyen, MD and Kim, SH and Pfeffer, G},
title = {The Oral Microbiome in Amyotrophic Lateral Sclerosis Shows Differentially Abundant Organisms in Limb Versus Bulbar Onset Disease: A Binational Study.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {1},
pages = {66-75},
pmid = {41517814},
issn = {1738-6586},
support = {//ALS Canada Discovery Grant/Canada ; //Barry Barrett Foundation/Canada ; /CAPMC/CIHR/Canada ; //International Development Research Council/Canada ; //Rose Family Foundation/Canada ; //Fondation Brain Canada/Canada ; /MOHW/Ministry of Health and Welfare/Korea ; RS-2024-00348451/MSIT/Ministry of Science and ICT, South Korea/Korea ; },
abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons leading to progressive disability and death. Approximately 10% of cases are caused by single-gene disorders with the remaining 90% of cases presumed to be caused by a combination of environmental and genetic factors. The microbiome (the ensemble of microorganisms that colonize body surfaces and organs) was recently identified for its importance in the pathogenesis of ALS.

METHODS: In this study, we recruited 100 participants from two ethnically and geographically distinct sites (71 from Calgary, Canada, and 29 from Seoul, Republic of Korea) which included 59 ALS participants and 41 controls. All participants provided saliva samples for oral microbial analysis using 16S rRNA sequencing. Basic demographic information was collected from all participants, and ALS participants provided additional clinical information including site of disease onset, disease duration, and ALS Functional Rating Scale - Revised score.

RESULTS: Significant differences in beta diversity of the oral microbiomes were seen between limb- and bulbar-onset ALS participants. Two bacterial genera were differentially abundant between these groups, Bifidobacteriaceae Bifidobacterium was enriched in bulbar-onset cases, while Pasteurellaceae Haemophilus was enriched in limb-onset cases. No significant differences were found between ALS participants and controls, but there were significant differences when comparing participants from different sites of recruitment. Amongst household pairs (n=35 pairs), ALS participants differed from control participants at the Seoul site.

CONCLUSIONS: Despite the cohort and household effects, our study identified differentially abundant organisms that may be important to the phenotypic variability of ALS and should be considered for future study. Our study provides novel insights into design for future multi-site microbiome research in ALS.},
}

@article {pmid41517820,
year = {2026},
author = {Choi, SJ and Park, H and Sung, JJ},
title = {First Korean Case of C9orf72-Related Amyotrophic Lateral Sclerosis With Progressive Supranuclear Palsy-Like Features.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {1},
pages = {125-127},
pmid = {41517820},
issn = {1738-6586},
}

@article {pmid41517981,
year = {2026},
author = {Xu, X and Xu, J and Zhao, B and Guo, B and Wei, S and Li, B and Qi, Z and Chen, S and Wang, G and Liu, X},
title = {Target-site mutations and non-target-site detoxification confer ALS-inhibitor resistance in Bromus japonicus populations in China.},
journal = {Pest management science},
volume = {82},
number = {4},
pages = {3874-3883},
doi = {10.1002/ps.70510},
pmid = {41517981},
issn = {1526-4998},
support = {//the HAAFS Science and Technology Innovation Special Project (2022KJCXZX-LYS-13)/ ; //the Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences (2024060203)/ ; //the HAAFS Youth Innovation Fund Project (2023LYS03)/ ; },
mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicides/pharmacology ; China ; Mutation ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Inactivation, Metabolic ; },
abstract = {BACKGROUND: The emergence of herbicide-resistant Japanese brome (Bromus japonicus) populations has been increasingly documented throughout China. Two such populations, DZ-R and XL-R, exhibit resistance to acetolactate synthase (ALS)-inhibiting herbicides, yet their resistance level and mechanism remain undetermined. This study sought to: (i) quantify resistance levels to flucarbazone-sodium, mesosulfuron-methyl, and pyroxsulam; (ii) screen for ALS mutations conferring target-site resistance (TSR); and (iii) characterize non-target-site resistance (NTSR) mechanisms using a multi-omics approach.

RESULTS: Whole-plant bioassay results indicated that the resistance indices of DZ-R and XL-R populations were 111.3 and 90.5 to flucarbazone-sodium, 36 and 206.4 to mesosulfuron-methyl, and 109.8 and 429.5 to pyroxsulam. The TSR mechanism was mediated by distinct ALS gene mutations: a Pro197-Ser substitution in DZ-R and a Pro197-Thr substitution in XL-R. Integrated transcriptomic, metabolomics and malathion-inhibited bioassay analyses revealed the NTSR mechanism, identifying two ABCB4, ABCG48, ABCB11 genes, two unnamed ABC, POD 35, POD P7-like, GST1, GSTU17, 2 GSTU6, IN2-1-like isoform X3 genes, three unnamed GST, GT 73C6-like, ZWY2020_001091, cis-zeatin O-GT, CYP74A15, noroxomaritidine synthase 2-like, indole-2-monooxygenase-like genes and four unnamed CYP450 genes as candidate genes. These genes participated in ATP-binding cassette transporters, phenylpropanoid biosynthesis, glutathione metabolism and zeatin biosynthesis metabolic pathways that synergistically mediate herbicide detoxification. Notably, two putative flucarbazone-sodium degradation pathways were deduced in the resistant populations.

CONCLUSION: Collectively, these findings demonstrated that both TSR and NTSR mechanisms contributed to herbicide resistance in the DZ-R and XL-R populations. Future research should prioritize functional validation of the identified candidate genes to elucidate their specific roles in herbicide metabolism. © 2026 Society of Chemical Industry.},
}

*Herbicide Resistance/genetics
*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism
*Herbicides/pharmacology
China
Mutation
*Plant Proteins/genetics/metabolism/antagonists & inhibitors
Inactivation, Metabolic

@article {pmid41518572,
year = {2026},
author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P},
title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {1},
pages = {11},
pmid = {41518572},
issn = {1573-675X},
support = {82171363//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Neoplasms/genetics/metabolism/pathology ; *Stress, Physiological ; Animals ; Tumor Suppressor Protein p53/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; Signal Transduction ; Chromosomal Proteins, Non-Histone ; },
abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.},
}

Humans
*Apoptosis/genetics
*Ribosomes/metabolism/genetics
*Neoplasms/genetics/metabolism/pathology
*Stress, Physiological
Animals
Tumor Suppressor Protein p53/metabolism/genetics
*Neurodegenerative Diseases/genetics/metabolism/pathology
Cell Nucleolus/metabolism
Signal Transduction
Chromosomal Proteins, Non-Histone

@article {pmid41518628,
year = {2026},
author = {Chevet, ML and Garnier, M and Fadel, M and Scherer, C and Cassereau, J and Levaillant, M and Codron, P},
title = {Epidemiology of Amyotrophic Lateral Sclerosis in the Pays de la Loire, France: A 20-Year Study from a Centralized Diagnostic Center.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-8},
pmid = {41518628},
issn = {1423-0208},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal motor neurons disease with multifactorial etiology. The epidemiology of ALS in France is mainly documented through the Limousin regional registry (FRALim). We aimed to determine the incidence and clinical characteristics of ALS cases over a 20-year period in another French region, the Pays de la Loire, served by a single centralized diagnostic center.

METHODS: All patients diagnosed with ALS at the Angers University Hospital reference center between 2003 and 2023 were retrospectively included. Demographic and clinical data were extracted from medical records, and incidence rates were calculated using annual population estimates from the National Institute of Statistics and Economic Studies. Spatial analyses were performed to identify over-incidence areas and potential environmental or occupational determinants.

RESULTS: A total of 1,316 patients were diagnosed with ALS during the study period, corresponding to a crude incidence rate of 1.88 cases per 100,000 person-years (95% CI: 1.78-1.98), with no significant variation over time. The standardized incidence rate was 1.73 (95% CI: 1.63-1.83). The mean age at symptom onset was 63.6 ± 11.2 years, 58.7% of patients were male. The mean disease duration was 3.7 ± 3.5 years. ALS onset was spinal in 70.3%, bulbar in 27.9%, and respiratory in 1.7% of cases. Familial or genetic forms accounted for 6% of patients. Four geographical over-incidence areas were identified, with no correlation found with pesticide use, air pollution, or other environmental indicators. One occupational cluster was observed among farmers in a specific commune, prompting a dedicated investigation.

CONCLUSION: This 20-year retrospective study provides the first epidemiological data on ALS in western France. The incidence and clinical features are consistent with national and European data. The identification of spatial and occupational clusters underlines the importance of continued regional surveillance and of prospective, registry-based studies to clarify environmental and occupational risk factors for ALS.},
}

@article {pmid41518742,
year = {2026},
author = {Milella, G and Carlone, S and Luisi, F and Velucci, V and Defazio, G},
title = {Facial-onset SOD1 amyotrophic lateral sclerosis: A case report and systematic review.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {145},
number = {},
pages = {111856},
doi = {10.1016/j.jocn.2026.111856},
pmid = {41518742},
issn = {1532-2653},
mesh = {Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Facial Paralysis/genetics/etiology ; *Superoxide Dismutase-1/genetics ; },
abstract = {BACKGROUND: Facial-onset weakness is an exceptionally rare presentation of SOD1-associated amyotrophic lateral sclerosis (ALS), and its natural history, anatomical spread, and prognostic implications remain unclear.

METHODS: We report a woman carrying a heterozygous SOD1 A5T variant who presented with isolated, rapidly progressive bilateral facial palsy, and we performed a PRISMA-compliant systematic review of MEDLINE, Scopus, and Web of Science to identify genetically confirmed SOD1-positive ALS with facial-onset weakness. Case-level demographic, genetic, clinical, neurophysiological, and outcome data were extracted and synthesised descriptively.

RESULTS: Eleven patients were included (7 men, 4 women; mean age at onset 52.3 years). Seven SOD1 variants were represented, predominantly associated with short survival (e.g. A5V, C7G, A5T). Facial weakness was initially confined to the lower face in 5/11 patients, while 6/11 had combined upper and lower facial involvement. Disease spread followed a stereotyped pattern: early contralateral facial recruitment (mean 3.6 months), rapid bulbar involvement (4.2 months), and later extension to the upper limbs (9.2 months), frequently with side-concordance between facial and arm involvement. Lower motor neuron (LMN) signs predominated in the early phases of the disease. Survival was short (median 16 months), lower than reported for unselected SOD1-ALS cohorts with the same genotypes. Three patients received tofersen, with heterogeneous outcomes.

CONCLUSIONS: Facial-onset SOD1 ALS defines a distinctive phenotype characterised by LMN-predominant facial palsy in early phases, near-neighbour spread, and an aggressive course exceeding genotype-based expectations. Prompt recognition and genetic testing in progressive facial palsy unresponsive to immunotherapy are essential to ensure access to gene-targeted treatments.},
}

Female
Humans
Male
Middle Aged
*Amyotrophic Lateral Sclerosis/genetics/complications
*Facial Paralysis/genetics/etiology
*Superoxide Dismutase-1/genetics

@article {pmid41519115,
year = {2026},
author = {Chen, MH and Bai, YM and Tsai, SJ},
title = {Depression, cognition, and GLP-1 receptors: Heterogeneity and therapeutic prospects.},
journal = {Med (New York, N.Y.)},
volume = {7},
number = {1},
pages = {100954},
doi = {10.1016/j.medj.2025.100954},
pmid = {41519115},
issn = {2666-6340},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Depression/drug therapy ; Glucagon-Like Peptide-1 Receptor ; Glucagon-Like Peptides/therapeutic use/pharmacology ; *Cognition/drug effects ; Quality of Life ; *Cognitive Dysfunction/drug therapy ; Glucagon-Like Peptide 1 ; Semaglutide ; },
abstract = {Cognitive impairments in depression, driven by both the illness per se and low-grade systemic inflammation, markedly reduce functional capacity and quality of life among patients who suffer. Findings from Badulescu et al.'s placebo-controlled trial reported that semaglutide, a GLP-1 receptor agonist, may improve attention and memory, although there was no significant improvement in overall depressive symptoms.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
*Depression/drug therapy
Glucagon-Like Peptide-1 Receptor
Glucagon-Like Peptides/therapeutic use/pharmacology
*Cognition/drug effects
Quality of Life
*Cognitive Dysfunction/drug therapy
Glucagon-Like Peptide 1
Semaglutide

@article {pmid41520601,
year = {2026},
author = {Squintani, G and Muzio, MD and Rasera, A and Paio, F and Borin, GU and Humaidan, K and Orlando, D and Refatti, N and Romito, S and Tinazzi, M and Bonetti, B and Ermani, M},
title = {Sensory and motor cortical hyperexcitability in patients with amyotrophic lateral sclerosis: are they related? a prospective pilot study.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {183},
number = {},
pages = {2111485},
doi = {10.1016/j.clinph.2025.2111485},
pmid = {41520601},
issn = {1872-8952},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Motor Cortex/physiopathology ; Pilot Projects ; *Evoked Potentials, Somatosensory/physiology ; Aged ; *Somatosensory Cortex/physiopathology ; *Evoked Potentials, Motor/physiology ; Transcranial Magnetic Stimulation/methods ; Prospective Studies ; Adult ; },
abstract = {OBJECTIVE: Our study evaluates sensory and motor cortical hyperexcitability as diagnostic biomarkers in ALS patients and investigates their relationship, identifying distinct or interconnected pathophysiological mechanisms in different sub-groups.

METHODS: We examined 26 ALS patients and 18 healthy controls. Motor cortex excitability was assessed using transcranial magnetic stimulation to measure the motor evoked potential (MEP) suppression ratio. Somatosensory cortex excitability was evaluated through upper-limb somatosensory evoked potentials (SEPs) with conventional and paired-pulse techniques. Statistical analyses included parametric/non-parametric tests, correlation analyses, and χ[2] tests. ROC analysis was used to assess diagnostic performance. Significance threshold was p < 0.05.

RESULTS: ALS patients showed a significantly reduced MEP suppression ratio (p < 0.001) with excellent discriminative power (100 % accuracy). SEP suppression ratio was significantly lower in ALS (p < 0.001), with sensitivity 76.3 %, specificity 91.7 %, and accuracy 84 %. In patients with giant SEPs, a strong inverse correlation was observed between MEP and SEP suppression ratios (r =  - 0.70, p < 0.001).

CONCLUSIONS: MEP and SEP suppression ratio are robust biomarkers of motor cortical dysfunction in ALS patients with a highlighting cortical heterogeneity between sub-groups, suggesting cortical interconnection.

SIGNIFICANCE: Alongside confirming motor and sensory cortical hyperexcitability as ALS hallmarks, this study reveals subgroup-specific patterns suggesting a compensatory interplay between sensory and motor cortex.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis
Male
Female
Middle Aged
*Motor Cortex/physiopathology
Pilot Projects
*Evoked Potentials, Somatosensory/physiology
Aged
*Somatosensory Cortex/physiopathology
*Evoked Potentials, Motor/physiology
Transcranial Magnetic Stimulation/methods
Prospective Studies
Adult

@article {pmid41520654,
year = {2026},
author = {Mehdiyoun, NF and Wright, J and Robinson, RL and Brandt, AU and Hoyt, M and Guo, J and Ball, N and Iqbal, H and Ringland, C and Milligan, G and Curtis, SE},
title = {Evaluating ALSFRS-R as an indicator of disease milestones and functional independence: An observational study of US neurologists and their patients with amyotrophic lateral sclerosis.},
journal = {Journal of the neurological sciences},
volume = {481},
number = {},
pages = {125732},
doi = {10.1016/j.jns.2026.125732},
pmid = {41520654},
issn = {1878-5883},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Activities of Daily Living ; Cross-Sectional Studies ; Aged ; *Neurologists ; *Disease Progression ; United States/epidemiology ; Severity of Illness Index ; Adult ; },
abstract = {BACKGROUND: The Revised Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALSFRS-R) is a clinician-reported outcome measure monitoring disease progression in people living with ALS (pALS). This study examined the relationship of ALSFRS-R scores with disease progression and independence levels for activities of daily living (ADLs) among pALS.

METHODS: Real-world data, including the ALSFRS-R, were drawn from a cross-sectional survey of US neurologists treating pALS (Adelphi ALS Disease Specific Programme™), conducted between July 2020 and March 2021. ALSFRS-R scores were modeled against 11 pre-defined disease milestones. The relationship between ALSFRS-R scores and levels of independence in 24 ADLs was examined using ordered logistic regression.

RESULTS: Fifty-nine neurologists provided data for 379 pALS (mean age: 59.5 years; mean disease duration: 16.1 months). Estimated mean ALSFRS-R total score decreased (worsened) from 46.1 at first consultation regarding ALS symptoms to 25.1 upon receipt of a feeding tube. In general, pALS were likely to be completely dependent in most ADLs when their ALSFRS-R total scores were ≤ 25. A 1-point decrease in ALSFRS-R total score was associated with increased risks of losing independence across all ADLs. For each ADL, a 1-point decrease in domain score was associated with varying risks of losing independence across different domains.

CONCLUSIONS: There is a correlation between ALSFRS-R scores and levels of independence in ADLs among pALS, facilitating score interpretation for monitoring disease and function status. Yet, the relevance of the ALSFRS-R total score diminishes in advanced stages of ALS, indicating a need for additional measures to provide comprehensive evaluation.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology
Male
Female
Middle Aged
*Activities of Daily Living
Cross-Sectional Studies
Aged
*Neurologists
*Disease Progression
United States/epidemiology
Severity of Illness Index
Adult

@article {pmid41521074,
year = {2026},
author = {Ham, HJ and Lee, JA},
title = {Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.},
journal = {BMB reports},
volume = {59},
number = {2},
pages = {85-100},
pmid = {41521074},
issn = {1976-670X},
mesh = {Humans ; *Aging/metabolism/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; *Stress Granules/metabolism/physiology ; Animals ; *Organelles/metabolism ; Mitochondria/metabolism ; Neurons/metabolism ; Cytoplasmic Granules/metabolism ; Autophagy ; Stress, Physiological ; },
abstract = {Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics-with an increased propensity to form SGs while displaying reduced efficiency in their clearance-resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging. [BMB Reports 2026; 59(2): 85-100].},
}

Humans
*Aging/metabolism/physiology
*Neurodegenerative Diseases/metabolism/pathology
*Stress Granules/metabolism/physiology
Animals
*Organelles/metabolism
Mitochondria/metabolism
Neurons/metabolism
Cytoplasmic Granules/metabolism
Autophagy
Stress, Physiological

@article {pmid41521076,
year = {2025},
author = {Lee, SP and Choi, J and Park, JH and Lee, KN and Lee, HL and Sung, W},
title = {Predictors of Percutaneous Endoscopic Gastrostomy-Related Complications in Amyotrophic Lateral Sclerosis: A 19-Year Retrospective Study From a Tertiary Center.},
journal = {Journal of digestive diseases},
volume = {26},
number = {11-12},
pages = {492-508},
doi = {10.1111/1751-2980.70025},
pmid = {41521076},
issn = {1751-2980},
mesh = {Humans ; *Gastrostomy/adverse effects/methods ; Male ; Retrospective Studies ; Female ; *Amyotrophic Lateral Sclerosis/complications ; Middle Aged ; Aged ; Risk Factors ; Tertiary Care Centers ; *Postoperative Complications/etiology/epidemiology ; *Deglutition Disorders/etiology/therapy/surgery ; Adult ; *Gastroscopy/adverse effects ; Enteral Nutrition/adverse effects/methods ; Ileus/complications ; },
abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that inevitably leads to swallowing difficulties as the disease progresses. Percutaneous endoscopic gastrostomy (PEG) is recommended for optimal supportive management of dysphagia among these patients. We aimed to investigate PEG-related complications and risk factors in patients with ALS.

METHODS: Medical records of the ALS patients who underwent PEG from March 2006 to February 2025 in a single tertiary care center were retrospectively reviewed. PEG-related complications and risk factors were assessed through chart review, endoscopic reports and images, radiological findings, and follow-up data.

RESULTS: Altogether 501 ALS patients (262 men) underwent PEG, of whom 60 developed early complications and 82 developed late complications, including 11 patients who developed both. Pneumoperitoneum was more common in underweight patients (p = 0.004), and wound infection was more common in patients with pre-PEG ileus (p = 0.044). Multivariate analysis revealed that low albumin level, long procedure time, and ileus were significantly associated with early complications. Obesity and ileus were independent risk factors for buried bumper syndrome. Those with an internal bolster at the upper body of the stomach and with an external bolster in the midline of the abdomen were at significant risk of inadvertent PEG removal.

CONCLUSIONS: Albumin and body mass index extremes are predictors of complications, and care is needed when PEG is performed on patients with pre-PEG ileus. To reduce such risks, the PEG tube should not be inserted into the upper body of the stomach or the midline of the abdomen.},
}

Humans
*Gastrostomy/adverse effects/methods
Male
Retrospective Studies
Female
*Amyotrophic Lateral Sclerosis/complications
Middle Aged
Aged
Risk Factors
Tertiary Care Centers
*Postoperative Complications/etiology/epidemiology
*Deglutition Disorders/etiology/therapy/surgery
Adult
*Gastroscopy/adverse effects
Enteral Nutrition/adverse effects/methods
Ileus/complications

@article {pmid41523053,
year = {2025},
author = {Nagmode, P and Deshmukh, V and Abraham, S and Lokhande, N and Diggikar, K and Chavhan, G},
title = {Comparative Evaluation of Effectiveness of 35% and 20% Concentration of Hydrogen Peroxide Alone and in Combination with Pomegranate Extract on Human Enamel Used for Tooth Bleaching - An Invitro Study.},
journal = {Journal of pharmacy & bioallied sciences},
volume = {17},
number = {Suppl 4},
pages = {S3322-S3324},
pmid = {41523053},
issn = {0976-4879},
abstract = {AIM: To evaluate the color change in human enamel bleached with two concentrations of hydrogen peroxide (35% and 20%) alone and in combination with pomegranate extract using a reflectance spectrophotometer.

MATERIALS AND METHODS: Forty extracted permanent maxillary incisors were randomly divided into four groups: Group 1a: 35% hydrogen peroxide alone, Group 1b: 35% hydrogen peroxide + pomegranate extract, Group 2a: 20% hydrogen peroxide alone, Group 2b: 20% hydrogen peroxide + pomegranate extract. Pomegranate extract was prepared from 1500 g of peeled white pomegranate blended with 25 ml distilled water and centrifuged at 2000 rpm for 2 minutes at 4°C. Teeth were artificially stained following Sulieman et al.'s protocol and immersed in respective bleaching agents for 20 minutes. Color change (ΔE) was measured using a reflectance spectrophotometer.

RESULTS: Groups using pomegranate extract with hydrogen peroxide exhibited significantly greater ΔE values, indicating enhanced bleaching efficacy compared to hydrogen peroxide alone.

CONCLUSION: Hydrogen peroxide combined with pomegranate extract significantly improves tooth color change compared to hydrogen peroxide alone.},
}

@article {pmid41523190,
year = {2026},
author = {Jiang, Y and Fu, Y and Song, X and Wang, X and Li, J and Cheng, L and Chen, Y and Zhang, Y and Wang, J and Yi, X and Palaniyappan, L},
title = {Microstructure and gene expression influence gyrification in amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf491},
pmid = {41523190},
issn = {2632-1297},
abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Beyond well-established grey and white matter pathology, alterations in cortical gyrification have recently been observed, yet their clinical relevance and molecular underpinnings remain to be understood. Here, we investigated this premise by examining its microstructural and transcriptional basis in 60 patients with amyotrophic lateral sclerosis (median age = 55, range = 25-72 years) and 60 matched controls (median age = 56, range = 27-72 years) using structural and diffusion MRI. Patients exhibited a significant reduction in local gyrification index within bilateral precentral and postcentral gyri, left middle frontal gyrus and left superior parietal lobule. This was accompanied by reduced fractional anisotropy in the white matter tracts, primarily involving the corticospinal tract and corpus callosum. Higher local gyrification index and fractional anisotropy values were associated with better motor function as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, and local gyrification index also showed positive associations with global cognitive status. A mediation analysis indicated that fractional anisotropy partially accounted for the relationship between local gyrification index and functional disability, suggesting that disrupted white matter pathways contribute to the clinical impact of gyrification changes. To explore underlying mechanisms, we integrated neuroimaging findings with transcriptomic data from the Allen Human Brain Atlas. Regions of reduced local gyrification index showed spatial convergence with cortical expression of amyotrophic lateral sclerosis-related genes such as TARDBP and C9orf72, enriched for biological processes related to protein aggregation, axon guidance and synaptic signalling. Together, these findings suggest that cortical gyrification abnormalities in amyotrophic lateral sclerosis are closely linked to white matter degeneration, functional impairment and genetic vulnerability, thereby offering an integrative window into the multiscale pathology of amyotrophic lateral sclerosis.},
}

@article {pmid41524979,
year = {2026},
author = {Sun, Y and Huang, C and Pan, Y and Zhang, H and He, X},
title = {Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {357},
pmid = {41524979},
issn = {1559-1182},
support = {2021KY727//Health Commission of Zhejiang Province, Medical and health project/ ; A20210510//Hangzhou Municipal Health Commission, Medical and health science project/ ; },
mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology/diagnosis/metabolism/complications ; Fibrosis ; *Muscle, Skeletal/pathology/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily characterized by the degeneration of motor neurons. However, the pathological process of ALS extends beyond the central nervous system, with dynamic changes in skeletal muscle playing a crucial role in the progression of the disease. Recent research has shown that muscle fibrosis, marked by the abnormal accumulation of extracellular matrix (ECM), leads to reduced muscle elasticity, compromised contractile function, and impaired regeneration of neuromuscular junctions (NMJs). This condition represents not only the final stage of muscle atrophy in ALS but also a significant factor accelerating disease progression through "neuromuscular interactions." We conducted a systematic review of the molecular mechanisms of muscle fibrosis in ALS. This included examining the dysregulation of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF/CCN2), and the Wnt/β-catenin signaling pathways. We also considered key cellular contributors, such as fibro-adipogenic precursor cells and macrophages. The review also covers the use of non-invasive imaging techniques, such as MRI and muscle ultrasound, for early detection and monitoring. We also evaluate potential therapeutic approaches, ranging from anti-fibrotic drugs and gene therapy to physical interventions. In summary, muscle fibrosis is a promising therapeutic target that could complement strategies focused on motor neurons, ultimately improving functional outcomes in patients with amyotrophic lateral sclerosis.},
}

Animals
Humans
*Amyotrophic Lateral Sclerosis/therapy/pathology/diagnosis/metabolism/complications
Fibrosis
*Muscle, Skeletal/pathology/metabolism

@article {pmid41525811,
year = {2026},
author = {Pradhan, LK and Das, SK},
title = {Zebrafish neural regeneration: mechanistic insights into human nervous system repair.},
journal = {Neuroscience},
volume = {596},
number = {},
pages = {1-15},
doi = {10.1016/j.neuroscience.2026.01.009},
pmid = {41525811},
issn = {1873-7544},
mesh = {Animals ; Zebrafish/physiology ; *Nerve Regeneration/physiology ; Humans ; Disease Models, Animal ; Neurogenesis/physiology ; },
abstract = {The zebrafish (Danio rerio) is a powerful vertebrate model for studying neurodegenerative diseases and regenerative medicine due to its genetic similarity to humans and its unique ability to regenerate the central nervous system (CNS). This review synthesizes key findings on zebrafish neural regeneration across the retina, spinal cord, and brain, emphasizing translational relevance. Zebrafish effectively model disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, stroke, epilepsy, autism spectrum disorders, and CNS injuries. Unlike mammals, they restore damaged axons and recover function through a permissive extracellular matrix, transient inflammation, and glial plasticity. In the retina, Müller glia reprograms after injury to generate progenitors that replace lost neurons, regulated by Wnt/β-catenin, Shh, EGF, Hippo/YAP, and ROCK signaling. In the spinal cord, ependymo-radial glia forms a laminin- and fibronectin-rich "glial bridge," guided by FGF and CTGF signaling, supporting axon regrowth. In the brain, GFAP- and Olig2-positive radial glia drive neurogenesis within ventricular niches, integrating new neurons while maintaining circuit integrity. Regeneration involves transient Notch suppression, context-specific Wnt and FGF activation, and immune modulation without fibrosis. Advances in single-cell RNA sequencing, CRISPR-Cas9, lineage tracing, and multi-omics have identified injury-induced progenitor states, regulators (ascl1a, lin28, sox2, stat3), and epigenetic programs enabling regeneration. Emerging research on bioelectric signaling, microbiota-brain interactions, and lipid mediators further expands systemic understanding. Overall, zebrafish provide a unified model for decoding vertebrate CNS regeneration and guiding therapeutic strategies to restore neural repair in humans.},
}

Animals
Zebrafish/physiology
*Nerve Regeneration/physiology
Humans
Disease Models, Animal
Neurogenesis/physiology

@article {pmid41525886,
year = {2026},
author = {Zimyanin, V and Dash, BP and Simolka, T and Glaß, H and Pal, A and Haidle, F and Zarnack, K and Verma, R and Khatri, V and Deppmann, C and Zunder, E and Müller-McNicoll, M and Redemann, S and Hermann, A},
title = {Compartment-specific transcriptome of motor neurons reveals impaired extracellular matrix signaling and activated cell cycle kinases in FUS-ALS.},
journal = {Neurobiology of disease},
volume = {219},
number = {},
pages = {107268},
doi = {10.1016/j.nbd.2026.107268},
pmid = {41525886},
issn = {1095-953X},
mesh = {*Motor Neurons/metabolism/pathology ; *RNA-Binding Protein FUS/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Transcriptome ; *Extracellular Matrix/metabolism ; Humans ; *Cell Cycle Proteins/metabolism/genetics ; Animals ; Signal Transduction/physiology ; Axons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; },
abstract = {Mutations in FUSED IN SARCOMA (FUS) cause juvenile-onset amyotrophic lateral sclerosis (ALS). Early pathogenesis of FUS-ALS involves impaired transcription and splicing, DNA damage response, and axonal degeneration. However, the molecular pathophysiology and the link between somatic and axonal phenotypes are still poorly understood. We evaluated whether compartment-specific transcriptome differences could distinguish and drive early axonal degeneration. We used iPSC-derived motor neurons (MNs) coupled with microfluidic approaches to generate RNA-sequencing profiles from axonal and somatodendritic compartments. We demonstrate that the axonal transcriptome is unique and distinct, with RNA metabolism, extracellular secretion, and matrix disassembly pathways particularly enriched in distal axonal compartments. FUS mutation leads to changes in distinct pathways that were clustered in only a few distinct protein-protein interaction (PPI) networks. Somatodendritic changes upon FUS mutation include WNT signaling, mitochondrial, extracellular matrix (ECM)-, and synapse-related functions. In contrast, analysis of the axonal transcriptome in mutant MNs centers on the PLK1 pathway, mitochondrial gene expression, and regulation of inflammation. Comparison to CLIP-seq data revealed a significant enrichment for PLK1 and DNA replication pathways in axons. PLK1 upregulation did not activate cell-cycle re-entry but contributed to mutant MNs survival, and its inhibition increased neuronal cell death. We propose that upregulation of PLK1 represents an early event in the pathogenesis of ALS and could act in response to DNA damage, mitochondrial damage, and immune response activation in the affected cells. Additionally, downregulation of ECM pathways in the somatodendritic compartment and axons could explain strongly compromised dynamics of axonal outgrowth. Overall, we provide a novel valuable resource of the potential targets and affected processes changed in the specific compartments of FUS-ALS motor neurons.},
}

*Motor Neurons/metabolism/pathology
*RNA-Binding Protein FUS/genetics/metabolism
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*Transcriptome
*Extracellular Matrix/metabolism
Humans
*Cell Cycle Proteins/metabolism/genetics
Animals
Signal Transduction/physiology
Axons/metabolism
Induced Pluripotent Stem Cells/metabolism

@article {pmid41525888,
year = {2026},
author = {Tessitore, S and Torazza, C and Bonifacino, T and Bacchetti, F and Roselli, F and Raiteri, L and Milanese, M and Bonanno, G},
title = {Focus on the excitatory and inhibitory neurotransmission imbalance in amyotrophic lateral sclerosis: a harmful disease player or a potential therapeutic opportunity?.},
journal = {Neurobiology of disease},
volume = {219},
number = {},
pages = {107272},
doi = {10.1016/j.nbd.2026.107272},
pmid = {41525888},
issn = {1095-953X},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/metabolism/drug therapy ; Humans ; *Synaptic Transmission/physiology ; Animals ; Motor Neurons/metabolism/physiology ; Glutamic Acid/metabolism ; *Neural Inhibition/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. Evidence indicates that ALS is a "multifactorial" and "multicellular" disease; however, the causes of ALS remain elusive, as the mechanisms underlying the disease have not yet been completely clarified. One major proposed mechanism, first described in 1990, is the glutamate excitotoxicity theory. This theory suggests that excessive glutamatergic neurotransmission, combined with impaired glutamate clearance, significantly contributes to motor neuron degeneration. Aberrant glutamate neurotransmission may lead to precocious motor neuron hyperexcitability in the brain cortex and spinal cord, which can be later followed by hypoexcitability phases. Accumulating evidence suggests that impairment in inhibitory neurotransmission is relevant for excitation/inhibition imbalance, leading to excitotoxicity, a critical feature of ALS. Gamma-aminobutyric acid (GABA) and glycine are the primary inhibitory neurotransmitters that modulate neuronal excitability, including that of motor neurons. In ALS, dysfunction of inhibitory processes and loss of cortical and spinal inhibitory interneurons are observed. Renshaw cells, which mediate recurrent inhibition in the spinal cord, seem particularly vulnerable. The interactions among neurotransmitters, including glutamate, GABA, and glycine, play pivotal roles in regulating the excitation/inhibition balance. Auto- or hetero-receptor-mediated interactions are crucial, but auto- or hetero-transporter-mediated neurotransmission control, as well as other molecular mechanisms that regulate neuronal interplay, are also relevant, as they can be altered in pathological conditions such as ALS. To facilitate the search for new effective therapies for ALS, attention toward the impairment of inhibitory neurotransmission is essential to determine the role of excitation/inhibition imbalance on excitotoxicity. Different pharmacological agents are being used to treat other pathologies in which the excitation/inhibition ratio is impaired. Among these, we highlighted the potential of novel glycine and GABA receptor ligands and transporter inhibitors, as stand-alone interventions or in combination with other treatments. The present review aims to elucidate the complex interplay between excitatory and inhibitory neurotransmission in ALS, exploring the potential to target this imbalance for therapeutic purposes.},
}

*Amyotrophic Lateral Sclerosis/physiopathology/metabolism/drug therapy
Humans
*Synaptic Transmission/physiology
Animals
Motor Neurons/metabolism/physiology
Glutamic Acid/metabolism
*Neural Inhibition/physiology

@article {pmid41527739,
year = {2026},
author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W},
title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {110},
number = {1},
pages = {5-25},
doi = {10.1177/13872877251411546},
pmid = {41527739},
issn = {1875-8908},
mesh = {Humans ; Biomarkers/metabolism ; *Phosphoproteins/metabolism ; *Proteomics/methods ; *Brain Diseases/metabolism/diagnosis ; Phosphorylation ; Animals ; },
abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.},
}

Humans
Biomarkers/metabolism
*Phosphoproteins/metabolism
*Proteomics/methods
*Brain Diseases/metabolism/diagnosis
Phosphorylation
Animals

@article {pmid41530082,
year = {2026},
author = {Cooper, P and Lu, M and Chan, M and Wilman, A and Kalra, S and Ghavanini, AA},
title = {Exploring the Value of Brain T2* Weighted and FLAIR Imaging for Diagnosing Amyotrophic Lateral Sclerosis.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-6},
doi = {10.1017/cjn.2026.10527},
pmid = {41530082},
issn = {0317-1671},
abstract = {OBJECTIVES: Early diagnosis of amyotrophic lateral sclerosis (ALS) is essential for treatment initiation and symptom management, yet it remains challenging due to nonspecific symptoms and the lack of reliable diagnostic biomarkers. Although conventional MRI sequences such as T2* weighted and fluid-attenuated inversion recovery (FLAIR) have shown potential in identifying upper motor neuron abnormalities, their diagnostic utility in ALS is not well established. This study aimed to evaluate the sensitivity and specificity of brain T2* weighted and FLAIR MRI sequences in diagnosing ALS using prospectively collected data and to assess associations with disease severity.

METHODS: Data were analyzed from 20 patients with ALS and 20 healthy controls enrolled at the Edmonton site of the Canadian ALS Neuroimaging Consortium 1 (CALSNIC-1) study. Single-slice 2D axial susceptibility-weighted echo planar imaging (SWEPI) and FLAIR images were independently rated by a blinded neurologist and radiologist for signs of corticospinal tract and motor cortex abnormalities. Sensitivity and specificity were calculated, and linear regression was used to examine associations with ALS Functional Rating Scale-Revised (ALSFRS-R) scores.

RESULTS: T2* weighted and FLAIR MRI sequences showed high specificity (0.95 and 0.85, respectively) but low sensitivity (both 0.25) for ALS diagnosis. No significant correlation was found between imaging abnormalities and ALSFRS-R scores. Inter-rater reliability was poor (κ = 0.25 for SWEPI; κ = 0.14 for FLAIR).

CONCLUSION: While T2* weighted and FLAIR MRI sequences may have some specificity for ALS, our study suggests they are not sufficiently sensitive to be used as reliable diagnostic tools for ALS.},
}

@article {pmid41530593,
year = {2026},
author = {Muneer, MA and Tariq, I and Zulfiqar, E and Saaki, SS and Gupta, I and Bokhari, SMNA and Verma, A and Mehta, R and Sah, R and Ahmed, SI},
title = {Efficacy and safety of dextromethorphan/quinidine in treating pseudobulbar affect in neurological disorders: A systematic review and dose-classified network meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {159},
pmid = {41530593},
issn = {1590-3478},
mesh = {Humans ; *Dextromethorphan/administration & dosage/adverse effects/pharmacology/therapeutic use ; Drug Combinations ; *Nervous System Diseases/drug therapy/complications ; *Pseudobulbar Palsy/drug therapy ; *Quinidine/administration & dosage/adverse effects/pharmacology/therapeutic use ; Randomized Controlled Trials as Topic ; },
abstract = {BACKGROUND: Pseudobulbar affect (PBA) is a disabling neuropsychiatric condition characterized by sudden, involuntary episodes of crying or laughing incongruent with mood. It occurs in several neurological disorders, including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury (TBI). Dextromethorphan/quinidine (DM/Q) is the only Food and Drug Administration (FDA)-approved therapy for PBA, but optimal dosing and safety profiles remain uncertain.

OBJECTIVE: To evaluate the efficacy and safety of different DM/Q dosing regimens for treating PBA through a systematic review and network meta-analysis.

METHODS: A comprehensive search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted through March 2025. Randomized controlled trials reporting outcomes on the Center for Neurologic Study-Lability Scale (CNS-LS), Visual Analog Scale-Quality of Life (VAS-QOL), Visual Analog Scale-Quality of Recovery (VAS-QOR), and adverse events were included. Analyses were performed using R (netmeta package), and bias was assessed with the Cochrane RoB 2.0 tool.

RESULTS: Five randomized controlled trials comprising 605 participants were analyzed. DM/Q 20/10 mg and 30/10 mg significantly improved CNS-LS scores (mean difference [MD] - 2.52 and - 2.45, respectively), while DM/Q 30/30 mg produced greater gains in VAS-QOL (MD 17.20) and VAS-QOR (MD 14.90). Dizziness was the only statistically significant, dose-related adverse event.

CONCLUSION: DM/Q combination therapy provides effective symptom control for PBA, with favorable tolerability. Both 20/10 mg and 30/10 mg doses improve emotional lability, while 30/30 mg yields additional quality-of-life benefits. Further studies should assess long-term safety and disorder-specific dosing optimization.},
}

Humans
*Dextromethorphan/administration & dosage/adverse effects/pharmacology/therapeutic use
Drug Combinations
*Nervous System Diseases/drug therapy/complications
*Pseudobulbar Palsy/drug therapy
*Quinidine/administration & dosage/adverse effects/pharmacology/therapeutic use
Randomized Controlled Trials as Topic

@article {pmid41531269,
year = {2026},
author = {Elmaleh, B and Faust, O and Rosenzweig, R},
title = {The ALS-associated E425K mutation uncouples DNAJC7 from the Hsp70 chaperone cycle.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70395},
pmid = {41531269},
issn = {1742-4658},
support = {1093/22//Israel Science Foundation/ ; //Minerva Foundation/ ; ERC-CoG-2024 101169856//H2020 European Research Council/ ; },
abstract = {DNAJC7, a member of the J-domain protein (JDP/Hsp40) family, plays a key role in protein homeostasis by regulating Hsp70 activity and preventing protein aggregation. Mutations in DNAJC7 have been linked to amyotrophic lateral sclerosis (ALS); yet, the molecular mechanisms by which these variants impair chaperone function remain poorly understood. DNAJC7 is a conserved chaperone featuring both a canonical J-domain, essential for Hsp70 activation, and three TPR domains, which serve as protein-protein binding interfaces. Here, we investigate the structural and functional consequences of the ALS-associated E425K mutation located within the conserved J-domain. Using NMR spectroscopy, we show that although the E425K mutation does not alter the structure of the protein, it significantly disrupts the conserved J-domain-Hsp70 interaction. We further identify a second Hsp70-binding interface within the TPR domains, which interacts with the C-terminal EEVD motif of Hsp70. This TPR-EEVD interaction is preserved in the E425K mutant but cannot compensate for the loss of J-domain binding or restore DNAJC7-dependent Hsp70 activation. Functionally, we show that the TPR domains of DNAJC7 directly bind TDP-43 and prevent its aggregation and that this holdase activity is retained in the E425K mutant. However, the mutant fails to support client transfer to Hsp70 and the subsequent Hsp70-mediated substrate refolding. Together, these findings demonstrate that DNAJC7 requires coordinated action of both J-domain and TPRs to regulate Hsp70 function and that disruption of J-domain-mediated activation uncouples DNAJC7 from the Hsp70 cycle, providing a mechanistic basis for its dysfunction in ALS.},
}

@article {pmid41531792,
year = {2026},
author = {Yang, X and Huang, S and Wang, Y and Yuan, J and Yao, X},
title = {Identification of Comprehensive Landscape of Peripheral Immunity and Chemokine-Related Genes in Amyotrophic Lateral Sclerosis.},
journal = {ImmunoTargets and therapy},
volume = {15},
number = {},
pages = {566733},
pmid = {41531792},
issn = {2253-1556},
abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive loss of motor neuron function and disruption of the blood-brain barrier are key features of ALS. Under the influence of chemokines, peripheral immune cells migrate into the central nervous system, thereby affecting the neuronal microenvironment. The aim of this study is to classify ALS based on the immune characteristics of peripheral blood in patients with the disease, and to construct prognostic models.

PATIENTS AND METHODS: A total of 397 ALS patients and 645 healthy controls (GSE112676 and GSE112680) were included. ALS chemotactic subtypes were constructed based on differentially expressed genes of chemokine and chemokine receptors (CCRs). The Cibersort algorithm was used to investigate the abundance of immune cells in peripheral blood. Univariate Cox regression analysis was performed to screen for CCRs genes, clinical characteristics, and immune cells associated with prognosis. Prognostic models were constructed based on these variables. Finally, external validation was conducted using samples from ALS patients diagnosed at the First Affiliated Hospital of Sun Yat-sen University.

RESULTS: There were significant differences in the abundance of peripheral immune cells between ALS patients and healthy controls. 17 CCRs genes were identified as differentially expressed. CCL23, CCR8, CXCR4, site of onset, age of onset, and "CD4 naive T cells" were demonstrated to be significantly correlated with survival time. Two chemotactic subtypes were established. Eight prognostic models could distinguish between high-risk and low-risk ALS patients. At year five, the areas under the receiver operating characteristic curves for the PlsRcox, Coxboost, and Xgboost algorithms were 0.747, 0.733, and 0.728, respectively. External test sets successfully validated these results.

CONCLUSION: ALS patients exhibit peripheral immune abnormalities. Peripheral immune status could be used to distinguish ALS subtypes and construct prognostic models. Understanding peripheral immune changes in ALS patients may inform potential immunotherapies.},
}

@article {pmid41531877,
year = {2025},
author = {Finsterer, J},
title = {There is currently no evidence that long-COVID-19 leads to neurodegenerative diseases such as SDAT, amyotrophic lateral sclerosis, or Parkinson's disease.},
journal = {Brain circulation},
volume = {11},
number = {4},
pages = {354-355},
pmid = {41531877},
issn = {2455-4626},
}

@article {pmid41532955,
year = {2026},
author = {Bernal-Vicente, BN and Ponce, I and Ríos-Castro, E and Moreno-Castilla, P and Tovar-Y-Romo, LB},
title = {Unveiling the Proteomic Landscape of Extracellular Vesicles: Implications for Neurodegeneration and Neuroprotection.},
journal = {Journal of neurochemistry},
volume = {170},
number = {1},
pages = {e70350},
pmid = {41532955},
issn = {1471-4159},
support = {IN214723//Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México/ ; },
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Proteomics/methods ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroprotection/physiology ; Biomarkers/metabolism ; },
abstract = {Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to elucidate their roles in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and ischemic stroke. Across these conditions, EVs carry disease-relevant proteins that reflect and influence key pathological processes such as synaptic dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death. Proteomic profiling of brain- and biofluid-derived EVs has uncovered specific biomarkers and signaling pathways, ranging from tau and α-synuclein in AD and PD to mutant SOD1 in ALS and complement activation in stroke and TBI. Moreover, cell-type-specific EVs (e.g., from neurons, astrocytes, microglia, and stem cells) have been shown to exert either protective or deleterious effects, modulating apoptosis, axonal regeneration, and immune responses. Recent evidence highlights the translational potential of EVs as non-invasive biomarkers and therapeutic vectors across multiple disorders. By mapping shared and divergent proteomic signatures in EVs, we review the mechanistic relevance and clinical utility of EVs in neurodegeneration and CNS injury.},
}

Humans
*Extracellular Vesicles/metabolism
*Proteomics/methods
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Neuroprotection/physiology
Biomarkers/metabolism

@article {pmid41533211,
year = {2026},
author = {Shu, X and Zeng, J and Zhang, K},
title = {TREM2-mediated Crosstalk in ALS: Microglial Fate Transition, Protein Aggregate Clearance, and Peripheral Nerve Repair.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41533211},
issn = {1995-8218},
}

@article {pmid41534282,
year = {2026},
author = {Hosseinpour Moghaddam, M and Karimian, N and Johnston, SG and Choppala, G and Rastegari, M and Burton, ED},
title = {Goethite as an antimony host-phase: Atomic-scale retention mechanisms and the selectivity of commonly-applied extraction schemes.},
journal = {Journal of hazardous materials},
volume = {503},
number = {},
pages = {141097},
doi = {10.1016/j.jhazmat.2026.141097},
pmid = {41534282},
issn = {1873-3336},
abstract = {Goethite (α-FeOOH) is one of the most important host-phases for Sb(V) in soils, sediments and geogenic wastes. This study examines, for the first time, how variability in the atomic-scale mechanisms of Sb(V) retention by goethite impacts the selectivity of commonly-applied Sb extraction schemes. EXAFS spectroscopy shows that Sb(V) retention via coprecipitation involves Sb(V) incorporation into goethite's structure through Sb(V)-for-Fe(III) substitution. In contrast, Sb(V) retention via sorption involves edge and double-corner sharing between SbO6 and FeO6 octahedra at the goethite surface. Incorporation of Sb(V) into goethite's structure causes Sb(V) to be largely inaccessible to 1 M HCl, steps 1, 2 and 3 of Wenzel et al.'s sequential extraction scheme and all 3 steps of the BCR extraction scheme. In contrast, Sb(V) sorption to goethite's surface facilitates more substantial Sb(V) extractability, which varies with the relative abundance of SbO6-FeO6 linkages. Importantly, Sb(V) sorption to the goethite surface is underestimated by both the Wenzel et al. and BCR schemes. In addition, the BCR scheme misidentifies a significant portion of goethite-sorbed Sb(V) as oxidisable phases (e.g. sulfides or organic matter). Hence, in soils, sediments or geogenic wastes where Sb(V) is sorbed to goethite, the BCR scheme is not appropriate for quantifying Sb(V) fractionation. Overall, our results demonstrate that variability in the atomic-scale mechanisms by which goethite retains Sb(V) translate to substantial complexity in Sb(V) extractability.},
}

@article {pmid41534442,
year = {2026},
author = {Nomura, E and Morihara, R and Osakada, Y and Yunoki, T and Takemoto, M and Yamashita, T and Ishiura, H},
title = {The utility of Gold Coast criteria for amyotrophic lateral sclerosis.},
journal = {Journal of the neurological sciences},
volume = {481},
number = {},
pages = {125733},
doi = {10.1016/j.jns.2026.125733},
pmid = {41534442},
issn = {1878-5883},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Male ; Middle Aged ; Female ; Retrospective Studies ; Aged ; Sensitivity and Specificity ; Adult ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Current diagnostic criteria, including the revised El Escorial (rEE) and Awaji (AW) criteria, have limitations in sensitivity. The Gold Coast (GC) criteria were proposed to simplify diagnosis and improve early detection, but their real-world performance remains unclear.

METHODS: We retrospectively analyzed 260 patients suspected of ALS who were admitted to our department between 2013 and 2022. The GC, AW, and rEE criteria were applied to data from initial hospitalization. Final diagnoses were based on follow-up data, and sensitivity/specificity were compared using McNemar's test.

RESULTS: The GC criteria showed equivalent sensitivity (91.6 %), but higher specificity (75.9 %) compared to all combined AW and rEE categories. GC sensitivity was significantly higher than that of AW/rEE definite/probable categories. False negatives of GC criteria were often due to insufficient LMN signs, particularly in bulbar-onset cases. Subgroup analysis showed consistent trends.

CONCLUSION: The GC criteria demonstrated high sensitivity and moderate specificity, supporting their clinical utility in early ALS diagnosis. However, variability in clinical presentation and retrospective limitations suggest the need for further prospective validation.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis
Male
Middle Aged
Female
Retrospective Studies
Aged
Sensitivity and Specificity
Adult

@article {pmid41534462,
year = {2026},
author = {Mortensen, CK and Jokinen, CLV and Sørensen, CLH and Løkkegaard, SS},
title = {Beyond the birthing body: Towards a relational and inclusive understanding of birth trauma. A commentary on Donegan et al. (2025).},
journal = {Midwifery},
volume = {154},
number = {},
pages = {104705},
doi = {10.1016/j.midw.2026.104705},
pmid = {41534462},
issn = {1532-3099},
mesh = {Humans ; Female ; Pregnancy ; Qualitative Research ; Adult ; *Parturition/psychology ; Denmark ; },
abstract = {In their recent scoping review, Donegan, Zhao, and Mansu (2025) provide a valuable synthesis of international best practice guidelines on birth trauma support for birthing women. While several reviews have explored fathers' experiences of traumatic or complicated births and proposed recommendations for improved care, systematic implementation and empirical evaluation remain limited. In this commentary, we broaden Donegan et al.'s focus on birthing women by extending the scope of trauma-informed perinatal care to also include non-birthing parents. Drawing on findings from a Danish qualitative study conducted in spring 2025, as well as existing research and theoretical perspectives, we explore how non-birthing parents can be profoundly affected by traumatic births - often without recognition or adequate support. We conclude by offering six recommendations for practice and future research aimed at broadening the scope of trauma-informed perinatal care to meaningfully include non-birthing parents and thereby reduce the triadic impact of birth trauma and support individual and family functioning.},
}

Humans
Female
Pregnancy
Qualitative Research
Adult
*Parturition/psychology
Denmark

@article {pmid41534629,
year = {2026},
author = {Ortega Douville, C},
title = {First evidence supporting the theory of the sensorimotor paradox on the origins of mind and language.},
journal = {Bio Systems},
volume = {262},
number = {},
pages = {105691},
doi = {10.1016/j.biosystems.2026.105691},
pmid = {41534629},
issn = {1872-8324},
mesh = {Humans ; *Language ; *Feedback, Sensory/physiology ; Electroencephalography ; *Biological Evolution ; Movement/physiology ; Brain/physiology ; },
abstract = {For now 15 years, I have been developing a hypothesis on the origins of mind and language during our evolution, called theory of the sensorimotor paradox. The core neuroimaging part of the hypothesis is that the switch in our relation to our hands, coming with bipedal stance, would have allowed us to disrupt the function of sensory prediction to resolve into motor action and sensory feedback: we can't take our hand as an object of interaction and have it grasp itself at the same time. This would later on be autonomised as mental representation. From there, non-resolution of prediction into motor action would prevent a system from liberating tension in order to be available again and collect feedback (meta-prediction). Using Schalk, G. et al.'s extensive dataset of EEG recordings on motor movement and imagery (2009), I am now able to support some of the theory's claims. Notably, meta-analysis of movement and imagery recordings tends to stress a higher variability of frequency activation amongst motor signals than imagery's. This would indicate a greater difficulty for a system to release tension in an effort to produce and maintain mental representation. Similar short oscillatory predictive change, but greater uncoupling of frontal and prefrontal regions suggests sensory suppression of efference-copy and greater instability toward the eventuality of collecting feedback when motor action is triggered, relying on somatosensory support. Event-related time-frequency analysis on proprioceptive areas shows delay of neural signal to mental representation compared to motor action, which could be a strong evidence of dissociation.},
}

Humans
*Language
*Feedback, Sensory/physiology
Electroencephalography
*Biological Evolution
Movement/physiology
Brain/physiology

@article {pmid41534661,
year = {2026},
author = {Costa, I and Barbosa, DJ and Remião, F and Sousa, ME and Silva, R},
title = {A dive into the untapped potential of marine compounds in counteracting neurodegeneration.},
journal = {Pharmacology & therapeutics},
volume = {279},
number = {},
pages = {108982},
doi = {10.1016/j.pharmthera.2026.108982},
pmid = {41534661},
issn = {1879-016X},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology ; Animals ; *Aquatic Organisms/chemistry ; *Biological Products/pharmacology/therapeutic use/isolation & purification ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by the progressive breakdown and eventual loss of synapses and neurons, primarily driven by the accumulation of pathologically altered proteins within the brain and spinal cord. These diseases have complex and multifactorial etiologies, involving a broad spectrum of pathophysiological mechanisms, many of which remain incompletely understood. Nonetheless, several key pathways are consistently implicated across these conditions, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. Given their rising prevalence and the persistent lack of effective disease-modifying therapies, the development of novel therapeutic strategies capable of targeting multiple pathophysiological processes is of critical importance for delaying or halting disease progression. In this context, marine natural compounds have emerged as promising candidates for counteracting neurodegeneration, owing to their ability to modulate key pathophysiological hallmarks of distinct neurodegenerative diseases. Derived from a wide range of marine organisms - including algae, sponges, fungi, and cyanobacteria - these bioactive molecules possess unique chemical structures and exhibit a broad spectrum of neuroprotective effects. Many have demonstrated potent antioxidant, anti-apoptotic, and mitochondrial-stabilizing activities in preclinical models. This review highlights recent advances in the discovery and characterization of marine-derived compounds with therapeutic potential in neurodegenerative diseases, contextualizing their pathologic mechanisms.},
}

Humans
*Neurodegenerative Diseases/drug therapy/physiopathology
Animals
*Aquatic Organisms/chemistry
*Biological Products/pharmacology/therapeutic use/isolation & purification
*Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification

@article {pmid41534682,
year = {2026},
author = {Sangari, S and Lackmy-Vallée, A and Peyre, I and Pradat, PF and Marchand-Pauvert, V},
title = {Afferent-driven modulation of spinal interneuron circuits across disease stages in amyotrophic lateral sclerosis.},
journal = {Neurobiology of disease},
volume = {219},
number = {},
pages = {107270},
doi = {10.1016/j.nbd.2026.107270},
pmid = {41534682},
issn = {1095-953X},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; *Interneurons/physiology ; Humans ; Female ; Male ; Middle Aged ; Aged ; *Spinal Cord/physiopathology ; Motor Neurons/physiology ; *Afferent Pathways/physiopathology ; Adult ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively disrupts voluntary motor command through combined cortical and spinal motor neuron degeneration. However, how spinal circuits reorganize during the disease remains poorly understood, particularly in humans. This study examined the function of excitatory and inhibitory spinal interneuron circuits that control upper and lower limb movements, using non-invasive electrophysiological techniques targeting specific afferent-motoneuron pathways at cervical and lumbar levels. These segments are clinically relevant, as spinal-onset forms constitute the predominant clinical presentation of ALS. We compared patients with ALS at different stages of functional impairment to healthy individuals. Spinal circuits predominantly driven by muscle spindle afferents (group Ia and II) showed, at the group level, a marked reduction in inhibition together with enhanced propriospinal excitation. In contrast, pathways mediated by tendon afferents (group Ib) and cutaneous inputs appeared preserved in unstratified analyses. However, when accounting for disease stage, inhibitory dysfunction emerged as an early feature, whereas excitation increased progressively with functional impairment, and modulations also became detectable in Ib- and cutaneous-driven responses. These findings reveal an afferent- and stage-dependent hierarchy of spinal dysfunction, following a reproducible sequence from early disinhibition to maladaptive excitation. This dynamic pattern mirrors the organization observed in preclinical spinal models and aligns with cortical pathophysiology, where widespread loss of inhibition precedes selective increases in excitation. Together, these results refine the mechanistic understanding of motor network disorganization in ALS and identify inhibitory interneurons as potential therapeutic targets to stabilize spinal network function.},
}

*Amyotrophic Lateral Sclerosis/physiopathology
*Interneurons/physiology
Humans
Female
Male
Middle Aged
Aged
*Spinal Cord/physiopathology
Motor Neurons/physiology
*Afferent Pathways/physiopathology
Adult

@article {pmid41535729,
year = {2026},
author = {Tong, SC and Zhang, J and Diao, CJ and Zhao, L and Lu, ZY},
title = {Tuning the Liquid-Liquid Phase Separation of FUS by Phosphorylation: A Role of Domain-Specific Compensation.},
journal = {The journal of physical chemistry. B},
volume = {130},
number = {4},
pages = {1437-1446},
doi = {10.1021/acs.jpcb.5c07950},
pmid = {41535729},
issn = {1520-5207},
mesh = {Phosphorylation ; *RNA-Binding Protein FUS/chemistry/metabolism ; Molecular Dynamics Simulation ; Protein Domains ; Humans ; Biomolecular Condensates/chemistry ; Phase Separation ; },
abstract = {Biomolecular condensates, a type of subcellular or membraneless organelle, form through liquid-liquid phase separation (LLPS) driven by multivalent interactions. As an RNA-binding protein, FUS participates in biological processes by forming dynamic liquid condensates via LLPS, with its abnormal fibrous aggregation associated with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Experiments show that phosphorylation inhibits LLPS of the FUS low-complexity domain (LCD) under low salt conditions, whereas for full-length FUS, phosphorylation does not block initial LLPS but inhibits the conversion of liquid droplets to toxic aggregates. The molecular mechanism underlying the difference between the two remains unknown. In this molecular dynamics simulation study, we examined condensate structural characteristics and compared wild-type (WT) versus phosphorylated condensates, revealing the molecular details of how full-length FUS avoids LLPS impairment through synergistic compensatory regulation among various domains. As for the FUS-LCD system, the extent to which their LLPS is reduced by phosphorylation is associated with the number of phosphorylation sites. Moreover, we have developed a model for analyzing the viscoelasticity of the condensates, which revealed that altered interaction patterns impact condensate viscoelasticity. This study characterizes the postphosphorylation architecture of FUS condensates and elucidates the molecular mechanisms by which phosphorylation regulates condensate formation and properties.},
}

Phosphorylation
*RNA-Binding Protein FUS/chemistry/metabolism
Molecular Dynamics Simulation
Protein Domains
Humans
Biomolecular Condensates/chemistry
Phase Separation

@article {pmid41535829,
year = {2026},
author = {Fang, C and Jin, J and Shi, W and Xu, X and Li, H and Duan, Q and Yu, X and Wu, S and Lu, T and Hu, F and Qin, X and Huang, J and Sun, D and Zhang, M and He, S and Dang, J and He, Q and Zhang, Q and Gan, S},
title = {Accelerated brain aging in amyotrophic lateral sclerosis and its prognostic associations: a cohort study.},
journal = {BMC medicine},
volume = {24},
number = {1},
pages = {86},
pmid = {41535829},
issn = {1741-7015},
support = {2020SF-098//Key Research and Development Projects of Shaanxi Province/ ; 32400880//National Natural Science Foundation of China/ ; 32400926//National Natural Science Foundation of China/ ; 2022JQ-964//Natural Science Basic Research Program of Shaanxi Province/ ; 2408085MC081//Anhui Provincial Natural Science Foundation/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/mortality ; Male ; Female ; Middle Aged ; *Brain/pathology/diagnostic imaging ; Prognosis ; Aged ; *Aging/pathology ; Magnetic Resonance Imaging ; Cohort Studies ; Neuropsychological Tests ; Adult ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, appearing to be associated with accelerated brain aging. Although increased brain age has been associated with mortality risk in older adults, it remains unclear how the brain aging process is accelerated in ALS and how this acceleration relates to patient prognosis.

METHODS: One hundred seventy sporadic ALS patients and 84 age- and sex-matched HCs were recruited and underwent neuropsychological tests and T1-weighted magnetic resonance imaging (MRI) scans. A brain-age prediction model was developed using a 3D-Conformer deep learning framework trained on 4310 healthy T1-weighted MRI data from public datasets. Brain age was predicted in HCs and ALS patients, and then the predicted-age difference (PAD = brain age-chronological age) was calculated. In the ALS cohort, the neuroanatomical association of PAD was examined, and cell-specific gene expression of PAD-related volume loss was analyzed using transcriptomic data from the Allen Human Brain Atlas. Associations between PAD, neuropsychological performance, clinical characteristics, and survival outcomes were further evaluated in ALS patients.

RESULTS: The brain aging process was accelerated in ALS by an average PAD of 1.77 years, which was predominantly associated with a widespread loss of gray matter volume. Cell-specific gene expression analyses showed microglia, inhibitory neurons, endothelial cells, and pericytes as significant contributors to the accelerated brain aging in ALS, with endothelial cells and pericytes being essential for constructing the blood-brain barrier (BBB) and microglia being involved in neuroinflammation. The acceleration in brain aging was more prominent in older patients and was associated with cognitive impairments. Notably, older brain age at initial diagnosis was an independent risk factor for death (hazard ratio, 1.026; 95% CI [1.008, 1.045]) and was associated with shorter survival and more rapid disease progression.

CONCLUSIONS: Accelerated brain aging is common in ALS; this could be hypothesized to be associated with the interplay between BBB breakdown and neuroinflammation, leading to gray matter degeneration. Furthermore, older brain age at initial diagnosis is associated with worse clinical outcomes. These findings suggest that therapeutic strategies targeting neuroinflammation and BBB integrity may help attenuate accelerated brain aging and improve prognosis.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/mortality
Male
Female
Middle Aged
*Brain/pathology/diagnostic imaging
Prognosis
Aged
*Aging/pathology
Magnetic Resonance Imaging
Cohort Studies
Neuropsychological Tests
Adult

@article {pmid41536515,
year = {2026},
author = {Voldřich, R and Svoboda, N and Kachlířová, Z and Bartáková, L and Charvát, F and Netuka, D},
title = {Urodynamic outcomes and prognostic determinants following endovascular treatment of spinal dural arteriovenous fistulas.},
journal = {Brain & spine},
volume = {6},
number = {},
pages = {105913},
pmid = {41536515},
issn = {2772-5294},
abstract = {INTRODUCTION: The prognosis of untreated spinal dural arteriovenous fistulas (SDAVFs) is unfavorable. Current outcome scales used to assess the effect of surgery or endovascular treatment (EVT) rely largely on patient-reported symptoms and may underestimate actual impairment. Moreover, prognostic factors remain debated and conclusions in the literature are inconsistent.

RESEARCH QUESTION: The aim was to quantify urological outcomes after SDAVF embolization using specialized urodynamic testing, compare these objective findings with subjective outcomes derived from traditional scales, and identify prognostic factors associated with unfavorable clinical results.

METHODS: In this single-center retrospective study, all patients underwent EVT as first-line therapy. Clinical status was assessed using Aminoff-Logue scale (ALS), compared with preoperative data, and correlated with angiographic findings. Urodynamic testing was performed to objectively evaluate bladder function.

RESULTS: Twent-four patients met the inclusion criteria. Urodynamic testing was performed in 14 (58 %) patients. The most frequent abnormal finding was bladder hyposensitivity (79 %), followed by pathological post-void residual volume (64 %) and elevated bladder capacity (50 %). Six (43 %) patients reported no subjective urological symptoms (ALS = 0); urodynamic testing revealed two or more pathological parameters in all of them. EVT failure and subsequent surgery predicted gait deterioration (p = 0.011) as well as detrusor overactivity (p = 0.001). Symptom duration over one year (p = 0.038) and fistula location above the T9 level (p = 0.021) were negative prognostic factors for bladder function.

CONCLUSION: The results suggest a potential underestimation of urological impairment when relying on subjective scales and highlight the need for standardized urodynamic testing. They also emphasize the importance of early treatment of SDAVF.},
}

@article {pmid41536906,
year = {2025},
author = {Yang, X and Zheng, J and Wang, X and Cai, H and Yu, J},
title = {Pathogenic mechanisms of amyotrophic lateral sclerosis-linked VAPB P56S mutation in the degeneration of corticospinal motor neurons.},
journal = {Ageing and neurodegenerative diseases},
volume = {5},
number = {3},
pages = {},
pmid = {41536906},
issn = {2769-5301},
support = {Z01 AG000959/ImNIH/Intramural NIH HHS/United States ; ZIA AG000946/ImNIH/Intramural NIH HHS/United States ; },
abstract = {AIM: The endoplasmic reticulum (ER)-localized vesicle-associated membrane protein-associated protein B (VAPB) is implicated in many cellular processes, such as ER-organelle tethering, calcium homeostasis, and unfolded protein response. The P56S missense mutation in VAPB has been associated with familial forms of motor neuron diseases such as typical amyotrophic lateral sclerosis (ALS), atypical ALS, and spinal muscular atrophy. However, it has not been determined how the VAPB P56S mutation induces the degeneration of corticospinal motor neurons (CSMNs) in ALS.

METHODS: Using homozygous knock-in (KI) mice expressing P56S VAPB, we investigated the mutation's pathogenic impacts and underlying mechanisms on the survival and function of CSMNs. We performed a wide variety of assays to examine the behavioral, histological, cellular, and molecular abnormalities of KI mice.

RESULTS: Compared with wild-type controls, KI mice showed the downregulated protein level of mutant VAPB, proteinase K-resistant cytoplasmic inclusions of mutant VAPB in CSMNs, abnormal hyperactivity, impaired motor coordination, neuronal loss of CSMNs, and axonal degeneration of pyramidal and corticospinal tracts. Mechanistic studies revealed that the VAPB P56S mutation rendered the mutant protein destabilized and inclusion-prone in cortical neurons, and the proteasomal degradation played a critical role in modulating mutant VAPB's protein level and inclusion formation. In addition, the VAPB P56S mutation disrupted ER-mitochondria contacts, impaired VAPB-PTPIP51 interaction and IP3R-VDAC interaction, elevated cytosolic Ca[2+], activated CaMKII, and increased CRMP2 phosphorylation. Moreover, the VAPB P56S mutation activated the IRE1-XBP1/p38 mitogen-activated protein kinase (MAPK)/ c-Jun N-terminal kinase (JNK) pathway, increased tau hyperphosphorylation, and upregulated p53 expression and phosphorylation.

CONCLUSION: These findings demonstrate the progressive degeneration of CSMNs induced by VAPB P56S mutation and indicate the involvement of the Ca[2+]-CaMKII-CRMP2 and IRE1-p38 MAPK/JNK-tau/p53 pathways in the pathogenic process.},
}

@article {pmid41538404,
year = {2026},
author = {Zhao, Y and Liu, Y and Yuan, B and Yu, W and Li, T and Zhang, J and Ye, F and Fu, Y},
title = {Pharmacophore Reorganization-Based Design, Synthesis, and Safener Activity of Novel Isoxazole-Piperazinone Derivatives.},
journal = {Journal of agricultural and food chemistry},
volume = {74},
number = {3},
pages = {2737-2748},
doi = {10.1021/acs.jafc.5c15324},
pmid = {41538404},
issn = {1520-5118},
mesh = {*Herbicides/chemistry/pharmacology/chemical synthesis ; Acetolactate Synthase/antagonists & inhibitors/chemistry/metabolism ; Oryza/drug effects/growth & development/enzymology ; Drug Design ; *Isoxazoles/chemistry/pharmacology ; *Piperazines/chemistry/pharmacology/chemical synthesis ; Plant Proteins/chemistry/metabolism/antagonists & inhibitors/genetics ; Structure-Activity Relationship ; Molecular Structure ; Plant Weeds/drug effects/enzymology/growth & development ; Molecular Docking Simulation ; Sulfonylurea Compounds/chemistry ; Enzyme Inhibitors/chemistry/pharmacology/chemical synthesis ; Pharmacophore ; },
abstract = {Bensulfuron, an acetolactate synthase (ALS)-inhibiting herbicide, is widely used in rice cultivation for the effective control of sedge and broadleaf weeds. However, japonica varieties are highly sensitive to this herbicide and can develop phytotoxicity when it is improperly applied. Herbicide safeners enhance crop tolerance to herbicides without reducing their weed control efficacy, offering a significant strategy for the safe use of herbicides. To alleviate bensulfuron-induced phytotoxicity in rice, a series of novel isoxazole-piperazinone derivatives were designed through pharmacophore recombination. The structures of the target compounds were confirmed by infrared spectroscopy, [1]H and [13]C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. The spatial configuration of compound II-1 was further determined by single-crystal X-ray diffraction. Bioactivity assays demonstrated that most target compounds effectively reduced bensulfuron-induced phytotoxicity in rice. Evaluation of key physiological parameters, including plant growth indices, ALS enzyme activity, and detoxification enzyme activity, revealed that compounds II-10 and II-40 exhibited superior safener activity compared to isoxadifen-ethyl. Molecular structure analysis and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions indicated that compound II-10 possesses good pharmacokinetic properties comparable to those of isoxadifen-ethyl. Molecular docking analysis revealed that compound II-10 exerts its protective effect by competitively binding to the ALS active site with bensulfuron. Furthermore, ecological risk predictions suggested that compound II-10 poses low or negligible toxicity risks to nontarget organisms such as mammals, birds, and algae. Overall, these results highlight compound II-10 as a promising structure for the development of novel herbicide safeners.},
}

*Herbicides/chemistry/pharmacology/chemical synthesis
Acetolactate Synthase/antagonists & inhibitors/chemistry/metabolism
Oryza/drug effects/growth & development/enzymology
Drug Design
*Isoxazoles/chemistry/pharmacology
*Piperazines/chemistry/pharmacology/chemical synthesis
Plant Proteins/chemistry/metabolism/antagonists & inhibitors/genetics
Structure-Activity Relationship
Molecular Structure
Plant Weeds/drug effects/enzymology/growth & development
Molecular Docking Simulation
Sulfonylurea Compounds/chemistry
Enzyme Inhibitors/chemistry/pharmacology/chemical synthesis
Pharmacophore

@article {pmid41538578,
year = {2026},
author = {Khan, M and Saeed, U and Piracha, ZZ and Ozsahin, I and Shao-Chun, C},
title = {Innovative public-health strategies for neurodegenerative disease: leveraging diversified ultraviolet irradiation as a next-generation therapy.},
journal = {Brazilian journal of biology = Revista brasleira de biologia},
volume = {85},
number = {},
pages = {e297765},
doi = {10.1590/1519-6984.297765},
pmid = {41538578},
issn = {1678-4375},
mesh = {Humans ; *Neurodegenerative Diseases/radiotherapy/therapy ; *Ultraviolet Therapy/methods ; *Ultraviolet Rays ; *Public Health ; Oxidative Stress/radiation effects ; },
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis are escalating worldwide, straining healthcare systems and leaving patients with therapies that are largely palliative. Emerging evidence positions diversified ultraviolet (UV) irradiation as a groundbreaking, non-invasive strategy to counter these disorders. Beyond its traditional use in sterilization, specific UV spectra, UV-B (280-320 nm), UV-C (200-280 nm), and far-UV (207-222 nm), are now recognized for modulating oxidative stress, restoring mitochondrial function, correcting apoptotic dysregulation, and enhancing DNA repair. Innovative approaches such as riboflavin-mediated phototherapy and photobiomodulation (PBM) show the capacity to disaggregate toxic protein aggregates like β-amyloid and α-synuclein, boost antioxidant defenses, stimulate neurotrophic factors, and quell neuroinflammation. Preclinical models and early clinical trials reveal preserved cognition, enhanced neurogenesis, and reduced disease biomarkers, suggesting real translational promise. From a public-health perspective, UV-based interventions offer a cost-effective, scalable option for aging populations and resource-limited settings, especially when integrated with community-level health technologies and remote delivery platforms. Continued investigation of optimal dosing, long-term safety, and mechanistic pathways will be pivotal to unlock the full therapeutic and population-wide impact of this novel modality.},
}

Humans
*Neurodegenerative Diseases/radiotherapy/therapy
*Ultraviolet Therapy/methods
*Ultraviolet Rays
*Public Health
Oxidative Stress/radiation effects

@article {pmid41539219,
year = {2026},
author = {Gawronski, B and Rokosz, M and Stefanczyk, MM and Białek, M},
title = {Many heads are more utilitarian than one, but are they also less deontological? Reply to Baron and Skovgaard-Olsen (2026).},
journal = {Cognition},
volume = {271},
number = {},
pages = {106441},
doi = {10.1016/j.cognition.2026.106441},
pmid = {41539219},
issn = {1873-7838},
mesh = {Humans ; *Morals ; *Judgment ; *Ethical Theory ; },
abstract = {Using the CNI model to quantify three factors underlying moral-dilemma judgments, Rokosz et al. (2025) found that groups show greater concerns about outcomes than individuals, but do not differ in terms of norm adherence and general action tendencies. In a commentary on this work, Baron and Skovgaard-Olsen (2026) argue that (a) groups show less "nonsensical" judgments and (b) analyses controlling for this difference reveal that groups additionally show weaker concerns about moral norms. The current reply identifies conceptual and empirical problems with Baron and Skovgaard-Olsen's (2026) arguments. Expanding on this discussion, we present an alternative reanalysis of Rokosz et al.'s (2025) data to gauge the robustness of their findings against model specifications. Our reanalysis revealed (a) robust evidence that groups are more concerned about outcomes than individuals and (b) some evidence for differential concerns about moral norms, but this evidence is less reliable in that it depends on data-analytic choices.},
}

Humans
*Morals
*Judgment
*Ethical Theory

@article {pmid41540277,
year = {2026},
author = {Hutchinson, DR and Little, DR and Osth, AF},
title = {Recency is sufficient for reconciling categorisation and memory: Commentary on Devraj et al. (2024).},
journal = {Psychonomic bulletin & review},
volume = {33},
number = {1},
pages = {48},
pmid = {41540277},
issn = {1531-5320},
mesh = {Humans ; *Memory/physiology ; *Mental Recall/physiology ; },
abstract = {Devraj et al. (Psychonomic Bulletin and Review. https://doi.org/10.3758/s13423-023-02448-2 , 2024) argued that findings which suggest that memories for items become less accessible over time conflict with categorisation findings where exemplar performance improves across training. To reconcile this, they highlighted that under real-world conditions items tend to reappear less frequently over time, thus preferentially maintaining new items can improve performance. Typical categorisation experiments instead distribute exemplars uniformly across trials. However, under a power-law stimulus distribution, Devraj et al. showed worsening fit for exemplar classification models across trials. They used this as evidence that forgetting behaviour adapted to task demands, reducing exemplar accessibility and encouraging prototype use for classification decisions. By re-analysing the same data, we argue instead that this pattern can be produced with exemplar-forgetting in both conditions. By systematically increasing in the delays across which stimuli were tested, their Experimental condition exaggerated the effects of forgetting on performance in later trials compared to the Control condition. This resulted in a reversal of performance growth across trials - instead leading to a steady decline in performance. As exemplar model-fit advantage is expected to vary with performance, we suggest that trends in this advantage are not diagnostic of a shift in classification strategy. We found that a forgetting-function improved exemplar model fit to Devraj et al.'s data, and under reasonable parameters could predict the observed patterns of performance and model-fit a priori. Compared with a strategy-shifting mixture model, exemplar-forgetting provided equivalent fits despite being more theoretically parsimonious. We suggest power-law memory decay does not produce a tension between categorisation and memory findings, as increased forgetting is found across longer retention intervals, whereas the delay between exemplar learning and classification remains constant across typical categorisation experiments.},
}

Humans
*Memory/physiology
*Mental Recall/physiology

@article {pmid41540870,
year = {2026},
author = {Ghika, N and Accolla, E and Girardin, F and Theaudin, M},
title = {[Pharmacotherapy of neuromuscular diseases : what's new in 2025].},
journal = {Revue medicale suisse},
volume = {22},
number = {945},
pages = {66-70},
doi = {10.53738/REVMED.2026.22.945.48049},
pmid = {41540870},
issn = {1660-9379},
mesh = {Humans ; *Neuromuscular Diseases/drug therapy ; Oligonucleotides, Antisense/therapeutic use/pharmacology ; *Oligonucleotides/therapeutic use/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Switzerland ; Friedreich Ataxia/drug therapy ; Oxidative Stress/drug effects ; Superoxide Dismutase-1/genetics ; },
abstract = {Two new drugs have recently become available for treating neuromuscular diseases: omaveloxolone and tofersen. Omaveloxone, which is available in Switzerland, mitigates mitochondrial oxidative stress and has been shown to slow the clinical progression of Friedreich's ataxia. Tofersen is an antisense oligonucleotide that induces posttranscriptional silencing of the SOD1 (superoxide dismutase 1) gene, which is involved in familial forms of amyotrophic lateral sclerosis. Although its efficacy has so far only been indirectly demonstrated through its ability to reduce serum neurofilament levels, it is available on a compassionate use basis in Switzerland.},
}

Humans
*Neuromuscular Diseases/drug therapy
Oligonucleotides, Antisense/therapeutic use/pharmacology
*Oligonucleotides/therapeutic use/pharmacology
Amyotrophic Lateral Sclerosis/drug therapy/genetics
Switzerland
Friedreich Ataxia/drug therapy
Oxidative Stress/drug effects
Superoxide Dismutase-1/genetics

@article {pmid41542389,
year = {2026},
author = {Bolger, I and Shaw, R and Tam, OH and Roque, CG and Jackson, CA and O'Neill, K and , and Smith, C and Phatnani, H and Natarajan, K and Hammell, MG},
title = {TDP-43 dysfunction leads to the accumulation of cryptic transposable element-derived exons, crypTEs, in iPSC derived neurons and ALS/FTD patient tissues.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41542389},
issn = {2692-8205},
support = {P30 CA016087/CA/NCI NIH HHS/United States ; R01 NS118570/NS/NINDS NIH HHS/United States ; },
abstract = {TDP-43 is an RNA and DNA binding protein that plays major roles in regulating RNA processing. In particular, TDP-43 dysfunction leads to the accumulation of cryptic splice isoforms that result from improperly spliced mRNAs. In addition to its role in regulating splicing, TDP-43 is also known to regulate the expression of transposable elements (TEs). TEs are mobile genetic elements which comprise a significant proportion of the human genome, but are normally silenced in healthy somatic cells. TEs are interspersed throughout the genome, both in gene-depleted regions and within gene introns and gene regulatory sequences. We used optimized long-read RNA sequencing assays to generate catalogs of mis-spliced and mis-expressed genes and TEs in human neurons depleted for TDP-43. In addition to known TDP-43 driven cryptic isoforms, we identified hundreds of TDP-43 dependent spliced RNAs that form cryptic gene-TE fusion events as a result of mis-splicing of TE sequences into gene transcripts. Among these TDP-43 dependent cryptic gene-TE transcripts (crypTEs), we found: TEs that provide alternate gene promoters/5'UTRs, TEs that act as cassette exons inside host gene mRNAs, as well as TEs that provide alternate transcript 3' ends. These cryptic gene-TE fusions are predicted to induce aberrant expression of ALS relevant genes, nonsense mediated decay (NMD) products, as well as novel peptides from gene-TE fusions within the gene coding sequence. Using coupled long-read RNA (Iso-seq) and single-nucleus (snRNA-seq) profiles from postmortem ALS tissues, we further verified that many of these crypTE transcripts are enriched in frontal cortex samples from ALS donors with cognitive involvement (ALSci) and associated with altered expression of those genes in deep layer cortical excitatory neurons. In short, TDP-43 dependent crypTEs greatly expand the catalogs of TDP-43 dependent cryptic splice isoforms and represent a novel mechanism by which TE dysregulation impacts ALS.},
}

@article {pmid41542616,
year = {2026},
author = {Cheng, T and Tripathi, S and Guo, Y and Vedula, P and Li, R and Potanin, M and Soley, N and Yan, AY and Vatsaraj, I and Harris, C and Greenstein, JL and Taylor, CO and Coyne, AN and Rothstein, JD},
title = {Identification of molecular and clinical ALS subgroups based on TDP-43 loss of function molecular markers from population-based patient-derived iPS motor neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41542616},
issn = {2692-8205},
support = {R01 NS122236/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disease characterized by progressive cortical and spinal motor neuron loss, with most patients surviving only 2-5 years post-diagnosis. While approximately 10% of cases are familial (fALS), the remaining 90% are sporadic (sALS) with unknown genetic drivers. Importantly, clinical presentations are heterogeneous in both sporadic and familial ALS, underscoring the complexity of the disease. A pathological hallmark of ALS is the mislocalization of RNA-binding protein TDP-43 from the nucleus to the cytoplasm. This mislocalization produces both loss of function consequences, such as widespread RNA processing and splicing defects, as well as potential toxic gain of function effects associated with cytoplasmic aggregation.

RESULTS: In this study, we used RT-PCR data from induced pluripotent stem cell-derived motor neurons derived from 180 sALS and C9orf72 fALS patients from the Answer ALS collection to identify biological subgroups based on TDP-43 loss-of-function signatures. Spectral embedding revealed four distinct molecular clusters, including one subgroup genetically similar to controls and another with the most dysregulated mRNA expression, suggesting differing disease severity. Linear mixed models were then used to assess the longitudinal trajectory of over 90 clinical measures, and the between-cluster interaction effects were evaluated.

CONCLUSIONS: 36 clinical outcomes showed significant differences across clusters, supporting the presence of biologically and clinically distinct ALS subtypes based on the TDP-43 associated pathogenic cascade. These findings demonstrate a critical role of RNA profiling in uncovering biologically meaningful subtypes of ALS, potentially allowing for more precise prognostic tools and the development of future personalized therapeutic approaches.},
}

@article {pmid41543999,
year = {2026},
author = {Robinson, GA and Phillips, MR and Horne, K and Ceslis, A and McCombe, PA and Henderson, RD},
title = {Assessment of language and executive functions in ALS: the brief executive Language screen.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2025.2607398},
pmid = {41543999},
issn = {2167-9223},
abstract = {Objective: Language and executive functioning are two domains commonly impacted in ALS and should be assessed sensitively and briefly. This paper investigates the utility of the Brief Executive Language Screen (BELS) in ALS. Methods: ALS patients (N = 27) were compared to age, education, and pre-morbid intelligence-matched healthy controls (N = 91) at the group level using ANCOVA and t-tests. A case series was also conducted to explore individual and subgroup performance on the BELS and Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Results: Groups were largely matched on neuropsychology baseline measures. The ALS group performed significantly worse on BELS Propositional Language and Executive Function subtests, and on overall BELS scores. Group results suggest setting a goal can increase phonemic fluency and spontaneous speech output, after controlling for motor speed. The case series revealed almost half of patients (across all subgroups) were impaired on the BELS, compared to 15% impaired on the ECAS (patients on the more severe end of the ALS-FTD spectrum). Conclusions: The BELS rapidly assesses language and executive functions, and provides valuable information for management of cognitive difficulties (i.e., goal setting), which can help improve or maintain conversational speech. The BELS may help to identify subtle impairments that may otherwise go undetected.},
}

@article {pmid41545051,
year = {2026},
author = {Trad, G and Lenglet, T and Ledoux, I and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF},
title = {Safety and efficacy of the Atalante exoskeleton in the rehabilitation of French patients with amyotrophic lateral sclerosis: a prospective, monocentric, open, uncontrolled, interventional protocol, EXALS.},
journal = {BMJ open},
volume = {16},
number = {1},
pages = {e109620},
pmid = {41545051},
issn = {2044-6055},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; Prospective Studies ; *Exoskeleton Device ; France ; Quality of Life ; Female ; Male ; Middle Aged ; Walking ; Gait ; *Exercise Therapy/methods/instrumentation ; Aged ; Muscle Strength ; Adult ; Postural Balance ; *Gait Disorders, Neurologic/rehabilitation/etiology ; Treatment Outcome ; },
abstract = {INTRODUCTION: Robotic rehabilitation on locomotion is a new approach in amyotrophic lateral sclerosis (ALS) and previous studies showed its feasibility. In this study, we aim to evaluate safety, patient's experience and efficacy of a gait training programme with the Atalante exoskeleton, compared with usual care, on walking ability, functional capacity and other symptoms associated with ALS.

METHODS AND ANALYSIS: EXALS is a monocentric, prospective, interventional, open trial. 20 slowly progressing patients with gait deficits will be recruited. The study is conducted in three phases, each lasting 6 weeks, following the ABA procedure. Phase B represents the intervention phase, during which patients practise their gait training at a rhythm of three sessions/week, as an add-on to usual care. In the two phases A, patients receive usual care with no additional treatment. An evaluation is planned before, in the middle and at the end of each phase. The primary outcome of the study is safety and tolerability of the Atalante exoskeleton. Secondary outcomes include: participants' subjective impact and experience, attitude and motivation, efficacy and interactivity of the exoskeleton, walking ability, functional capacity, spasticity, balance, postural stability, lower limb muscle strength, quality of life, pain, fatigue, anxiety and depression. Statistical analyses will include descriptive methods for all variables and adverse events. Quantitative outcomes are analysed using repeated-measures ANOVA (analysis of variance) across the seven visits, with post hoc tests applied when appropriate. Nominal outcomes are evaluated using Cochran's Q test with McNemar pairwise comparisons when significant. Associations between variables are examined using Spearman correlation coefficients. Missing data will be replaced using linear interpolation, and sensitivity analyses will be planned. Qualitative interview data are analysed using thematic analysis.

ETHICS AND DISSEMINATION: This study was approved by the French ethics committee CPP Nord-Ouest I (no. 23.02378.000201). Participant data are anonymised and securely stored in the laboratory's database, accessible only to the research team. Results will be disseminated through peer-reviewed journals and conferences.NCT06199284.},
}

Humans
*Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology
Prospective Studies
*Exoskeleton Device
France
Quality of Life
Female
Male
Middle Aged
Walking
Gait
*Exercise Therapy/methods/instrumentation
Aged
Muscle Strength
Adult
Postural Balance
*Gait Disorders, Neurologic/rehabilitation/etiology
Treatment Outcome

@article {pmid41545763,
year = {2026},
author = {Schmidt, T and Wolkersdorfer, MP and Lee, XY and Jubran, O},
title = {Unconscious cognition without post hoc selection artifacts: From selective analysis to functional dissociations.},
journal = {Behavior research methods},
volume = {58},
number = {2},
pages = {39},
pmid = {41545763},
issn = {1554-3528},
mesh = {Humans ; *Unconscious, Psychology ; *Cognition ; Artifacts ; Signal Detection, Psychological ; },
abstract = {One of the most popular approaches to unconscious cognition is the technique of "post hoc selection": Priming effects and visibility ratings are measured in multitasks on the same trial, and only trials with the lowest visibility ratings are selected for analysis of (presumably unconscious) priming effects. In the past, the technique has been criticized for creating statistical artifacts and capitalizing on chance. Here, we argue that post hoc selection constitutes a sampling fallacy, confusing sensitivity and response bias, wrongly ascribing unconscious processing to stimulus conditions that may be far from indiscriminable. In response to a high-profile "best practice" paper by Stockart et al. (2025) that condones the technique, we use standard signal detection theory to show that post hoc selection only isolates trials with neutral response bias, irrespective of actual sensitivity, and thus fails to isolate trials where the critical stimulus is "unconscious". Our own data demonstrate that zero-visibility ratings are consistent with uncomfortably high levels of sensitivity. As an alternative to post hoc selection, we advocate the study of functional dissociations, where direct (D) and indirect (I) measures are conceptualized as spanning a two-dimensional D-I space wherein simple, sensitivity, and double dissociations appear as distinct curve patterns. While Stockart et al.'s recommendations cover only a single line of that space where D is close to zero, functional dissociations can utilize the entire space. This circumvents requirements like null visibility and exhaustive reliability, allows for dissociations among different measures of awareness, and supports the planful measurement of functional relationships between direct and indirect measures.},
}

Humans
*Unconscious, Psychology
*Cognition
Artifacts
Signal Detection, Psychological

@article {pmid41545942,
year = {2026},
author = {Sun, W and Luan, H and Li, S and Wang, P and Gong, J and Xu, C and Han, X and Wen, B and Lv, S and Wei, C},
title = {Circulating adipokines level and the risk of neurodegenerative diseases: a two‑sample mendelian randomization study and proteomic analysis.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {90},
pmid = {41545942},
issn = {1471-2377},
support = {2017YFC1310103//the National Key Research and Development Program of China/ ; 2021ZD0201802//the STI2030-Major Projects/ ; },
abstract = {BACKGROUND: Observational studies have suggested associations between circulating adipokines and neurodegenerative diseases, but the causal nature of these relationships remains unclear. This study evaluated the causal effects of adipokines on neurodegenerative diseases using Mendelian randomization (MR) and validated key findings through proteomic analysis.

METHODS: Two-sample MR was performed using genome-wide association study (GWAS) summary statistics for adiponectin (N = 39,883), leptin (N = 57,232), resistin (N = 21,758), and monocyte chemoattractant protein-1 (MCP-1; N = 21,758). Outcomes included Alzheimer’s disease (AD; N = 63,926), Parkinson’s disease (PD; N = 482,730), and amyotrophic lateral sclerosis (ALS; N = 36,052). The inverse-variance weighted (IVW) method was applied for primary causal estimates, with sensitivity analyses assessing pleiotropy and heterogeneity. Significant MR findings were further examined in a proteomic cohort.

RESULTS: Higher genetically predicted adiponectin levels were significantly associated with a reduced risk of AD (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.65–0.96, p = 0.019). This association remained robust across multiple sensitivity analyses, with no evidence of horizontal pleiotropy or heterogeneity. By contrast, no causal relationships were identified for leptin, resistin, or MCP-1 with the risk of AD, PD, or ALS. Complementing the genetic findings, proteomic analysis further revealed that plasma adiponectin levels were downregulated in mild cognitive impairment patients who experienced cognitive deterioration compared with those showing cognitive improvement.

CONCLUSION: The findings provide genetic evidence supporting a potential protective role of adiponectin in AD, with the proteomic results offering complementary, directionally consistent support. Adiponectin may represent a potential biomarker and therapeutic target for AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-026-04636-8.},
}

@article {pmid41546073,
year = {2026},
author = {Dewan, MF and Rayani, AM and Hannan, J},
title = {Improving nursing students' clinical experience with genetics: the influence of prior knowledge and leadership support through the Donabedian Model.},
journal = {BMC nursing},
volume = {25},
number = {1},
pages = {},
pmid = {41546073},
issn = {1472-6955},
abstract = {BACKGROUND: As advancements in genetics and genomics continue to evolve, nursing students need to be equipped with prior knowledge and academic leadership support (ALS) to interpret genetic information, educate patients, and participate in clinical decision-making. ALS is actions or behaviors by leaders to support, guide, and empower their students. The incorporation of genetics/genomics into the nursing curriculum has been recognized on a global scale.

AIM: To evaluate the impact of nursing students’ prior knowledge of genetics/Genomics and genomics and academic leadership support on their clinical experience.

METHOD AND DESIGN: A cross-sectional study was conducted among nursing students at xxxxx University College of Nursing, Saudi Arabia, between December 2024 and February 2025 (IRB# KSU-HE-24-1055). A total of 169 participants completed an online survey.

RESULTS: Most participants were in their fourth year, internship year, or enrolled in postgraduate programs (BSN = 118; Master’s = 46; PhD = 3). The average age was 26.6 years (SD = 5.8), and more participants were female (58.5%) than male (41.5%). Male participants reported receiving higher levels of leadership support than their female counterparts did. ALS on clinical experience (p < 0.01); and prior knowledge (p < 0.008); R[2] = 0.440 with large effect size = 0.78.

CONCLUSIONS: Integrating genetics and genomics education into the nursing curriculum is needed to meet today’s healthcare standards. Academic nursing leaders in educational settings play a key role in advancing nursing students’ curriculum thereby increasing their knowledge and preparedness for clinical practice.

Educational settings that integrate nursing genetics and genomics courses into curricula and provide leadership support to students will improve their clinical experience and enhance patients’ care.

IMPACT: What problem did the study address? ALS is a key driver of improving students’ clinical experience. What were the main findings? Male nursing students reported higher levels of leadership support than female nursing students highlighting the need for strategies that support equity and prevent disparities in educational settings on the basis of gender. Who will benefit? Nurse educators and nurse leaders could utilize these findings to improve educational environments. Nurses with up-to-date knowledge will benefit their patients’ outcomes by being better informed.

REPORTING METHOD: We adhered to the STROBE guidelines for cross-sectional research.},
}

@article {pmid41546756,
year = {2026},
author = {White, MA and Crowley, L and Massenzio, F and Li, X and Niblock, M and Milani, S and Coleman, MP and Barmada, SJ and Sreedharan, J},
title = {Inhibiting Glycogen Synthase Kinase 3 Suppresses TDP-43-Mediated Neurotoxicity in a Caspase-Dependent Manner.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {370},
pmid = {41546756},
issn = {1559-1182},
mesh = {Animals ; Humans ; *DNA-Binding Proteins/metabolism/toxicity ; *Glycogen Synthase Kinase 3/antagonists & inhibitors/metabolism ; *Caspases/metabolism ; Mice ; Neurons/drug effects/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Phosphorylation/drug effects ; Amyotrophic Lateral Sclerosis ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by TAR DNA-binding protein 43 kDa (TDP-43) pathology. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. We show that TDP-43 activates GSK3 and promotes caspase-dependent cleavage of TDP-43, generating C-terminal fragments. We determine the functional importance of the N-terminal Asp89 caspase cleavage site in regulating TDP-43 proteostasis in both wild-type and ALS-linked TDP-43 variants and show that GSK3 inhibition selectively reduces truncated TDP-43 species, lowers nuclear TDP-43 levels, and improves neuronal survival. Neuroprotective effects were conserved in primary rodent cortical neurons, primary mouse motor neurons, and human iPSC-derived cortical neurons, highlighting the potentially broad therapeutic potential of GSK3 inhibition. We also find that the GSK3 inhibitor CHIR99021 reduces GSK3 RNA and protein expression and increases GSK3 phosphorylation, indicating novel mechanisms by which it acts to inhibit GSK3 activity. Unexpectedly, an N-terminally truncated variant (TDP-43[N-Del]), originally designed as a negative transfection control, exerted modest toxicity, potentially through retained susceptibility to caspase cleavage. Together, our findings uncover a caspase-mediated mechanism linking GSK3 activity to TDP-43 turnover, localisation, and neurotoxicity, and position GSK3 inhibition as a promising strategy to mitigate TDP-43-driven neurodegeneration in ALS-FTD.},
}

Animals
Humans
*DNA-Binding Proteins/metabolism/toxicity
*Glycogen Synthase Kinase 3/antagonists & inhibitors/metabolism
*Caspases/metabolism
Mice
Neurons/drug effects/metabolism
Motor Neurons/drug effects/metabolism/pathology
Induced Pluripotent Stem Cells/metabolism/drug effects
Phosphorylation/drug effects
Amyotrophic Lateral Sclerosis

@article {pmid41546910,
year = {2026},
author = {Elyasi, L and Wężyk, M},
title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {119001},
doi = {10.1016/j.biopha.2026.119001},
pmid = {41546910},
issn = {1950-6007},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics/metabolism ; *Tooth, Deciduous/cytology/metabolism ; *Exosomes/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; Animals ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; },
abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.},
}

Humans
*Neurodegenerative Diseases/therapy/genetics/metabolism
*Tooth, Deciduous/cytology/metabolism
*Exosomes/metabolism/genetics
*MicroRNAs/metabolism/genetics
Animals
*Stem Cells/metabolism
*Stem Cell Transplantation/methods

@article {pmid41547243,
year = {2026},
author = {Dorothy Wong, ZY and Kang, X and Shi, Y and Fan, R and Zhang, C and Min, D and Sun, N and Ma, Y and Tang, ML},
title = {Autophagy-tethering compounds (ATTECs) as an emerging and potentially transformative drug discovery approach.},
journal = {European journal of medicinal chemistry},
volume = {305},
number = {},
pages = {118585},
doi = {10.1016/j.ejmech.2026.118585},
pmid = {41547243},
issn = {1768-3254},
mesh = {Humans ; *Autophagy/drug effects ; *Drug Discovery ; Lysosomes/metabolism/drug effects ; Proteolysis/drug effects ; Molecular Structure ; Animals ; },
abstract = {Targeted protein degradation (TPD) strategies leveraging the ubiquitin-proteasome system (UPS), such as proteolysis-targeting chimeras (PROTACs), have gained wide recognition. While the UPS predominantly degrades short-lived soluble proteins, the lysosome-mediated system (LMS) excels at processing larger substrates, including protein aggregates, organelles, and macromolecular complexes. Recently, autophagy-tethering compounds (ATTECs) have emerged as a promising strategy for targeted degradation, harnessing the autophagy-lysosome system (ALS) to enable proximity-induced degradation. These heterobifunctional molecules, composed of LC3-binding warheads and TOI (target of interest) ligands linked together, provide therapeutic potential against disease-causing targets. This review outlines the therapeutic applications of ATTECs in human diseases, highlights recent progress in their development, and explores future opportunities for expanding this emerging class of degradation technologies through ALS from medicinal chemistry perspective.},
}

Humans
*Autophagy/drug effects
*Drug Discovery
Lysosomes/metabolism/drug effects
Proteolysis/drug effects
Molecular Structure
Animals

@article {pmid41547996,
year = {2026},
author = {Iacono, D and Murphy, EK and Perl, DP and Day, RM},
title = {γ-Radiation induces region-specific subcellular alterations of amyotrophic lateral sclerosis and frontotemporal dementia markers in swine brain.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {5627},
pmid = {41547996},
issn = {2045-2322},
support = {312516-1.00-66721//DoW/USU Brain Tissue Repository and Neuropathology Research Program/ ; DM178018//US Defense Medical Research and Development Program/ ; },
mesh = {Animals ; Swine ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/etiology ; *Brain/metabolism/radiation effects/pathology ; Male ; *Gamma Rays/adverse effects ; Biomarkers/metabolism ; *Frontotemporal Dementia/metabolism/pathology/etiology ; Swine, Miniature ; },
abstract = {Low-dose radiation (LDR) effects on the brain have been poorly investigated. Studies have also questioned whether radiation increases ALS risk. We assessed the expression levels of a series of proteins associated with ALS and ALS-FTD in the brains of swine exposed to low-dose radiation to explore this notion. Male Gottingen minipigs were exposed to a single total-body γ-radiation (1.79 Gy). After 28 days, brains from 9 RAD to 6 SH animals were collected. Using neuroanatomically based dissection and Western Blotting, we compared levels of ALS/ALS-FTD markers (SOD1, FUS/TLS, C9orf72, STMN2, ubiquitin, TDP43 (N and C terminal), and pTDP43) in RAD vs. SH animals in frontal cortex (FCtx), striatum (Str), hippocampus (Hip), thalamus/hypothalamus (Thal/Hyp), and cerebellum (Cere). Cytosolic FUS/TLS decreased in the Thal/Hyp and remained unchanged in all other regions; nuclear levels increased in the FCtx and decreased in the Hip of RAD vs. SH. Cytosolic C9orf72 remained unchanged across all brain regions; nuclear levels decreased in the Hip of RAD vs. SH. Cytosolic STMN2 remained unchanged in all brain regions and decreased in the nuclear fraction of the Hip of RAD vs. SH. Cytosolic and nuclear ubiquitin remained unchanged across brain regions, except for an increase in the FCtx. TDP-43 (N and C terminal) levels remained unchanged in cytosolic and nuclear fractions across all brain regions; finally, cytosolic pTDP43 (S403/404) increased in the FCtx, Str and Thal/Hyp of RAD vs. SH. LDR-induced ALS/ALS-FTD-marker changes differ across brain regions and subcellular compartments. These changes are not necessarily associated with increased activation or potentiation of the main molecular processes associated with ALS pathogenesis; surprisingly, they may produce beneficial effects.},
}

Animals
Swine
*Amyotrophic Lateral Sclerosis/metabolism/pathology/etiology
*Brain/metabolism/radiation effects/pathology
Male
*Gamma Rays/adverse effects
Biomarkers/metabolism
*Frontotemporal Dementia/metabolism/pathology/etiology
Swine, Miniature

@article {pmid41548000,
year = {2026},
author = {Potla, KM and Cheerlin Mishma, JN and Vankayalapati, S and Suchetan, PA and Sebastian, R and Gayatri, B and Tawfeek, AM and Alam, M and Islam, MS},
title = {Comprehensive analysis of florasulam: crystal structure, reactivity, sensitivity, and bioactivity using structural, spectroscopic, and computational approaches.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {3416},
pmid = {41548000},
issn = {2045-2322},
abstract = {UNLABELLED: The title compound, N-(2,6-difluorophenyl)-8-fluoro-5-methoxy-[1,2,4]triazolo[1,5-c]pyrimidine-2-sulfonamide (Florasulam), a triazolopyrimidine sulfonanilide herbicide, was investigated using experimental and computational techniques. Single-crystal X-ray diffraction revealed a V-shaped geometry stabilized by intramolecular C–F···π interactions and a unique 1D ribbon packing formed through N–H···N, C–H···O, and S = O···π interactions. Hirshfeld surface and energy framework analyses confirmed the nature and strength of intermolecular forces. DFT and TD-DFT calculations provided insights into optimized geometry, vibrational frequencies, and electronic transitions consistent with experimental spectra. The HOMO–LUMO gap indicated high chemical stability, while MEP analysis highlighted reactive sites. Autoxidation susceptibility was assessed through bond dissociation energies. Molecular docking against ALS (Acetolactate Synthase) proteins demonstrated strong binding affinity, supported by molecular dynamics simulations confirming protein–ligand complex stability. This integrative study highlights Florasulam’s potential in herbicide design.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-33458-w.},
}

@article {pmid41548100,
year = {2026},
author = {Colgrove, N and Snyder, M},
title = {Abortion and Infant Mortality: Termination Does Not Prevent Death.},
journal = {The New bioethics : a multidisciplinary journal of biotechnology and the body},
volume = {32},
number = {1},
pages = {1-13},
doi = {10.1080/20502877.2025.2589634},
pmid = {41548100},
issn = {2050-2885},
mesh = {Humans ; *Infant Mortality/trends ; Texas/epidemiology ; Infant ; Female ; *Abortion, Induced/legislation & jurisprudence ; Pregnancy ; Infant, Newborn ; *Abortion, Legal/legislation & jurisprudence ; Adolescent ; Fetal Mortality ; },
abstract = {Alison Gemmill et al. claim that infant mortality in Texas increased following its 2021 abortion restrictions, and several sources reported that abortion restrictions harm infants. This is misleading. Gemmill et al.'s findings show that infant deaths increased primarily because abortion for "congenital anomalies" decreased, and a subset of those subjects died in infancy. In other words, infant mortality rose because fetal mortality fell. By analogy, one can reduce teenage deaths by causing deaths before age thirteen, but this does not save lives. Likewise, abortion restrictions may lead to more infants dying (since fewer subjects are aborted), but this does not imply that abortion restrictions harm infants. The opposite seems true. We argue that it is reasonable to regard Texas's abortion restrictions as a net benefit for infants. We also highlight ableist assumptions surrounding Gemmill et al.'s study and call for bipartisan efforts to support people with disabilities and their families.},
}

Humans
*Infant Mortality/trends
Texas/epidemiology
Infant
Female
*Abortion, Induced/legislation & jurisprudence
Pregnancy
Infant, Newborn
*Abortion, Legal/legislation & jurisprudence
Adolescent
Fetal Mortality

@article {pmid41548719,
year = {2026},
author = {Li, X and Wan, R and Zhao, Y and Wu, Y and Chen, X and Li, Q and Luo, C},
title = {Decoding synaptic imbalance in neurodegenerative diseases: From pathological analysis to targeted intervention.},
journal = {Ageing research reviews},
volume = {115},
number = {},
pages = {103028},
doi = {10.1016/j.arr.2026.103028},
pmid = {41548719},
issn = {1872-9649},
mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology ; *Synapses/pathology/metabolism/physiology ; Animals ; Neuronal Plasticity/physiology ; Synaptic Transmission/physiology ; *Aging/pathology ; },
abstract = {Synapses serve as the central functional components mediating information transmission, integration, and storage within the central nervous system (CNS). Their functionality depends on the synergistic interplay of the presynaptic membrane, synaptic cleft, and postsynaptic membrane-three structures that collectively sustain neurotransmitter secretion, postsynaptic signaling, and synaptic plasticity. Of note, synaptic impairment represents an early, shared pathological hallmark across aging and age-related neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). This damage emerges prior to the demise of neuronal cell bodies and the manifestation of clinical symptoms, with its location and severity directly shaping disease phenotypes. Importantly, such synaptic dysfunction is closely linked to the pathological proteins specific to each disorder. This review comprehensively synthesizes current research advances regarding synaptic impairment in age-related neurodegenerative diseases. It elaborates on the location-specific pathological features of synaptic damage in AD, PD, HD, and ALS, with particular emphasis on their associations with disease-related pathological markers. Additionally, the work unpacks five core mechanisms driving synaptic dysfunction: the toxic effects of pathological proteins, dysregulated synaptic protein homeostasis, excitotoxicity coupled with disrupted calcium balance, oxidative stress and inflammatory responses, and deficiencies in neurotrophic factors. Ultimately, it summarizes potential biomarkers and targeted intervention strategies, aiming to provide a systematic reference for mechanistic investigations, early diagnosis, and clinical management of neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/pathology/metabolism/physiopathology
*Synapses/pathology/metabolism/physiology
Animals
Neuronal Plasticity/physiology
Synaptic Transmission/physiology
*Aging/pathology

@article {pmid41548740,
year = {2026},
author = {Qaisar, R},
title = {Fiber-type-specific architecture and pathophysiology of the neuromuscular junction.},
journal = {Neuroscience},
volume = {597},
number = {},
pages = {13-26},
doi = {10.1016/j.neuroscience.2026.01.015},
pmid = {41548740},
issn = {1873-7544},
mesh = {*Neuromuscular Junction/physiopathology/pathology/physiology ; Humans ; Animals ; *Muscle Fibers, Slow-Twitch/physiology/pathology ; *Muscle Fibers, Fast-Twitch/physiology/pathology ; },
abstract = {The neuromuscular junction (NMJ) is a specialized synapse essential for translating neuronal signals into muscle contraction. This review examines the complex structural, functional, and molecular differences in NMJs that innervate fast- and slow-twitch skeletal muscle fibers. Fast-twitch fibers, optimized for rapid and powerful contractions, possess elaborate NMJs with deep folds, high neurotransmitter turnover, and greater vulnerability to synaptic fatigue and degeneration. In contrast, slow-twitch fiber NMJs exhibit simpler but more stable architectures that support sustained, fatigue-resistant activity. These differences are not fixed but subject to activity-dependent plasticity and pathological remodeling. Chronic stimulation, injury, and aging influence NMJ morphology, with fast-twitch junctions more prone to degeneration in conditions such as ALS, myasthenia gravis, and diabetic neuropathy. Slow-twitch NMJs often resist early deterioration due to superior trophic support, metabolic stability, and more robust expression of synaptic organizers, such as agrin and PGC-1α. Several key signaling pathways, including agrin-MuSK-LRP4, Wnt/β-catenin, and neuregulin/ErbB, govern NMJ maintenance with fiber-type-specific nuances. These insights underscore the importance of tailoring therapeutic strategies to the muscle fiber phenotype. Gene therapies, neuromuscular electrical stimulation, and biomaterial scaffolds are emerging as promising modalities for preserving or restoring NMJ integrity, especially in fast-twitch fibers at higher risk of degeneration. Understanding fiber-type-specific NMJ biology enhances our understanding of motor control, muscle aging, and neuromuscular disease progression, and it opens pathways for precision therapeutics that target vulnerable synapses with structural and functional specificity. This review introduces a novel perspective by emphasizing fiber-type-specific NMJ differences and their implications for targeted therapies.},
}

*Neuromuscular Junction/physiopathology/pathology/physiology
Humans
Animals
*Muscle Fibers, Slow-Twitch/physiology/pathology
*Muscle Fibers, Fast-Twitch/physiology/pathology

@article {pmid41549027,
year = {2026},
author = {Shenouda, M and Shenouda, S and Kartono, B and Eid, S and Cheng, C and Robertson, J},
title = {Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {1},
pages = {e00834},
pmid = {41549027},
issn = {1878-7479},
mesh = {Humans ; Animals ; *beta Karyopherins/metabolism ; *DNA-Binding Proteins/metabolism ; Mice ; Neurons/drug effects/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; *Molecular Chaperones/metabolism ; *TDP-43 Proteinopathies/metabolism/drug therapy ; Male ; Cells, Cultured ; },
abstract = {Neuronal cytoplasmic aggregation and nuclear depletion of the TAR DNA-binding protein 43 (TDP-43) is the most characteristic pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing toxicity through cytoplasmic gain and nuclear loss of function mechanisms. In addition to its canonical role in nuclear cytoplasmic transport (NCT), the nuclear import receptor, importin-β1 (KPNB1) also acts as a molecular chaperone capable of preventing and reversing aberrant protein aggregation. Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization. Here, we identify JRMS, a small molecule that enhances the chaperone activity of KPNB1 by increasing its cytoplasmic availability. JRMS treatment reduced cytoplasmic aggregation and promoted nuclear localization of full-length and pathological truncated TDP-43 variants across multiple experimental systems, including cell lines, primary neurons, iPSC-derived cortical neurons, organotypic brain slices and in vivo model. The effects of JRMS were KPNB1 dependent and occurred without inducing cytotoxicity or perturbing basal NCT. These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.},
}

Humans
Animals
*beta Karyopherins/metabolism
*DNA-Binding Proteins/metabolism
Mice
Neurons/drug effects/metabolism
Amyotrophic Lateral Sclerosis/metabolism
*Molecular Chaperones/metabolism
*TDP-43 Proteinopathies/metabolism/drug therapy
Male
Cells, Cultured

@article {pmid41551521,
year = {2026},
author = {Xu, S and Lu, GR},
title = {Potential of lysine succinylation as a therapeutic target for gallstone formation: An insightful strategy.},
journal = {World journal of gastroenterology},
volume = {32},
number = {1},
pages = {114865},
pmid = {41551521},
issn = {2219-2840},
mesh = {Animals ; Humans ; Mice ; AMP-Activated Protein Kinases/metabolism ; Disease Models, Animal ; Gallbladder/pathology/cytology ; *Gallstones/pathology/metabolism/prevention & control/etiology/drug therapy ; *Lysine/metabolism ; Protein Processing, Post-Translational/drug effects ; Signal Transduction/drug effects ; Succinic Acid/metabolism ; },
abstract = {Cholelithiasis has a complex pathogenesis, necessitating better therapeutic and preventive strategies. We recently read with interest Wang et al's study on lysine acetyltransferase 2A (KAT2A)-mediated adenosine monophosphate-activated protein kinase (AMPK) succinylation in cholelithiasis. Using mouse models and gallbladder mucosal epithelial cells, they found that KAT2A inhibits gallstones through AMPK K170 succinylation, thereby activating the AMPK/silent information regulator 1 pathway to reduce inflammation and pyroptosis. This study is the first to connect lysine succinylation with cholelithiasis, offering new insights and identifying succinylation as a potential therapeutic target. Future research should confirm these findings using patient samples, investigate other post-translational modifications, and use structural biology to clarify succinylation-induced conformational changes, thereby bridging basic research to clinical applications.},
}

Animals
Humans
Mice
AMP-Activated Protein Kinases/metabolism
Disease Models, Animal
Gallbladder/pathology/cytology
*Gallstones/pathology/metabolism/prevention & control/etiology/drug therapy
*Lysine/metabolism
Protein Processing, Post-Translational/drug effects
Signal Transduction/drug effects
Succinic Acid/metabolism

@article {pmid41551727,
year = {2026},
author = {Singh, S and Singh, P and Varada, MP and Vijaivasudev, MJ and Kumar, R and Malik, I},
title = {eVGeMdb: a manually curated database for experimentally validated genetic modifiers of neurodegenerative disorders.},
journal = {NAR molecular medicine},
volume = {3},
number = {1},
pages = {ugaf044},
pmid = {41551727},
issn = {2976-856X},
abstract = {Genetic modifiers are genes that, while not directly causing disease, can alter the onset, progression, severity, or specific phenotypes of a disease by interacting with the primary disease-causing genes. Despite their importance, knowledge of these modifiers remains fragmented across different experimental models of neurodegenerative disorders (NDs). To address this lacuna, we developed eVGeMdb (https://project.iith.ac.in/cgntlab/eVGeMdb/), a manually curated, comprehensive database of experimentally validated genetic modifiers of major NDs, including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinocerebellar ataxias, Fragile X-associated Tremor/Ataxia Syndrome, and other general PolyQ disorders. eVGeMdb integrates modifiers from commonly used diverse experimental model systems, including Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, cellular models (human, mice, Drosophila cells), and mouse. The database currently incorporates over 17000 entries, each annotated with experimental context, gene-specific functional information, relevant human orthologs, and links to protein-protein interaction networks and enriched pathways. The resource enables cross-disease and model-specific comparisons, allowing the identification of both universal and disease-specific modifiers. By consolidating dispersed genetic modifier information into a single, accessible platform, eVGeMdb provides a comprehensive tool for researchers in the field to explore modifier effects, prioritize experimental validations, formulate novel hypotheses, and investigate pathophysiological mechanisms underlying neurodegenerative disorders.},
}

@article {pmid41552526,
year = {2026},
author = {Turcatel, GA and Moura, S},
title = {Glutamate Receptor Agonists as Triggers of Neurotoxicity: Decoding Pathways of Five Neurotoxins and Potential Therapeutic Targets.},
journal = {ACS omega},
volume = {11},
number = {1},
pages = {70-81},
pmid = {41552526},
issn = {2470-1343},
abstract = {l-Glutamate (l-Glu) is one of the primary excitatory neurotransmitters in the nervous system, functioning through both ionotropic and metabotropic receptors. The release of l-Glu into the synaptic cleft, its interaction with receptors, and its reuptake are meticulously regulated by excitatory amino acid transporters. The structural similarity of various compounds to l-glutamate is crucial to their ability to interact with NMDA, AMPA, and kainate receptors. These interactions can significantly influence neural communication and function. Overstimulation of these receptors, which operate as ion channels, results in an increased level of calcium ion influx, a phenomenon known as excitotoxicity, which is often linked to neurodegeneration. Many neurodegenerative conditions are linked to both acute and chronic exposures to neurotoxins, whether they originate within the body (endogenous) or from external sources (exogenous). These neurotoxins often function as l-glutamate receptor agonists, potentially contributing to the progression of these diseases. This perspective focuses on key neurotoxins, including β-N-methylamino-l-alanine (l-BMAA), quinolinic acid (QUIN), domoic acid, β-N-oxalyl-l-α,β-diaminopropionic acid (β-ODAP), homocysteine (Hcy), and l-homocysteate, all of which exhibit complementary mechanisms of action. We will explore their structural characteristics and mechanisms through which they induce neurotoxicity. Understanding the neurotoxic mechanisms of these compounds is essential for elucidating the pathology of neurodegenerative diseases, such as amyotrophic lateral sclerosis, neurolathyrism, and amnesic shellfish poisoning. This review summarizes the findings of 64 studies to clarify these relationships involving classic events associated with neurodegeneration such as mitochondrial damage, oxidative stress, and activation of proapoptotic pathways. In summary, the distinctive properties of these neurotoxins provide valuable insights that could help in the development of future therapeutic drugs aimed at treating and alleviating the effects of neurodegenerative diseases. Understanding how these neurotoxins interact with neuronal pathways can guide researchers in designing more effective interventions.},
}

@article {pmid41552817,
year = {2025},
author = {Chen, Y and Xiao, W and Qian, C and Huang, L and Lv, J and Wang, Z and Luo, Y},
title = {System Xc-pathway as a potential regulatory target in neurological disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1701320},
pmid = {41552817},
issn = {1663-9812},
abstract = {The System Xc-pathway is composed of the 12-transmembrane transporter protein SLC7A11 (xCT) and the single-channel transmembrane protein SLC3A2 (CD98hc). We detail the pathway's characteristics and distribution within the central nervous system, as well as its canonical role in maintaining glutathione synthesis and inhibiting ferroptosis, and its emerging non-canonical functions in metabolic coupling and neuroimmunity. A core theme is the pathway's context-dependent and often paradoxical role across major neurological disorders, including ischemic stroke, Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Critically, we analyze how pathological activation of N-methyl-D-aspartate receptors (NMDARs) can dysregulate System Xc-through mechanisms involving calcium overload, reactive oxygen species, and specific signaling axes (e.g., Nrf2, PP2A/AMPK/HMGB1), thereby exacerbating excitotoxicity and oxidative damage. Conversely, System Xc-dysfunction can further fuel NMDAR-mediated injury, creating vicious pathogenic cycles. This analysis reveals that System Xc-is not a unitary target but a dynamic node within a complex network. Consequently, effective therapeutic strategies must move beyond broad inhibition and instead aim for nuanced, cell-type-specific, and disease-stage-precise modulation. This approach will selectively correct the dysfunction of System Xc-while preserving its essential physiological roles. It presents both a significant challenge and a promising frontier for future neuroprotective drug development.},
}

@article {pmid41553037,
year = {2026},
author = {Shahid, N and Azhar, L and Hussain, I and Khan, MS},
title = {Emerging Alzheimer's therapies: clinical efficacy versus economic feasibility.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/17582024.2026.2617857},
pmid = {41553037},
issn = {1758-2032},
}

@article {pmid41553108,
year = {2026},
author = {Rudnicki, SA and Giacomelli, E and Herder, K and Ingre, C and Kupfer, S and Malik, FI and Meng, L and Paganoni, S and Schellenberg, K and Scirocco, E and Simkins, T and Wei, J and Shefner, JM and , },
title = {The Use of Durable Medical Equipment in COURAGE-ALS, a Phase 3, Multicentre, Randomized Clinical Trial for ALS.},
journal = {Muscle & nerve},
volume = {73},
number = {4},
pages = {608-614},
doi = {10.1002/mus.70150},
pmid = {41553108},
issn = {1097-4598},
support = {//Cytokinetics, Incorporated/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Male ; Middle Aged ; Double-Blind Method ; Aged ; *Durable Medical Equipment ; Noninvasive Ventilation/instrumentation ; *Wheelchairs ; Treatment Outcome ; Canada ; },
abstract = {INTRODUCTION/AIMS: Durable medical equipment (DME)-wheelchairs, non-invasive ventilation, gastrostomy tubes, and communication devices-provides vital support for individuals with amyotrophic lateral sclerosis (ALS). Here, we describe DME use in COURAGE-ALS evaluating reldesemtiv's efficacy and safety in ALS, to evaluate if DME use can be considered an endpoint of interest in ALS trials.

METHODS: COURAGE-ALS, a multicentre, double-blind, randomized, placebo-controlled clinical trial was conducted at 83 sites in the United States, Canada, Europe, and Australia. Participants were randomized 2:1 to receive reldesemtiv or placebo for 24 weeks, followed by 24 weeks of active drug treatment. Exploratory outcomes included reasons for prescribing, extent of use, DME types, and regional differences.

RESULTS: Among 482 participants, 166 (34.4%) were using at least one DME item at baseline. Among 276 participants completing study visits through Week 24, 130 (47.1%) initiated use of a total of 188 new DME items post-baseline through 24 weeks. Manual wheelchairs were most used at baseline (89 items) and initiated (47 items) during the trial. Both baseline DME use and initiating a new item were associated with lower ALS Functional Rating Scale-Revised scores and worse quality of life. The trial was terminated early due to futility. Treatment assignment did not impact DME use. Regional disparities were noted.

DISCUSSION: This study shows that DME is commonly prescribed to ALS trial participants. Further understanding of geographic differences in DME access and their impact on clinical outcomes is warranted prior to including DME use as an endpoint in ALS trials.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: (NCT04944784).},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy
Female
Male
Middle Aged
Double-Blind Method
Aged
*Durable Medical Equipment
Noninvasive Ventilation/instrumentation
*Wheelchairs
Treatment Outcome
Canada

@article {pmid41553204,
year = {2026},
author = {Sánchez-Lloria, P and Barcala-Furelos, R and Otero-Agra, M and Aranda-García, S and Martínez-Isasi, S and Muñoz-Barús, I and Rodríguez-Núñez, A and Iglesias-Vázquez, JA},
title = {[Intentional drowning as a method of self-inflicted injury and suicide: a 21-year analysis of Galicia].},
journal = {Revista espanola de salud publica},
volume = {100},
number = {},
pages = {},
pmid = {41553204},
issn = {2173-9110},
mesh = {Humans ; Female ; Male ; Retrospective Studies ; Adult ; Middle Aged ; *Drowning/epidemiology ; Spain/epidemiology ; Adolescent ; Young Adult ; Aged ; Child ; Child, Preschool ; Aged, 80 and over ; Longitudinal Studies ; Infant ; *Self-Injurious Behavior/epidemiology ; *Suicide/statistics & numerical data ; *Suicide, Attempted/statistics & numerical data ; },
abstract = {OBJECTIVE: Drowning and suicide are interconnected complex phenomena and represent significant Public Health issues. The aim of this paper was to identify and describe the characteristics and factors associated with intentional drownings in Galicia (Spain), analyzing a retrospective cohort of twenty-one years.

METHODS: A descriptive, retrospective, and longitudinal study (2001-2021) was conducted analyzing a cohort of patients aged 0 to 100 years who were treated by Basic and Advanced Life Support (BLS/ALS) units of the FPUS 061 and by hospitals within the Galician Health Service (SERGAS). Records coded with a diagnosis of drowning or near-drowning were included and were recoded as fatal or non-fatal drowning according to international recommendations. Additionally, records containing the terms suicide, self-harm, or suicide attempt in prehospital or hospital documentation were also included.

RESULTS: Ninety-nine cases were documented, representing 9% of all drownings in Galicia and 14% of individuals aged over sixty five who drowned. Eighty-two percent of the victims were residents of the municipality where the incident occurred, and 60% were women. Ninety-nine percent had a prior diagnosis of mental health disorder. Individuals over sixty five accounted for 53% of the cases, with a mortality rate of 50%. The presence of witnesses was associated with lower mortality.

CONCLUSIONS: There is a relationship between intentional drownings and mental health disorders. In these events, the presence of witnesses is a protective factor, while advanced age is a risk factor for mortality. Intentional drowning is a complex and understudied health issue, so prevention and Public Health strategies should be implemented to reduce these preventable deaths.},
}

Humans
Female
Male
Retrospective Studies
Adult
Middle Aged
*Drowning/epidemiology
Spain/epidemiology
Adolescent
Young Adult
Aged
Child
Child, Preschool
Aged, 80 and over
Longitudinal Studies
Infant
*Self-Injurious Behavior/epidemiology
*Suicide/statistics & numerical data
*Suicide, Attempted/statistics & numerical data

@article {pmid41553546,
year = {2026},
author = {Dey, A and Baumeister, TR and Evans, KC and Koppelmans, V and Luk, C and McLaren, DG and Parnianpour, P and Seres, P and Kalra, S and , },
title = {Data-driven disease subgrouping in ALS: a multicenter cerebral functional connectivity study.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {87},
pmid = {41553546},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/classification/drug therapy ; Male ; Female ; Middle Aged ; Magnetic Resonance Imaging ; Aged ; Disease Progression ; Adult ; },
abstract = {BACKGROUND: In a clinically-heterogeneous disease such as ALS, it is crucial to identify early disease changes that impair real-world functioning. The lack of consensus across clinical approaches, coupled with the subjectiveness of their evaluation, impedes our understanding of disease processes underlying early and advanced disease. This study presents neuroimaging as a potential supplementary approach that provides objectivity to the identification and evaluation of disease stage-specific ALS subgroups.

METHODS: Cerebral functional connectivity and its association with clinical function was evaluated in 174 ALS patients and 165 healthy controls enrolled in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants were subgrouped using two approaches: (1) a data-driven hierarchical clustering of cerebral activation and 2) contemporary clinical criteria. The data-driven approach utilized data from resting-state functional magnetic resonance imaging. The clinical approach utilized three clinical subgrouping methods - two derived from trial enrollment criteria for the drugs Riluzole and Edaravone, and the third on the median disease progression rate of the patient sample.

RESULTS: Each subgrouping approach identified two patient subgroups with different symptom durations, disease progression rates, and cognitive/motor/lung functions - albeit with differences across approaches. The data-driven approach identified greater spatial extents of cerebral connectivity alterations compared to the clinical approaches.

CONCLUSION: Observations of clinical and cerebral connectivity differences were specific to the stratification approach. Given the ability of the data-driven approach to identify alterations in both clinical and cerebral function corresponding to disease stage, this approach presents a potential biomarker for patient stratification, clinical trial enrichment, disease and therapeutic monitoring.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/classification/drug therapy
Male
Female
Middle Aged
Magnetic Resonance Imaging
Aged
Disease Progression
Adult

@article {pmid41553588,
year = {2026},
author = {Bjørklund, G and Butnariu, M and Caunii, A and Peana, M},
title = {Metallothioneins in Neurodegenerative Diseases: Metal Homeostasis, Autoimmunity, and Therapeutic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {373},
pmid = {41553588},
issn = {1559-1182},
mesh = {Humans ; *Homeostasis/physiology ; *Metallothionein/metabolism ; *Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy ; *Autoimmunity/physiology ; Animals ; *Metals/metabolism ; },
abstract = {Neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and are frequently linked to metal dysregulation, oxidative stress, and immune dysfunction. Metallothioneins (MTs), a family of cysteine-rich, metal-binding proteins, are critical in maintaining metal homeostasis, mitigating oxidative damage, and modulating immune responses, functions highly relevant in these pathologies. MTs regulate essential metals like copper and iron by preventing their participation in harmful redox reactions and control zinc availability for enzymatic and signaling processes. They also detoxify neurotoxic metal(oid)s such as cadmium, mercury, lead, and arsenic, thereby reducing their adverse neurological and immunological effects. In autoimmune neurodegeneration, MTs modulate pro- and anti-inflammatory cytokines (e.g., IL-6, TNF-α, IL-10) and influence immune cell activity, particularly microglia and T cells, which are central to neuroinflammation and autoimmunity. Through these mechanisms, MTs play a dual role in sustaining immune homeostasis and counteracting oxidative stress. Their capacity to integrate metal regulation with immune modulation positions them as promising therapeutic targets, with preclinical and some clinical evidence supporting strategies to enhance MT expression or develop MT-mimetic agents to address both metal dysregulation and immune imbalance. Additionally, MTs show emerging utility as biomarkers, as alterations in MT isoform expression and metal-bound complexes in biofluids have been associated with disease onset, progression, and therapeutic response in specific neurodegenerative conditions. This article reviews the multifaceted roles of MTs in neurodegenerative diseases, emphasizing their function in metal and immune regulation and their emerging potential as therapeutic targets and clinical biomarkers.},
}

Humans
*Homeostasis/physiology
*Metallothionein/metabolism
*Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy
*Autoimmunity/physiology
Animals
*Metals/metabolism

@article {pmid41554189,
year = {2026},
author = {Pehlivanova, M and Lange, R and Greyson, B and Houran, J},
title = {Operationalizing near‑death experiences: Stability of the NDE Rasch hierarchy over two decades.},
journal = {Consciousness and cognition},
volume = {139},
number = {},
pages = {103979},
doi = {10.1016/j.concog.2025.103979},
pmid = {41554189},
issn = {1090-2376},
mesh = {Humans ; *Psychometrics/instrumentation/standards ; Female ; Male ; Adult ; Middle Aged ; Young Adult ; *Death ; Aged ; },
abstract = {This study presents the first comprehensive psychometric comparison of Greyson's (1983) 16-item Near-Death Experience Scale (NDE Scale) and Martial et al.'s (2020) 20-item Near-Death Experience Content Scale (NDE-C) using Rasch modeling and differential item functioning (or response bias) analyses. A total of 705 self-identified "near-death experiencers" (64% women) completed both measures, which were randomly intermingled and rated for experiential relevance. Results confirmed that the two scales measure the same underlying construct of NDE phenomenology, as evidenced by a near-perfect disattenuated Pearson correlation (r = 0.98, p < 0.001). However, Rasch analysis revealed limitations in the category structures of both scales-particularly the NDE-C-and identified psychometric and conceptual weaknesses in its five novel items. Critically, the core Rasch item hierarchy derived from the original NDE Scale was replicated both in this sample and a previously simulated dataset based on the NDE-C's development research, confirming its long-term structural stability. Based on the present evidence and the principle of parsimony, we recommend the original NDE Scale supported by Rasch scoring and a validated cut-off of 7 (out of 32), as it is conceptually coherent and psychometrically robust, while maintaining historical comparison with previous research. These findings reinforce the value of Rasch modeling for cumulative theory-building and underscore the Rasch NDE hierarchy's foundational role in operationalizing legitimate near-death experiences.},
}

Humans
*Psychometrics/instrumentation/standards
Female
Male
Adult
Middle Aged
Young Adult
*Death
Aged

@article {pmid41554495,
year = {2026},
author = {Phillips, EM and Edwards, JG and Aiello, L and Gilliam, CA and Seltz, LB and Spencer, DJ and Rassbach, CE},
title = {The Effect of Mistreatment From Patients and Families on Pediatric Resident Professional Identity Formation.},
journal = {Academic pediatrics},
volume = {26},
number = {3},
pages = {103221},
doi = {10.1016/j.acap.2026.103221},
pmid = {41554495},
issn = {1876-2867},
mesh = {Humans ; *Internship and Residency ; Female ; Male ; Qualitative Research ; *Pediatrics/education ; Adult ; *Physician-Patient Relations ; Social Identification ; Attitude of Health Personnel ; Patient-Centered Care ; },
abstract = {OBJECTIVE: Mistreatment by patients and families is linked to adverse patient outcomes and physician burnout, and particularly affects women and underrepresented in medicine (UIM) physicians. We sought to explore how this source of mistreatment affects trainee professional identity formation (PIF), a key process in the development of altruistic physicians.

METHODS: We conducted this multi-institutional qualitative study between May and October 2023 with semistructured interviews of pediatric residents. We used the constant comparative method consistent with modified grounded theory to analyze data through a lens of Cruess et al's model of PIF in medicine.

RESULTS: We interviewed 32 pediatric residents and identified 4 primary themes, which we used to develop a conceptual model. 1) Residents identify patient- and family-centered care as core to their professional identity, while acknowledging their vulnerability to mistreatment from patients and families. 2) Mistreatment threatens resident PIF through fractured patient-provider relationships, negative impacts on patient care, and decreased psychological safety of the learning environment. 3) Mistreatment that is frequent, unaddressed, and centered around personal traits is particularly damaging to PIF. 4) Residents employ various strategies to mitigate the negative impacts of mistreatment and ultimately deepen their professional identity.

CONCLUSIONS: Mistreatment from patients and families negatively affects pediatric residents' well-being, learning, and professional identity, with particular impacts on women and UIM residents. Our study informs ways that institutions can best structure support to navigate mistreatment while optimizing trainee learning and PIF, along with patient care.},
}

Humans
*Internship and Residency
Female
Male
Qualitative Research
*Pediatrics/education
Adult
*Physician-Patient Relations
Social Identification
Attitude of Health Personnel
Patient-Centered Care

@article {pmid41555948,
year = {2026},
author = {Deniz, R and Çiftçi, B},
title = {Emphasizing the biopsychosocial dimension in post-traumatic orthopedic recovery.},
journal = {World journal of psychiatry},
volume = {16},
number = {1},
pages = {115015},
pmid = {41555948},
issn = {2220-3206},
abstract = {Chronic pain and disability following acute orthopedic trauma are not only physical concerns but also deeply intertwined with psychological well-being. The recent retrospective cohort study by Yang et al, published, provides compelling evidence of significant associations between depression, anxiety, and postoperative recovery. These findings align with an expanding body of literature that confirms the need for orthopedic rehabilitation to adopt a biopsychosocial perspective. This letter contextualizes Yang et al's study within current evidence, highlighting the roles of sleep disturbance, catastrophizing, stress, neurobiological mechanisms, and coping strategies in shaping recovery. It further emphasizes the importance of integrating nursing-led and multidisciplinary interventions to address both physical and psychological domains, ultimately promoting holistic recovery.},
}

@article {pmid41556284,
year = {2026},
author = {Cao, W and Yu, L and Wang, Z and Deng, B and Fan, D},
title = {Neutrophil-Secreted Enzymes and ALS Risk: Exploring a Potential Mechanistic Link.},
journal = {Annals of neurology},
volume = {99},
number = {3},
pages = {591-605},
doi = {10.1002/ana.78161},
pmid = {41556284},
issn = {1531-8249},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/enzymology/epidemiology/blood ; Female ; Male ; *Neutrophils/enzymology ; Middle Aged ; Aged ; Neurofilament Proteins/blood/metabolism ; Biomarkers/blood ; Risk Factors ; },
abstract = {OBJECTIVE: Peripheral immunity plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously showed that elevated neutrophil counts are associated with increased risk of ALS occurrence and faster disease progression, potentially through axonal damage. However, the mechanisms linking neutrophils to ALS occurrence remain unclear. Neutrophil-secreted enzymes, key markers of neutrophil activity, may mediate these effects. We therefore investigated the role of neutrophil-secreted enzymes in ALS occurrence.

METHODS: Six neutrophil-secreted enzymes were selected from the UK Biobank-Proteomics Platform. Cox proportional hazards regression was used to examine associations between these enzymes and ALS occurrence. Multiple sensitivity analyses were conducted to ensure robustness. Stratified analyses evaluated potential effect modifications by age, sex, and body mass index (BMI). To investigate whether neutrophil-secreted enzymes contribute to ALS occurrence via a "dying-back" mechanism, mediation analysis was performed to assess the indirect effect of neurofilament light chain (NfL) levels in this relationship.

RESULTS: Individuals who later developed ALS showed significantly higher levels of neutrophil-secreted enzymes prior to disease onset, suggesting that neutrophil activation occurs before ALS occurrence. Elevated enzyme levels were associated with an increased risk ALS occurrence. Furthermore, we observed a linear positive correlation between enzyme levels and NfL concentrations. Mediation analysis indicated that the effects of MPO and S100A12 on ALS onset were partially mediated through axonal injury.

INTERPRETATION: Elevated neutrophil-secreted enzymes are associated with an increased risk of ALS occurrence. This finding provides mechanistic insight into neutrophil involvement in ALS and identifies these enzymes as potential therapeutic targets. ANN NEUROL 2026;99:591-605.},
}

Humans
*Amyotrophic Lateral Sclerosis/enzymology/epidemiology/blood
Female
Male
*Neutrophils/enzymology
Middle Aged
Aged
Neurofilament Proteins/blood/metabolism
Biomarkers/blood
Risk Factors

@article {pmid41556400,
year = {2026},
author = {Howard, I and Lyerly, M and Reimer, R and Patwa, H and Darling, L},
title = {Symptom Burden and Care Satisfaction in US Military Veterans With ALS: Results of a National Survey.},
journal = {Muscle & nerve},
volume = {73},
number = {4},
pages = {623-629},
doi = {10.1002/mus.70147},
pmid = {41556400},
issn = {1097-4598},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/psychology ; United States/epidemiology ; *Veterans/psychology ; Male ; Female ; Middle Aged ; *Patient Satisfaction ; Aged ; United States Department of Veterans Affairs ; Surveys and Questionnaires ; Adult ; *Cost of Illness ; Symptom Burden ; },
abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) affects military veterans at a higher rate than the general civilian population. The aim of the present study is to assess symptom burden and satisfaction with care among persons with ALS care enrolled in the US Veterans Health Administration (VA).

METHODS: A custom online survey was created with questions about symptom prevalence and management as well as care satisfaction. A survey link was sent by email to all veterans with an ICD-10 diagnosis of ALS in the VA for whom an email address was available in the electronic health record.

RESULTS: Responses were received from 413 individuals (16% response rate). Respondents reported high care satisfaction and higher prevalence of treatment of symptoms compared to prior surveys of persons with ALS in the United States. Self-reported outcomes, including treatment, education, and satisfaction, were better for Veterans receiving care exclusively within the VA compared to those receiving care at both VA and non-VA facilities or receiving care exclusively at non-VA facilities. Areas for further improvement identified in the survey include education on genetic testing and research and management of non-motor symptoms.

DISCUSSION: This survey indicates that, overall, veterans with ALS receive comprehensive symptom-based care within the nationalized VA care system and report high levels of satisfaction. Furthermore, this study provides baseline data and findings that may be used for quality improvement efforts across a large healthcare system and may serve as a model for similar efforts in other health systems.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/epidemiology/psychology
United States/epidemiology
*Veterans/psychology
Male
Female
Middle Aged
*Patient Satisfaction
Aged
United States Department of Veterans Affairs
Surveys and Questionnaires
Adult
*Cost of Illness
Symptom Burden

@article {pmid41557054,
year = {2026},
author = {Shi, Y and Wang, H and Chen, J and Ren, J and Sun, X and Qu, M and Zhao, T and Han, C and Yuan, J and Meng, F and Lu, L},
title = {α-Synuclein Deletion Leads to Hyposmia: due to Defective Autophagy Induced by Abnormal PI3K/mTOR Signaling Pathway in Olfactory Bulb.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {378},
pmid = {41557054},
issn = {1559-1182},
mesh = {*alpha-Synuclein/deficiency/metabolism/genetics ; Animals ; *TOR Serine-Threonine Kinases/metabolism ; *Signal Transduction/physiology ; *Olfactory Bulb/metabolism/pathology ; *Autophagy/physiology ; Mice, Knockout ; *Phosphatidylinositol 3-Kinases/metabolism ; *Olfaction Disorders/pathology/metabolism/genetics ; Apoptosis ; *Gene Deletion ; Proto-Oncogene Proteins c-akt/metabolism ; Mice ; Mice, Inbred C57BL ; },
abstract = {α-Synuclein has been the center of focus in understanding synucleinopathies such as Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, dementia with Lewy bodies, for decades. Most researches focus on its pathology. However, its physiological function remains elusive, especially in olfactory system, one of the original sites to find α-synuclein accumulation in Parkinson's disease. In the present study, α-synuclein knockout (KO) mice were employed to study its physiological function. KO mice exhibited olfaction impairment with cell apoptosis in olfactory bulb. To identify molecules underlying olfactory dysfunction, we employed proteomics based on isobaric tags for relative and absolute quantification (iTRAQ). 188 differentially expressed proteins were identified between KO mice and its littermate control of wildtype mice. Bioinformatic analysis highlighted Phosphatidyl-inositol-3-kinase (PI3K) pathway. Hence, we examined its activation and found that both PI3K and its downstream, protein kinase B(AKT) is hyperactivated with α-synuclein deficiency. Mammalian target of Rapamycin (mTOR), a switch of autophagy, was activated followed by uncoordinated 51-like kinase 1, the autophagy initiator, inhibition. The specific substrate of autophagy, P62 was accumulated, indicating that autophagy was blocked. This blockade of autophagy led to Caspase 8 mediated apoptosis characterized by an increased ratio of B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) to BCL-2 (BAX/BCL-2), reduced mitochondrial complex I activity, and decreased mitochondrial membrane potential. To summarize, α-synuclein played roles in maintaining the normal structure and function of olfactory system. α-Synuclein deletion induced Caspase 8 mediated apoptosis due to the defective autophagy by PI3K/mTOR hyperactivation.},
}

*alpha-Synuclein/deficiency/metabolism/genetics
Animals
*TOR Serine-Threonine Kinases/metabolism
*Signal Transduction/physiology
*Olfactory Bulb/metabolism/pathology
*Autophagy/physiology
Mice, Knockout
*Phosphatidylinositol 3-Kinases/metabolism
*Olfaction Disorders/pathology/metabolism/genetics
Apoptosis
*Gene Deletion
Proto-Oncogene Proteins c-akt/metabolism
Mice
Mice, Inbred C57BL

@article {pmid41557441,
year = {2026},
author = {Wu, J and Pyko, A and Chourpiliadis, C and Hu, Y and Hou, C and Brauner, S and Piehl, F and Ljungman, P and Ingre, C and Fang, F},
title = {Long-Term Exposure to Air Pollution and Risk and Prognosis of Motor Neuron Disease.},
journal = {JAMA neurology},
volume = {83},
number = {3},
pages = {213-222},
pmid = {41557441},
issn = {2168-6157},
support = {R01 TS000348/TS/ATSDR CDC HHS/United States ; },
mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Air Pollution/adverse effects ; Case-Control Studies ; Disease Progression ; *Environmental Exposure/adverse effects ; *Motor Neuron Disease/epidemiology/diagnosis/etiology ; Particulate Matter/adverse effects ; Prognosis ; Registries ; Risk Factors ; Sweden/epidemiology ; },
abstract = {IMPORTANCE: Air pollution exposure has been associated with an increased risk of neurodegenerative diseases; however, evidence is limited for motor neuron disease (MND), especially regarding disease progression.

OBJECTIVE: To determine whether long-term exposure to air pollution is associated with the risk and prognosis of MND.

This population-based, nested case-control study used Swedish health register data of incident MND cases diagnosed between 2015 and 2023 with up to 8 years of follow-up. Participants included patients with MND, 5 age- and sex-matched population controls without MND per patient with MND, and full siblings of the patients with MND. Data were analyzed between November 6, 2024, and November 4, 2025.

EXPOSURES: Mean yearly concentrations of particulate matters of 2.5 µm or less, 10 µm or less, or 2.5 to 10 µm in diameter (PM2.5, PM10, PM2.5-10) and nitrogen dioxide (NO2) were assessed at the residential address using a spatiotemporal model to approximate accumulated air pollution exposure.

MAIN OUTCOME AND MEASURES: Association between air pollution and risk of MND was assessed by comparing cases to both population and sibling controls. Flexible parametric survival models estimated the association between air pollution exposure and the risk of mortality (or use of invasive ventilation) after MND diagnosis (case-only analyses). Based on the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score and its subscores after diagnosis, patients were classified into fast (upper 25th percentile) or slow (lower 75th percentile) progression. Logistic regression was used to assess air pollution exposure and the risk of fast progression.

RESULTS: The study included 1463 patients with MND, 7310 population controls, and 1768 sibling controls. The mean (SD) age for all patients with MND was 67.3 (11.7) years, and 814 (55.6) were male. In the population comparison, long-term air pollution was associated with an increased risk of MND; per IQR increase in the 10-year average level, the odds ratio was 1.21 (95% CI, 1.09-1.34) for PM2.5, 1.30 (95% CI, 1.19-1.42) for PM2.5-10, 1.29 (95% CI, 1.18-1.42) for PM10, and 1.20 (95% CI, 1.12-1.29) for NO2. A higher level of PM10 or NO2 was associated with a higher hazard of mortality, whereas a higher level of all PMs was associated with faster functional decline, particularly motor and respiratory functions, after MND diagnosis.

CONCLUSIONS AND RELEVANCE: The findings of this case-control study suggest that air pollution, even at relatively low levels typical of Sweden, may contribute both to the risk of developing MND and disease prognosis after MND diagnosis.},
}

Aged
Female
Humans
Male
Middle Aged
*Air Pollution/adverse effects
Case-Control Studies
Disease Progression
*Environmental Exposure/adverse effects
*Motor Neuron Disease/epidemiology/diagnosis/etiology
Particulate Matter/adverse effects
Prognosis
Registries
Risk Factors
Sweden/epidemiology

@article {pmid41557593,
year = {2026},
author = {Meyer, T and Maier, A and Grehl, T and Weyen, U and Rödiger, A and Smesny, U and Steinbach, R and Grosskreutz, J and Göricke, B and Bernsen, S and Weydt, P and Fabian, R and Petri, S and Lumi, R and Bjelica, B and Boentert, M and Lingor, P and Kettemann, D and Norden, J and Walter, B and Riitano, A and Schumann, P and Münch, C and Spittel, S},
title = {Minimum important slowing of disease progression as determined by the ALS functional rating scale - a survey of patient expectations toward disease-modifying drugs in ALS.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/21678421.2026.2615117},
pmid = {41557593},
issn = {2167-9223},
abstract = {Objective: To define the minimum important slowing (MIS) of ALS progression that patients would expect from disease-modifying drug treatment in ALS. Methods: In a survey of ALS patients, the MIS in ALS progression (change in the ALS Functional Rating Scale-Revised, ALSFRS-R) was assessed by asking: "At what point of slowing of ALS, as determined by the ALSFRS-R, do you consider a drug to be important?" Data were collected during clinic visits or remotely via the ALS App. Participants were differentiated in the prognostic groups of slower (<0.5), intermediate (≥0.5 and ≤1.0), or faster (>1.0) ALS progression (ALSPR; ALSFRS-R/month). Results: Of 522 participants (ALS App, n = 397; clinic, n = 125), 395 (75.7%) completed the survey, while 127 (24.3%) selected the option "cannot estimate". The distribution of MIS was as follows: modest slowing of ALS progression (5% and 10% slowing, n = 146 patients, 36.9%), moderate slowing (20%, 30%, and 40% slowing, n = 135, 34.2%), and major slowing (≥50% slowing, n = 114, 28.9%). Median MIS was 20% (IQR 10-50%). Patients with faster ALSPR more frequently assessed a major slowing as the MIS (n = 18, 36.0%) compared to those with slower ALSPR (n = 54, 25.2%). Conclusion: A considerable number of participants viewed a modest slowing in ALS progression as the MIS, followed closely by preferences for moderate and major slowing. Expectations varied according to patients' individual ALS progression. These insights may inform the design of future clinical trials in ALS. Study limitations include potential selection and response biases, as well as the predominantly remote digital assessment.},
}

@article {pmid41558230,
year = {2026},
author = {Ye, J},
title = {Beyond binary diagnosis: Key questions on AI accuracy, real-world applicability, and safety in clinical decision support.},
journal = {International journal of medical informatics},
volume = {209},
number = {},
pages = {106292},
doi = {10.1016/j.ijmedinf.2026.106292},
pmid = {41558230},
issn = {1872-8243},
mesh = {*Artificial Intelligence ; *Decision Support Systems, Clinical ; Humans ; *Patient Safety ; },
abstract = {This comment relates to Kücking et al.'s (2026) study on the bidirectional effects of artificial intelligence recommendations and healthcare provider related factors on the accuracy of wound impregnation diagnosis. While acknowledging the valuable contributions of this research, including distinguishing between correct/incorrect artificial intelligence outputs, rigorous simulation design, and emphasis on clinical safety, we have raised key questions to enhance the interpretation of results and real-world translation. The main focuses include the moderating role of artificial intelligence system accuracy in automation bias, external effectiveness in real clinical environments, potential mechanisms for gender differences in diagnostic performance, the impact of visual cue design on decision-making, and the potential of explainable artificial intelligence (XAI) in risk mitigation. This review aims to promote further research and facilitate the safe and effective integration of artificial intelligence based clinical decision support systems (CDSS) into clinical practice.},
}

*Artificial Intelligence
*Decision Support Systems, Clinical
Humans
*Patient Safety

@article {pmid41558795,
year = {2026},
author = {Yi, W and Xu, Z and Feng, D and Guan, L and Tang, J and Zou, Y},
title = {Computational Exploration of the Molecular Mechanism of Epigallocatechin Gallate against TDP-43 Aggregation.},
journal = {Journal of chemical information and modeling},
volume = {66},
number = {3},
pages = {1826-1839},
doi = {10.1021/acs.jcim.5c02616},
pmid = {41558795},
issn = {1549-960X},
mesh = {*Catechin/analogs & derivatives/pharmacology/chemistry/metabolism ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism/antagonists & inhibitors ; *Protein Aggregates/drug effects ; Humans ; },
abstract = {Cytoplasmic accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates represents the primary pathological hallmark of TDP-43 proteinopathies including amyotrophic lateral sclerosis (ALS) and chronic traumatic encephalopathy (CTE). Inhibiting TDP-43 aggregation or disrupting its preformed fibrils might be promising strategies to prevent or delay the development of TDP-43 proteinopathies. Recently, the green tea polyphenol, epigallocatechin gallate (EGCG), was observed to prevent the formation of TDP-43 oligomeric species and fibrillar aggregates. Nevertheless, the atomic-level mechanism of this inhibition has been incompletely characterized. In this study, we performed a multitude of replica exchange with solute tempering 2 (REST2) and all-atom molecular dynamics (MD) simulations of 46.8 μs in total on TDP-43 models with and without EGCG. The REST2 simulation results revealed that EGCG impedes the β-sheet structure formation and interferes the interchain interaction of TDP-43304-348 dimer. Subsequent analyses show that EGCG could alter the distribution of free energy landscape and hinder the residue-residue interaction of the dimer. The binding analyses confirmed that EGCG preferentially bound to M307, F313, F316, W334, M339, Q344, and Q346 residues, and hydrophobic, polar, and π-π stacking interactions dominate the binding of EGCG on the dimer. Additional conventional molecular dynamics (MD) simulations demonstrated that the protofibrillar tetramer is the minimal stable TDP-43304-348 protofibril. Taking the tetramer as a protofibril model, we found that EGCG could reduce the structural stability and disrupt the β-sheet structure of TDP-43304-348 protofibril, thus possessing a destabilization effect on its higher-order structure. This investigation unveils the atomic-level mechanism by which EGCG against TDP-43 aggregation, which may provide potential fundamental knowledge of therapeutic strategies for TDP-43 proteinopathies.},
}

*Catechin/analogs & derivatives/pharmacology/chemistry/metabolism
*Molecular Dynamics Simulation
*DNA-Binding Proteins/chemistry/metabolism/antagonists & inhibitors
*Protein Aggregates/drug effects
Humans

@article {pmid41558895,
year = {2026},
author = {Gupta, AK and Patil, C and Vadhithala, V and Paul, JR},
title = {Improving risk-stratified use of preoperative MRI in young women with breast.},
journal = {Clinical imaging},
volume = {131},
number = {},
pages = {110721},
doi = {10.1016/j.clinimag.2026.110721},
pmid = {41558895},
issn = {1873-4499},
mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging/surgery ; *Magnetic Resonance Imaging/methods ; *Preoperative Care/methods ; Adult ; Risk Assessment ; Mastectomy ; },
abstract = {This Letter to the Editor critiques Erguven et al.'s single centre study of universal preoperative breast MRI in women 40 years or younger with newly diagnosed breast cancer. We place their findings within mixed evidence on the effect of MRI on re-excision, mastectomy rates and outcomes, and highlight design and reporting limitations that restrict causal inference and generalisability in this young, higher risk population. We then outline priorities for future prospective, risk stratified research and policy, linking MRI use to tumour biology, surgical planning, patient reported outcomes and equity to ensure that expanded imaging leads to better and fairer care.},
}

Humans
Female
*Breast Neoplasms/diagnostic imaging/surgery
*Magnetic Resonance Imaging/methods
*Preoperative Care/methods
Adult
Risk Assessment
Mastectomy

@article {pmid41559796,
year = {2026},
author = {Jun, YW and Hass, EP and Lee, S and Fazzio, TG and Gao, FB},
title = {Mislocalization of FTD3-associated mutant CHMP2B to the nucleus of human neurons due to loss of a nuclear export signal.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {45},
pmid = {41559796},
issn = {2051-5960},
support = {R01 HD072122/HD/NICHD NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Neurons/metabolism/pathology ; *Cell Nucleus/metabolism ; *Nuclear Export Signals/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; Mutation/genetics ; *beta Karyopherins/metabolism/genetics ; Active Transport, Cell Nucleus ; Cells, Cultured ; Exportin 1 Protein ; Endosomal Sorting Complexes Required for Transport ; },
abstract = {Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B, resulting in the production of mutant proteins CHMP2B[In5] and CHMP2B[Δ10]. Here, we found that wildtype CHMP2B (CHMP2B[WT]) is mostly present in the cytoplasm, but CHMP2B[In5] is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2B[WT] and ALS-associated CHMP2B[Q206H], and its loss in CHMP2B[In5] is responsible for the observed nuclear mislocalization. CHMP2B[Δ10] remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2B[In5] in FTD3 pathogenesis.},
}

Humans
*Neurons/metabolism/pathology
*Cell Nucleus/metabolism
*Nuclear Export Signals/genetics
*Frontotemporal Dementia/genetics/metabolism/pathology
Induced Pluripotent Stem Cells/metabolism
Mutation/genetics
*beta Karyopherins/metabolism/genetics
Active Transport, Cell Nucleus
Cells, Cultured
Exportin 1 Protein
Endosomal Sorting Complexes Required for Transport

@article {pmid41560764,
year = {2026},
author = {Ge, Y and Zhu, J and Ren, Y and Wu, X and Zhou, B and Wu, Y and Ge, Y},
title = {Trans-Generational Morphological Trait Plasticity in Parthenogenetic Offspring of Two Brachionus dorcas Morphotypes Induced by Asplanchna Kairomones.},
journal = {Ecology and evolution},
volume = {16},
number = {1},
pages = {e72956},
pmid = {41560764},
issn = {2045-7758},
abstract = {We compared trans-generational (F0-F12) morphological trait plasticity induced by Asplanchna kairomones between two Brachionus dorcas morphotypes (long-posterior spines, LS; short-posterior spines, SS) along with life-table parameters of the non-induced morphotypes. Under control conditions, SS rotifers tended to show higher fertility and smaller body size than LS rotifers. Low kairomone concentrations (50 and 200 ind./L) tended to increase body size in SS offspring, while exposure to 50, 200, and 800 ind./L kairomones induced spine elongation in both morphotypes, with posterolateral spine (PS) length increasing with kairomone concentration. Compared to the F0 generation, offspring of both morphotypes in unexposed controls showed generational fluctuations in body size; LS offspring exhibited shortening or no change in anteromedian spine (AMS) and anterolateral spine (ALS) lengths, while SS offspring showed elongation or no change in these spine lengths and PS length. Across all kairomone treatments, significant elongation of AMS and ALS in LS offspring was typically observed only in later generations, whereas SS offspring exhibited significant elongation from F1 through F12; LS offspring showed significant PS elongation from F2 through F12, with maximum lengths in the later generations (F5-F12), while SS offspring showed significant PS elongation from F1 through F12, peaking in early generations (F2-F4). Notably, the multi-generational mean PS length in SS offspring remained significantly shorter than that in LS offspring under each kairomone treatment. Overall, SS offspring appeared to employ a synergistic defense combining increased body size and spine elongation favoring a "rapid and moderate response," whereas LS offspring exhibited a "slow and extreme defense" strategy. These divergent strategies may result from evolutionary trade-offs involving resource allocation, environmental predictability, and genetic constraints.},
}

@article {pmid41561436,
year = {2025},
author = {Ishaq, SM and Russell, AP},
title = {Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1686230},
pmid = {41561436},
issn = {1662-5099},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurones, leading to muscle wasting, paralysis and respiratory failure. Pathological cytoplasmic aggregation of the RNA-binding protein transactive response DNA-binding protein 43 (TDP-43) protein occurs in neural tissues in ~97% of all ALS cases, and is also observed in skeletal muscle. Cytoplasmic aggregation of TDP-43 is believed to contribute to ALS pathogenesis; however, its precise mechanistic role/s continues to elude the field. This mini review explores the potential role and regulation of two TDP-43-associated RNA-protein assemblies, stress granules (SGs) and myogranules (MGs). We review the current understanding of SG and MG formation and their potential role in ALS-related neurodegeneration and muscle pathology. We also highlight limitations and strengths and suggest future directions for research.},
}

@article {pmid41561437,
year = {2025},
author = {Kim, SH and Boos, CE and Scalf, M and Wilkemeyer, AK and Smith, LM and Tibbetts, RS},
title = {Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS/FTD.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1720347},
pmid = {41561437},
issn = {1662-5099},
support = {R01 CA180765/CA/NCI NIH HHS/United States ; R35 GM126914/GM/NIGMS NIH HHS/United States ; RF1 AG069483/AG/NIA NIH HHS/United States ; T32 HG002760/HG/NHGRI NIH HHS/United States ; },
abstract = {Ubiquilin-2 (UBQLN2) is a ubiquitin (Ub)-binding shuttle protein that is mutated in X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS/FTD-linked mutations in UBQLN2 disrupt its conformation, increasing its tendency to form cytoplasmic aggregates that may disrupt cellular regulation through loss-of-function (LOF) and gain-of-function (GOF) effects. Here, we performed quantitative mass spectrometry (MS)-based interactome analysis of wild-type (UBQLN2[WT]) and ALS-mutant UBQLN2 (UBQLN2[ALS]) proteins using inducible pluripotent stem cells (iPSCs) and induced motor neurons (iMNs). Proteins showing enhanced association with UBQLN2[ALS] proteins included PEG10, a known degradation target of UBQLN2, and BAG6, a chaperone involved in the triage of mislocalized proteins (MLPs). BAG6 knockdown inhibited the solubility recovery of both UBQLN2[WT] and UBQLN2[ALS] proteins following heat stress (HS), suggesting it functions as a UBQLN2 holdase. In addition, knockdown of BAG6 or knockout of UBQLN2 led to PEG10 accumulation, implicating both in PEG10 turnover; however, neither BAG6 nor UBQLN2 was required for PEG10 degradation in response to HS. A highly aggregation-prone UBQLN2[4XALS] mutant harboring four different ALS-associated mutations showed increased PEG10 binding and modestly delayed PEG10 turnover while PEG10 degradation was not significantly different between UBQLN2[WT] and iPSCs expressing a UBQLN2[P497H] clinical mutant. The combined findings implicate BAG6 as a UBQLN2 holdase and identify a suite of proteins whose altered binding may contribute to pathologic changes in UBQLN2-associated ALS/FTD.},
}

@article {pmid41561680,
year = {2026},
author = {Lizio, A and Lops, J and Farè, M and Pezzera, S and Piras, R and Sideri, R and Tornabene, D and Lunetta, C and Diamanti, L and Sansone, VA and Cerri, F},
title = {Development and validation of predictive models for 6-month gastrostomy timing in amyotrophic lateral sclerosis.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001336},
pmid = {41561680},
issn = {2632-6140},
abstract = {BACKGROUND: Dysphagia is common in amyotrophic lateral sclerosis (ALS), contributing to malnutrition and accelerated disease progression. Although early nutritional intervention is recommended, the optimal timing for percutaneous endoscopic gastrostomy (PEG) placement remains uncertain. This study aimed to develop and validate simple prediction models, accessible via an online calculator, to identify ALS patients likely to require PEG within 6 months.

METHODS: We conducted a retrospective cohort study including ALS patients followed at three Italian reference centres between February 2018 and October 2023. Predictors of PEG placement within 6 months were identified using univariate and multivariable binary logistic regression models. Prediction models were developed following Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines and underwent both internal and external validation.

RESULTS: In the development cohort (n=263; median age 63.8 years), 138 patients (52.5%) underwent PEG within 6 months. Three models were developed: the Anamnestic Prediction Model, based on age, onset site and non-invasive ventilation (NIV), showed fair predictive performance. The Anamnestic and Functional Prediction Model, incorporating age, bulbar subscore of Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-r) and forced vital capacity (%), demonstrated strong predictive performance (Brier score: 0.1230), excellent discrimination (concordance index (c-index) 0.91) and good calibration (Hosmer-Lemeshow p=0.59). The Anamnestic and Nutritional Prediction Model, including age, onset site, NIV, body mass index and weight loss, showed good predictive performance (Brier score: 0.1719), discrimination (c-index 0.81) and calibration (Hosmer-Lemeshow p=0.48). These findings were confirmed in an external validation cohort of 116 ALS patients.

CONCLUSIONS: The prediction models provide accurate, easily implementable tools to predict PEG need within 6 months, enabling timely nutritional interventions that may improve outcomes and care quality in ALS.},
}

@article {pmid41562832,
year = {2026},
author = {Aranda-Abreu, GE and Rojas-Durán, F and Hernández-Aguilar, ME and Herrera-Covarrubias, D and Tlapa-Monge, LR and Mestizo-Gutiérrez, SL},
title = {The Molecular Architecture of Neurodegeneration: An Integrative Overview of Convergent Mechanisms.},
journal = {NeuroSci},
volume = {7},
number = {1},
pages = {},
pmid = {41562832},
issn = {2673-4087},
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease represent a major challenge in neuroscience due to their complex, multifactorial nature and the absence of curative treatments. These disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, proteostasis collapse, calcium dyshomeostasis, chronic neuroinflammation, and the prion-like propagation of misfolded proteins. Together, these processes trigger a cascade of cellular damage that culminates in synaptic dysfunction and programmed neuronal death. This review integrates current evidence on the sequential stages of neurodegeneration, emphasizing the convergence of oxidative, inflammatory, and proteotoxic pathways that drive neuronal vulnerability. Moreover, it explores emerging therapeutic strategies aimed at restoring cellular homeostasis, such as Nrf2 activation, modulation of the unfolded protein response (UPR), enhancement of autophagy, immunotherapy against pathological proteins, and gene therapy approaches. The dynamic interplay among mitochondria, endoplasmic reticulum, and glial cells is highlighted as a central element in disease progression. Understanding these interconnected mechanisms provides a foundation for developing multi-targeted interventions capable of halting or delaying neuronal loss and improving clinical outcomes in neurodegenerative disorders. This work provides an integrative and introductory overview of the convergent mechanisms underlying neurodegeneration rather than an exhaustive mechanistic analysis.},
}

@article {pmid41562880,
year = {2026},
author = {Fiorella, ML and Ballini, L and Lavermicocca, V and Ragno, MS and Restivo, DA and Marchese-Ragona, R},
title = {Dysphagia and Dysarthria in Neurodegenerative Diseases: A Multisystem Network Approach to Assessment and Management.},
journal = {Audiology research},
volume = {16},
number = {1},
pages = {},
pmid = {41562880},
issn = {2039-4330},
abstract = {Dysphagia and dysarthria are common, co-occurring manifestations in neurodegenerative diseases, resulting from damage to distributed neural networks involving cortical, subcortical, cerebellar, and brainstem regions. These disorders profoundly affect patient health and quality of life through complex sensorimotor impairments. Objective: The aims was to provide a comprehensive, evidence-based review of the neuroanatomical substrates, pathophysiology, diagnostic approaches, and management strategies for dysphagia and dysarthria in neurodegenerative diseases with emphasis on their multisystem nature and integrated treatment approaches. Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science databases (2000-2024), focusing on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Search terms included "dysphagia", "dysarthria", "neurodegenerative diseases", "neural networks", "swallowing control" and "speech production." Studies on neuroanatomy, pathophysiology, diagnostic tools, and therapeutic interventions were included. Results: Contemporary neuroscience demonstrates that swallowing and speech control involve extensive neural networks beyond the brainstem, including bilateral sensorimotor cortex, insula, cingulate gyrus, basal ganglia, and cerebellum. Disease-specific patterns reflect multisystem involvement: PD affects basal ganglia and multiple brainstem nuclei; ALS involves cortical and brainstem motor neurons; MSA causes widespread autonomic and motor degeneration; PSP produces tau-related damage across multiple brain regions. Diagnostic approaches combining fiberoptic endoscopic evaluation, videofluoroscopy, acoustic analysis, and neuroimaging enable precise characterization. Management requires multidisciplinary Integrated teams implementing coordinated speech-swallowing therapy, pharmacological interventions, and assistive technologies. Conclusions: Dysphagia and dysarthria in neurodegenerative diseases result from multifocal brain damage affecting distributed neural networks. Understanding this multisystem pathophysiology enables more effective integrated assessment and treatment approaches, enhancing patient outcomes and quality of life.},
}

@article {pmid41563042,
year = {2026},
author = {Bergh, S and Simonsson, O and Petersén, Å},
title = {Analyses of the Effects of Wild-Type TDP-43 Overexpression in Oxytocin Neurons in Mice.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {1},
pages = {e70059},
pmid = {41563042},
issn = {1365-2990},
support = {2022/01092//Swedish Research Council/ ; //Brain Foundation/ ; //Region Skåne/ ; 2019.0467//Knut and Alice Wallenberg Foundation/ ; },
mesh = {Animals ; *Oxytocin/metabolism ; *Neurons/metabolism ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Paraventricular Hypothalamic Nucleus/metabolism ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; },
abstract = {Selective TDP-43 overexpression in oxytocin neurons in the paraventricular nucleus of the hypothalamus causes a decrease in oxytocin-immunopositive cells compared to uninjected mice. AAV-mediated TDP-43 overexpression in oxytocin neurons does not appear to be a major driver of behavioural and metabolic phenotypes in mice.},
}

Animals
*Oxytocin/metabolism
*Neurons/metabolism
Mice
*DNA-Binding Proteins/metabolism/genetics
*Paraventricular Hypothalamic Nucleus/metabolism
Male
Mice, Inbred C57BL
Mice, Transgenic

@article {pmid41563518,
year = {2026},
author = {Boomsma, A and Doyle, C and Sai, N and Rogers, ML and Lee, SH and Benyamin, B},
title = {The differences in sex ratio between sporadic and familial amyotrophic lateral sclerosis: a systematic review.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {92},
pmid = {41563518},
issn = {1432-1459},
support = {Research Training Program//Australian Government/ ; DIS-202303-00932//FightMND/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; *Sex Ratio ; Male ; Female ; *Sex Characteristics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is more prevalent in males than in females. However, it is unclear whether the difference in sex ratio is observed similarly in sporadic compared to familial ALS. Here, we conducted a systematic review to investigate the differences in sex ratio between familial and sporadic ALS. Following the meta-analysis of observational studies in epidemiology (MOOSE) guidelines, this study searched Ovid MEDLINE, Embase, Emcare, SCOPUS and Cochrane databases. We used a random-effects meta-analysis to estimate sex ratios in a total of 9269 ALS patients (4135 female, 5134 male) across 20 included studies. We confirmed that ALS is more prevalent in males than in females (sex ratio: 1.25 (95%CI 1.14-1.37). However, when we stratified the analyses, the sex ratio was only different in sporadic ALS. Male-to-female ratios were 1.29 (95% CI 1.16-1.42) for sporadic ALS and 1.05 (95% CI 0.93-1.18) for familial ALS. A further analysis showed a pooled risk ratio of 1.07 (95% CI 1.00-1.15), indicating a 7% higher likelihood of males being diagnosed with sporadic rather than familial ALS. These findings highlight the importance of considering sex-specific factors in ALS research and clinical practice.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/genetics
*Sex Ratio
Male
Female
*Sex Characteristics

@article {pmid41564501,
year = {2026},
author = {Han, L and Zang, S and Li, W and Yue, H and Zhou, X and Chen, J and Geng, M and Duan, W and Xie, Z and Zhan, Z},
title = {Discovery of the thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors.},
journal = {Bioorganic & medicinal chemistry},
volume = {135},
number = {},
pages = {118571},
doi = {10.1016/j.bmc.2026.118571},
pmid = {41564501},
issn = {1464-3391},
mesh = {Humans ; Animals ; *Membrane Proteins/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; Mice ; Molecular Structure ; *Drug Discovery ; Dose-Response Relationship, Drug ; *Thiazines/pharmacology/chemistry/chemical synthesis ; STING Protein ; },
abstract = {The adaptor molecule STING is embedded in the endoplasmic reticulum (ER) membrane. In innate immunity, STING is a critical cascade in regulating the cytoplasmic DNA-recognizing signaling. Aberrant STING signaling facilitates the host body to secrete an intolerable level of inflammatory cytokines as well as interferons, causing interferonopathies including STING-associated infantile vasculopathy, familial chilblain lupus, and amyotrophic lateral sclerosis. Suppressing the disordered STING signaling has demonstrated to ameliorate the inflammatory impairments of interferonopathy diseases. In this article, we provide the discovery of thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors. Through the structure-activity relationship (SAR) exploration, we identified compound 11 h as an oral-available STING inhibitor possessing cellular mouse- or human-STING inhibiting IC50 of 8.8 or 11.5 nM. Compound 11 h markedly hindered the cellular STING cascade in both murine- and human-derived cells. Furthermore, 11 h achieved robust in vivo activity opposing MAS-2-caused systemic inflammatory damage and cisplatin-caused renal inflammation and injury. Proposed binding model of 11 h-STING indicates that 11 h engages the transmembrane area of STING.},
}

Humans
Animals
*Membrane Proteins/antagonists & inhibitors/metabolism
Structure-Activity Relationship
Mice
Molecular Structure
*Drug Discovery
Dose-Response Relationship, Drug
*Thiazines/pharmacology/chemistry/chemical synthesis
STING Protein

@article {pmid41564770,
year = {2026},
author = {Lee, H and Jo, Y and Jung, M and Lee, JH and Kim, TH and Lee, J and Kim, DJ and Rahmati, M and Smith, L and Pizzol, D and Son, Y and Park, J and Ahn, SH and Yon, DK and Choi, DW and Kang, J},
title = {Heavy metal exposure and all health outcomes: An umbrella review of meta-analyses.},
journal = {Journal of hazardous materials},
volume = {503},
number = {},
pages = {141141},
doi = {10.1016/j.jhazmat.2026.141141},
pmid = {41564770},
issn = {1873-3336},
mesh = {Humans ; *Metals, Heavy/toxicity ; *Environmental Exposure/adverse effects ; Meta-Analysis as Topic ; *Environmental Pollutants/toxicity ; Female ; Arsenic ; },
abstract = {We aimed to systematically evaluate the strength and credibility of evidence linking exposure to five major heavy metals, including arsenic, cadmium, lead, mercury, and chromium, with health outcomes (PROSPERO, CRD420251169899). Literature searches of PubMed/Embase, CINAHL, and Google Scholar up to April 20, 2025, identified meta-analyses of observational studies assessing these associations. Effect sizes were recalculated using random-effects models and expressed as equivalent odds ratios (eOR) with 95 % confidence intervals (CIs). The methodological quality of the included reviews was assessed using the AMSTAR2, and the credibility of associations was graded according to predefined criteria: Class I (convincing), Class II (highly suggestive), Class III (suggestive), Class IV (weak), and non-significant (NS). A total of 35 meta-analyses encompassing 103 health outcomes were included. Arsenic exposure was associated with melanoma (eOR 1.50 [95 % CI, 1.0-2.24], CE=IV), digestive cancers (1.23 [1.07-1.41], CE=III), gestational diabetes mellitus (1.47 [1.11-1.95], CE=III), hypertension (1.15 [1.06-1.24], CE=III), and preterm birth (1.12 [1.04-1.21], CE=III). Lead exposure showed significant associations with autistic disorder in children (12.70 [3.93-41.10], CE=IV), hearing loss (7.55 [6.69-8.53], CE=III), age-related eye disease (9.80 [1.72-55.85], CE=IV), and amyotrophic lateral sclerosis (1.46 [1.16-1.83], CE=III). Mercury exposure was linked to increased risk in membranous nephropathy (5.75 [1.54-21.44], CE=IV) and thyroid cancer (1.90 [1.55-2.33], CE=IV). Cadmium exposure was associated with renal cancer (1.47 [1.26-1.71], CE=II), cardiovascular disease (1.33 [1.05-1.69], CE=IV), stroke (1.36 [1.10-1.68], CE=III), diabetes mellitus (1.27 [1.07-1.52], CE=III), fracture risk (1.30 [1.13-1.49], CE=III), and age-related eye disease (113.26 [16.86-760.68], CE=III). Chromium exposure was associated with stomach cancer (1.28 [1.16-1.41], CE=I), supporting convincing evidence. Overall, exposures to these metals were consistently associated with diverse diseases across organ systems and life stages, suggesting proactive implications against heavy metal exposures.},
}

Humans
*Metals, Heavy/toxicity
*Environmental Exposure/adverse effects
Meta-Analysis as Topic
*Environmental Pollutants/toxicity
Female
Arsenic

@article {pmid41565003,
year = {2026},
author = {Baek, Y and Lee, H and Park, ES and Park, M and Wee, Y and Kim, H and Roh, SH and Ha, NC},
title = {Structural Comparison of the Human G93A Mutant SOD1 to the Wild-type SOD1 Filaments.},
journal = {Journal of molecular biology},
volume = {438},
number = {6},
pages = {169642},
doi = {10.1016/j.jmb.2026.169642},
pmid = {41565003},
issn = {1089-8638},
mesh = {*Superoxide Dismutase-1/chemistry/genetics/metabolism/ultrastructure ; Humans ; Cryoelectron Microscopy ; Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Models, Molecular ; Protein Conformation ; Superoxide Dismutase ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by Cu, Zn-superoxide dismutase (SOD1) misfolding and aggregation, particularly in familial cases. The G93A mutation in SOD1, strongly associated with familial ALS, is widely studied in transgenic mouse models of the disease. In this study, we investigated the filament structure of the G93A mutant SOD1 using cryo-electron microscopy. The resulting fibrils consisted of a single protofilament with a left-handed helical twist, closely resembling those formed by wild-type (WT) SOD1 under identical conditions. Self- and cross-seeding experiments promoted filament formation in both WT and G93A mutant SOD1, compared to the no-seed condition. Notably, the G93A mutant exhibited significantly higher susceptibility to proteolysis in its native state than WT SOD1. Mass spectrometry analysis suggested that the structurally disordered electrostatic loop acts as a key common intermediate structure in filament formation for both WT and G93A mutant SOD1. These findings suggest that shared filament formation pathways underlie the aggregation of both WT and G93A mutant SOD1, providing new insights into the molecular mechanisms contributing to ALS pathogenesis.},
}

*Superoxide Dismutase-1/chemistry/genetics/metabolism/ultrastructure
Humans
Cryoelectron Microscopy
Amyotrophic Lateral Sclerosis/genetics
Mutation
Models, Molecular
Protein Conformation
Superoxide Dismutase

@article {pmid41565302,
year = {2026},
author = {Warita, H and Urushitani, M and Atsuta, N and Izumi, Y and Kano, O and Shimizu, T and Nakayama, Y and Narita, Y and Nodera, H and Fujita, T and Mizoguchi, K and Morita, M and Aoki, M},
title = {Addendum to the 2023 clinical practice guidelines for amyotrophic lateral sclerosis in Japan: approval and integration of novel disease-modifying therapies.},
journal = {Rinsho shinkeigaku = Clinical neurology},
volume = {66},
number = {2},
pages = {67-73},
doi = {10.5692/clinicalneurol.cn-002198},
pmid = {41565302},
issn = {1882-0654},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/therapy ; Japan ; *Practice Guidelines as Topic ; Edaravone/administration & dosage ; Vitamin B 12/administration & dosage/analogs & derivatives ; Genetic Therapy ; Drug Approval ; Oligonucleotides/administration & dosage ; Genetic Testing ; Oligonucleotides, Antisense/administration & dosage ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an intractable motor neuron disease characterized by progressive degeneration of motor neurons with varying degrees of frontotemporal lobe dysfunction. This English summary of the addendum to the Japanese clinical practice guidelines for ALS outlines major recent advances in pharmacological therapy in Japan. Following the development of the 2023 guidelines, three additional medications-oral edaravone, high-dose intramuscular mecobalamin, and tofersen-have been introduced. Oral edaravone, with its ease of administration, demonstrates pharmacokinetics comparable to the intravenous formulation. High-dose mecobalamin reduces functional decline when initiated early in the disease course. Tofersen, an antisense oligonucleotide, is the first gene-targeted therapy approved in Japan for patients with copper/zinc superoxide dismutase gene-related ALS, highlighting the importance of genetic testing and counseling in all ALS cases. This addendum provides updated expert consensus recommendations for the use, dosing, and monitoring of these therapies, while emphasizing the need for thorough communication about the ethical and psychological dimensions of genetic testing. It also addresses practical considerations for combination therapy, noting that up to three or four anti-ALS agents are now available in Japan. The long-term safety and efficacy of these therapies, as well as their potential synergistic or additive effects, remain to be clarified through real-world data and prospective registries. The objectives of this addendum are twofold: to present these advances and recommendations in English to foster international collaboration, and to inform the global ALS community about the latest therapeutic strategies in Japan. In addition, ongoing efforts to harmonize clinical evaluation standards and promote international clinical trials are highlighted, with the goal of improving patient outcomes and advancing ALS research worldwide.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/therapy
Japan
*Practice Guidelines as Topic
Edaravone/administration & dosage
Vitamin B 12/administration & dosage/analogs & derivatives
Genetic Therapy
Drug Approval
Oligonucleotides/administration & dosage
Genetic Testing
Oligonucleotides, Antisense/administration & dosage

@article {pmid41565509,
year = {2026},
author = {Lee, NC and Lin, CH and Chien, YH and Hwu, WL},
title = {Genetic testing for adult-onset neurodegenerative diseases: A clinical perspective.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.01.021},
pmid = {41565509},
issn = {0929-6646},
abstract = {Adult-onset neurodegenerative diseases (AOND), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, severely affect patients' quality of life. Pathogenic single-nucleotide variations (SNVs) and small insertions and deletions (indels) can disrupt genes involving ANOD, and expansion of short tandem repeats such as trinucleotide repeats is an important etiology of hereditary ataxia. Variations in more than one gene combined to create polygenic risk scores (PRS) for multifactorial types of AOND. Recently, genome structural variations (SVs) like copy number variations (CNVs) and expansion of long repeats are increasingly identified as the etiologies of AOND. Tools for molecular diagnosis of AOND have evolved from Sanger sequencing to next-generation sequencing (NGS) such as short-read whole-exome sequencing (WES) and whole-genome sequencing (WGS), and long-read sequencing is especially helpful in solving SVs and expansions of long repeats. Patients might have affected and/or at-risk family members at the time of diagnosis, so genetic counseling for risk handling and birth planning need to be conducted with caution. This review will help readers to better understand the genetic testing for AOND.},
}

@article {pmid41567979,
year = {2025},
author = {Hamdalla, RH and Bhaskar, VB and Tian, C},
title = {Brain-derived extracellular vesicles potentially mediate crosstalk with peripheral organs in neurodegenerative diseases.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1710150},
pmid = {41567979},
issn = {2296-634X},
support = {R01 HL153176/HL/NHLBI NIH HHS/United States ; },
abstract = {Brain-Derived Extracellular vesicles (BDEVs) are emerging mediators of intra- and interorgan communication in neurodegenerative diseases (NDs) such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). A growing body of evidence suggests that BDEVs play an important role in modulating intercellular communication within the central nervous system in the pathogenesis of many NDs. By transporting non-coding RNAs (e.g., miRNAs) and important pathological proteins, BDEVs also influence peripheral organs and contribute to the progression of disease in the central nervous system (CNS). This review extends the understanding of NDs beyond solely brain dysfunction and gives a novel framework for the progression of these diseases, uniquely emphasizing the currently underexplored mechanisms by which BDEV-mediated communication exacerbates or potentially initiates peripheral dysfunction or complications. It maps and clarifies the specific and potential mechanisms by which CNS-originating EV activity proliferates systemic dysfunction, presenting new opportunities and areas for therapeutic and diagnostic treatments for NDs. These findings are contextualized across multiple NDs, including Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), by incorporating data on dysregulated BDEV miRNAs and toxic proteins to map the pathway of BDEV-mediated disease spread.},
}

@article {pmid41569095,
year = {2026},
author = {Charbonnel, T and Richard, E and Dupuis, A and Palla, M and Vourc'h, P and Corcia, P and Al Ojaimi, Y and Blasco, H},
title = {The preclinical discovery and development of edaravone for the treatment of amyotrophic lateral sclerosis: what lessons have we learnt?.},
journal = {Expert opinion on drug discovery},
volume = {21},
number = {2},
pages = {147-160},
doi = {10.1080/17460441.2026.2619067},
pmid = {41569095},
issn = {1746-045X},
mesh = {*Edaravone/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; Animals ; *Neuroprotective Agents/pharmacology/administration & dosage ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/administration & dosage/pharmacokinetics ; Drug Development/methods ; Drug Discovery/methods ; Oxidative Stress/drug effects ; Mice, Transgenic ; Mice ; Drug Evaluation, Preclinical ; Blood-Brain Barrier/metabolism ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with limited therapeutic options. Among the few approved drugs, edaravone, a free radical scavenger developed originally for ischemic stroke, has attracted particular attention for its ability to counteract oxidative stress, a key driver of neurodegeneration. Its amphipathic structure and ability to cross the blood-brain barrier support its potential neuroprotective action.

AREAS COVERED: The authors discuss preclinical studies demonstrating edaravone's ability to reduce oxidative damage, preserve mitochondrial function, and modulate neuroinflammatory responses in ALS cellular and animal models. They discuss variations in dosage, timing, and disease models that produced heterogeneous results. In transgenic mice, edaravone may delay symptom onset and modestly extend survival, but these effects are inconsistent and often limited to early disease stages.

EXPERT OPINION: Clinically, edaravone provides modest benefits in a subset of patients, reflecting the translational gap between preclinical efficacy and clinical relevance. This case highlights broader challenges in ALS drug discovery, including limited model predictivity, methodological variability, and lack of patient stratification. The edaravone experience highlights key lessons for future neuroprotective approaches: the importance of standardized preclinical design, integration of human-based models, early pharmacokinetic validation, and biomarker-driven trials to advance precision neuroprotection in ALS.},
}

*Edaravone/pharmacology/administration & dosage
*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology
Humans
Animals
*Neuroprotective Agents/pharmacology/administration & dosage
Disease Models, Animal
Free Radical Scavengers/pharmacology/administration & dosage/pharmacokinetics
Drug Development/methods
Drug Discovery/methods
Oxidative Stress/drug effects
Mice, Transgenic
Mice
Drug Evaluation, Preclinical
Blood-Brain Barrier/metabolism

@article {pmid41569391,
year = {2026},
author = {Raymond, KF and Hodge, T and St Jean, B and Liu, BF},
title = {Barriers to Long COVID Care in the U.S.: An Application of Levesque et al.'s Access Framework.},
journal = {Health care analysis : HCA : journal of health philosophy and policy},
volume = {},
number = {},
pages = {},
pmid = {41569391},
issn = {1573-3394},
support = {Pandemic Readiness Initiative//University of Maryland/ ; Pandemic Readiness Initiative//University of Maryland/ ; },
abstract = {Long COVID is a condition that arose during the COVID-19 pandemic in individuals who developed the multi-system chronic condition after a COVID-19 infection. During the pandemic in the United States (U.S.), these "COVID long-haulers" navigated a complex and overburdened health care system in pursuit of diagnoses and treatments. This qualitative secondary analysis used the 2013 Levesque et al. Conceptual Model of Healthcare Access to examine multidimensional health care access issues faced by 29 COVID long-haulers in the U.S. Our analysis showed that long-haulers faced complementary issues from both individual and health systems perspectives related to the inability to get diagnoses or treatments, long waiting times for providers and difficulty reaching services, underinformed providers and biased interpersonal experiences, and struggles with the financial costs of treating the condition, which impacted care decisions. Interviewees also described relying on alternative medicine to provide symptom relief. Overall, this study extends international research by offering a comprehensive examination of Long COVID health care access issues in the U.S. and identifying specific insights related to health care access that made obtaining Long COVID care difficult, such as the mismatch between individual expectations of what health care should look like and how it actually operates. Our use of the full Conceptual Model of Healthcare Access provides new insights into the overlap across layers of access issues and offers suggestions for how public health and clinical health practitioners can collaborate to meet the needs of vulnerable populations such as these in future health emergencies.},
}