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

@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 = {},
number = {},
pages = {e00834},
doi = {10.1016/j.neurot.2026.e00834},
pmid = {41549027},
issn = {1878-7479},
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.},
}

@article {pmid41548740,
year = {2026},
author = {Qaisar, R},
title = {Fiber-type-specific architecture and pathophysiology of the neuromuscular junction.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.01.015},
pmid = {41548740},
issn = {1873-7544},
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.},
}

@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 = {},
number = {},
pages = {103028},
doi = {10.1016/j.arr.2026.103028},
pmid = {41548719},
issn = {1872-9649},
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.},
}

@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 = {},
number = {},
pages = {1-13},
doi = {10.1080/20502877.2025.2589634},
pmid = {41548100},
issn = {2050-2885},
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.},
}

@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 = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-36208-8},
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/ ; },
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.},
}

@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},
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.},
}

@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},
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.},
}

@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 {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 {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},
doi = {10.1136/bmjopen-2025-109620},
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 {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 {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 = {},
doi = {10.64898/2025.12.28.696512},
pmid = {41542616},
issn = {2692-8205},
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 {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 = {},
doi = {10.64898/2026.01.09.698641},
pmid = {41542389},
issn = {2692-8205},
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 {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 {pmid2025077,
year = {1991},
author = {Boldt, J and Zickmann, B and Fedderson, B and Herold, C and Dapper, F and Hempelmann, G},
title = {RETRACTED: Six different hemofiltration devices for blood conservation in cardiac surgery.},
journal = {The Annals of thoracic surgery},
volume = {51},
number = {5},
pages = {747-753},
doi = {10.1016/0003-4975(91)90116-8},
pmid = {2025077},
issn = {0003-4975},
mesh = {Aged ; Blood Coagulation/physiology ; Blood Preservation/*methods ; Coronary Artery Bypass/*methods ; Equipment Design ; Hemofiltration/*instrumentation ; Hemoglobins/analysis ; Humans ; Middle Aged ; Oxygen/blood ; Platelet Count ; },
abstract = {This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor. Reason: By comparing the results of this article with results reported by Berend Fedderson (Hämofiltration als blutsparendes Verfahren in der Herzchirurgie: sechs verschiedene Hämofilter im Vergleich; Niebüll, Germany; http://d-nb.info/930239350), it has been determined that experimental outcomes have been altered. Thus, the research published in this article was misrepresented to The Annals of Thoracic Surgery and the article should be retracted from the scientific record.},
}

Aged
Blood Coagulation/physiology
Blood Preservation/*methods
Coronary Artery Bypass/*methods
Equipment Design
Hemofiltration/*instrumentation
Hemoglobins/analysis
Humans
Middle Aged
Oxygen/blood
Platelet Count

@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 {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},
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.},
}

@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 {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 = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c15324},
pmid = {41538404},
issn = {1520-5118},
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.},
}

@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},
support = {Z01 AG000959/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 {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 {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 = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04631-3},
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/ ; },
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.},
}

@article {pmid41422050,
year = {2025},
author = {Valletta, M and Briel, N and Yuksekel, I and Barboure, M and Coward, A and De Houwer, JFH and Fawad, A and González-Mayoral, A and Iaccarino, G and Martínez-Dubarbie, F and Moukaled, S and Andreasson, U and Gobom, J and Brinkmalm, A and Tijms, B and Zetterberg, H and Blennow, K and Suárez-Calvet, M and Schöll, M and Paterson, RW and Montoliu-Gaya, L and Sogorb-Esteve, A},
title = {Fluid biomarkers for neurodegenerative diseases: a comprehensive update.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {12},
pmid = {41422050},
issn = {1758-9193},
abstract = {UNLABELLED: Fluid biomarkers are revolutionizing the diagnosis and management of neurodegenerative diseases by enabling earlier diagnosis and disease monitoring. In particular, blood-based biomarkers have emerged as a minimally invasive and scalable alternative to cerebrospinal fluid analysis. Recent advances in blood-based tau biomarkers have shown high diagnostic accuracy for Alzheimer’s disease (AD). Other neurodegenerative diseases—such as synucleinopathies, frontotemporal lobar degeneration, limbic-predominant age-related TDP-43 encephalopathy (LATE), and amyotrophic lateral sclerosis—pose substantial challenges due to their heterogeneous clinical presentations and the current absence of robust biomarkers for hallmark pathologies. Nonetheless, promising candidate markers are emerging for improved disease characterization and staging. Technological innovations, including single-molecule arrays (Simoa), advanced mass spectrometry workflows and nucleic acid linked immune-sandwich assay (NULISA) have markedly enhanced the sensitivity and precision of biomarker quantification from low-concentration biological matrices. More recently, the development of fully automated platforms shows great promise for routine measurement of blood-based biomarkers in clinical settings. Despite this progress key challenges remain, including the need for improved assay reproducibility, standardization, and the optimization of clinical workflows. In this review, we provide a comprehensive update on recent progress in fluid biomarker research across AD and major neurodegenerative diseases, highlight technological advances in detection methods, and discuss current challenges and opportunities for clinical translation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01919-z.},
}

@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 = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c07950},
pmid = {41535729},
issn = {1520-5207},
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.},
}

@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 interneurofn 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},
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.},
}

@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 = {},
number = {},
pages = {108982},
doi = {10.1016/j.pharmthera.2026.108982},
pmid = {41534661},
issn = {1879-016X},
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.},
}

@article {pmid41534629,
year = {2026},
author = {Douville, CO},
title = {First evidence supporting the theory of the sensorimotor paradox on the origins of mind and language.},
journal = {Bio Systems},
volume = {},
number = {},
pages = {105691},
doi = {10.1016/j.biosystems.2026.105691},
pmid = {41534629},
issn = {1872-8324},
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.},
}

@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},
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.},
}

@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},
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.},
}

@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 {pmid41533560,
year = {2026},
author = {Lautenbach, A and Seitz, L and Knerr-Rupp, K and Hartmann, C and McMillan, A and Cooper, C and Meadows, R},
title = {Characteristics of individuals living with obesity in Germany, weight loss methods attempted, and response over a 12-month period: results from a cross-sectional survey.},
journal = {Obesity facts},
volume = {},
number = {},
pages = {1-19},
doi = {10.1159/000550050},
pmid = {41533560},
issn = {1662-4033},
abstract = {INTRODUCTION: This study aimed to describe the demographic and clinical characteristics of individu-als with obesity (IWO) in Germany and to explore weight loss methods and their effectiveness.

METHODS: Data were drawn from a cross-sectional survey of adults with obesity (≥18 years of age) conducted in Germany between November - December 2022 through an online consumer panel. Data were captured using a self-administered questionnaire, and included demographic and clini-cal characteristics, weight loss methods attempted in the last 12 months, and how successful these attempts were. Logistic regression analysis assessed the effect of variables including age, sex and weight loss method on the odds of weight reduction. Data were presented as odds ratios, p-values and confidence intervals. For descriptive statistics, continuous variables were presented as means and standard deviations (SDs). Categorical variables were presented as frequency counts and per-centages.

RESULTS: Overall, the 1000 IWO in this study had a mean age (SD) of 42.8 (10.7) years, 94% were White, 45% were female, and mean (SD) body mass index was 37.6 (8.3) kg/m2. In total, 73% had ≥1 comorbid conditions, the most common being musculoskeletal pain (19%). Just 43% were being managed for a weight condition, however, 95% had attempted to lose weight over the previous 12 months, with 33% utilizing an anti-obesity medication and 26% utilizing a calorie-controlled diet. IWO on a calorie-controlled diet or a digital health application were more likely to lose weight than people using other methods (p<0.05).

CONCLUSION: Our results highlight gaps in obesity recognition and management in Germany, under-scoring the importance of enhancing access to effective interventions and improving support sys-tems for this population.},
}

@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 {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},
doi = {10.1111/jnc.70350},
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 {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},
doi = {10.4103/bc.bc_81_25},
pmid = {41531877},
issn = {2455-4626},
}

@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 = {1-15},
doi = {10.2147/ITT.S566733},
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 {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 {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 ; *Quinidine/administration & dosage/adverse effects/pharmacology/therapeutic use ; *Pseudobulbar Palsy/drug therapy ; Network Meta-Analysis as Topic ; Drug Combinations ; *Nervous System Diseases/drug therapy/complications ; 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
*Quinidine/administration & dosage/adverse effects/pharmacology/therapeutic use
*Pseudobulbar Palsy/drug therapy
Network Meta-Analysis as Topic
Drug Combinations
*Nervous System Diseases/drug therapy/complications
Randomized Controlled Trials as Topic

@article {pmid41530082,
year = {2026},
author = {Cooper, P and Lu, M and Chan, M and Wilman, AH 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 = {1-17},
doi = {10.1017/cjn.2026.10527},
pmid = {41530082},
issn = {0317-1671},
}

@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 = {},
number = {},
pages = {13872877251411546},
doi = {10.1177/13872877251411546},
pmid = {41527739},
issn = {1875-8908},
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.},
}

@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 = {},
number = {},
pages = {107272},
doi = {10.1016/j.nbd.2026.107272},
pmid = {41525888},
issn = {1095-953X},
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.},
}

@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 motorneurons reveals impaired extracellular matrix signaling and activated cell cycle kinase in FUS-ALS.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107268},
doi = {10.1016/j.nbd.2026.107268},
pmid = {41525886},
issn = {1095-953X},
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 MN 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 motoneurons.},
}

@article {pmid41525811,
year = {2026},
author = {Pradhan, LK and Das, SK},
title = {Zebrafish neural regeneration: mechanistic insights into human nervous system repair.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.01.009},
pmid = {41525811},
issn = {1873-7544},
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.},
}

@article {pmid41524979,
year = {2026},
author = {Sun, Y and Huang, C and Pan, Y and He, X and Zhang, H},
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 = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology/diagnosis/metabolism/complications ; Fibrosis ; Animals ; *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.},
}

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

@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 {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 {pmid41521076,
year = {2026},
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 = {},
number = {},
pages = {},
doi = {10.1111/1751-2980.70025},
pmid = {41521076},
issn = {1751-2980},
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.},
}

@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 = {},
number = {},
pages = {},
pmid = {41521074},
issn = {1976-670X},
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.},
}

@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},
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.},
}

@article {pmid41497595,
year = {2025},
author = {Zhong, W and Scialò, C and Gatta, B and Häfliger, M and Leu, N and Lurati, F and Peter, M and Ramesh, N and Roschitzki, B and Jagannath, S and Manglunia, R and de Cecco, E and Lim, SM and Wilkins, OG and Aguzzi, A and Ward, M and Fratta, P and Petrucelli, L and Lagier-Tourenne, C and Polymenidou, M},
title = {Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41497595},
issn = {2692-8205},
support = {RM1 NS133601/NS/NINDS NIH HHS/United States ; },
abstract = {Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) shows striking clinical and neuropathological heterogeneity, yet a systematic analysis of subtype-specific features and inter-patient variability was missing. We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43. Our work establishes a mechanistic link between TMEM106B and TDP-43 aggregation, identifies lysosomal escape as a key driver of pathology and introduces the strongest model yet for seeded TDP-43 aggregation and loss of function, to enable discovery of disease modifiers.},
}

@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},
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.},
}

@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 ; },
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

@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},
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.},
}

@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 = {1-15},
doi = {10.1159/000550417},
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 {pmid41518598,
year = {2026},
author = {La, N and K Rattanapitoon, S and Arunsan, P and Rattanapitoon, NK},
title = {Re: Real-World Use of Dual Biological Therapy in Severe Asthma: Insights from Four Cases.},
journal = {The Journal of asthma : official journal of the Association for the Care of Asthma},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/02770903.2026.2614959},
pmid = {41518598},
issn = {1532-4303},
abstract = {In response to the report by Salameh et al. on dual biologic therapy in severe asthma, we highlight several considerations that warrant careful evaluation before routine adoption of combination biologics. Key issues include the unclear criteria for "suboptimal control" prior to therapy escalation, potential confounding factors such as adherence and comorbidities, and limitations of relying solely on classical type-2 biomarkers to guide biologic selection. Observed clinical improvements may reflect natural variability or stabilization of extrinsic factors rather than true pharmacologic synergy. We emphasize the need for structured phenotyping, including biomarker panels and treatable-trait assessment, to identify patients likely to benefit from dual-pathway blockade. Importantly, phenotyping should be viewed not only as a safeguard against inappropriate escalation, but as a prerequisite for identifying mechanistically suitable candidates. While Salameh et al.'s report underscores the complexity of residual inflammation in severe asthma, future work should focus on mechanistic rationale, patient stratification, and prospective evaluation of safety, efficacy, and cost-effectiveness to advance combination biologic therapy from anecdotal experience to evidence-based precision care.},
}

@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 {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 = {},
number = {},
pages = {},
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)/ ; },
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.},
}

@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},
doi = {10.3988/jcn.2025.0483},
pmid = {41517820},
issn = {1738-6586},
}

@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},
doi = {10.3988/jcn.2025.0219},
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 {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},
doi = {10.1097/MD.0000000000045225},
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 {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 = {},
doi = {10.3390/jcm15010287},
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 {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 = {},
doi = {10.3390/jcm15010258},
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 {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 = {},
doi = {10.3390/ijms27010281},
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 {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 = {},
doi = {10.3390/plants15010103},
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 {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 {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 {pmid41512846,
year = {2026},
author = {Zou, C and Li, P and Li, B and Sparwasser, T and Yuan, J},
title = {Next steps in regulatory T cells: Biology and clinical application.},
journal = {Cell},
volume = {189},
number = {1},
pages = {6-22},
doi = {10.1016/j.cell.2025.11.035},
pmid = {41512846},
issn = {1097-4172},
mesh = {Humans ; *T-Lymphocytes, Regulatory/immunology/cytology ; Animals ; Interleukin-2/therapeutic use ; Graft vs Host Disease/immunology/prevention & control/therapy ; Immune Tolerance ; Amyotrophic Lateral Sclerosis/therapy/immunology ; },
abstract = {Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a "living drug" to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.},
}

Humans
*T-Lymphocytes, Regulatory/immunology/cytology
Animals
Interleukin-2/therapeutic use
Graft vs Host Disease/immunology/prevention & control/therapy
Immune Tolerance
Amyotrophic Lateral Sclerosis/therapy/immunology

@article {pmid41512823,
year = {2026},
author = {Guo, L and Mann, JR and Mauna, JC and Copley, KE and Wang, H and Rubien, JD and Bergmann, CA and Carey, JL and Merjane, J and Ngo, M and Xu, J and Odeh, HM and Lin, J and Lee, BL and Ganser, L and Robinson, E and Kim, KM and Murthy, AC and Paul, T and Portz, B and Gleixner, AM and Diaz, Z and Smirnov, A and Padilla, G and Lavorando, E and Espy, C and Shang, Y and Huang, EJ and Chesi, A and Fawzi, NL and Myong, S and Donnelly, CJ and Shorter, J},
title = {Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.},
journal = {Molecular cell},
volume = {86},
number = {1},
pages = {114-134.e10},
doi = {10.1016/j.molcel.2025.12.009},
pmid = {41512823},
issn = {1097-4164},
mesh = {Humans ; *RNA-Binding Protein FUS/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; *Prions/genetics/metabolism/chemistry ; *Oligonucleotides/genetics/pharmacology ; Phase Transition ; Protein Domains ; Motor Neurons/metabolism/pathology ; *RNA/genetics ; RNA-Binding Proteins/metabolism/genetics ; Protein Aggregates ; Mice ; },
abstract = {RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs that prevent FUS fibrillization by promoting liquid phases and distinct short RNAs that prevent and reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. We define a short RNA that dissolves cytoplasmic FUS aggregates, restores nuclear FUS, and mitigates FUS toxicity in optogenetic models and ALS patient-derived motor neurons. Another short RNA dissolves cytoplasmic TDP-43 aggregates, restores nuclear TDP-43, and mitigates TDP-43 toxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have utility for ALS/FTD and related disorders.},
}

Humans
*RNA-Binding Protein FUS/genetics/metabolism/chemistry
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*DNA-Binding Proteins/metabolism/genetics/chemistry
*Frontotemporal Dementia/genetics/metabolism/pathology
Animals
*Prions/genetics/metabolism/chemistry
*Oligonucleotides/genetics/pharmacology
Phase Transition
Protein Domains
Motor Neurons/metabolism/pathology
*RNA/genetics
RNA-Binding Proteins/metabolism/genetics
Protein Aggregates
Mice

@article {pmid41512036,
year = {2026},
author = {Zhu, B and Liu, Z and Van, R and Wang, H and Kuang, S and Jia, Y and Leon, EC and Yang, F and Zhang, J and Yang, J and Hong, H and Lobo, F and Yu, A and Wang, J and Tanzi, RE and Zhang, C and Mao, X and Shao, Y and Ran, C},
title = {Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {2},
pages = {e2513311123},
doi = {10.1073/pnas.2513311123},
pmid = {41512036},
issn = {1091-6490},
support = {R01AG083759//HHS | NIH (NIH)/ ; R01AG085562//HHS | NIH (NIH)/ ; R01AG055413//HHS | NIH (NIH)/ ; R21AG059134//HHS | NIH (NIH)/ ; R56AG059814//HHS | NIH (NIH)/ ; R21AG078749//HHS | NIH (NIH)/ ; S10OD028609//HHS | NIH (NIH)/ ; CSTB2024NSCQ-MSX0365//CSTC | Natural Science Foundation of Chongqing Municipality ()/ ; 2025MSXM061//CQMHC | Science-Health Joint Medical Scientific Research Project of Chongqing ()/ ; },
mesh = {Animals ; Mice ; *Protein Folding ; alpha-Synuclein/metabolism/chemistry/cerebrospinal fluid ; *Luminescent Measurements/methods ; Humans ; Disease Models, Animal ; *Neurodegenerative Diseases/metabolism/diagnostic imaging ; Parkinson Disease/metabolism ; *Proteostasis Deficiencies ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism ; Brain/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; *Optical Imaging/methods ; Luminescence ; Mice, Transgenic ; },
abstract = {Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of α-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of α-synuclein from Aβ. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.},
}

Animals
Mice
*Protein Folding
alpha-Synuclein/metabolism/chemistry/cerebrospinal fluid
*Luminescent Measurements/methods
Humans
Disease Models, Animal
*Neurodegenerative Diseases/metabolism/diagnostic imaging
Parkinson Disease/metabolism
*Proteostasis Deficiencies
Amyloid beta-Peptides/metabolism
Alzheimer Disease/metabolism
Brain/metabolism
Amyotrophic Lateral Sclerosis/metabolism
*Optical Imaging/methods
Luminescence
Mice, Transgenic

@article {pmid41511908,
year = {2026},
author = {Tsujisawa, Y and Takahashi-Iwata, I and Yabe, I and Mukaino, M and Shibamoto, I},
title = {Utility of simple speech measures in amyotrophic lateral sclerosis assessment: Focus on alternating motion rate as a screening tool.},
journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)},
volume = {},
number = {},
pages = {1-26},
doi = {10.1159/000550424},
pmid = {41511908},
issn = {1421-9972},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of motor neurons. Early detection of bulbar symptoms is crucial for timely diagnosis and intervention; however, variability in symptom progression complicates clinical assessment. This retrospective observational study aimed to classify patients with ALS into three groups-spinal onset, spinal onset with bulbar involvement, and bulbar onset-and to identify speech evaluation metrics that effectively differentiate these groups. Data from 68 patients with ALS were retrospectively analyzed. Speech samples were collected and evaluated for alternating motion rate (AMR), maximum phonation time (MPT), nasality, maximum tongue pressure (MTP), speech rate, and speech intelligibility. Group comparisons and receiver operating characteristic (ROC) curve analyses were conducted to assess discriminatory ability. AMR significantly differed among the three groups, with the spinal-onset group demonstrating the highest rates and the bulbar-onset group showing the lowest rates. ROC analysis indicated that AMR exhibited excellent discriminatory power, particularly in distinguishing spinal- from bulbar-onset ALS. Significant differences were also observed in MTP, nasality, speech rate, and speech intelligibility, although some metrics were less effective in differentiating the intermediate group. No significant group differences were found in MPT. These findings suggest that the AMR is a sensitive and easily administered measure for detecting bulbar symptoms and distinguishing ALS subtypes. The intermediate characteristics observed in the spinal-onset with bulbar involvement group support this classification as a distinct clinical phenotype. Combining AMR with secondary measures such as MTP, nasality, speech rate, and speech intelligibility may enhance early detection of bulbar symptoms and improve clinical decision-making.},
}

@article {pmid41511885,
year = {2025},
author = {Zhang, L and Häkkinen, S and Jung, Y and Mandelli, ML and Leichter, D and Onyike, CU and Rojas, JC and Tempini, MLG and Yokoyama, JS and Boeve, BF and Boxer, AL and Forsberg, LK and Heuer, HW and Kantarci, K and Ramos, EM and Rosen, HJ and Miller, BL and Seeley, WW and Flagan, TM and Lee, SE and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105253},
doi = {10.1002/alz70856_105253},
pmid = {41511885},
issn = {1552-5279},
mesh = {Humans ; Male ; Magnetic Resonance Imaging ; Female ; Biomarkers/blood ; Middle Aged ; *C9orf72 Protein/genetics ; *Neurofilament Proteins/blood ; *Brain/diagnostic imaging/pathology ; Longitudinal Studies ; Aged ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging ; Disease Progression ; Cross-Sectional Studies ; Prodromal Symptoms ; DNA Repeat Expansion/genetics ; },
abstract = {BACKGROUND: A hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. There remains a critical need for biomarkers that track disease progression across clinical stages. Cross-sectionally, intrinsic connectivity networks (ICNs) derived from task-free fMRI (tf-fMRI) detects abnormalities in C9orf72 expansion carriers (C9orf72+), even when brain structural differences are subtle (Lee et al., 2017). Few studies have examined longitudinal connectivity changes in C9orf72+, however.

METHODS: We analyzed longitudinal structural and tf-fMRI data and plasma neurofilament light chain (NfL) concentrations of C9orf72+ recruited from UCSF and the ALLFTD Consortia. Mean time from first to last scan was 2.4±1.3 years. Participants included 36 asymptomatic (aSx-C9), 17 prodromal (prodromal-C9), 29 symptomatic (Sx-C9) carriers, and 107 healthy controls (HC). For structural MRI analyses, smoothed gray matter maps were parcellated into 246 regions-of-interest based on the Brainnetome atlas. We conducted voxelwise seed-based tf-fMRI analyses to examine ICNs showing alterations C9orf72+ based on previous literature: salience network (SN), sensorimotor network (SMN), default mode network (DMN), and a medial pulvinar thalamus network (pulvinar). General linear models and linear mixed models (LMM) compared C9orf72+ groups to HC in baseline and longitudinal gray matter and functional connectivity, as well as examined associations between longitudinal functional connectivity changes and baseline NfL concentrations.

RESULTS: Despite a lack of longitudinal gray matter decline, aSx- and Sx-C9orf72+ showed functional connectivity changes. Compared to HC, aSx-C9 had baseline hypoconnectivity in the SN, SMN, and pulvinar network. Longitudinally, this group showed declines in the SN and pulvinar network, alongside DMN increases. Prodromal-C9 exhibited baseline SMN hypoconnectivity and hyperconnectivity in the DMN and pulvinar network, but no significant longitudinal changes. Sx-C9 showed baseline hypoconnectivity in SN, SMN, and DMN, with additional regions of DMN hyperconnectivity, while longitudinally, SN and SMN connectivity increased. In aSx-C9, higher baseline NfL concentrations correlated with regions of SMN decreases over time and both increases and decreases in the pulvinar network. In prodromal-C9 and Sx-C9 combined, higher NfL was associated with DMN increases longitudinally.

CONCLUSIONS: Though gray matter declines were undetectable over a span of several years, functional connectivity networks changed dynamically in C9orf72+.},
}

Humans
Male
Magnetic Resonance Imaging
Female
Biomarkers/blood
Middle Aged
*C9orf72 Protein/genetics
*Neurofilament Proteins/blood
*Brain/diagnostic imaging/pathology
Longitudinal Studies
Aged
*Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging
Disease Progression
Cross-Sectional Studies
Prodromal Symptoms
DNA Repeat Expansion/genetics

@article {pmid41511639,
year = {2026},
author = {Keerthipriya, MS and Kotambail, A and Deekshitha, M and Mahima, R and Ramyashree, MB and Rao, BM and Biswas, P and Baskar, D and Balaji, P and Mehta, M and Gray, O and Wasik, KA and Emde, AK and Polavarapu, K and Preethish-Kumar, V and Reddy, P and Thomas, PT and Nashi, S and Arunachal, G and Vengalil, S and Nalini, A},
title = {Clinical trajectories and genetic profiles of SOD1-related amyotrophic lateral sclerosis: insights from a single-center cohort in India.},
journal = {Journal of neurology},
volume = {273},
number = {1},
pages = {72},
pmid = {41511639},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/epidemiology ; Male ; India/epidemiology ; *Superoxide Dismutase-1/genetics ; Female ; Middle Aged ; Adult ; Cohort Studies ; Retrospective Studies ; Mutation/genetics ; Exome Sequencing ; Aged ; },
abstract = {Mutations in the superoxide dismutase 1 (SOD1) gene are a predominant, genetic cause of amyotrophic lateral sclerosis (ALS). Given the marked variability in SOD1 variant prevalence and clinical manifestations across global populations, this study aimed to characterize the genetic and clinical profile of SOD1-associated ALS (SOD1-ALS) in a large cohort of Indian patients. Whole-exome sequencing (WES) was performed for the retrospective cohort, along with comprehensive bioinformatic analyses and interpretation of genetic variants. Data were analyzed using descriptive statistics and Kaplan-Meier survival analysis to assess clinical and survival outcomes. Among 765 individuals who underwent WES, 37 probands (4.8%) from 33 families were identified with SOD1-ALS, representing a substantial 24.2% of familial ALS (fALS) cases. Patients showed a male preponderance (1.64:1) with a mean age at onset of 41.9 ± 13.1 years. Analysis revealed 23 distinct pathogenic/likely pathogenic SOD1 variants, including four novel variants. Remarkably, a high frequency of homozygous variants (6 patients) were observed in the cohort, which were associated with earlier disease onset. Most patients presented with a lower limb onset (67.6%) and a lower motor neuron phenotype. Survival was noted to be prolonged in carriers of H47R, V88M, and I152N variants, while those with juvenile onset showed reduced survival. In conclusion, this study provides the first comprehensive characterization of SOD1-ALS in the Indian population, revealing a distinct genetic profile with a unique spectrum of SOD1 variants and a higher prevalence of homozygous cases. These detailed genotype-phenotype correlations contribute significantly to the genetic etiology of ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/physiopathology/epidemiology
Male
India/epidemiology
*Superoxide Dismutase-1/genetics
Female
Middle Aged
Adult
Cohort Studies
Retrospective Studies
Mutation/genetics
Exome Sequencing
Aged

@article {pmid41511321,
year = {2025},
author = {Borgheai, SB and Achorn, BE and Zisk, AH and Hosni, SM and Richter, KEG and Menniti, FS and Shahriari, Y},
title = {A Comprehensive Overview of Neurophysiological Correlates of Cognitive Impairment in Amyotrophic Lateral Sclerosis.},
journal = {Cells},
volume = {15},
number = {1},
pages = {},
doi = {10.3390/cells15010037},
pmid = {41511321},
issn = {2073-4409},
support = {NSF-1913492//U.S. National Science Foundation/ ; NSF-2006012//U.S. National Science Foundation/ ; P20GM103430//Institutional Development Award (IDeA) Network for Biomedical Research Excellence/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/genetics ; *Cognitive Dysfunction/physiopathology ; Brain/physiopathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the gradual loss of motor control, typically resulting in paralysis and death within 3 to 5 years of diagnosis. ALS shares neuropathological and genetic associations with fronto-temporal dementia (FTD), a neurodegenerative condition primarily impacting cognitive functions. These two conditions are increasingly viewed as manifestations of a single molecular disease process that affects distinct brain systems, impacting motor neuronal pathways in ALS and fronto-cortical functions in FTD. However, this simple dichotomy belies the complexity of these conditions. In particular, patients with primary motor ALS can also experience significant cognitive deficits. Investigating the pathobiological and neurophysiological underpinnings of these impairments is essential for a comprehensive understanding of ALS and may open avenues for targeted therapies to alleviate these debilitating symptoms. Moreover, the biophysical correlates of cognitive deficits in ALS may serve as sensitive biomarkers for evaluating potential therapeutics. In this narrative review, we begin with an overview of the clinical features and genetics of ALS, followed by a review of the associated cognitive deficits that are adjunctive to motor decline. We then highlight neuroimaging studies from our laboratory and the broader literature, using EEG and other modalities that are beginning to uncover systems-level brain disruptions potentially underlying cognitive impairment in motor-dominant ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/complications/genetics
*Cognitive Dysfunction/physiopathology
Brain/physiopathology

@article {pmid41511175,
year = {2026},
author = {Gomez Becerra, ML and Choi-Tucci, A and Albudoor, N and Bedore, LM and Peña, ED},
title = {Improving the Efficiency of the Bilingual Input-Output Survey-Home.},
journal = {American journal of speech-language pathology},
volume = {},
number = {},
pages = {1-13},
doi = {10.1044/2025_AJSLP-25-00169},
pmid = {41511175},
issn = {1558-9110},
abstract = {PURPOSE: The Bilingual Input-Output Survey (BIOS)-Home (Peña et al., 2018) is used to provide speech-language pathologists (SLPs) with an estimate of children's exposure to two languages. The current hour-by-hour approach of the BIOS can be time consuming to administer and calculate. The current study seeks to improve the efficiency of the BIOS-Home by replicating Calandruccio et al.'s (2021) finding that the BIOS can be shortened by time periods around children's routines and extending these findings by preliminarily exploring the relationship of the shortened BIOS with results of a bilingual screener.

METHOD: The current study includes 1,337 Spanish-English bilingual children from two data sets. Children's ages ranged from 49 to 71 months (M = 60.58, SD = 4.96). BIOS-Home data were collected by trained bilingual research assistants and SLPs who interviewed caregivers on their children's language input and output hour by hour. Principal components analysis (PCA) was conducted using caregiver-reported BIOS-Home data from both data sets to determine the smallest number of time chunks that could be used to measure language exposure. To explore the validity of the shortened BIOS-Home, bivariate correlation analyses were conducted to examine the relationship between children's semantics and morphosyntax scores and the original and shortened versions of the BIOS-Home.

RESULTS: PCAs using the two data sets identified three time periods (morning, afternoon, and late afternoon/evening) for weekday receptive language and three time periods (morning, afternoon, and evening) for weekend receptive language. Language test score correlations comparing the hour-by-hour and the shortened approaches are highly similar, supporting the validity of the shortened approach.

CONCLUSION: Consolidating the BIOS-Home questionnaire is a viable approach that can save time and elicit valid information about children's bilingual input and output.},
}

@article {pmid41510728,
year = {2026},
author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M},
title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249397580251117044621},
pmid = {41510728},
issn = {1875-6166},
abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.},
}

@article {pmid41510716,
year = {2026},
author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A},
title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575415521251021091530},
pmid = {41510716},
issn = {1875-5607},
abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

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

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

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

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

@article {pmid41510529,
year = {2026},
author = {Reedy, MB and Abdul Azeem, M and Subramaniam, T and Salamat, S and Rowley, H and Beinlich, B},
title = {Neuroinvasive West Nile Virus Presenting as Subacute Progressive Quadriparesis and Intractable Pain: A Case Report.},
journal = {Case reports in neurological medicine},
volume = {2026},
number = {},
pages = {5565739},
pmid = {41510529},
issn = {2090-6668},
abstract = {West Nile virus (WNV) is the most common mosquito-borne infection in North America; while most cases are asymptomatic, fewer than 1% develop neuroinvasive disease with significant morbidity and mortality. We report a 57-year-old man from rural Wisconsin who presented with a 10-week history of progressive asymmetric quadriparesis and severe intractable pain, preceded by fatigue, shoulder pain, and paresthesias. Neurologic examination demonstrated mild encephalopathy, bulbar involvement, and mixed upper and lower motor neuron signs. MRI showed patchy thoracic cord T2 hyperintensities and diffuse lumbar ventral root enhancement. Electrodiagnostic studies revealed diffuse active denervation and reduced compound muscle action potentials, initially raising concern for amyotrophic lateral sclerosis. Elevated WNV IgM and IgG titers in serum and cerebrospinal fluid confirmed neuroinvasive WNV infection. Despite treatment with corticosteroids and intravenous immunoglobulin, the patient deteriorated and was transitioned to hospice care. Autopsy demonstrated T-cell-mediated meningoencephalitis with widespread lymphocytic inflammation involving motor neurons, spinal cord, ventral rootlets, and peripheral nerves, consistent with diffuse axonopathy. This case underscores that neuroinvasive WNV may closely mimic motor neuron disease and emphasizes the importance of serologic testing for accurate diagnosis. Management remains supportive, and outcomes can be severe due to extensive central and peripheral nervous system involvement.},
}

@article {pmid41510219,
year = {2025},
author = {Moll, S and Tannemann, N and Gestmann, M and Brenner, T and Herbstreit, F and Szalai, C},
title = {Redesigning Advanced Life Support teaching and assessment using a constructive alignment approach.},
journal = {MedEdPublish (2016)},
volume = {15},
number = {},
pages = {48},
pmid = {41510219},
issn = {2312-7996},
abstract = {Advanced Life Support (ALS) is a crucial component of medical training. Previously, a single-person OSCE-Station (Objective Structured Clinical Exam) was used to assess these skills, focusing primarily on the team leader role and emphasizing theoretical knowledge. However, students demonstrated deficiencies in key algorithm-compliant practical skills, such as cardiac massage, mask ventilation and defibrillator use, and struggled to integrate into a team-based resuscitation approach. To address this, a constructive alignment approach was used to revise the course and offer a guideline-appropriate, three-person resuscitation model. Learning outcomes and assessment targets were aligned with the course activities to increase student engagement and increase desired skill attainment. In the summer semester 2023, students and lecturers were briefed on the new structure of the course and assessment, specific skills were highlighted, and a model video was provided. The OSCE format was adjusted to assess both practical and non-technical skills. In the new setup, each student was randomly assigned one of three roles and assessed using role-specific checklists with defined criteria, focusing on non-technical and practical abilities. Course activity included training and practice in the three-person resuscitation approach. A team OSCE (tOSCE) approach for assessment was used, with one student for each role being examined. Results indicated both subjective and objective markers of satisfaction in course activities and tOSCE results. A team-based OSCE station proves effective for teaching combined practical and non-technical competencies.},
}

@article {pmid41509476,
year = {2025},
author = {Saez-Calveras, N and Verheijen, BM and Morgan, N and Hill, E and Taylor, S and Oyanagi, K and Kakita, A and Song, Y and Joachimiak, LA and Vaquer-Alicea, J and Diamond, MI and Lu, Y},
title = {Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.22.696002},
pmid = {41509476},
issn = {2692-8205},
abstract = {UNLABELLED: Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disorder that was once hyperendemic in the island of Guam (Mariana Islands, US) and a few other Pacific locales. Despite extensive investigations into its origins, the etiology of ALS/PDC remains unclear. ALS/PDC is, at the neuropathology level, characterized by tau-dominant multiple proteinopathy in brain and spinal cord. It was recently reported that Guam ALS/PDC brain extracts exhibit tau seeding activity in fluorescence resonance energy transfer (FRET)-based biosensor cells. To build upon those findings and explore the nature of tau seeds in ALS/PDC in more detail, we used an alanine mutational scanning (Ala scan) approach to determine the seeding profile of tau in nervous tissues of Guam ALS/PDC cases. First, we confirmed the detection of tau seeding activity in ALS/PDC brain samples in tau biosensor cells. Notably, we could also detect potent tau seeding activity in spinal cord. Subsequent Ala scan assays demonstrated that ALS/PDC tau displays an aggregate incorporation pattern that resembles that of chronic traumatic encephalopathy (CTE)-type tau. This result is consistent with recent electron cryo-microscopy studies of tau, which revealed that ALS/PDC tau filaments are predominantly of the CTE-type. The structural characteristics and seeding behavior of ALS/PDC tau, as well as the regional distribution of tau pathology at post-mortem, suggest that ALS/PDC is a CTE-like tauopathy.

SIGNIFICANCE STATEMENT: Neurodegenerative tauopathies are characterized by proteinaceous deposits containing microtubule-associated tau in nervous tissue. Emerging evidence suggests that disease-associated tau proteins adopt abnormal, self-propagating conformations characteristic of prions. Here, we employed alanine mutational scanning (Ala scan) to determine the nature of prion-like tau seeds in ALS/PDC, a mysterious disorder that occurred formerly in high incidence in certain regions in the western Pacific. We show that the Ala scan incorporation profile of ALS/PDC tau is similar to that of abnormal tau proteins in chronic traumatic encephalopathy (CTE). The findings lend support to the idea that ALS/PDC can be classified structurally as a CTE-like tauopathy. This work may have important implications for our understanding of ALS/PDC as well as common neurological disorders beyond the Pacific.},
}

@article {pmid41509469,
year = {2025},
author = {Park, J and Stepanova, A and Dash, J and Southwell, N and Zhao, D and Konrad, C and Tyagi, P and Kwan, JY and Shneider, NA and Mentis, GZ and Manfredi, G and Kawamata, H},
title = {A mouse model of CHCHD10 p.R15L familial ALS presents mild, age-related motor neuron degeneration without protein instability or mitochondrial dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.29.696888},
pmid = {41509469},
issn = {2692-8205},
abstract = {Mutations in the mitochondrial protein CHCHD10 (D10) cause a spectrum of hereditary neurodegenerative disorders. Among these, the p.R15L variant is linked to a slowly progressive, late-onset familial form of amyotrophic lateral sclerosis (ALS) with unclear pathogenic mechanisms. To better understand this, we investigated a knock-in (KI) mouse model carrying the p.R15L mutation in the endogenous protein. Unlike previously described mutant D10 KI models, p.R15L KI mice exhibited normal D10 protein levels, with no evidence of large protein aggregates. Mitochondrial respiration and hydrogen peroxide emission in mitochondria isolated from muscle and brain were unaltered. Similarly, fibroblasts from human p.R15L carriers exhibited normal D10 levels and unchanged oxidative phosphorylation function. Histochemical analyses of p.R15L KI muscle revealed mild increases in mitochondrial enzymatic activity in a subset of muscle fibers and muscle transcriptomics showed elevated expression of PGC-1α, suggesting enhanced mitochondrial biogenesis. p.R15L KI mice developed subtle, late-onset phenotypes, including reduced body weight and motor activity and increased anxiety-like behavior. Importantly, in aged mice electrophysiological studies demonstrated decreased amplitude of the compound muscle action potential, commensurate with a moderate loss of spinal cord motor neurons and elevated serum neurofilament light levels, indicative of neurodegeneration. Together, these results indicate that the p.R15L mutation produces a mild, late-onset motor neuron phenotype in mice, partially recapitulating the human disease, without mitochondrial functional or morphological alterations. The findings indicate that p.R15L D10 selectively impairs mouse motor neurons through a gain-of-function mechanism, providing a genetically accurate yet mild in vivo model of familial ALS.},
}

@article {pmid41509200,
year = {2025},
author = {Mahendran, TS and Bremer, A and Gui, X and Singh, A and Basalla, JL and Chittori, S and Marzahn, MR and Das, T and Mittag, T and Banerjee, PR},
title = {Viscoelasticity and interface properties of multi-component condensates govern protein sequestration and suppression of amyloid formation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.29.695806},
pmid = {41509200},
issn = {2692-8205},
abstract = {Stress granules (SGs) are multi-component protein-RNA condensates widely viewed as crucibles for fibril formation in neurodegenerative diseases such as amyotrophic lateral sclerosis. Here, we test this model by examining whether SG-mimics promote or suppress amyloid formation. Using multi-component programmable peptide-nucleic acid condensates, we show that condensates delay amyloid assembly by sequestering soluble proteins, and that fibrils grow in the dilute phase. Systematic tuning of condensate material properties reveals two key modulating mechanisms: the density of fibril-forming proteins at condensate interfaces dictates the lag phase of fibril assembly, and condensate viscoelasticity regulates protein efflux-driven fibril growth. These principles extend to SG-mimic condensates formed by G3BP1 and RNA, suggesting that SGs may function as potent suppressors rather than crucibles of pathological amyloid assembly.},
}

@article {pmid41508039,
year = {2026},
author = {Kim, SH and So, JH and Kim, YH and Kim, HS and Park, NY and Kim, JB and Jo, DS and Yeom, E and Lee, JA and Bae, JE and Cho, DH},
title = {Proteasome inhibition by VR23 enhances autophagic clearance of FUS[P525L]-mediated persistent stress granule in SH-SY5Y cells.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-025-01273-z},
pmid = {41508039},
issn = {1756-6606},
support = {RS-2024-00463344//Ministry of Education/ ; P0025489//Ministry of Trade, Industry and Energy/ ; },
abstract = {Autophagy is a conserved catabolic pathway that preserves cellular homeostasis through lysosomal degradation. Beyond its general role in proteostasis, selective autophagy mediates the clearance of selective cellular targets such as persistent stress granules (SGs), in a process termed granulophagy. SGs are dynamic cytoplasmic assemblies that normally disassemble after stress relief; however, their aberrant persistence has arisen as a pathological feature of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, the molecular regulation of granulophagy remains incompletely understood. Here, we established a tandem fluorescent SG reporter system with mCherry-pHluorin-FUS[P525L], enabling live-cell visualization of granulophagic flux. Using this system, we screened a chemical library and identified VR23, a proteasome inhibitor, as a potent inducer of granulophagy. VR23 promoted SG clearance through autophagic mechanisms, as evidenced by enhanced LC3 colocalization, lysosome-dependent degradation, and Bafilomycin A1-sensitive flux. Notably, disruption of SG assembly via G3BP1 inhibition abolished VR23-induced clearance, confirming its SG selectivity. These findings suggest a link between proteasome inhibition and granulophagy, highlighting VR23 as a valuable tool compound to dissect the mechanisms of SG turnover, and provide a platform for discovering modulators of pathological SG clearance in protein aggregation.},
}

@article {pmid41506565,
year = {2026},
author = {Liang, HY and Huang, PH},
title = {Concerns Regarding the Causal Inference and Statistical Methods in Laine et al.'s Study on Obstetric Anal Sphincter Injuries (Letter-to-the-Editor).},
journal = {American journal of obstetrics and gynecology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajog.2026.01.001},
pmid = {41506565},
issn = {1097-6868},
}

@article {pmid41505016,
year = {2026},
author = {Bronovitsky, E and Chaprov, K and Khizeva, A and Ivanova, T and Pravdivceva, E and Bobkov, T and Morozova, O and Krayushkina, A and Nebogatikov, V and Ninkina, N and Ustyugov, A},
title = {Retrospective Study of the Physiological and Molecular Features of the S-FUS (1-359) Mouse Transgenic Model with an ALS-like Phenotype: Lifespan, Body Weight Dynamics, Movement Disorders, and Dysregulation of the Dopaminergic System.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {1},
pages = {8},
pmid = {41505016},
issn = {1559-1166},
support = {FFSG-2024-0020//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/physiopathology/pathology ; Mice ; Mice, Transgenic ; Male ; *Dopamine/metabolism ; Female ; *RNA-Binding Protein FUS/genetics/metabolism ; Body Weight ; Spinal Cord/metabolism ; Disease Models, Animal ; Longevity ; Movement Disorders/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to disability and death. Genetic animal models, like transgenic mice, are critical for studying disease mechanisms and developing therapies. Model validity, experimental standardization, and predictability are key to successful research. This retrospective study analyzed physiological parameters of the S-FUS (1-359) transgenic mouse model over 10 years, focusing on lifespan, body weight dynamics, symptomatic stages, and molecular changes. Hemizygous mice had a mean lifespan of 137.8 days (males) and 125.1 days (females), longer than homozygous counterparts. The symptomatic stage, marked by motor deficits, began at ~ 123 days and lasted 10-15 days. Body weight loss correlated with disease progression, reaching 28.93% of baseline at death. Molecular analysis revealed regional FUS expression differences (midbrain > spinal cord), alongside proinflammatory cytokine activation (Il6, Tnf alpha) and oxidative stress. Dopaminergic dysregulation was evident, with striatal dopamine/metabolite levels rising 40-60%, linked to Maob downregulation and impaired GABAergic inhibition. Midbrain-selective caspase-3 suppression suggested a shift from apoptosis to necroptosis, while spinal cord astrogliosis indicated compensatory mechanisms. Heterogeneity in lifespan, symptom onset timing, and disease duration was observed, underscoring the need for rigorous experimental design, particularly for therapies aiming to delay symptoms or extend survival. Dopamine oxidation emerged as a novel neurotoxicity contributor, highlighting potential therapeutic targets: modulating dopaminergic signaling and reducing oxidative stress.},
}

Animals
*Amyotrophic Lateral Sclerosis/metabolism/genetics/physiopathology/pathology
Mice
Mice, Transgenic
Male
*Dopamine/metabolism
Female
*RNA-Binding Protein FUS/genetics/metabolism
Body Weight
Spinal Cord/metabolism
Disease Models, Animal
Longevity
Movement Disorders/genetics

@article {pmid41504939,
year = {2026},
author = {Evola, V and Parmar, MS},
title = {Targeting neuroinflammation in neurodegenerative disorders: the emerging potential of semaglutide.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {13},
pmid = {41504939},
issn = {1420-908X},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/immunology ; *Glucagon-Like Peptides/therapeutic use/pharmacology ; Animals ; *Neuroprotective Agents/therapeutic use ; *Neuroinflammatory Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Glucagon-Like Peptide 1 ; },
abstract = {BACKGROUND: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and Lewy body dementia (LBD), dysregulated glial activity, marked by sustained microglial and astrocytic activation, initiates a cascade of cytokine release, oxidative stress, and impaired neuronal support. This review synthesizes recent advances in understanding these shared inflammatory processes, emphasizing how glia-centric pathology shapes disease-specific trajectories and therapeutic responses.

FINDINGS: Within this framework, we evaluate the therapeutic potential of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) with emerging neuroprotective properties. Preclinical studies suggest that semaglutide can suppress pro-inflammatory signaling, mitigate oxidative injury, and enhance key anti-inflammatory and neuroprotective pathways that restore trophic support and cellular resilience. We also examine real-world evidence and emerging human clinical trial data, which recently demonstrated that semaglutide rapidly modulates AD pathology by significantly reducing cerebrospinal fluid (CSF) levels of p-tau, t-tau, and neurogranin, and promoting a less inflammatory CD8[+]T-cell signature. In addition to reduction in neuroinflammation marker, YKL-40. While subsequent large-scale Phase 3 trials in early AD did not meet primary cognitive endpoints (CDR-SB) despite favorable biomarker modulation.

CONCLUSION: Positioning semaglutide as a therapeutic option targeting neuroinflammation-mediated neuropathology, this review underscores its potential for repurposing as a disease-modifying therapy across diverse neurodegenerative disorders and highlights the urgent need for targeted trials in MS, ALS, FTD, HD, and LBD-conditions that remain without effective immunomodulatory treatments despite clear inflammatory origins. However, while direct CSF measurements confirm limited but measurable BBB penetration, the clinical translation of its effects remains a key challenge.},
}

Humans
*Neurodegenerative Diseases/drug therapy/immunology
*Glucagon-Like Peptides/therapeutic use/pharmacology
Animals
*Neuroprotective Agents/therapeutic use
*Neuroinflammatory Diseases/drug therapy
*Anti-Inflammatory Agents/therapeutic use
Glucagon-Like Peptide-1 Receptor Agonists
Glucagon-Like Peptide 1

@article {pmid41504787,
year = {2026},
author = {de Barros, JAMM and Vasconcelos, AFB and Gomes, ALCB and de Sousa, LMG and Meira, AT},
title = {"Bright Tongue" and "Wine Glass" signs in amyotrophic lateral sclerosis.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {41504787},
issn = {1432-1920},
abstract = {A 43-year-old male patient presented with monoparesis in his left leg, which had persisted for one year, then progressed to spastic dysarthria, tetraparesis, wide-based gait, muscle atrophy, weakness, fasciculations, and signs of pyramidal signs in all limbs. Brain MRI findings revealed hyperintensities on T2/FLAIR and diffusion-weighted imaging (DWI) along the corticospinal tracts, extending from the corona radiata and internal capsules to the brainstem, the "bright tongue sign" and the "wine glass sign,". This case highlights the classic findings in amyotrophic lateral sclerosis, which was confirmed by electroneuromyography.},
}

@article {pmid41504722,
year = {2026},
author = {Bąkowska-Żywicka, K},
title = {[Erratum for: Genetic and Molecular Pathomechanisms of Amyotrophic Lateral Sclerosis and Therapeutic Perspectives – Current State of Knowledge, K. Kalkowski Postepy Biochem. 71(3):252-259].},
journal = {Postepy biochemii},
volume = {71},
number = {4},
pages = {435-436},
doi = {10.18388/pb.2025_643},
pmid = {41504722},
issn = {0032-5422},
}

@article {pmid41504202,
year = {2025},
author = {Wu, JY and Ye, S and Yin, TL and Zhang, S and Zheng, DF and Fu, JY and Ma, GW and Fan, DS},
title = {Amyotrophic Lateral Sclerosis With Concurrent LHON-associated m.14484T>C Mutation: A Case Report and Literature Review.},
journal = {Revista de neurologia},
volume = {80},
number = {11},
pages = {44110},
doi = {10.31083/RN44110},
pmid = {41504202},
issn = {1576-6578},
support = {81873784//National Natural Sciences Foundation of China/ ; 82071426//National Natural Sciences Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; *Mutation ; Adult ; Female ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that mostly presents as sporadic cases. Currently, no mitochondrial-related gene mutations have been identified as the cause of ALS. Mitochondrial gene mutations cause rare hereditary diseases, and the symptoms of pure muscle weakness and muscle atrophy are rarely observed.

CASE REPORT: We report the case of a young patient clinically diagnosed with ALS concurrently associated with a pathogenic mutation in the mitochondrially encoded nicotinamide adenine dinucleotide: ubiquinone oxidoreductase core subunit 6 (MT-ND6) gene. However, the pathogenic relationship between the MT-ND6 gene and ALS has not been confirmed.

CONCLUSION: We provide a case report and a literature review aimed at increasing the understanding of the connection between the two. It is essential to consider the potential modifying role of mitochondrial pathogenic genes in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
Male
*Mutation
Adult
Female

@article {pmid41504098,
year = {2026},
author = {Aazmi, O and Aswale, AR and Chugh, J},
title = {H[+] Ions and ATP Reshape the Conformational Landscape of an RNA Recognition Motif and Regulate Its Fibrillation.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c15374},
pmid = {41504098},
issn = {1520-5126},
abstract = {Proteins exist as dynamic ensembles, with their native states comprising interconverting conformational substates critical to their physiological functions and participation in disease states. Fused in sarcoma (FUS), an RNA-binding protein implicated in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), contains an RNA recognition motif (RRM) known to form fibrillar aggregates. Here, we investigate the conformational plasticity of FUS-RRM in its native state using advanced NMR techniques, particularly [15]N chemical exchange saturation transfer and heteronuclear adiabatic relaxation dispersion experiments, to capture slow and fast microsecond (μs) time scale dynamics. We further examine the influence of environmental factors such as pH and ATP on the conformational plasticity and the aggregation behavior of FUS-RRM. Our findings show that both ATP and pH perturb the fast and slow μs time scale dynamics of FUS-RRM and thus the aggregation behavior. Specifically, a contrasting effect of ATP on slow and fast μs-ms dynamics at pH 6.4 and 4.6, along with the corresponding changes in aggregation behavior, suggests a complex relationship among ATP, pH, and protein aggregation kinetics. The study suggests that these environmental perturbations behave as kinetic regulators of FUS-RRM's propensity for aggregation.},
}

@article {pmid41504056,
year = {2025},
author = {Lymperopoulos, A and M'Sadoques, AJ and Stoicovy, RA and Altsman, VL},
title = {Why Is Epinephrine Preferred for Cardiac Arrest? The Answer May Lie in β2-Adrenergic Receptor Activation.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {12},
pages = {47927},
doi = {10.31083/FBL47927},
pmid = {41504056},
issn = {2768-6698},
support = {R01 #HL155718-01//National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant/ ; #333609-2025//American Foundation for Pharmaceutical Education (AFPE) Gateway to Research Scholarship/ ; },
mesh = {*Epinephrine/therapeutic use/pharmacology ; Humans ; *Heart Arrest/drug therapy ; *Receptors, Adrenergic, beta-2/metabolism ; *Vasoconstrictor Agents/therapeutic use/pharmacology ; Cardiopulmonary Resuscitation/methods ; Animals ; },
abstract = {Epinephrine (Epi, adrenaline) is routinely used during cardiopulmonary resuscitation (CPR) for cardiac arrest and is a first line treatment according to the international advanced life support (ALS) guidelines, which recommend 1 mg Epi be administered every 3-5 minutes during CPR. However, specific pharmacological factors that may distinguish Epi from other vasopressor agents used during CPR are unclear. This opinion article argues that one such factor, perhaps even the most important, is the activation of the β2-adrenergic receptor (AR) subtype, which only Epi, among all vasopressor hormones, can induce. β2AR activation equips Epi with more robust capabilities for pulse generation in the pacemaker cells (sinoatrial node) for the heart and of restoring contractile function in ischemic/hypoxic cardiomyocytes via sodium/potassium pump activation, compared to all other vasopressor hormones, including the closely related catecholamine norepinephrine (NE, noradrenaline). These additional actions of Epi via the β2AR, which are probably not shared by NE or other vasopressor agents, may make it particularly useful in situations where simple blood pressure elevation is insufficient, such as cardiac arrest.},
}

*Epinephrine/therapeutic use/pharmacology
Humans
*Heart Arrest/drug therapy
*Receptors, Adrenergic, beta-2/metabolism
*Vasoconstrictor Agents/therapeutic use/pharmacology
Cardiopulmonary Resuscitation/methods
Animals

@article {pmid41503832,
year = {2026},
author = {Tuli, S and Patel, P and Shethji, A and Gau, D},
title = {Mitochondria and the Actin Cytoskeleton in Neurodegeneration.},
journal = {Cytoskeleton (Hoboken, N.J.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/cm.70095},
pmid = {41503832},
issn = {1949-3592},
support = {CA267180/NH/NIH HHS/United States ; TL1 TR001858/NH/NIH HHS/United States ; },
abstract = {Mitochondrial dysfunction and cytoskeletal disorganization are widely recognized hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although these disorders differ in clinical presentation and etiology, accumulating evidence points to a shared cellular vulnerability at the intersection of mitochondrial dynamics and actin cytoskeletal regulation. In this review, we examine the emerging role of actin-mitochondria crosstalk as a convergent mechanism in neurodegeneration. We discuss how disruptions in actin filament remodeling, mitochondrial fission and fusion, organelle transport, and mitophagy contribute to neuronal dysfunction and loss across these diseases. Particular attention is given to disease-specific pathways, including cofilin-actin rod formation in AD, α-synuclein-driven actin disruption in PD, mutant huntingtin's effects on mitochondrial fragmentation in HD, and profilin-1-associated mitochondrial defects in ALS. By synthesizing findings from diverse models, we highlight how perturbations in the cytoskeleton-mitochondria interface may act as an upstream trigger and amplifier of neurodegenerative cascades. We also outline key knowledge gaps and propose future directions for research, with an emphasis on targeting actin-mitochondrial interactions as a potential therapeutic strategy across multiple neurodegenerative conditions.},
}

@article {pmid41500873,
year = {2026},
author = {Pérez-Bonilla, M and Borrego, PD and Mora-Ortiz, M and Fernández-Baillo, R and Mayordomo-Riera, FJ and López, EG},
title = {Voice-Based Prediction of Survival in Amyotrophic Lateral Sclerosis (ALS) Patients Using Biomechanical Acoustic Markers.},
journal = {Journal of voice : official journal of the Voice Foundation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jvoice.2025.12.014},
pmid = {41500873},
issn = {1873-4588},
abstract = {OBJECTIVE: To evaluate whether voice-derived acoustic and biomechanical features can serve as non-invasive biomarkers for mortality-risk prediction and survival stratification in patients with amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a retrospective study including 50 ALS patients evaluated in a phoniatrics consultation with available sustained vowel recordings, demographic data, and functional assessments. Nested logistic regression models were developed to predict clinical outcomes, progressively incorporating demographic variables, functional indices (Grade, Roughness, Breathiness, Asthenia, Strain, and Barthel), acoustic features (fundamental frequency, jitter, shimmer, harmonics-to-noise ratio), and biomechanical voice parameters (Pr1-Pr22). Model performance was assessed using receiver operating characteristic curves and area under the curve (AUC) comparisons via DeLong tests. Stepwise Akaike Information Criterion (StepAIC) was applied to optimize the final model. A Cox proportional hazards model was used to evaluate the association between voice parameters and survival time.

RESULTS: The final StepAIC model, which included a subset of biomechanical features, achieved excellent predictive performance (AUC = 0.903, 95% confidence interval: 0.816-0.989), significantly outperforming baseline and acoustic-only models. Bootstrapping confirmed the model's robustness and generalizability. Cox regression analysis showed that the derived risk scores stratified patients into tertiles with significantly different survival probabilities (log-rank P < 0.0001; hazard ratio for high vs. low-risk group = 11.2).

CONCLUSION: Biomechanical voice features are strong predictors of mortality in ALS and outperform traditional clinical and acoustic indices. These findings support the integration of voice analysis into ALS monitoring protocols as a non-invasive, cost-effective, and scalable prognostic tool.},
}

@article {pmid41500819,
year = {2026},
author = {Zorotovich, J and Andrews, C},
title = {Multidisciplinary care for amyotrophic lateral sclerosis in rural Appalachia: Tales from the Clinic Coordinator.},
journal = {Palliative & supportive care},
volume = {24},
number = {},
pages = {e29},
doi = {10.1017/S1478951525101454},
pmid = {41500819},
issn = {1478-9523},
}

@article {pmid41500294,
year = {2026},
author = {Zhang, Y and Wang, Y},
title = {Response letter to Chi-Tung Lu et al.'s Comment on "Efficacy and safety of Gutong Patch compared with NSAIDs for knee osteoarthritis: A real-world multicenter, prospective cohort study in China".},
journal = {Pharmacological research},
volume = {224},
number = {},
pages = {108086},
doi = {10.1016/j.phrs.2026.108086},
pmid = {41500294},
issn = {1096-1186},
}

@article {pmid41499987,
year = {2026},
author = {Poulidou, V and Tseriotis, VS and Bombaci, A and Vucic, S and Pavey, N and Papagiannopoulos, S and Kimiskidis, VK and Arnaoutoglou, M},
title = {The split elbow sign in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {Neurophysiologie clinique = Clinical neurophysiology},
volume = {56},
number = {2},
pages = {103134},
doi = {10.1016/j.neucli.2025.103134},
pmid = {41499987},
issn = {1769-7131},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) patients can exhibit split phenomena, with preferential weakness of specific muscle groups. The aim of this review is to investigate the split elbow (SE) phenomenon (different weakness/wasting pattern between biceps and triceps) as a potential clinical and neurophysiological feature in ALS.

METHODS: Our study was reported according to the PRISMA statement and registered in PROSPERO (CRD42024528359). MEDLINE, SCOPUS, Web of Science, and grey literature sources were searched using the terms "split elbow" and "amyotrophic lateral sclerosis" up to April 2025. English-written peer-reviewed, randomized, non-randomized, observational, diagnostic accuracy, and case-control studies were included. Study quality was assessed using Joanna Briggs Institute critical appraisal tool. Regarding muscle strength, we pooled the standardized mean difference of normalized Medical Research Council (MRC) scores using random effects. We used a bivariate random-effects model to evaluate SE index (SEICMAP, compound muscle action potential of biceps/triceps) in distinguishing ALS from controls.

RESULTS: Seven studies with 1941 ALS patients (61.8 % male) met inclusion criteria. Pooled standardized mean difference (triceps - biceps MRC scores) was -0.17 [95 % CI, -1.03 to 0.69], p = 0.63, indicating no significant difference in muscle strength between elbow flexion and extension. Between-study heterogeneity was high (I[2] = 97.1 % [95.5 %; 98.2 %], p < 0.0001). The SEICMAP demonstrated only moderate accuracy in distinguishing ALS from controls (pooled sensitivity, specificity, and AUC of 0.789 [0.655-0.880], 0.580 [0.487-0.668], and 0.661, respectively).

CONCLUSIONS: Current evidence does not support a consistent SE pattern in ALS. Methodological variability and small sample sizes limit the generalizability of available findings, indicating that the SE is unlikely to provide meaningful diagnostic utility in routine clinical practice.},
}

@article {pmid41499157,
year = {2026},
author = {Sousa-Leite, M and Gameiro, S},
title = {A multi-country study to co-design and evaluate digital educational resources to support conversations about ending fertility treatment.},
journal = {Human reproduction (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/humrep/deaf248},
pmid = {41499157},
issn = {1460-2350},
support = {//Research Wales Innovation Fund/ ; JA1710IF63//Higher Education Funding Council for Wales/ ; SFRH/BD/144429/2019//Portuguese Foundation for Science and Technology/ ; ES/Z503125/1//UK Economic and Social Research Council/ ; UIDB/04750/2020//FTC/ ; LA/P/0064/2020//FTC/ ; },
abstract = {STUDY QUESTION: How can educational resources be feasibly co-designed and used to support conversations between staff and patients about ending fertility treatment?

SUMMARY ANSWER: Co-design workshops allow for the development of educational resources that account for all stakeholders' perspectives and are considered sensitive, informative, and helpful to support end-of-treatment conversations, but staff and patients have different views about how these can be used within the treatment pathway.

WHAT IS KNOWN ALREADY: Ending treatment without children is a common outcome but seldom discussed with patients. Preventive end-of-treatment care aims to promote healthy transitions at the end of treatment by preparing and helping patients cope with this possible outcome. Nine in ten patients want to receive such care, but only 3 in 10 report receiving it. Knowledge of perceived barriers to implementing preventive end-of-treatment care at clinics and whether digital educational resources can be developed to support its provision is lacking.

STUDY DESIGN, SIZE, DURATION: Co-design workshops with fertility staff (March 2022), patients, and patient advocates (March-December 2022) from Europe (Belgium, Finland, Germany, Italy, Portugal, Spain, and UK) and South America (Argentina, Brazil, and Chile). Staff were invited to participate through fertility professional and scientific associations, and patients and advocates via charities and social media. Eligibility criteria were being aged 18 or older and working in fertility care (for staff) or charity (for advocates) or being waiting to initiate, undergoing, or having undergone treatment within 6 months (for patients).

A preliminary specification and initial prototypes of digital educational resources to support staff and patients, respectively, in having conversations about ending treatment were developed with relevant stakeholders. Co-design workshops with study participants were conducted. A semi-structured script, following Bowen et al.'s (2009)feasibility framework, was used to guide the workshops. Questions covered: (i) experiences, views, and preferences on the provision of preventive end-of-treatment care at clinics and iterative prototypes of the resources to support this provision (acceptability); (ii) perceived need and benefits (demand); and (iii) perceived barriers and facilitators to its implementation at clinics (practicalities). Workshops were recorded and transcribed verbatim, and data were analysed using Framework Analysis.

Fifteen fertility staff, 34 patients, and 7 advocates participated. Staff were mainly psychologists/counsellors (40.0%) or clinicians (26.7%) working in the field for around 23 years. Patients were mostly women (91.2%), on average aged 38 years. Most were childless (73.5%) and trying to conceive for around 3 years. Framework analysis of data collected during the co-design workshops generated four themes and one meta-theme, reflecting a need for a normative shift across countries towards the routine implementation of preventive end-of-treatment care. Themes reflected: (i) demand for routine provision of holistic psychosocial care, including preventive end-of-treatment care; (ii) different views between staff and patients about the risks and extent of benefits of routinely implementing preventive end-of-treatment care; (iii) patient high clarity about the functions of preventive end-of-treatment care (ensuring patients feel prepared and supported in moving through the grief and cope with short-term challenges; explore other pathways to parenthood and re-orient one's life goals; and ensure informed consent for fertility treatment) versus staff lower clarity, with care being equated to signposting patients for timely psychological support; and (iv) co-designed digital educational resources are helpful to support the routine provision of preventive end-of-treatment care at clinics.

Non-probability sample. Although the patient sample was heterogeneous (heterosexual and same-sex couples; private and public sectors), patients were primarily White, well-educated, employed, and childless women, limiting the generalization and comparisons across gender and other personal characteristics (ethnicity, socioeconomically disadvantaged, and disabled), where access to and acceptance of psychosocial support are expected to be lower.

Routine discussions about the end of treatment are needed and beneficial, but staff will require reassurance and training on with whom, when, and how to engage in these. The final version of the digital educational resources is seen as valuable to support a cultural shift in implementing end-of-treatment preventive care at clinics. The co-designed webpages are freely available online in four languages (for staff: www.myjourney.pt/clinics, for patients: www.myjourney.pt/patients). Future research is needed to raise awareness and further investigate how best to support staff in such care provision and measure its impact.

This work was supported by a Research Wales Innovation Fund from the Higher Education Funding Council for Wales (HEFCW, grant No.: JA1710IF63). M.S.-L. was supported by the Portuguese Foundation for Science and Technology (FCT; fellowship No.: SFRH/BD/144429/2019) and the UK Economic and Social Research Council (ESRC; fellowship No.: ES/Z503125/1). The EPIUnit and ITR were funded by the FTC through the Portuguese State Budget (projects No.: UIDB/04750/2020 and LA/P/0064/2020 and DOI identifiers https://doi.org/10.54499/UIDB/04750/2020 and https://doi.org/10.54499/LA/P/0064/2020). S.G. reports grants from the European Society for Human Reproduction and Embryology (ESHRE), the Wellcome Fund (UK), and the Health and Care Research Wales (UK). Cardiff University holds the Intellectual Property rights for the tool www.myjourney.pt, licensed under a Creative Commons AttributionNonCommercial-ShareAlike 4.0 International Licence (CC BY-NCSA 4.0).

TRIAL REGISTRATION NUMBER: n/a.},
}

@article {pmid41498748,
year = {2026},
author = {Byrd, A and Marmorale, LJ and Marcinowski, S and Dykstra, MM and Addison, V and Barmada, SJ and Buchan, JR},
title = {Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.},
journal = {The Journal of cell biology},
volume = {225},
number = {2},
pages = {},
doi = {10.1083/jcb.202212064},
pmid = {41498748},
issn = {1540-8140},
support = {R01GM114564/NH/NIH HHS/United States ; R56NS128110/NH/NIH HHS/United States ; R01NS097542/NH/NIH HHS/United States ; R01NS113943/NH/NIH HHS/United States ; T32GM136536/NH/NIH HHS/United States ; F31NS141379/NH/NIH HHS/United States ; F31NS134123-01/NH/NIH HHS/United States ; DGE-1746060//National Science Foundation/ ; //University of Arizona/ ; P330AG072931//Michigan Alzheimer's Disease Research Center/ ; },
mesh = {*Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics/toxicity ; *Nedd4 Ubiquitin Protein Ligases/metabolism/genetics ; *Lysosomes/metabolism ; Ubiquitination ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Ubiquitin-Protein Ligase Complexes/metabolism/genetics ; *Endosomes/metabolism ; HEK293 Cells ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; Multivesicular Bodies/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; },
abstract = {A pathological hallmark in >97% of amyotrophic lateral sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of TDP-43, a nuclear RNA-binding protein, in motor neurons. Driving clearance of cytoplasmic TDP-43 reduces toxicity in ALS models, though how TDP-43 clearance is regulated remains controversial. We conducted an unbiased yeast screen using high-throughput dot blotting to identify genes that affect TDP-43 levels. We identified ESCRT complex genes, which induce membrane invagination (particularly at multivesicular bodies; MVBs) and genes linked to K63 ubiquitination (particularly cofactors of the E3 ubiquitin ligase Rsp5; NEDD4 in humans), as drivers of TDP-43 endolysosomal clearance. TDP-43 colocalized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to either increased TDP-43 aggregation, stability, and toxicity. NEDD4 also ubiquitinates TDP-43. Lastly, TDP-43 accumulation induces giant MVB-like vesicles, within which TDP-43 accumulates in a NEDD4-dependent manner. Our studies shed light on endolysosomal-mediated cytoplasmic protein clearance, a poorly understood proteostasis mechanism, which may help identify novel ALS therapeutic strategies.},
}

*Endosomal Sorting Complexes Required for Transport/metabolism/genetics
Humans
*DNA-Binding Proteins/metabolism/genetics/toxicity
*Nedd4 Ubiquitin Protein Ligases/metabolism/genetics
*Lysosomes/metabolism
Ubiquitination
Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*Ubiquitin-Protein Ligase Complexes/metabolism/genetics
*Endosomes/metabolism
HEK293 Cells
*Saccharomyces cerevisiae Proteins/metabolism/genetics
Multivesicular Bodies/metabolism
Saccharomyces cerevisiae/genetics/metabolism

@article {pmid41498587,
year = {2026},
author = {Maskell, KG and Cook, AL and King, AE and Dickson, TC and Blizzard, CA},
title = {Modeling amyotrophic lateral sclerosis (ALS) in vitro: from mechanistic studies to translatable drug discovery.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5lc00577a},
pmid = {41498587},
issn = {1473-0189},
abstract = {Amyotrophic lateral sclerosis is a rapidly progressing, fatal neurodegenerative disease that causes selective degeneration of the corticomotor system. Currently, ALS remains incurable, and the available treatment options offer little in the way of extending life or improving quality of life. This is due, at least in part, to a lack of representative disease models. In vitro modeling offers rapid, experimentally accessible platforms for mechanistic discovery research and drug screening, but modeling the complexity of ALS - a multicellular, multisystem disease - in a dish, is not without its challenges. Here, we review the current landscape of in vitro pre-clinical ALS research, with emphasis on the development of compartmentalised culture and the promise this holds for translatable modeling of ALS.},
}