@article {pmid42639443,
year = {2026},
author = {Potla, KM and Justin Nathaniel, CM and Parameshwar Adimule, S and Vincent Raj Shanthi, JR and Bilal, H and Tawfeek, AM and Islam, MS},
title = {Electron-withdrawing group effects on the structural, electronic, reactivity, and binding characteristics of triazolopyrimidine herbicides: a comparative study of diclosulam, cloransulam-methyl, and cloransulam.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42639443},
issn = {2046-2069},
abstract = {Diclosulam (DS, I), cloransulam-methyl (CSM, II), and cloransulam (CS, III) are widely used herbicidal inhibitors of the AHAS/ALS enzyme for selective weed control. In the present work, a comparative experimental and theoretical study has been conducted on the impact of substituents on their structural, electronic, and reactive properties. Structural differences have been established using single-crystal X-ray diffraction. The crystal packing and interaction energy have been investigated using the Hirshfeld surface approach, while density functional theory confirmed the experimental geometry. The analysis of the electronic structure, reactivity descriptors, localization of electrons, and non-covalent interactions was carried out by the methods of frontier molecular orbitals, MEP, ELF/LOL, and RDG calculations. The binding interactions of compounds with AHAS/ALS protein targets were determined using molecular docking. The combined results reveal clear interdependencies between the structure, electronic properties, non-covalent interactions, and the behavior of molecules upon the interaction with enzymes.},
}

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

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

@article {pmid42640452,
year = {2026},
author = {Copenhaver, AE and Puglisi, C and Eslami, MA},
title = {Comparison of classic statistical methods and machine learning approaches to classify readiness.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag585},
pmid = {42640452},
issn = {1367-4811},
abstract = {MOTIVATION: Predicting physical and cognitive readiness in warfighters is critical for mission success. These predictions can be improved by identifying key biomarkers using multiple omics modalities. The MASTR-E study conducted by McKetney and colleagues is one of the most comprehensive multi-omics studies of saliva samples collected from warfighters, which also applied classic linear statistical (CLS) techniques to discover key biomarkers of readiness. Aligning with McKetney et al.'s assumptions, we operationalize readiness as a binary proxy, where pre-mission samples are labeled as 'ready' to reflect a rested, unstressed physiological baseline, while post-mission samples are labeled 'not ready' to reflect cumulative physical and cognitive load from the mission. As such, readiness here is not a direct biological or physiological construct, but an inferred state likely dominated by stress-related physiological changes. This assumption and definition is discussed further in the Introduction and Limitations sections. Here, we apply machine learning (ML) analyses to better assess generalizability, consider hidden interactions, and identify nonlinear patterns in the data. We investigated whether ML approaches could predict readiness and identify relevant biomarkers. ML models were trained on proteomics-only or metabolomics-only datasets to classify participants as ready or not ready and important model features were considered as putative biomarkers. Training and testing datasets were curated for two objectives: 1) recognize biomolecular signatures indicative of readiness within the same donor and 2) assess generalizability across warfighters by withholding donors for testing.

RESULTS: Proteomics-based models achieved AUCs of 0.907±0.034 and 0.860±0.063 for Objectives 1 and 2, respectively. Metabolomics-based models achieved Objective 1 AUC of 0.994±0.007 and Objective 2 AUC of 0.993±0.010. Comparative analysis with existing literature validates the model's feature importances, but the identified putative biomarkers significantly differ from those discovered through CLS analyses, as only one ML-identified biomarker overlapping with those identified through CLS methods. We show that these ML models and identified features are more robust to noise and generalizable across participants than those identified using CLS methods.

AVAILABILITY: The analysis pipelines are provided as Jupyter notebooks, including all code and documentation, and are available publicly on GitHub at {{https://github.com/netrias/ReadinessClassification}}
.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid42641169,
year = {2026},
author = {Kodama, K and Ando, M and Higuchi, Y and Yuan, JH and Yoshimura, A and Samukawa, M and Suzuki, M and Ogaya, S and Kawata, Y and Gamo, N and Hisahara, S and Yano, C and Nagatomo, R and Hobara, T and Kojima, F and Hiramatsu, Y and Nozuma, S and Sakiyama, Y and Mitsui, J and Tsuji, S and Takashima, H},
title = {Biallelic SIGMAR1 variants in early-onset distal hereditary motor neuropathy: A Japanese case series.},
journal = {Journal of neuromuscular diseases},
volume = {},
number = {},
pages = {22143602261477464},
pmid = {42641169},
issn = {2214-3602},
abstract = {BackgroundDistal hereditary motor neuropathy (dHMN) is characterized by slowly progressive distal muscle weakness and amyotrophy, and it exhibits clinical overlap with Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). Biallelic variants in SIGMAR1, encoding sigma nonopioid intracellular receptor 1, have been linked to autosomal recessive dHMN with pyramidal features. This study investigated the clinical and genetic features of patients with dHMN associated with SIGMAR1 variants in Japan.MethodsWe conducted genetic screening of Japanese patients with clinically suspected inherited peripheral neuropathies using targeted gene panels and whole-exome sequencing. SIGMAR1 variants were evaluated via segregation analysis using Sanger sequencing. Detailed clinical and electrophysiological data were systematically reviewed.ResultsBiallelic SIGMAR1 variants, including three novel variants and one previously reported variant, were identified in six patients from five unrelated families. The genotypes comprised compound heterozygous variants in four patients and homozygous variants in two patients. All patients presented with early-onset distal muscle weakness and atrophy. Enhanced tendon reflexes and pyramidal tract signs were frequently observed, whereas bulbar or respiratory involvement was absent. Nerve conduction studies consistently revealed motor-predominant axonal neuropathy with minimal sensory involvement. Disease progression was slow, and all patients remained ambulatory for years to decades after onset.ConclusionOur findings expand the clinical and genetic spectrum of SIGMAR1-associated disease and support its classification as dHMN rather than ALS. SIGMAR1 variants should be considered in the genetic evaluation of early-onset motor neuropathies, particularly in patients with dHMN accompanied by pyramidal features.},
}

@article {pmid42641283,
year = {2026},
author = {Yoo, HE and Issenberg, SB and Roh, YS},
title = {Psychometric evaluation and responsiveness of the resuscitation self-efficacy scale among ward nurses: A pretest-posttest study.},
journal = {Nurse education in practice},
volume = {96},
number = {},
pages = {104954},
doi = {10.1016/j.nepr.2026.104954},
pmid = {42641283},
issn = {1873-5223},
abstract = {AIM: To evaluate the psychometric properties and responsiveness of the Resuscitation Self-Efficacy Scale (RSES) among ward nurses before and after simulation-based advanced life support (ALS) training.

BACKGROUND: Although the RSES was developed to measure nurses' perceived capability in resuscitation, evidence regarding its psychometric evaluation among ward nurses participating in ALS training remains limited.

DESIGN: Secondary psychometric analysis of data obtained from a simulation-based ALS training study.

METHODS: Ward nurses (N = 191) from general hospitals completed the RSES before and immediately after participation in a simulation-based ALS training program. Psychometric evaluation included item analysis, internal consistency reliability, evidence based on internal structure, construct validity through convergent and discriminant validity, relations with an external performance measure and responsiveness.

RESULTS: The RSES demonstrated good internal consistency, with a Cronbach's α of.80 for the total scale and.88-.91 across the four factors. Factor analysis supported the original four-factor structure, with satisfactory model fit (CFI =.958, TLI =.949, RMSEA =.052 and SRMR =.072). Evidence of convergent and discriminant validity met recommended criteria. Individual resuscitation self-efficacy showed modest positive associations with team-level ALS performance and the RSES demonstrated moderate responsiveness to change (standardized response mean =.77).

CONCLUSIONS: The findings provide psychometric evidence supporting the use of the RSES for assessing resuscitation self-efficacy among ward nurses participating in simulation-based ALS training. The RSES may be useful for evaluating educational outcomes and monitoring changes in learners' self-efficacy following educational interventions.},
}

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

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

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

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

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

@article {pmid42642938,
year = {2026},
author = {Zou, L and Song, L and Yin, P and Cui, H and Lian, L and Peng, X and Jin, T and Wang, H and Liu, W},
title = {Glutathione S-transferase genes PfGSTU6 and PfGSTL1 involved in mesosulfuron-methyl resistance in Polypogon fugax.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71227},
pmid = {42642938},
issn = {1526-4998},
support = {//National Natural Science Foundation of China (32372570, 32572857)/ ; //Shandong Provincial Natural Science Foundation (ZR2025MS289)/ ; },
abstract = {BACKGROUND: Polypogon fugax is a major weed in wheat and winter canola fields in China. Two populations, SD-4 and JS-13, showing resistance to the ALS inhibitor mesosulfuron-methyl, were collected from winter wheat fields. This study aimed to characterize their resistance level and cross-resistance profile, investigate the resistance mechanism and identify its functional genes.

RESULTS: Dose-response assays showed that SD-4 and JS-13 have high-level resistance to mesosulfuron-methyl (15.9-and 16.4-fold, respectively) and cross-resistance to the ACCase inhibitors clodinafop-propargyl, fenoxaprop-P-ethyl, quizalofop-p-ethyl, and the PDS inhibitor diflufenican. Sequencing of the ALS gene revealed no known target-site mutations within the eight conserved resistance-associated regions. Pre-treatment with the cytochrome P450 monooxygenase (P450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor NBD-Cl increased herbicide sensitivity in resistant plants. The resistant plants showed higher inducible GST activity. Herbicide residues analysis observed that resistant plants exhibiting increased mesosulfuron-methyl metabolism, and the enhanced metabolism could be reduced by both inhibitors. Integrated transcriptomic and qRT-PCR analysis identified 17 stably upregulated genes, including PfGSTU6 and PfGSTL1. Escherichia coli and rice callus overexpressing PfGSTU6 and PfGSTL1 exhibit significantly enhanced herbicide tolerance to mesosulfuron-methyl, and molecular docking analysis confirmed the strong binding affinity of GST proteins to the target herbicide.

CONCLUSIONS: The P450s and GSTs mediated herbicide metabolism confer mesosulfuron-methyl resistance in P. fugax. This study elucidates the resistance mechanism and provides genetic resources for resistance monitoring and crop breeding. In addition, we characterized the cross-resistance profile of the resistant P. fugax population, which provides guidance for developing targeted field weed resistance management strategies. © 2026 Society of Chemical Industry.},
}

@article {pmid42643027,
year = {2026},
author = {Christen, AL and Sobanski, E and Bitto, H and Abt-Mörstedt, B and Stieglitz, RD and Corbisiero, S},
title = {Emotional Dysregulation, Emotional Lability, Emotional Impulsiveness and Emotion in Adults with ADHD: Do All Scales Define the Same Concept?.},
journal = {Journal of attention disorders},
volume = {},
number = {},
pages = {10870547261475724},
doi = {10.1177/10870547261475724},
pmid = {42643027},
issn = {1557-1246},
abstract = {BACKGROUND: Various studies highlight emotional symptoms as a crucial component of ADHD in adulthood, suggesting independent diagnostic approaches that incorporate patients' emotional experiences into the assessment. However, the emotional symptomatology appears to be defined differently within the disorder's different constructs: Emotional Dysregulation (ED), Emotional Lability (EL), Emotional Impulsiveness (EI) and Emotion (E). Hence, the question arises: Do these symptom domains represent the same psychopathological spectrum?

METHOD: A total of 1240 adults seeking diagnostic evaluation at the ADHD specialist consultation in two different clinics (University Psychiatric Clinics (UPK) in Basel and Central Institute of Mental Health in Mannheim) were examined, whereas 611 participants were diagnosed with ADHD. They were further assessed in regard of their emotional symptoms using the following scales: ED, EL, EI and E. Additionally, affective lability was measured as a control using the Affective Lability Scale (ALS-18).

RESULTS AND DISCUSSION: The convergent and construct validity using correlations and principal component analysis (PCA) revealed that individuals with ADHD experience distinct emotional symptoms divergent from a general concept of affective lability as assessed by the ALS-18. The PCA shows that the ADHD-specific emotional symptoms may be classified into (1) difficulties with temper control and anger, (2) emotional distress and (3) emotional overreactivity and mood changes.},
}

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

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

@article {pmid42645064,
year = {2026},
author = {Sonkar, KS and Levi D'Ancona, V and Cramp, J and Shilling, H and Giles, E and Howell-Bray, T and Fillingham, B and Cudkowicz, ME and Nath, A and Rothstein, JD and Bowser, R and Borroni, B and Berry, JD and Sadri-Vakili, G and Buratti, E and Thrippleton, IP},
title = {Functional Activity of TDP-43: A Direct Biomarker for ALS.},
journal = {Biosensors},
volume = {16},
number = {8},
pages = {},
pmid = {42645064},
issn = {2079-6374},
mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis ; Humans ; *DNA-Binding Proteins/blood/metabolism ; Biomarkers/blood ; Fluorescence Resonance Energy Transfer ; *Biosensing Techniques ; C9orf72 Protein/genetics ; },
abstract = {TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA binding activity using synthetic UU-rich RNA probes. We analyzed 1080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 functional activity was elevated in ALS (mean 390 a.u.) versus controls (302 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); a 366 a.u. threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal in serum likely reflects increased extracellular release of probe-competent TDP-43 species during cell death and exosomal shedding, rather than restored intracellular nuclear splicing function. This assay provides a proof-of-concept platform for the direct functional measurement of probe-competent TDP-43 species in serum. While it demonstrates moderate group-level discrimination, individual diagnostic performance requires prospective validation. The assay may support exploratory applications in genotype stratification and progression monitoring in future clinical studies.},
}

*Amyotrophic Lateral Sclerosis/blood/diagnosis
Humans
*DNA-Binding Proteins/blood/metabolism
Biomarkers/blood
Fluorescence Resonance Energy Transfer
*Biosensing Techniques
C9orf72 Protein/genetics

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

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

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

@article {pmid42646494,
year = {2026},
author = {Shevchuk, D and Kuzmenko, Y and Zakharova, M and Karpov, V and Starodubova, E and Latanova, A},
title = {NLRP3 Inflammasome and Inflammation-Related Proteins Expression Characterized in Non-Cultivated Versus Cultivated Peripheral Blood Cells of Patients with Amyotrophic Lateral Sclerosis.},
journal = {NeuroSci},
volume = {7},
number = {4},
pages = {},
pmid = {42646494},
issn = {2673-4087},
support = {25-74-10090//Russian Science Foundation/ ; },
abstract = {BACKGROUND: Cell and mouse models studies demonstrate NLRP3 inflammasome involvement in amyotrophic lateral sclerosis (ALS) neuroinflammation. Peripheral blood mononuclear cells (PBMCs) are a promising, yet understudied, source of in vivo inflammasome activation biomarkers. Our study reviewed the literature on PBMC-based inflammasome studies of ALS and other neurodegenerative diseases and tested different conditions for PBMC handling to evaluate inflammasome and inflammation-related protein expression in these cells.

METHODS: Expression of NLRP3 inflammasome components and inflammation-related proteins was analyzed by Real-time qPCR and Western blot in non-cultivated/cultivated PBMCs of 23 ALS patients and 20 Healthy controls. IL-1β and IL-18 levels were measured in plasma and cultivated PBMC supernatants by ELISA.

RESULTS: Cultivation of PBMCs decreased expression of inflammasome components and inflammation-related cytokines on the mRNA but not protein level. NLRP3 mRNA expression was significantly higher in ALS-cultivated PBMCs. In both ALS and Healthy controls, IL-18 was detected in plasma, and IL-1β in supernatants of cultivated PBMCs.

CONCLUSIONS: Our findings suggest that PBMC handling conditions, i.e., cell cultivation, may determine particular parameters associated with NLRP3 inflammasome expression and activation pathway, so they should be carefully selected for PBMC-based studies of inflammasome in neurodegenerative and non-neurological disorders and taken into account when interpreting the study results.},
}

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

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

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

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

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

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

@article {pmid42647657,
year = {2026},
author = {Denčevski, A and Bataveljić, D and Bogdanović Pristov, J and Krmpot, AJ and Rabasović, MD and Nikolić, L},
title = {Characterizing Single-Cell Differences in Aquaporin-4 and Glutamate Transporter-1 Between Control and hSOD1G93A Astrocytes Using Integrated Epifluorescence and Structured Illumination Microscopy.},
journal = {Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada},
volume = {32},
number = {4},
pages = {},
doi = {10.1093/mam/ozag095},
pmid = {42647657},
issn = {1435-8115},
support = {451-03-33/2026-03/200053//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; 451-03-33/2026-03/200178//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; 451-03-33/2026-03/200007//Ministry of Science, Technological Development and Innovation of Republic of Serbia/ ; //Institute of Physics Belgrade/ ; //Science Fund of the Republic of Serbia/ ; },
mesh = {*Astrocytes/chemistry/metabolism ; *Aquaporin 4/analysis/metabolism ; Animals ; *Excitatory Amino Acid Transporter 2/analysis ; Microscopy, Fluorescence/methods ; *Single-Cell Analysis/methods ; Cells, Cultured ; Humans ; },
abstract = {Astrocytes, the abundant glial cells of the central nervous system (CNS), maintain water and glutamate homeostasis through aquaporin-4 (AQP4) and glutamate transporter-1 (EAAT2). In the hSODG93A animal model of amyotrophic lateral sclerosis, astrocytes exhibit alterations in these homeostatic proteins. AQP4 and EAAT2 changes are observed in both hSODG93A-expressing astrocytes in the CNS and in cell cultures. Here, we provide a detailed analysis of differences between cultured control and hSOD1G93A astrocytes in AQP4 and EAAT2 fluorescence patterns, subcellular localization, and spatial overlap, using side-by-side epifluorescence and structured illumination microscopy modes of a custom imaging system [two-dimensional structured illumination microscopy (2D SIM)]. 2D SIM system characterization and fluorescence signal analysis demonstrated uniform epifluorescence illumination and high-contrast SIM patterns, enabling whole-cell imaging of AQP4 and EAAT2 and resolving their signals into distinct puncta in both control and hSOD1G93A astrocytes with SIM. Compared with control astrocytes, AQP4 expression increased and EAAT2 expression decreased in the plasma membrane and cytoplasm of hSOD1G93A astrocytes at both diffraction-limited and superresolution scales. Subdiffraction-scale analysis revealed differences in the spatial distributions of AQP4 and EAAT2, showing increased colocalization between these proteins in hSOD1G93A astrocytes. These findings demonstrate the utility of integrated imaging approaches for quantitative, single-cell-resolution analysis of disease-associated protein alterations in astrocytes.},
}

*Astrocytes/chemistry/metabolism
*Aquaporin 4/analysis/metabolism
Animals
*Excitatory Amino Acid Transporter 2/analysis
Microscopy, Fluorescence/methods
*Single-Cell Analysis/methods
Cells, Cultured
Humans

@article {pmid42648119,
year = {2026},
author = {Wu, D and Kojic, A and Ross, JP and Li, D and Walther, P and Goyal, N and Sampson, J and Wu, JC},
title = {Generation of two iPSC lines from ALS patients harboring C9orf72 hexanucleotide repeat expansions.},
journal = {Stem cell research},
volume = {95},
number = {},
pages = {104085},
doi = {10.1016/j.scr.2026.104085},
pmid = {42648119},
issn = {1876-7753},
abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene constitutes the leading genetic driver of amyotrophic lateral sclerosis (ALS). This fatal neurodegenerative disorder is characterized by the systematic loss of both the upper and lower motor neurons across both the central and peripheral nervous systems. This work describes the successful reprogramming of two human induced pluripotent stem cell (iPSC) lines originating from two independent ALS patients, both of whom carry a C9orf72 HRE mutation. Validation of the two established iPSC lines confirmed the expression of pluripotency markers, normal karyotypes, and successful trilineage differentiation. Consequently, these lines provide a robust in vitro platform to model ALS and study C9orf72-mediated disease mechanisms.},
}

@article {pmid42648633,
year = {2026},
author = {Akamatsu, H and Kodama, Y and Terai, A and Imamura, M and Oda, K and Jono, H and Ohyama, K},
title = {Development and validation of machine learning model for selecting the optimal population pharmacokinetic model for vancomycin.},
journal = {Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy},
volume = {},
number = {},
pages = {103058},
doi = {10.1016/j.jiac.2026.103058},
pmid = {42648633},
issn = {1437-7780},
abstract = {INTRODUCTION: Therapeutic drug monitoring (TDM) of vancomycin is recommended based on the area under the concentration-time curve (AUC). The Practical Antimicrobial TDM (PAT) software incorporates two population pharmacokinetic (popPK) models developed by Oda et al. and Yasuhara et al.; however, no objective criteria for model selection have been established. This study aimed to develop and validate a machine learning (ML) model to optimize popPK model selection for initial vancomycin dosing.

METHODS: The primary outcome was comparison of the two models to identify which yielded a lower absolute relative prediction error for AUC in each patient. Thirty-three clinical variables were screened using Lasso regression to select predictors. Six ML algorithms were compared using nested cross-validation. Performance was evaluated using the area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, specificity, calibration plots, and decision curve analysis (DCA).

RESULTS: Among 531 patients, Oda et al.'s model was more accurate in 60.1% of cases. Lasso selected 22 predictors. Among the algorithms, logistic regression showed the highest mean AUROC (0.720±0.084), whereas the support vector machine demonstrated favorable calibration performance (intercept=0.01, slope=0.97). The multi-layer perceptron achieved the lowest Brier score (0.307). Longer hospitalization, lower C-reactive protein (CRP), and female sex were associated with a high predictive probability of accuracy for Oda et al.'s model. DCA suggested the clinical utility of ML-based model selection.

CONCLUSION: We developed an ML model for selecting between two popPK models for planning vancomycin dosing regimens in PAT. Considering length of hospital stay, CRP levels, and sex may aid accurate popPK model selection.},
}

@article {pmid42649099,
year = {2026},
author = {, and Kassardjian, CD and Desai, U and Živković, SA and Simmons, Z and Narayanaswami, P},
title = {It's Virtually Here: Telemedicine, Virtual Care, and Neuromuscular Disease.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70382},
pmid = {42649099},
issn = {1097-4598},
abstract = {The COVID-19 pandemic forced a partial shift in neuromuscular clinical practice away from in-person care to remote means. However, this shift was unexpected, abrupt, reactive to the emergency of a pandemic, and disruptive to the usual manner of care, without adequate time to adapt or study the optimal manner to provide care remotely. While traditionally associated with hub-and-spoke telemedicine models, the pandemic popularized direct-to-home virtual care, mostly unsupported by on-site examiners or standardized platforms. In chronic neuromuscular disorders such as amyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG), virtual care has demonstrated feasibility, patient satisfaction, and potential cost savings, particularly for geographically or functionally disadvantaged populations. Disease-specific adaptations such as the Myasthenia Gravis Core Exam and wearable-based assessments (e.g., home spirometry, grip strength monitoring, and digital outcome measures) have enabled more structured remote evaluations. However, diagnostic accuracy may be compromised by the inability to perform detailed neurological examinations or electrodiagnostic studies. Equity concerns persist due to variability in digital literacy, internet and digital device access, and socioeconomic status. Post-pandemic, patients with disabilities may continue to benefit in a combined virtual/in-person paradigm of care. More evidence is required to evaluate the impact of virtual care on neuromuscular practice quality of care and outcomes. We outline some of the questions that require further study, hoping to spur research and quality improvement investigations of these new care models.},
}

@article {pmid42649384,
year = {2026},
author = {Guo, H and Savard, A and Manser, C and Dutta, K and Taylor, JA and Rousseaux, MWC and Pozzi, S and Julien, JP and Baird, S and Gibbings, D},
title = {Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.},
journal = {Nature biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {42649384},
issn = {2157-846X},
support = {183767//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; TR180076//Weston Brain Institute/ ; },
abstract = {In neurodegenerative diseases such as frontotemporal dementia and amyotrophic lateral sclerosis, pathological forms of proteins such as Tau and TDP-43 accumulate within large heterogeneous inclusions inside cells. Current strategies to eliminate such aberrant protein species in patients encounter three main challenges: crossing the blood-brain barrier and plasma membrane, specifically recognizing pathological forms of proteins, and engaging mechanisms to eliminate large entities. Here we fuse LC3A, a central protein in the recruitment of substrates into autophagosomes, to cytoplasm-stable antibodies. These engineered autophagy receptors, targeting Tau or TDP-43, are delivered using small extracellular vesicles and reduce pathology in models, including Tau P301S adult primary mouse neurons, TDP-43[G298S] iPSC-derived motor neurons and after intravenous injection in Tau P301S mice. Similarly, adeno-associated-virus-mediated delivery in TDP-43[ΔNLS] mice enhances clearance of pathological TDP-43. This targeted degradation strategy allows delivery into the brain while capitalizing on the specificity of antibodies and the ability of autophagy to degrade large intracellular entities.},
}

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

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

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

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

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

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

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

@article {pmid41387577,
year = {2026},
author = {Major, AJ and Abdaltawab, A and Phillips, JM and Wang, T and Lee, EK and Lichtenfeld, MJ and Chandrasekaran, C and Saalmann, YB and Maier, A and Desimone, R and Miller, EK and Bastos, AM and Mendoza-Halliday, D},
title = {A. J. Major et al. reply.},
journal = {Nature neuroscience},
volume = {29},
number = {2},
pages = {284-286},
pmid = {41387577},
issn = {1546-1726},
support = {R01 MH110311/MH/NIMH NIH HHS/United States ; R01MH110311//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; NS135361//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 1R01MH131715//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R21 NS135361/NS/NINDS NIH HHS/United States ; R01 EY029666/EY/NEI NIH HHS/United States ; NS121409//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R00 NS092972/NS/NINDS NIH HHS/United States ; CAREER 2339210//National Science Foundation (NSF)/ ; P51 OD011106/OD/NIH HHS/United States ; R01 MH131715/MH/NIMH NIH HHS/United States ; R01 NS121409/NS/NINDS NIH HHS/United States ; R00 MH116100/MH/NIMH NIH HHS/United States ; R00NS092972//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; Young Investigator Award//Brain and Behavior Research Foundation (Brain & Behavior Research Foundation)/ ; NS122969//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R00MH116100//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01 NS122969/NS/NINDS NIH HHS/United States ; },
abstract = {Our study made two contributions: (1) discovery of a ubiquitous cortical motif and (2) a tool derived from it—the Frequency-based Layer Identification Procedure (FLIP and vFLIP). Mackey et al. critique the tool, questioning its advantage over classic current source density (CSD) analysis, and reason backwards to challenge the motif’s ubiquity. In our rebuttal, we confirm the spectrolaminar motif in diverse cortical areas using data from multiple research groups (who joined us in this rebuttal) as well as Mackey et al.’s own dataset. Additionally, we introduce vFLIP2, an improved version of our tool that addresses their comments. It reliably identified and localized the motif in our data and Mackey et al.’s data. Our findings reaffirm the motif’s ubiquity. We value Mackey et al.’s comments, which helped refine our tool.},
}

@article {pmid42635322,
year = {2026},
author = {Palumbo, F and Iazzolino, B and Canosa, A and Manera, U and Vasta, R and Grassano, M and Matteoni, E and Cabras, S and Maccabeo, A and Pellegrino, G and Giai Merlera, F and Dei Giudici, A and Callegaro, S and Balz, L and Moglia, C and Chiò, A and Calvo, A and Lulé, D},
title = {Theory of mind impairment related to C9orf72 repeat expansion in amyotrophic lateral sclerosis: a case-control study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2026.2694499},
pmid = {42635322},
issn = {2167-9223},
abstract = {Objective: To investigate cognitive and affective theory of mind (ToM) in amyotrophic lateral sclerosis (ALS) patients carrying the C9orf72 repeat expansion (C9orf72+), compared with matched non-mutated (C9orf72-) ALS patients and healthy controls (HCs). Methods: We assessed 34 C9orf72+ ALS patients, 34 C9orf72- ALS patients matched for sex, age, education, and cognitive category, and 34 HC matched for sex, age, and education. Participants underwent neuropsychological evaluation, including the Story-Based Empathy Task (SET), assessing cognitive ToM (Intention Attribution, IA), affective ToM (Emotion Attribution, EA), and Causal Inference (CI). Results: C9orf72+ patients showed lower SET-global score than C9orf72- patients (p = 0.028). Compared with HC, C9orf72+ showed lower score in SET-global score and all SET subtests (all p < 0.05). C9orf72+ cognitively normal differed from HC in SET-global score, IA, and EA (all p < 0.038), whereas C9orf72- cognitively normal did not differ from HC. Multiple linear regression analyses indicated that ALS-specific cognitive domains only explained ∼25% of ToM variance, with no association with demographic, clinical, or behavioral variables. Cluster analysis identified three cognitive profiles based on SET performance, with the most impaired cluster showing the highest proportion of C9orf72+ patients (68%). Conclusion: C9orf72-mutated ALS patients showed more pronounced impairment in cognitive and affective ToM than non-mutated ALS patients, independent of demographic, clinical, and cognitive features. These findings, although requiring confirmation on larger samples, suggest that ToM dysfunction may represent a sensitive marker of cognitive involvement in ALS-C9orf72-associated disease, particularly in its affective component.},
}

@article {pmid42635866,
year = {2026},
author = {Chakraborty, S and Manickam, V},
title = {Decoding the Neuroinflammatory Potential of Non-Nutritive Sweeteners Through An Integrative Computational Approach.},
journal = {Neurotoxicity research},
volume = {44},
number = {5},
pages = {},
pmid = {42635866},
issn = {1476-3524},
support = {F.N. 5/9/1328/2020-Nut//Indian Council of Medical Research/ ; SG20250066//VIT University/ ; },
mesh = {Humans ; *Non-Nutritive Sweeteners/adverse effects/metabolism/chemistry ; *Neuroinflammatory Diseases/chemically induced/metabolism/genetics ; Molecular Docking Simulation/methods ; Molecular Dynamics Simulation ; Animals ; },
abstract = {Non-nutritive sweeteners (NNS) are commonly used in the beverage, food, and pharmaceutical industries, however, their possible link to neuroinflammation remains a contentious issue. Hence, to investigate this potential association and identify the molecular pathways involved, targets of the most frequently consumed NNSs, namely sucralose, aspartame, acesulfame, cyclamate, and saccharin, were extracted from the STITCH, Super-PRED, STP, SEA and CTD databases, while neuroinflammatory targets were extracted from GeneCards, OMIM, and NCBI databases. A total of 124 targets were obtained by overlapping NNS and neuroinflammatory targets, of which 20 key targets, including CASP3, PPARγ, MTOR, and MMP9, were identified for further analysis. KEGG enrichment analysis suggested a significant association of these targets with pathways related to Alzheimer's disease and neuroactive ligand-receptor interaction. Gene Ontology analysis revealed enrichment in biological processes associated with inflammatory response and reactive oxygen species. The associated cellular components were primarily localised in the axon, dendrite, and synaptic membrane. Molecular docking followed by molecular dynamics simulations was performed to evaluate the stability of the NNS-key target complexes, revealing favourable binding affinities and stable interaction profiles. Gene expression analysis of these key targets predicted their differential regulation across four majorly recognised neuroinflammatory disorders, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis, with a significant up or downregulation of these key targets. Results of this study suggest that NNS may be associated with neuroinflammatory processes through these key targets and identified pathways, highlighting the need for improving the standards in food safety.},
}

Humans
*Non-Nutritive Sweeteners/adverse effects/metabolism/chemistry
*Neuroinflammatory Diseases/chemically induced/metabolism/genetics
Molecular Docking Simulation/methods
Molecular Dynamics Simulation
Animals

@article {pmid42636000,
year = {2026},
author = {Benatar, M and Barmada, S and Jicha, GA and Lagier-Tourenne, C and Gregory, J and Al-Chalabi, A and Boeve, BF and Jack, CR and Seeley, WW and Maragakis, NJ and Wuu, J and Zeier, Z and Onyike, C and Lewcock, J and Hovinga, C and Jafar-Nejad, P and Uspenskaya, O and Simmons, A and Browne, SE and Rohrer, J and Petrucelli, L and Shapiro, J and Scharper, D and Boxer, A and Ostrow, LW and Staffaroni, AM and Dacks, P and Turner, MR and Dave, KD and de Majo, M and Mitic, L and Fradette, S and Budd Haeberlein, S and Simuni, T and Dunn, B and McMillan, CT and Lee, EB},
title = {TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.2812},
pmid = {42636000},
issn = {2168-6157},
abstract = {IMPORTANCE: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development.

OBSERVATIONS: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear.

CONCLUSIONS AND RELEVANCE: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.},
}

@article {pmid42636496,
year = {2026},
author = {Jonsdottir, G and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Jonsdottir, H},
title = {End-of-Life Care in an Acute Neurological Ward: A Retrospective Analysis of Clinical Practices During the Last Week of Life.},
journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses},
volume = {},
number = {},
pages = {},
doi = {10.1097/JNN.0000000000000906},
pmid = {42636496},
issn = {1945-2810},
support = {//Icelandic Nurses Association, University of Iceland Research Fund of Ingibjorg R. Magnusdottir, Landspitali, National University Hospital of Iceland/ ; },
abstract = {BACKGROUND: The care of patients with neurological diseases near the end of life (EOL) is challenging and often complicated by prognostic uncertainty. Difficulty recognizing the terminal phase may delay transitions to EOL care, leading to continued use of diagnostic procedures and medical interventions with a limited focus on comfort.

METHODS: This retrospective observational study included medical records of 209 deceased patients with neurological diseases who died in an acute hospital ward. Diagnostic procedures and medical and supportive interventions delivered during the final 7 days of life were extracted. Patients were categorized into 2 groups: acute neurological diseases (ischemic stroke and hemorrhagic stroke) and progressive neurological diseases (Parkinson disease or extrapyramidal and movement disorders, and amyotrophic lateral sclerosis). Frequencies of interventions were compared between diagnostic groups and according to documented EOL decision status.

RESULTS: In both groups, documented EOL decisions were associated with reduced use of diagnostic procedures and increased use of support measures. Medication administration and supportive care patterns differed between the acute and progressive disease groups and were related to documented EOL decisions. The most frequently administered interventions were oral suctioning (97%), intravenous fluids (70%), antibiotics (45%), pain relief medications (98%), and benzodiazepines (93%). Patients with progressive neurological diseases received more respiratory support interventions than those with acute neurological diseases.

CONCLUSIONS: Our findings suggest that documenting EOL decisions was related to comfort-focused care, although the frequency varied by disease group. Neurological disease-specific EOL guidelines should be implemented to identify the terminal phase in alignment with the goals of comfort-focused care in a timely manner.},
}

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

@article {pmid42637046,
year = {2026},
author = {Lauck, KC and Ahmed, A and Tolkachjov, SN},
title = {Response to Jean et al's "Alopecia after glucagon-like peptide-1 agonist therapy: A TriNetX Database active comparator retrospective cohort study".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.08.074},
pmid = {42637046},
issn = {1097-6787},
}

@article {pmid42637106,
year = {2026},
author = {Heinsinger, N and Wang, Y and Grauer, S and Zhang, Z and Wong, J and Simov, V and Bukhtiyarova, M and Ai, X and Parish, C and Klein, RM and Uslaner, J and Smith, S and Tian, Y},
title = {Splicing modulation of ATXN2 as a therapeutic strategy to regulate Ataxin-2 protein levels in ALS.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107582},
doi = {10.1016/j.nbd.2026.107582},
pmid = {42637106},
issn = {1095-953X},
abstract = {ATXN2 is associated with an increased risk of Amyotrophic Lateral Sclerosis (ALS), while down-regulation of ATXN2 has been shown to mitigate TDP-43 proteinopathy in ALS models. In this study, we demonstrated that Ataxin-2 protein levels were upregulated in rNLS8 mice following doxycycline withdrawal, which coincided with TDP-43 overexpression, phosphorylation, and aggregation. To reduce Ataxin-2 protein levels, we explored the approach of splicing modulation at the RNA level. Through bioinformatical analysis, we identified an alternative 5' splicing site of ATXN2 in intron 8. This alternative splicing results in an additional 47 base pairs at the 3' end after Exon 8. The insertion of the extra nucleotides causes a frameshift that leads to reduced mRNA production and, consequently, protein levels. Following the discovery of this alternative splicing site, we conducted an antisense oligonucleotide (ASO) micro-walk to screen ASOs targeting this region. We identified ASOs that specifically modulate this splicing, including those that either enhance or inhibit alternative splicing. We validated that the ASOs that promote alternative splicing and reduce constitutive splicing can lower Ataxin-2 protein levels, which in turn decreases TDP-43 aggregation and stress granule formation in a cell-based model of TDP-43 toxicity. Furthermore, we confirmed that reducing Ataxin-2 levels via previously validated ASO delivery ameliorated TDP-43 pathology in rNLS8 mice. The discovery of ATXN2 alternative splicing, along with the confirmation of splicing modulation using ASOs in human cell-based assays, provides evidence for a proof-of-principle strategy to modulate Ataxin-2 protein levels for the treatment of ALS.},
}

@article {pmid42637886,
year = {2026},
author = {Rashed, AM and El-Sayed, IET and Lu, X and Abdel-Bary, HM and Fouad, MK and Tony, MA},
title = {Re-engineering alum sludge using choline-glycine ionic liquid for enhanced dewatering and dye adsorption in wastewater treatment.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42637886},
issn = {2045-2322},
abstract = {Large quantities of by-product alum sludge (Al-S) generated from drinking water treatment plants pose significant environmental and disposal challenges due to their high water content and large volume. This study aims to develop a sustainable conditioning and valorization strategy for Al-S using a choline-glycine ionic liquid ([Ch]-[AA]). The ionic liquid was synthesized and applied as a sludge conditioner to enhance dewatering performance. Under optimized conditions, the dewatering efficiency reached 47%, accompanied by a notable zeta potential shift, indicating partial charge neutralization and improved floc structure. To enable sludge valorization, the conditioned sludge was reused as an adsorbent, either directly or after thermal treatment. The modified materials exhibited high adsorption capacities toward Synozol KHL dyes, reaching 43.6 and 90.1 mg g[-][1] for Red and Blue dyes, respectively. Adsorption behavior was well described by the Langmuir isotherm and pseudo-second-order kinetic model. Thermodynamic analysis indicated an exothermic adsorption process, with spontaneity dependent on operating conditions. Overall, the results demonstrate an effective waste-to-resource approach in which enhanced dewatering facilitates the conversion of alum sludge into a functional adsorbent for wastewater treatment, supporting sustainable sludge management.},
}

@article {pmid42638006,
year = {2026},
author = {Sreekanth, D and Singh, C and Pawar, DV and Yadav, MK and Sahadeo, IK and Basavaraj, PS and Kumar, R and Mahesh, S},
title = {CRISPR/Cas-Mediated Genome Editing for Developing Herbicide Tolerant Rice: A Step-by-Step Protocol.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3017},
number = {},
pages = {47-57},
pmid = {42638006},
issn = {1940-6029},
mesh = {*Oryza/genetics/drug effects/growth & development ; *CRISPR-Cas Systems ; *Gene Editing/methods ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; Acetolactate Synthase/genetics ; Plants, Genetically Modified/genetics ; Benzoates ; Pyrimidines ; },
abstract = {Weed management in rice cultivation has predominantly relied on acetolactate synthase (ALS) and acetyl-CoA carboxylase (ACCase) inhibiting herbicides, particularly against Echinochloa spp. (watergrass). However, these herbicides carry a high risk of resistance evolution, as evidenced by the numerous resistant biotypes reported worldwide. The emergence of herbicide resistance necessitates innovative and sustainable weed control strategies. Genome editing, particularly through the CRISPR/Cas system, provides a precise and efficient platform for introducing targeted genetic modifications to develop herbicide-tolerant (HT) rice cultivars. In this protocol, we present a step-by-step approach for generating bispyribac sodium-tolerant rice using the CRISPR/Cas-mediated editing of the ALS gene. The method encompasses guide RNA design, vector construction, transformation, selection of edited plants, and molecular confirmation of targeted mutations. This approach offers a robust framework for producing HT rice lines, potentially reducing reliance on conventional herbicide regimes and mitigating the risk of resistance development in weed populations.},
}

*Oryza/genetics/drug effects/growth & development
*CRISPR-Cas Systems
*Gene Editing/methods
*Herbicides/pharmacology
*Herbicide Resistance/genetics
Acetolactate Synthase/genetics
Plants, Genetically Modified/genetics
Benzoates
Pyrimidines

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

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

@article {pmid42638122,
year = {2026},
author = {Zhang, Y and Liu, Y and Shi, S and Li, Q and Huo, Y and You, P and Shu, M and Cheng, X and Zhang, J and Liang, D and Zhang, A and Lu, C and Shen, B and Zhou, J and Niu, Q},
title = {JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice.},
journal = {BMC medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42638122},
issn = {1741-7015},
support = {82071434//the National Natural Science Foundation of China/ ; DL202410//the clinical Research Disease Project of Jiangsu Provincial People's Hospital/ ; LC202404//Jiangsu Provincial People's Hospital-Zero magnetic Medicine Special Project/ ; JSPH-MA-2023-5//Jiangsu Province Hospital Clinical Capacity Enhancement Project/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Autophagy/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Antioxidant Response Elements ; Signal Transduction/drug effects ; *Oligopeptides/pharmacology ; Male ; Humans ; Spinal Cord/metabolism ; },
abstract = {BACKGROUND: The simultaneous modulation of oxidative stress and autophagy represents a potential therapeutic strategy for amyotrophic lateral sclerosis (ALS), yet agents capable of coordinately regulating both processes remain scarce. The Keap1‑Nrf2‑ARE pathway serves as a critical hub linking redox homeostasis and autophagic regulation, making it an attractive target for ALS intervention. JWA is a stress‑responsive protein involved in cellular protection against oxidative injury, and its neuroprotective effects have been shown to depend on activation of the MEK/ERK‑Nrf2 axis. JP1 is a functional oligopeptide derived from the JWA protein that has been engineered to cross the blood-brain barrier and specifically target integrin αVβ3. Based on the link between JWA and Nrf2 signaling, we hypothesized that JP1 activates the Keap1‑Nrf2‑ARE pathway to coordinate antioxidant defense and autophagic clearance. Here, we evaluated this hypothesis in the SOD1‑G93A mouse model, a well‑established transgenic model of familial ALS, and elucidated the underlying mechanisms.

METHODS: We evaluated the efficacy of JP1 in the SOD1-G93A mice model using behavioral phenotyping and survival analysis. The coordinated mechanism was investigated in spinal cord tissues by profiling the Keap1-Nrf2-ARE pathway and oxidative stress, quantifying autophagic flux (by Western blotting and transmission electron microscopy) and neuronal apoptosis, and evaluating histology (by Nissl staining and immunofluorescence). Integrated transcriptomic and proteomic analyses further elucidated the global molecular landscape underlying the therapeutic effects of JP1.

RESULTS: JP1 treatment ameliorated motor deficits and extended survival in SOD1-G93A mice without adversely affecting liver or kidney function. JP1 crossed the blood-brain barrier, targeted motor neurons expressing integrin αVβ3, and activated the ERK pathway. This promoted Keap1/Cul3 degradation and Nrf2 nuclear translocation, thereby activating the Keap1-Nrf2-ARE pathway to alleviate oxidative stress. Concurrently, JP1 restored autophagic flux, increased autophagic activity, attenuated motor neuron injury, suppressed neuronal apoptosis, and preserved neuronal structural integrity. The Nrf2 inhibitor ML385 reversed the protective effects of JP1 on survival, motor function, autophagy, oxidative stress, and neuronal apoptosis, which confirms that JP1 acts via the Nrf2 pathway.

CONCLUSIONS: JP1 acts as a promising coordinator of antioxidant and autophagic processes by targeting the Keap1-Nrf2-ARE pathway, thus highlighting its therapeutic potential for ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism
*Oxidative Stress/drug effects
*NF-E2-Related Factor 2/metabolism
*Autophagy/drug effects
*Kelch-Like ECH-Associated Protein 1/metabolism
Disease Models, Animal
Mice
Mice, Transgenic
Antioxidant Response Elements
Signal Transduction/drug effects
*Oligopeptides/pharmacology
Male
Humans
Spinal Cord/metabolism

@article {pmid42638891,
year = {2026},
author = {Wollmann, L and Wolf, A and Cooke, L and Santana, M},
title = {The patient as teacher: a four-phase blueprint for institutional change.},
journal = {Frontiers in health services},
volume = {6},
number = {},
pages = {1920768},
pmid = {42638891},
issn = {2813-0146},
abstract = {INTRODUCTION: Over recent decades, patient involvement in medical education has shifted from passive case demonstrations toward active partnerships in teaching, assessment, and curriculum design, a transition that must recognize patients and relatives as persons with experiential knowledge, not merely as educational instruments. This perspective article argues that accumulated evidence now justifies a deliberate shift from scattered, champion-driven initiatives to embedded institutional strategy.

EVIDENCE AND GAPS: The evidence supports meaningful benefits across stakeholders: learners develop stronger clinical reasoning, communication skills, and empathy; patient educators report empowerment and enhanced self-esteem; and institutions advance their social accountability mission. However, the field continues to struggle with inconsistent terminology, fragmented implementation, short-term satisfaction-based outcomes, underexplored ethical considerations, and weak institutional commitment.

PROPOSED ROADMAP: To address these gaps, we propose a four-phase implementation roadmap. Phase 1 (Institutional Diagnosis) maps current practices against Towle et al.'s six-level taxonomy and establishes an institutional position statement. Phase 2 (Role Definition and Phased Goal-Setting) advocates stepwise progression, typically starting at Levels 3-4, where patients share experiences or act as trained teachers, advancing toward full curriculum governance partnership. Phase 3 (Implementation Planning and Capacity Building) addresses curriculum integration, resource allocation, faculty development, and community partnerships. Phase 4 (Outcomes Monitoring and Evaluation) calls for multilevel, longitudinal evaluation frameworks, including systematic assessment of patient educators' experiences.

DISCUSSION: We present this roadmap as an evidence-informed conceptual synthesis whose implementation depends on continued institutional commitment. Cross-cutting principles include incrementalism, sustained institutional commitment, patient co-production, representative recruitment, and rigorous longitudinal research.},
}

@article {pmid42639115,
year = {2026},
author = {Harbert, DH},
title = {EIF2S1-PELO co-expression architecture in human brain: pairing-family decomposition reveals constitutive transcriptional coupling and functional layer separation.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1817096},
pmid = {42639115},
issn = {1662-5099},
abstract = {EIF2S1 (eIF2α, translation initiation surveillance) and PELO (Pelota, ribosome rescue) operate within established ribosome-associated quality control and translation-initiation surveillance pathways. Direct cross-talk between these systems is mediated through ZAK/GCN-mediated eIF2α phosphorylation under ribosome-stall stress. At the transcriptional layer, however, EIF2S1-PELO co-regulation has not been quantitatively characterized. Using pairing-family architectural decomposition on multi-region GTEx co-expression and BA9 prefrontal cortex RNA-seq from Parkinson's disease and control donors (GSE68719, n = 44 controls, n = 29 PD), we find: (1) EIF2S1 and PELO share near-identical genome-wide co-expression architecture (continuous Weighted Jaccard = 0.914) with substantial top-partner overlap (binary Jaccard at top 5% = 0.490), producing a Type 1 dissociation gap of 0.424, significantly smaller than 200 random gene-pair gaps (mean 0.644, z = -2.57, permutation p = 0.015), and the lowest gap in a 21-pair quality-control gene panel; (2) the relationship is approximately linear-monotonic (Type 6 Pearson-Spearman gap ≈ 0.004); (3) cellular functional co-dependency in DepMap CRISPR screens is essentially zero (Jaccard = 0.006, gene-effect Pearson r = -0.07), consistent with layer separation between regulatory architecture and cellular phenotype; (4) in an exploratory single-cohort comparison of PD versus control prefrontal cortex, the dissociation gap was larger in PD (0.536 versus 0.424 in control), but this between-group difference did not reach statistical significance under a group-label permutation test (p = 0.40; bootstrap 95% CI on the difference [-0.14, 0.29]), so we present it as a hypothesis for replication rather than an established effect. These findings characterize EIF2S1-PELO transcriptional co-regulation as a constitutive architectural feature distinct from the ZAK/GCN-mediated direct mechanism. The constitutive coupling replicated in independent Alzheimer's disease and ALS frontal-cortex cohorts and across microarray and RNA-seq platforms; a disease-associated weakening of the coupling was directionally consistent across all three diseases but did not reach statistical significance. We note that co-expression patterns are consistent with shared upstream regulatory programs but do not by themselves establish direct co-regulation; the architectural findings reported here are correlational at the transcriptional layer.},
}

@article {pmid42627134,
year = {2026},
author = {Mahjoubin-Tehran, M and Sahebkar, A},
title = {RNA interference (RNA)-based therapeutics for treating neurodegenerative diseases.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/17582024.2026.2722300},
pmid = {42627134},
issn = {1758-2032},
}

@article {pmid42628519,
year = {2026},
author = {Mohassel, P},
title = {Rethinking ALS through the spatiotemporal vulnerability of the entire motor unit.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2026.08.011},
pmid = {42628519},
issn = {1525-0024},
support = {R01 NS138167/NS/NINDS NIH HHS/United States ; },
}

@article {pmid42628773,
year = {2026},
author = {Tani, H},
title = {A replicated astrocyte long non-coding RNA signature of Alzheimer's disease is inverted in amyotrophic lateral sclerosis.},
journal = {Brain research},
volume = {1891},
number = {},
pages = {150513},
doi = {10.1016/j.brainres.2026.150513},
pmid = {42628773},
issn = {1872-6240},
abstract = {Reactive astrocyte transitions are central to neurological disease, yet their long non-coding RNA (lncRNA) regulators remain poorly defined, and single-nucleus studies frequently treat nuclei rather than donors as replicates. This study analyses publicly available human single-nucleus RNA sequencing from four disorders using donors as the unit of inference throughout: Alzheimer's disease (AD; middle temporal gyrus, 88 donors), C9orf72-associated amyotrophic lateral sclerosis and ALS/frontotemporal dementia (ALS; frontal cortex), multiple sclerosis (MS; cortex and white matter), and major depressive disorder (MDD; amygdala). The public MDD release pools nuclei by condition, so that arm cannot support donor-level inference and is exploratory only. Covariate-adjusted pseudobulk analysis of 70,009 CE astrocytes, controlling for sex, age at death and assay chemistry, identified 1,019 down-regulated autosomal lncRNAs after sex-chromosome transcripts were removed. This signature was not attributable to astrocyte subtype composition, which did not differ between groups, and 99.9% of members remained down-regulated within the dominant homeostatic subtype alone. The signature replicated in an independent AD cohort (32 of 41 testable members concordant; resampling P < 0.0001). Testing it outside AD gave a directional result: it was concordant in the MS discovery cohort (P < 0.0001) but inconclusive in an independent MS cohort in which the transcripts lay near the detection floor, and it was reproducibly inverted in ALS, in the C9orf72 discovery cohort and in an independent motor-cortex cohort not restricted to C9orf72 carriers. The inversion survived negative controls for global normalisation and expression level. These astrocyte lncRNA changes are therefore disorder-specific rather than pan-neuroinflammatory.},
}

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

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

@article {pmid42630952,
year = {2026},
author = {Tang, C and De Vocht, J and Van Damme, P and Van Laere, K and Koole, M},
title = {Metabolic connectivity alterations in amyotrophic lateral sclerosis: Individual network analysis based on Wasserstein distances.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {42630952},
issn = {2837-6056},
abstract = {Molecular connectivity analysis with positron emission tomography (PET) imaging offers a promising approach for characterising brain network alterations in neurodegenerative disorders. In this study, we introduce Wasserstein distance (WD) as an alternative to Kullback-Leibler divergence similarity estimation (KLSE) for constructing single-subject metabolic connectivity networks. Using [18]F-FDG PET data from 167 individuals with amyotrophic lateral sclerosis (ALS), 36 healthy volunteers (HV), and 25 ALS mimics, we generated WD- and KLSE-based connectivity matrices across 77 atlas-defined brain regions and evaluated corresponding graph theory-based nodal metrics. WD- and KLSE-derived nodal measures were strongly correlated, indicating methodological consistency. Compared with HVs, age-matched subjects in the ALS group (ALSamHV) showed significant alterations in frontal, temporal, cerebellar, and occipital network nodes, with WD-based metrics revealing differences across more brain regions than the KLSE-based approach. Support vector machine classification of ALSamHV vs. HV demonstrated that both connectivity approaches matched voxel-wise PET performance with accuracy higher than 0.80 (yet significantly lower than voxel-wise data, p < 0.05), while significantly outperforming image-based classification for ALS vs. ALS mimics (p < 0.01), with WD achieving the highest accuracy of 0.65 (p < 0.001). These findings support WD-based metabolic connectivity as a sensitive, data-efficient framework for detecting disease-related network alterations and motivate its application to a broader range of PET tracers and cohorts.},
}

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

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

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

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

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

@article {pmid42632702,
year = {2026},
author = {Wu, L and Zhu, X and Wang, X and Wu, Y and Bu, Q and Dai, T and Wen, X and Zhong, K and Guo, H and Gao, H},
title = {Fermentation with aspergillus costiformis enhances the anti-migratory activity of Aquilaria sinensis leaves with possible involvement of MAPK-related pathways.},
journal = {Food research international (Ottawa, Ont.)},
volume = {242},
number = {Pt 2},
pages = {119955},
doi = {10.1016/j.foodres.2026.119955},
pmid = {42632702},
issn = {1873-7145},
mesh = {Humans ; *Aspergillus/metabolism ; *Plant Leaves/chemistry ; *Fermentation ; *Thymelaeaceae/chemistry/metabolism ; HeLa Cells ; *Plant Extracts/pharmacology ; *Cell Movement/drug effects ; *MAP Kinase Signaling System/drug effects ; Flavonoids ; Cell Proliferation/drug effects ; },
abstract = {Aquilaria sinensis leaves (ALs) are an underutilized plant resource rich in polyphenols and flavonoids. Microbial fermentation has been proposed as an effective strategy to enhance the functional value of plant materials. However, its impact on the bioactivity and mechanisms of ALs remains unclear. This study aimed to evaluate the effects of fermentation with Aspergillus costiformis AHHC on the chemical composition and biological activities of ALs, and to elucidate the molecular mechanisms underlying the fermentation-induced functional changes. Non-targeted metabolomic analysis was performed to assess fermentation-induced metabolic alterations. The biological activities of fermented ALs (ALDT) and non-fermented ALs (ALT) extracts were evaluated using HeLa S3 cell-based assays. Network pharmacology and transcriptomic analyses were integrated to identify potential pathways and molecular targets, which were further validated by molecular analyses. The results revealed that fermentation significantly reshaped the metabolite profile of ALDT, particularly in flavonoid-related pathways. Compared with ALT, ALDT showed a stronger inhibitory effect on HeLa S3 cell migration while maintaining comparable anti-proliferative activities at higher concentrations. The integrated analyses indicated that fermentation-enriched metabolites were mainly associated with pathways related to cell migration and stress response, with prominent involvement of MAPK signaling. Molecular assays confirmed enhanced phosphorylation of MAPK components and increased expression of regulatory genes such as GADD45B and NR4A1 in response to ALDT treatment. Overall, fermentation with A. costiformis enhanced the anti-migratory activity of ALDT in HeLa S3 cells, with possible involvement of MAPK-related signaling pathways. These findings provide molecular-level evidence supporting microbial fermentation as a strategy to improve the functional value of this plant resource.},
}

Humans
*Aspergillus/metabolism
*Plant Leaves/chemistry
*Fermentation
*Thymelaeaceae/chemistry/metabolism
HeLa Cells
*Plant Extracts/pharmacology
*Cell Movement/drug effects
*MAP Kinase Signaling System/drug effects
Flavonoids
Cell Proliferation/drug effects

@article {pmid42632821,
year = {2026},
author = {Tragesser, C and Joy, AG and Sodhi, CP},
title = {Early-onset inflammatory bowel disease: progress and persistent inequities.},
journal = {Pediatric research},
volume = {},
number = {},
pages = {},
pmid = {42632821},
issn = {1530-0447},
abstract = {This commentary discusses Yue et al.'s population-based study, "The Shifting Burden of Early-Onset Inflammatory Bowel Disease: A Global Analysis", and highlights how declining mortality, increasing prevalence, and widening socioeconomic disparities are reshaping the global landscape of early-onset inflammatory bowel disease.[1] The findings emphasize the importance of combining scientific advances with equitable healthcare delivery to improve outcomes for children worldwide.},
}

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

@article {pmid42634270,
year = {2026},
author = {Shen, D and Ding, J and Zhai, F and Shi, J and Liu, M and Liu, Q and Cui, L},
title = {A de novo FUS frameshift variant (p.Gly501Valfs*30) presenting with tremor and prominent extrapyramidal features in young-onset motor neuron disease: a case report.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/21678421.2026.2721279},
pmid = {42634270},
issn = {2167-9223},
abstract = {Fused in sarcoma (FUS) mutations are a recognized cause of juvenile-onset amyotrophic lateral sclerosis (ALS), typically associated with early age at onset and rapid disease progression. Here we report a 32-year-old Chinese man who presented with bilateral hand tremor as the initial symptom, followed by progressive dysarthria, bradykinesia, and multi-segment upper and lower motor neuron involvement. Whole-exome sequencing identified a de novo heterozygous FUS frameshift (p.Gly501Valfs*30), confirmed absent in both parents. Electromyography revealed predominantly chronic neurogenic changes. At approximately 2.5 years from symptom onset, the patient remains ambulatory with a walking frame, with a notably milder course than the previously reported frameshift at the same Gly501 codon. This case expands the phenotypic spectrum of FUS-associated motor neuron disease and highlights tremor and extrapyramidal features as potential early manifestations in adult patients.},
}

@article {pmid42634335,
year = {2026},
author = {Langmead, AP and Keane, BA and Jacob, JA and Ramana, KV},
title = {Metformin in Neurodegenerative Diseases: Mechanisms and Therapeutic Implications.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X476604260704180015},
pmid = {42634335},
issn = {1875-6190},
abstract = {As the global burden of neurodegenerative disorders continues to rise with aging populations, there is growing interest in identifying widely available drugs that can be repurposed to target shared metabolic and inflammatory mechanisms underlying these conditions. Increasing evidence suggests that metabolic dysfunction, mitochondrial impairment, and chronic neuroinflammation play central roles in the pathogenesis of neurodegeneration, demonstrating the need for therapeutics that can modulate these interconnected pathways. Metformin has served as the gold standard for the management of type 2 diabetes for 7 decades. It offers a superior safety profile, established metabolic advantages, and affordability. Recent studies suggest that, in addition to its antihyperglycemic actions, it could also be repurposed to treat several inflammatory complications and infectious diseases. Further, recent preclinical and clinical studies suggest that, by regulating AMPK, mTOR, and mitochondrial function, metformin could also control the initiation and progression of neurodegenerative diseases. Several studies also indicate that metformin suppresses neuroinflammation by inhibiting the NF-κB signaling pathway and the NLRP3 inflammasome, thereby improving insulin signaling and metabolic homeostasis. This review integrates metabolic, inflammatory, and mitochondrial mechanisms to present a unified mechanistic framework to explain how metformin may modulate the onset and progression of neurodegeneration. Specifically, we discuss recent studies showing the therapeutic significance of metformin in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, this review highlights metformin as a potential therapeutic candidate for future development in neurodegenerative diseases.},
}

@article {pmid42623241,
year = {2026},
author = {Yi, T and Guan, H and Li, J and Li, W and Li, B and Zhu, C},
title = {Elevated neuronal TAF15 expression induces oxidative stress and anxiety-related behavioral deficits.},
journal = {Cell reports},
volume = {45},
number = {9},
pages = {117885},
doi = {10.1016/j.celrep.2026.117885},
pmid = {42623241},
issn = {2211-1247},
abstract = {TAF15 is a DNA/RNA-binding protein involved in RNA processing whose dysfunction has been implicated in neurodegenerative diseases, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the relationship between TAF15 expression levels and neurodegeneration, as well as the specific downstream pathways mediating its neurotoxicity, remain unclear. Here, we find a consistent upregulation of TAF15 in prefrontal cortex neurons from patients across multiple FTD and ALS subtypes. Both in vitro and in vivo experiments demonstrate that neuronal TAF15 overexpression triggers oxidative stress, leading to neurotoxicity and gliosis. Mice overexpressing TAF15 in medial prefrontal cortex (mPFC) neurons exhibit heightened anxiety and impaired cued fear-conditioning responses. Notably, these pathological and behavioral phenotypes are rescued by the antioxidant N-acetylcysteine amide (NACA), supporting a role for oxidative stress in TAF15-associated neurodegeneration. Together, this study elucidates a TAF15-oxidative stress axis in neurodegeneration, providing a conceptual framework for future therapeutic development.},
}

@article {pmid42624563,
year = {2026},
author = {Mehta, B and Nambiar, S and Shirke, O and Pandita, S and Markandeya, YS},
title = {Histone deacetylases in neurodegeneration and neuronal plasticity.},
journal = {Methods in enzymology},
volume = {733},
number = {},
pages = {321-366},
doi = {10.1016/bs.mie.2026.06.025},
pmid = {42624563},
issn = {1557-7988},
mesh = {Humans ; *Histone Deacetylases/metabolism/genetics ; Animals ; *Neuronal Plasticity ; *Neurodegenerative Diseases/enzymology/metabolism/pathology/drug therapy/genetics ; Cell Nucleus/metabolism ; Neurons/metabolism/pathology ; Histone Deacetylase 6/metabolism ; Brain/metabolism/pathology ; Protein Transport ; },
abstract = {This chapter pulls together current research on how HDAC shuttling between the nucleus and cytoplasm affects neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and epilepsy. It takes a close look at why these shifts in HDAC localization matter so much in brain disease and its implications for new treatments. Histone deacetylases (HDACs) are a big deal when it comes to gene regulation in the brain. They play key roles in both neurodegeneration and the brain's ability to adapt, working inside the nucleus and out in the cytoplasm. This chapter unpacks the molecular mechanisms behind HDAC trafficking-how they move around-highlights the different roles of HDAC isoforms, and compares localization-specific effects. It digs into how HDACs impact protein aggregation and synaptopathies. Some findings stand out: HDAC4 and HDAC1 are tightly controlled by phosphorylation signals, which change their cellular localization and influence neuronal mortality. For example, HDAC6 is majorly involved in cellular trafficking and clearing protein aggregates, whereas HDAC4 aggregation in the nucleus is responsible for driving neuronal toxicity. If HDAC1 undergoes nuclear export, it interacts with motor proteins to impact mitochondrial transport. Drugs that block HDAC6 look promising in preclinical models-they help restore neuronal transport systems and clear protein aggregation. Moving HDAC4 out of the nucleus seems to support better synaptic function and motor skills. As a general rule, HDAC accumulation in the nucleus shuts down genes that keep neurons alive, but keeping them in the cytoplasm helps preserve connections between neurons. You'll also find thorough, practical advice on how to study HDACs in brain research-covering everything from enzyme assays and cell experiments to live animal models, plasticity tracking, drug testing, and data analysis. A major innovation featured here is using CRISPR-based tricks to control exactly where HDACs go inside cells: forced targeting using dCas9 fusions, editing natural localization signals, and even using optogenetics for precise on-demand control. In short, the chapter is a hands-on guide for anyone trying to unravel HDAC mechanisms in diseases like Alzheimer's, Parkinson's, Huntington's, or in studies of brain plasticity. Some standout methods include tracking HDAC localization in the cells, measuring how phosphorylation affects their shuttling, and using HDAC2 inhibitors for cognitive boosts. It also covers isoform-specific approaches in Huntington's models, manipulating HDAC location with CRISPR for deeper insights, and combining live-cell imaging with biochemical and chromatin studies for robust validation. This chapter sheds light on the latest advances, with a strong focus on precision, quantitative results, and translating these findings into real-world applications.},
}

Humans
*Histone Deacetylases/metabolism/genetics
Animals
*Neuronal Plasticity
*Neurodegenerative Diseases/enzymology/metabolism/pathology/drug therapy/genetics
Cell Nucleus/metabolism
Neurons/metabolism/pathology
Histone Deacetylase 6/metabolism
Brain/metabolism/pathology
Protein Transport

@article {pmid42624937,
year = {2026},
author = {Aboukhalil, FM and Khamis, EF and El-Sayed, MA and Youssef, RM and El-Yazbi, AF},
title = {Green analytical methods for quantification of a new combination therapy for amyotrophic lateral sclerosis: assessment by EPPI framework.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42624937},
issn = {2045-2322},
mesh = {*Celecoxib/therapeutic use/analysis ; *Ciprofloxacin/therapeutic use/analysis ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Chromatography, High Pressure Liquid/methods ; *Green Chemistry Technology/methods ; Spectrophotometry, Ultraviolet/methods ; Tablets ; Drug Therapy, Combination ; Reproducibility of Results ; },
abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to progressive muscle weakness, paralysis, and respiratory failure. The recently proposed combination therapy consisting of celecoxib and ciprofloxacin hydrochloride has emerged as a potential treatment for amyotrophic lateral sclerosis and other neurodegenerative disorders. The present study aimed to develop and validate simple, sensitive, environmentally friendly, and cost-effective analytical methods for the simultaneous determination of celecoxib and ciprofloxacin hydrochloride in bulk powders, laboratory-prepared tablets and plasma. Two ultraviolet spectrophotometric methods were established. The first method relies on direct absorbance measurements of ciprofloxacin hydrochloride at 318 nm and celecoxib at the isosbestic point at 266 nm, while the second one employs first-derivative ratio spectrophotometry for the selective determination of ciprofloxacin hydrochloride and celecoxib at 280 nm and 254 nm, respectively. Moreover, a reversed-phase high-performance liquid chromatographic method was developed using a C18 stationary phase, an optimized mobile phase composition and both diode array and fluorescence detectors, achieving efficient separation and accurate quantification of both analytes. The developed procedures were successfully applied to laboratory-prepared tablets and plasma following optimization of the sample preparation protocol to minimize matrix interference and to improve analytes recovery. Validation results showed excellent linearity over the investigated concentration ranges together with satisfactory accuracy, precision, selectivity, and sensitivity, confirming the reliability of the proposed methods for routine quality control and bioanalytical applications. The overall analytical performance and environmental sustainability of the developed methods were further assessed using the environmental performance and practicality Index framework, demonstrating their suitability as reliable and sustainable analytical approaches for the determination of celecoxib and ciprofloxacin hydrochloride.},
}

*Celecoxib/therapeutic use/analysis
*Ciprofloxacin/therapeutic use/analysis
*Amyotrophic Lateral Sclerosis/drug therapy
Humans
Chromatography, High Pressure Liquid/methods
*Green Chemistry Technology/methods
Spectrophotometry, Ultraviolet/methods
Tablets
Drug Therapy, Combination
Reproducibility of Results

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

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

@article {pmid42625845,
year = {2026},
author = {Wu, IH and Schwarze, JE and Helwig, C and D'Hooghe, T and Schellschmidt, I},
title = {Clinical Appraisal of "Micronized Vaginal Progesterone Dose and Serum Progesterone Thresholds Determine Reproductive Outcomes in Frozen-Thawed Embryo Transfer With Hormone Replacement Therapy".},
journal = {Reproductive medicine and biology},
volume = {25},
number = {1},
pages = {e70088},
pmid = {42625845},
issn = {1445-5781},
abstract = {This paper critically evaluates Sekiguchi et al.'s study of vaginal progesterone dose, serum progesterone thresholds, and reproductive outcomes in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles. The study conflates descriptive, predictive, and causal aims without a clearly prespecified primary question, limiting interpretability. Major concerns include non-random treatment allocation, potential residual confounding, absence of a causal framework for covariate selection, unaddressed temporal confounding related to Japan's 2022 insurance reform, and exclusion of an available progesterone formulation. Additionally, formulation specific pharmacokinetics, single-time-point progesterone measurement, and internally derived thresholding limit comparability, predictive validity, and clinical applicability.},
}

@article {pmid42625892,
year = {2026},
author = {Dimitrov, M and Grosskreutz, J and Ilse, B and Rakers, F and Steinbach, R},
title = {Short-term ambient temperature increases are associated with higher mortality in amyotrophic lateral sclerosis: a case-crossover study of weather conditions.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1868482},
pmid = {42625892},
issn = {1663-4365},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with vastly differing survival times. The influence of environmental exposures such as weather conditions on mortality among people living with ALS remain poorly defined. The aim of this study was to evaluate the association between short-term meteorological phenomena and the odds of death among patients with ALS.

METHODS: We conducted a retrospective case-crossover study of 298 deaths among clinically verified ALS patients that occurred within a weather-station catchment area. Daily mean data for temperature, atmospheric pressure, and relative humidity were analyzed. Associations were analyzed by comparing hazard intervals (1-3 days before death) with bidirectional control intervals in generalized linear mixed models. Results are expressed as odds ratios (OR) and 95% confidence intervals (CI).

RESULTS: Absolute meteorological conditions (temperature, pressure, humidity) showed no significant association with mortality, which was independently supported by seasonal/monthly death count analyses. Short-term temperature rises of 3 °C in the 24 h preceding the day before death were associated with 25% higher odds of death (OR 1.25; 95% CI 1.05-1.49). Exploratory subgroup analyses suggested that this association was most pronounced in female, ventilated, and older patients (≥65 years). Changes in relative humidity and atmospheric pressure were not significantly associated with the odds of death.

CONCLUSION: Short-term temperature increases are associated with higher odds of death among people living with ALS, independent of absolute weather conditions or seasonal patterns. These findings support attention of stable ambient temperatures in end-stage care, while further studies of weather-related hazards in ALS are needed.},
}

@article {pmid42626456,
year = {2026},
author = {Pollard, C and Miller, R and Stirland, I and Keni, M and Jenkins, A and Saito, E and Hill, JT and Jenkins, T},
title = {Circulating neuron-derived cfDNA for blood-based detection of Alzheimer's and other neurodegenerative conditions.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1822479},
pmid = {42626456},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; DNA Methylation ; *Neurons/metabolism ; *Cell-Free Nucleic Acids/blood ; Biomarkers/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Female ; Male ; Amyotrophic Lateral Sclerosis/blood/diagnosis ; },
abstract = {Blood-based biomarkers for neurodegenerative diseases are improving early detection and staging, but current assays primarily reflect aggregate neuropathology or generalized neuronal injury and do not resolve the specific neuronal populations affected. Circulating cell-free DNA (cfDNA) retains stable DNA methylation patterns reflective of tissue and cellular origin, making it a promising substrate for cell-of-origin analysis. However, conventional methylation approaches are limited by bisulfite-associated DNA damage and amplification-related bias, hindering the detection of neuron-derived cfDNA, a small fraction of total circulating cfDNA. Here, we present proof-of-concept evidence that native nanopore sequencing can support both brain methylation atlas generation and downstream cfDNA cell-of-origin classifier development in neurodegenerative disease. By directly profiling endogenous DNA methylation without bisulfite conversion or PCR amplification, nanopore sequencing preserves native molecules, reduces processing-related bias, and enables flexible, genome-wide methylation profiling that can be iteratively expanded as additional reference cell types are incorporated. Using whole-genome native nanopore sequencing, we generated a methylation reference atlas from six primary human neural cell populations-cortical neurons, dopaminergic neurons, spinal motor neurons, astrocytes, Schwann cells, and microglia-and developed cell-type-informed cfDNA classifiers. Classifier performance was assessed in silico using dilution series designed to model physiologic admixture. The framework was then applied to 137 blood plasma samples from individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and healthy controls. Elevated circulating cfDNA fragments exhibited methylation patterns similar to reference profiles from selectively vulnerable neuronal populations, including cortical neuron-like signatures in AD and progressive MCI, dopaminergic neuron-like signatures in PD, and spinal motor neuron-like signatures in ALS. Multivariate integration of neuronal signatures improved the separation of diagnostic groups within this cohort (AUC > 0.85). Although the reported atlas is limited and additional validation in larger and independent cohorts will be required, these results support the feasibility of native cfDNA nanopore methylation sequencing as a flexible platform for brain-derived cfDNA analysis and more cell-type-informed investigation of neurodegeneration from peripheral blood.},
}

Humans
*Alzheimer Disease/blood/diagnosis
DNA Methylation
*Neurons/metabolism
*Cell-Free Nucleic Acids/blood
Biomarkers/blood
*Neurodegenerative Diseases/blood/diagnosis
Female
Male
Amyotrophic Lateral Sclerosis/blood/diagnosis

@article {pmid42626598,
year = {2026},
author = {Pinky, PP and Wang, ZM and Khare, P and Jhaveri, JR and Sullivan, A and Basudkar, V and Rao, KS and Lawrence, A and Pingali, A and Dave, KM and Stolz, DB and Sun, M and Zheng, SY and Shiva, SS and Milligan, C and Delbono, O and Manickam, DS},
title = {Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.},
journal = {Extracellular vesicle},
volume = {7},
number = {},
pages = {},
pmid = {42626598},
issn = {2773-0417},
support = {R25 NS100118/NS/NINDS NIH HHS/United States ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1[G93A] transgenic mouse model of ALS.},
}

@article {pmid42626968,
year = {2026},
author = {Lautrup, S and Cao, SQ and Long, X and Liu, BHM and Escobar-Doncel, B and Ferrante, A and Frank, J and Schmauck-Medina, T and Leung, GHD and Liang, KX and Lu, N and Veverova, K and Vyhnalek, M and Pun, FW and Zhavoronkov, A and Fang, EF},
title = {A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD[+]-mitophagy axis on aging and neurodegeneration.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71680},
pmid = {42626968},
issn = {1552-5279},
support = {#119986//NordForsk Foundation/ ; PTC-Gene-25-1439553/ALZ/Alzheimer's Association/United States ; #334361//Research Council of Norway/ ; #101073251//HORIZON-TMA-MSCA-DN/ ; #269901//Akershus University Hospital/ ; #2020001//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #282952//Cure Alzheimer's Fund/ ; #2021021//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #281956//Norwegian Health Association/ ; /WT_/Wellcome Trust/United Kingdom ; #104617//Ellcome Leap's Dynamic Resilience Program (jointly funded by Temasek Trust)/ ; #TO01000215//Czech Republic-Norway KAPPA programme/ ; #262960//Akershus University Hospital/ ; #43622//Norwegian Health Association/ ; #262175//Research Council of Norway/ ; #NW26-04-00501//Czech Ministry of Health project/ ; #81971327//National Natural Science Foundation of China/ ; #284930//Cure Alzheimer's Fund/ ; #261973//Akershus University Hospital/ ; #2023093//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #207819//the Rosa sløyfe/Norwegian Cancer Society and Norwegian Breast Cancer Society/ ; #281931//Civitan Norges Forskningsfond/ ; },
mesh = {Humans ; Animals ; *Aging/metabolism ; Caenorhabditis elegans ; *NAD/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; *Mitophagy/physiology ; *Brain/metabolism/pathology ; *Artificial Intelligence ; Neurons/metabolism ; Alzheimer Disease/metabolism/genetics ; Induced Pluripotent Stem Cells ; },
abstract = {INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD[+]) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD[+]-mitophagy axis contributes to brain aging and neurodegeneration.

METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD[+]-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.

RESULTS: The NAD[+]-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.

DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD[+]-mitophagy axis as a central player in brain aging and AD.},
}

Humans
Animals
*Aging/metabolism
Caenorhabditis elegans
*NAD/metabolism
*Neurodegenerative Diseases/metabolism/genetics
*Mitophagy/physiology
*Brain/metabolism/pathology
*Artificial Intelligence
Neurons/metabolism
Alzheimer Disease/metabolism/genetics
Induced Pluripotent Stem Cells

@article {pmid42622006,
year = {2026},
author = {de la Rubia Ortí, JE and Bargues-Navarro, G and Sancho-Castillo, S and Privado, J and Benlloch García, M and Sanchis Sanchis, CE and Garcia Martinez, L and Cuerda-Ballester, M and Bolós, PM and Roig, FJ},
title = {Cross sectional analysis of gut microbiota of ALS patients with and without percutaneous endoscopic gastrostomy.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1842792},
pmid = {42622006},
issn = {1664-302X},
abstract = {INTRODUCTION: This cross-sectional study investigated the differences in gut microbiota in patients with Amyotrophic Lateral Sclerosis (ALS) with and without percutaneous endoscopic gastrostomy (PEG), exploring their cross-sectional associations with nutritional intake.

METHODS: Use of shotgun metagenomics and dietary assessments.

RESULTS: We identified significant taxonomic shifts and changes in diversity across groups. PEG patients exhibited reduced abundance of short-chain fatty acids (SCFAs)- producing genera, such as Faecalibacterium and Lachnospira, suggesting a dysbiotic profile; the Firmicutes/Bacteroidetes ratio was also lower in PEG patients but is reported as a descriptive indicator only. Correlations between specific bacterial taxa and nutrient intake, highlight the potential role of the gut microbiota in ALS pathophysiology. These findings describe cross-sectional differences in microbial composition associated with nutritional status and feeding route.

DISCUSSION: Our results provide a foundation for microbiome-targeted interventions in the management of ALS, although findings related to PEG should be interpreted as exploratory given the limited sample size. Furthermore, all comparisons involving the external control group (BioProject PRJNA961076) must be interpreted with caution due to potential batch effects from differences in sample collection, DNA extraction kits, and sequencing platforms.},
}

@article {pmid42622454,
year = {2026},
author = {Boccanegra, B and Tulimiero, L and Quarta, R and Conte, E and Licandro, SA and Decio, A and Lenti, R and Ladisa, A and Dinoi, G and Carbone, G and Claudione, L and Camerino, GM and Pierno, S and Mantuano, P and Cappellari, O and Fossati, G and Steinkühler, C and De Luca, A},
title = {LKB1 Dysregulation in Duchenne Muscular Dystrophy Models: Disease Specificity and Epigenetic Control by HDAC Inhibitors.},
journal = {Annals of the New York Academy of Sciences},
volume = {1562},
number = {1},
pages = {e70364},
pmid = {42622454},
issn = {1749-6632},
support = {22.004//Duchenne Parent Project/ ; GJC25P084//Fondazione Telethon/ ; PRIN MUR 2020ELYA32//Ministero dell'Università e della Ricerca/ ; 2023-UNBACLE-0245439//Università degli Studi di Bari "Aldo Moro"/ ; },
mesh = {Animals ; *Histone Deacetylase Inhibitors/pharmacology ; *Muscular Dystrophy, Duchenne/genetics/metabolism/drug therapy ; Mice ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Humans ; *Epigenesis, Genetic/drug effects ; Disease Models, Animal ; AMP-Activated Protein Kinase Kinases ; MicroRNAs/genetics/metabolism ; Mice, Inbred mdx ; Vorinostat ; AMP-Activated Protein Kinases/metabolism ; Muscle, Skeletal/metabolism/drug effects ; },
abstract = {Efficient skeletal muscle contraction requires tight mechano-metabolic coupling, a process regulated by AMP-activated protein kinase (AMPK). Duchenne muscular dystrophy (DMD) is characterized by aberrant AMPK activation and disrupted metabolic signaling. This study investigates the expression and regulation of the LKB1-STRADα-MO25 heterotrimeric complex, the primary upstream activator of AMPK, in DMD models. We analyzed muscles from dystrophic mice (BL10 mdx and D2 mdx) and patient-derived cells and found significant downregulation of the LKB1 complex across all disease stages in the DMD models, a defect not observed in an amyotrophic lateral sclerosis model. Treatment with the broad-spectrum HDAC inhibitor vorinostat effectively restored LKB1 expression at both transcript and protein levels in D2 mdx mice. This restoration was mechanistically linked to downregulation of miR-451, miR-195, and miR-17, which function as post-transcriptional repressors of LKB1. Conversely, the selective HDAC1/2 inhibitor Rodin-A increased Lkb1 mRNA but failed to rescue protein levels or alter miRNA expression. Our data identify the axis LKB1-STRADα-MO25 as a critical regulatory node that is disrupted in DMD, but remains responsive to epigenetic modulation. These findings suggest that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction.},
}

Animals
*Histone Deacetylase Inhibitors/pharmacology
*Muscular Dystrophy, Duchenne/genetics/metabolism/drug therapy
Mice
*Protein Serine-Threonine Kinases/genetics/metabolism
Humans
*Epigenesis, Genetic/drug effects
Disease Models, Animal
AMP-Activated Protein Kinase Kinases
MicroRNAs/genetics/metabolism
Mice, Inbred mdx
Vorinostat
AMP-Activated Protein Kinases/metabolism
Muscle, Skeletal/metabolism/drug effects

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

@article {pmid42621473,
year = {2026},
author = {Sabnis, RW and Sabnis, AR},
title = {Novel Compounds as TREM2 Agonists for Treating Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Nasu-Hakola Disease, and Stroke.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {8},
pages = {1723-1724},
pmid = {42621473},
issn = {1948-5875},
abstract = {Provided herein are novel compounds as TREM2 agonists, pharmaceutical compositions, use of such compounds in treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Nasu-Hakola disease, and stroke, and processes for preparing such compounds.},
}

@article {pmid42621714,
year = {2026},
author = {Wang, SL and He, L and Yang, J and Zhang, N and Sun, YZ and Liu, GP},
title = {["Jiaji" (EX-B2) electroacupuncture modulates NLRP3 inflammasome activation to improve limb dysfunction in amyotrophic lateral sclerosis mice].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {8},
pages = {1044-1052},
doi = {10.13702/j.1000-0607.20251237},
pmid = {42621714},
issn = {1000-0607},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/genetics/immunology/physiopathology/metabolism ; *Electroacupuncture ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism/immunology ; Mice ; Humans ; *Inflammasomes/genetics/metabolism/immunology ; Male ; Acupuncture Points ; Disease Models, Animal ; Interleukin-1beta/genetics/immunology ; *Extremities/physiopathology ; Female ; Spinal Cord/metabolism ; Mice, Inbred C57BL ; },
abstract = {OBJECTIVES: To investigate the regulatory effect of "Jiaji" (EX-B2) electroacupuncture (EA) on the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in the lumbar spinal cord and to explore its mechanism in improving limb dysfunction in amyotrophic lateral sclerosis (ALS) mice.

METHODS: Fifty-four mice carrying the human superoxide dismutase 1 G93A (hSOD1[G93A]) gene were randomly divided into model, Jiaji EA, and inhibitor groups, with 18 mice per group. Eighteen mice not carrying the hSOD1[G93A] gene served as wild group. At 60 d of age, the Jiaji EA group was given EA at L1-L2 and L5-L6 EX-B2 points with continuous wave, 1 mA, 2 Hz. The needles retained for 20 min, twice every week. The inhibitor group received intraperitoneal injection of the NLRP3 inhibitor (10 mg/kg, twice every week). All treatments were administered for 4 consecutive weeks. The survival period of mice in each group was observed to assess disease progression；the rotarod test was conducted to evaluate motor coordination and limb motor function；HE staining was used to observe pathological changes in the gastrocnemius, and muscle atrophy was assessed by measuring the cross-sectional area of the gastrocnemius fiber；Nissl staining was performed to evaluate the number of motor neurons in the lumbar spinal cord anterior horns；the protein expressions of NLRP3, Caspase-1, apoptosis-associated speck-like protein (ASC), interleukin-1β (IL-1β), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) in the lumbar spinal cord were detected by Western blot；the mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α were detected by real-time quantitative PCR.

RESULTS: Compared with the wild group, mice in the model group exhibited shortened survival time (P<0.01)；reduced time spent on the rotating rod starting from the 13[th] week of age (P<0.05)；significantly shorter and rounded gastrocnemius fibers with enlarged inter-fiber spaces, nuclear translocation and leakage. The cross-sectional area of the gastrocnemius fibers was reduced (P<0.01)；the number of motor neurons in the spinal anterior horns was decreased (P<0.01)；protein and mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α were increased in the lumbar spinal cord (P<0.01). Compared with the model group, survival time was prolonged in the Jiaji EA and inhibitor groups (P<0.01)；rotarod time was prolonged starting from the 13[th] week of age (P<0.05)；gastrocnemius fibers exhibited more regular margins and larger morphology, with reduced inter-fiber spaces, and reduced number of rounded fibers and improvement in nuclear translocation and leakage；cross-sectional areas of gastrocnemius fiber were increased (P<0.01)；the numbers of motor neurons in the spinal anterior horns were increased (P<0.01)；protein and mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α decreased in the lumbar spinal cord (P<0.05, P<0.01). Compared with the inhibitor group, mice in the Jiaji EA group exhibited prolonged rotarod time from the 17[th] week of age (P<0.05)；the cross-sectional area of the gastrocnemius fiber increased (P<0.05)；protein and mRNA expressions of NLRP3, Caspase-1 and IL-18 in the lumbar spinal cord were higher (P<0.05, P<0.01), while protein and mRNA expressions of TNF-α were lower (P<0.05, P<0.01).

CONCLUSIONS: EX-B2 EA improves limb function and prolongs survival in ALS mice, with its underlying mechanism potentially involving the alleviation of neuroinflammation through inhibition of NLRP3 inflammasome activation.},
}

Animals
*Amyotrophic Lateral Sclerosis/therapy/genetics/immunology/physiopathology/metabolism
*Electroacupuncture
*NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism/immunology
Mice
Humans
*Inflammasomes/genetics/metabolism/immunology
Male
Acupuncture Points
Disease Models, Animal
Interleukin-1beta/genetics/immunology
*Extremities/physiopathology
Female
Spinal Cord/metabolism
Mice, Inbred C57BL

@article {pmid42616178,
year = {2026},
author = {Nolen, A and Zweig, N and Selby, D and Bonares, MJ},
title = {Factors associated with requests for Medical Assistance in Dying (MAiD) referral among patients with amyotrophic lateral sclerosis receiving specialist palliative care.},
journal = {Journal of neurology},
volume = {273},
number = {9},
pages = {},
pmid = {42616178},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Female ; Male ; *Palliative Care/statistics & numerical data ; *Referral and Consultation/statistics & numerical data ; Retrospective Studies ; Aged ; Middle Aged ; *Suicide, Assisted/statistics & numerical data ; Noninvasive Ventilation/statistics & numerical data ; Cohort Studies ; Canada ; },
abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) have among the highest rates of medical assistance in dying (MAiD), yet factors associated with requesting MAiD remain poorly understood. We examined sociodemographic and clinical characteristics associated with MAiD referral and receipt among patients with ALS receiving specialist palliative care.

METHODS: We conducted a retrospective sequentially matched cohort study of patients attending a multidisciplinary ALS clinic at a Canadian tertiary care center. Patients who requested a MAiD referral were matched with the next consecutive patient without a MAiD request. Multivariable logistic regression identified factors associated with MAiD referral and, among referred patients, receipt of MAiD.

RESULTS: The cohort included 272 patients (130 MAiD referrals; 142 no referral). Rural residence was independently associated with higher odds of requesting a MAiD referral (adjusted odds ratio [aOR] 2.38, 95% confidence interval [CI] 1.02-5.58), whereas non-invasive ventilation (NIV) was associated with lower odds (aOR 0.56, 95% CI 0.32-0.90). Gastrostomy tube use demonstrated a non-significant trend toward lower odds of MAiD referral (aOR 0.59, 95%CI 0.33-1.07). Age, sex, and limb and bulbar symptom severity were not associated with MAiD referral. Among patients referred for MAiD, no factors were independently associated with receipt of MAiD.

CONCLUSION: In patients with ALS receiving specialist palliative care, use of NIV was associated with a lower likelihood of requesting a MAiD referral, while rural residence was associated with higher odds of referral. These findings suggest that decisions regarding MAiD may be influenced less by disease severity than by preferences regarding life-prolonging interventions and warrant further investigation.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy
Female
Male
*Palliative Care/statistics & numerical data
*Referral and Consultation/statistics & numerical data
Retrospective Studies
Aged
Middle Aged
*Suicide, Assisted/statistics & numerical data
Noninvasive Ventilation/statistics & numerical data
Cohort Studies
Canada

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

@article {pmid42618027,
year = {2026},
author = {Wolter, A and Ritz, L and Wolter, JS and Kurkevych, A and Thul, J and Bedei, I and Schenk, J and Königbauer, JT and Weichert, A and Axt-Fliedner, R},
title = {Prenatally diagnosed Ebstein's anomaly and tricuspid valve dysplasia: associated anomalies and predictors of outcome in a multicenter cohort study.},
journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2932-8445},
pmid = {42618027},
issn = {1438-8782},
abstract = {PURPOSE: To describe associated anomalies and outcomes of prenatally diagnosed Ebstein's anomaly (EA)/tricuspid valve dysplasia (TVD) in a multicenter cohort and to identify predictors of adverse outcome (intrauterine or postnatal death).

MATERIALS AND METHODS: In this retrospective study, cardiothoracic ratio, aortic valve diameter (AVD), pulmonary and atrioventricular valve measurements, ventricular dimensions, vena contracta, chamber areas, Celemajer index, peak tricuspid regurgitation velocity (TR_max), and pulmonary flow direction between survivors and non-survivors were compared across three gestational intervals.

RESULTS: Among 87 fetuses, 7 (8.0%) intrauterine deaths and 7 (8.0%) terminations occurred; 14 (16.1%) were lost to follow-up. Fifty-nine (67.8%) live births with follow-up were documented; 52 (88.1%) underwent active postnatal management, with a survival rate of 69.2% (36/52). Non-survivors more frequently had hydrops, earlier delivery, and lower birth weight. z-score AVD (zAVD) was lower and pulmonary flow more often retrograde in non-survivors before 32 weeks. TR_max was lower in interval 1 (<24 weeks), and right atrial area and vena contracta were larger in interval 2 (24-32 weeks). No significant differences were observed after 32 weeks.

CONCLUSION: This is one of the largest prenatal multicenter cohorts employing a longitudinal design, with echocardiographic data evaluation across three gestational intervals. Established predictors (pulmonary flow, TR_max) were confirmed and zAVD was identified as a simple, clinically applicable parameter, highlighting the relevance of left ventricular involvement in EA/TVD. Zusammenfassung: Ziel: Ziel dieser retrospektiven, multizentrischen Studie war es, assoziierte Anomalien und das Outcome bei pränatal diagnostizierter Ebstein-Anomalie /Trikuspidalklappendysplasie (EA/TVD) zu analysieren sowie Prädiktoren für ein ungünstiges Outcome (intrauteriner Fruchttod (IUFT), postnataler Tod) zu identifizieren.

MATERIAL UND METHODEN: Retrospektiv wurden kardiothorakale Ratio, Aortenklappendurchmesser (AVD), pulmonale und atrioventrikuläre Klappen, Ventrikeldimensionen, Vena contracta, Vorhof-/Ventrikelflächen, Celemajer-Index, maximale Trikuspidalinsuffizienzgeschwindigkeit (TR_max) und Pulmonalflussrichtung zwischen Überlebenden und Nicht-Überlebenden in drei3 Gestationsintervallen verglichen. Ergebnisse: Von 87 Feten traten 7 (8,0%) IUFT auf, 7 (8,0%) Schwangerschaftsabbrüche erfolgten, 14 (16,1%) waren lost to follow-up. Insgesamt wurden 59/87 (67,8%) Lebendgeburten dokumentiert; 52 (88,1%) erhielten ein aktives postnatales Management mit einer Überlebensrate von 69,2% (36/52). Nicht-Überlebende zeigten häufiger Hydrops, frühere Entbindung und geringeres Geburtsgewicht. Der Z-Score des AVD (zAVD) war <32 Wochen niedriger, der Pulmonalfluss häufiger retrograd. TR_max war <24 Wochen niedriger, rechte Vorhoffläche und Vena contracta zwischen 24-32 Wochen größer. Nach 32 Wochen bestanden keine signifikanten Unterschiede. Schlussfolgerung: : Dies ist eine der größten pränatalen, multizentrischen Kohorten mit longitudinaler Auswertung über drei3 Gestationsintervalle. Etablierte Prädiktoren (Pulmonalfluss, TR_max) wurden bestätigt, und zAVD als einfacher, klinisch anwendbarer Parameter identifiziert, der die Relevanz der linksventrikulären Beteiligung bei EA/TVD unterstreicht.},
}

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

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

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

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

*Amyotrophic Lateral Sclerosis/diagnosis
Humans
Sensitivity and Specificity

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

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

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

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

@article {pmid42619018,
year = {2026},
author = {Davias, A and Knekt, P and Rantakokko, P and Hansen, J and Weisskopf, MG},
title = {Associations between Pre-Disease Biomarkers of Persistent Organic Pollutants and Amyotrophic Lateral Sclerosis Survival in the Danish Diet, Cancer and Health Study Cohort.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78334},
pmid = {42619018},
issn = {1531-8249},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord. Most patients survive 3 to 5 years after diagnosis, although some live 10 years or more. Prognostic factors are incompletely understood, but previous case-control studies suggest that exposure to persistent organic pollutants (POPs) may be associated with ALS survival, but this has not been explored within prospective analysis of POP biomarkers. In this study, we aimed to prospectively investigate the relationship between exposure to POPs-assessed in pre-disease plasma samples-and survival with ALS in the Danish Diet, Cancer, and Health study cohort.

METHODS: We identified 166 incident ALS cases using the Danish National Patient Register via International Classification of Diseases (ICD) codes. We measured concentrations of 13 polychlorinated biphenyls (PCBs), 9 organochlorine pesticides, and 3 polybrominated diphenyl ethers in plasma samples collected at inclusion in the study (baseline). To assess the relationship between POP exposures and ALS survival, we used separate Cox models for each POP group adjusting for diagnosis age, sex, smoking status, body mass index, and marital status. We selected the most relevant POP groups for ALS survival using an elastic net penalized Cox proportional hazards regression model and then ran a model using a summary environmental risk score (ERS).

RESULTS: Single-pollutant Cox models showed that exposure to non-dioxin like PCBs, hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and chlordane compounds were associated with shorter survival. Elastic net penalized Cox proportional hazards regression selected HCB and chlordane compounds as the most relevant POPs for survival. The ERS Cox model showed a significant association with shorter survival (hazard ratio [HR]: 1.4, 95% confidence interval [CI]: 1.1-1.7). A 1 standard deviation (SD) higher ERS score was associated with an HR for death of 1.4 (95% CI: 1.1-1.7). Predicted median survival for those with an ERS score 1 SD higher than the mean was 12 months shorter (26 vs 38 months).

INTERPRETATION: Our study suggests that pre-disease exposure to some POPs such as HCB and chlordane compounds could negatively influence ALS survival. ANN NEUROL 2026.},
}

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

@article {pmid42619804,
year = {2026},
author = {Spillman, AM and Alsop, EB and Gittings, LM and Garcia-Mansfield, K and Piras, I and Bonfitto, A and Martinez, MN and Sharma, R and Preller, KR and Huentelman, M and Pirrotte, P and Van Keuren-Jensen, K and Sattler, R},
title = {Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72 -Frontotemporal Dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.26.740405},
pmid = {42619804},
issn = {2692-8205},
abstract = {Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.},
}

@article {pmid42619860,
year = {2026},
author = {Barretto, N and Fullerton, BT and Daly, AC and Casel, O and Kuksenko, O and Kang, K and Petrescu, J and Xia, M and Eschbach, J and Leung, M and Khiste, S and Gebremedhin, B and Smith, C and Jackson, CA and Phatnani, H},
title = {A multi-omics characterization reveals distinct molecular signatures in the human motor cortex and lumbar spinal cord in ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.24.740361},
pmid = {42619860},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by the loss of upper motor neurons in the motor cortex (MTC) and lower motor neurons in the spinal cord, leading to muscle atrophy and ultimately respiratory failure. While motor neurons (MNs) are the selectively vulnerable cell type, their interactions with glia contribute to the progression of ALS pathology. However, it remains unclear whether the site of ALS symptom onset influences the molecular alterations underlying MN and glial dysfunction and whether these alterations are shared between the MTC and lumbar spinal cord (LSC). To address these questions, we constructed spatially-resolved gene expression maps of the MTC and LSC by combining spatial and single-nucleus transcriptomic profiles from a cohort of non-neurological controls and ALS donors clinically stratified by site of symptom onset. In the ventral horn of the LSC, we see a decrease in genes associated with MNs and synaptic signaling in ALS donors. We also identify region-specific alterations in endothelial- and glial-related functions. Notably, the severity of these MN deficits and endothelial-related functions is influenced by the site of symptom onset, whereas alterations in glial function largely are not. In contrast to the LSC, we observe layer-specific increases in synaptic signaling in the MTC of ALS donors. Comparing the molecular and cellular changes within the LSC and MTC in ALS indicates that they are predominantly non-overlapping, and have different molecular signatures.},
}

@article {pmid42620667,
year = {2026},
author = {Hawley, ZCE and Guise, AJ and Pardo, ID and Chowdhury, T and Hana, S and Zavodszky, MI and Engle, L and Wiltberger, K and Bartlett, D and Raitcheva, D and Bommegowda, S and Lee, WH and Chen, SK and Sheehy, A and Driscoll, R and Peterson, M and Sebalusky, J and Hamann, S and Marsh, G and Doherty, J and Chicoine, KE and Cundiff, P and Dwyer, S and Clarner, P and Zeng, W and Ferretti, D and Tuczkewycz, T and Isaza, I and Patrovanie, M and Mcgladrigan, C and Chu, J and Morrison, JP and Arnold, HM and Shen, S and Hurt, JA and Trapa, P and Graham, DL and Plowey, ED and Lo, SC},
title = {Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice.},
journal = {Molecular therapy. Advances},
volume = {34},
number = {3},
pages = {201818},
pmid = {42620667},
issn = {3117-387X},
abstract = {Adeno-associated virus (AAV) artificial microRNAs (amiRNAs) targeting superoxide dismutase 1 (SOD1) have been proposed as a therapeutic strategy for people living with amyotrophic lateral sclerosis (ALS) who harbor toxic gain-of-function variants in the SOD1 gene. Clinical efforts have primarily focused on AAV delivery via the cerebrospinal fluid (CSF), as blood-brain-barrier-crossing capsids are still being developed preclinically. However, intra-CSF delivery has been shown to be highly variable and increases the risk for AAV-related adverse events such as dorsal root ganglion (DRG) toxicity. Here, we show that immunosuppressants (IMS) following intra-CSF delivery of AAV9-amiR-SOD1 in non-human primates (NHPs) prevented AAV-related DRG toxicity, and this benefit was maintained for over 300 days even after immunotherapy stopped at 90 days post-AAV treatment. In line with prior literature, we found intra-CSF delivery of AAV9-amiR-SOD1 to be highly variable in adult mice and NHPs, requiring higher doses of virus to achieve efficacious endpoints. To address this concern, we developed a proof-of-principle study showing that AAV9-amiR-SOD1, in combination with a SOD1-targeting antisense oligonucleotide, provided an additive therapeutic benefit in SOD1-G93A mice compared with AAV9-amiR-SOD1 alone. This combinatorial approach lowered the viral load needed to reach efficacious endpoints, which could mitigate AAV-related adverse events alongside IMS.},
}

@article {pmid42621206,
year = {2026},
author = {Couto, CM and de Melo Queiroz, E and da Cunha, MC and Santos, SCL and Ferreira, AR and Nascimento, OJM},
title = {Genetic profile of motor neuron disease in a multiregional Brazilian cohort: an 18-year real-world experience in 1,911 patients.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1883977},
pmid = {42621206},
issn = {1664-2295},
mesh = {Humans ; Brazil/epidemiology ; Female ; *Motor Neuron Disease/genetics/epidemiology ; Male ; Retrospective Studies ; Middle Aged ; Genetic Testing ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Aged ; *Genetic Profile ; C9orf72 Protein/genetics ; Cohort Studies ; Adult ; Superoxide Dismutase-1/genetics ; },
abstract = {BACKGROUND: Genetic testing in amyotrophic lateral sclerosis (ALS) is increasingly recommended for all patients, but real-world implementation in middle-income countries remains heterogeneous. Brazilian motor neuron disease genetics has largely been characterized through protocol-based cohorts focused on the founder VAPB p.Pro56Ser variant (amyotrophic lateral sclerosis type 8, ALS8). The broader genetic landscape beyond ALS8 in Brazilian clinical populations has not been described in a large multiregional cohort. We aimed to characterize this profile.

METHODS: We retrospectively analyzed 1,911 patients with motor neuron disease followed at six SARAH Network rehabilitation hospitals across Brazil between 2007 and 2024. Genetic testing was clinically directed; ALS8 cases (n = 78) were characterized separately. We assessed characteristics of genetically tested versus untested patients, the temporal evolution of testing modalities, and the diagnostic yield by gene and by Byrne family history classification.

RESULTS: Of 1,833 patients without ALS8, 318 (17.3%) underwent genetic testing, with selection bias toward younger age, higher educational attainment, and positive family history of ALS or frontotemporal dementia (all p < 0.001). Testing expanded markedly after 2020, particularly C9orf72 screening and next-generation sequencing panels. Panel/exome sequencing identified pathogenic or likely pathogenic variants in 13 of 66 patients (19.7%), consistent with international literature for mixed familial-sporadic cohorts. Across all modalities, 30 patients without ALS8 carried pathogenic or likely pathogenic variants in six genes: SOD1 (n = 15), C9orf72 (n = 11; 7.0% of 157 tested), and VCP, FUS, TBK1, and SETX (n = 1 each). ATXN2 intermediate-length CAG repeats were identified in 15 of 230 patients tested (6.5%), replicating the 6.3% previously reported in a Brazilian multicenter sample. Yield by Byrne classification followed a marked gradient (Definite: 89.7%, Probable: 24.0%, Possible: 15.4%, Sporadic: 4.9%; p < 0.001). The SOD1 spectrum included recurrent variants of likely Iberian/European origin.

CONCLUSION: This 18-year cohort defines a real-world genetic profile of motor neuron disease beyond ALS8, with diagnostic yield comparable to the literature and a Byrne gradient supporting universal testing. Beyond family history, socioeconomic factors appeared to shape access to testing, reinforcing the importance of equitable genetic testing for diagnostic precision, family counseling, and access to gene-targeted therapy.},
}

Humans
Brazil/epidemiology
Female
*Motor Neuron Disease/genetics/epidemiology
Male
Retrospective Studies
Middle Aged
Genetic Testing
*Amyotrophic Lateral Sclerosis/genetics/epidemiology
Aged
*Genetic Profile
C9orf72 Protein/genetics
Cohort Studies
Adult
Superoxide Dismutase-1/genetics

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

@article {pmid42612865,
year = {2026},
author = {Gerrit Noordergraaf, GJ and Przemek Jakubowski, P},
title = {SpO2 during CPR: from distraction towards a physiological goal.},
journal = {Resuscitation},
volume = {},
number = {},
pages = {111260},
doi = {10.1016/j.resuscitation.2026.111260},
pmid = {42612865},
issn = {1873-1570},
}

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

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

@article {pmid42613225,
year = {2026},
author = {Light, A and Peters, M and Ahmed, HU and Shah, TT},
title = {Reply to Marcio C. Moschovas, Ugo Falagario, Francesco Pellegrino, et al's Letter to the Editor re: Alexander Light, Max Peters, Manit Arya, et al's Salvage Focal Therapy vs Radical Prostatectomy for Localized Radiorecurrent Prostate Cancer. JAMA Oncol 2026;12:364-73.},
journal = {European urology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.eururo.2026.07.033},
pmid = {42613225},
issn = {1873-7560},
}

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

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

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

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

@article {pmid42613694,
year = {2026},
author = {Shukla, S and Srivastava, V and Gaur, H and Rai, A},
title = {Myelin and Oligodendrocyte Dysfunction in Demyelinating and Neurodegenerative Disorders: Signaling Pathways and Therapeutic Targets.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273437393260729093129},
pmid = {42613694},
issn = {1996-3181},
abstract = {INTRODUCTION: Oligodendrocytes (OLs) synthesize myelin, a substance that plays a significant role in ensuring proper functioning of the Central Nervous System (CNS). Myelin abnormalities are involved in disease pathogenesis in AD, MS, and ALS. In contrast, MS involves autoimmune reactions directed against myelin. On the other hand, AD and ALS are characterized by neurodegeneration. This article seeks to give a critical discussion on myelin and OL dysfunction in these diseases, among others.

METHODS: A narrative literature search was carried out in various databases including Scopus, Google Scholar, Web of Science, and PubMed, focusing on papers relating to myelination, remyelination, and OLs, particularly those addressing signaling pathways and treatment strategies.

RESULTS: MS is an autoimmune disease characterized by inflammation that causes demyelination and OL dysfunction. Oxidative stress and mitochondrial dysfunction play roles in the pathogenesis of ALS, whereas AD is a result of disrupted neuronal supportive functions and myelin damage. Important signaling pathways involved in OL formation and myelin repair include the Wnt/β-catenin, AKT/mTOR, and ERK/MAPK pathways. Drugs like edaravone, ocrelizumab, and siponimod have been identified for promoting myelin repair.

DISCUSSION: The relationship between abnormal oligodendrocyte function, demyelination, and specific disease-related pathological processes demonstrates that although there is a similarity among MS, AD, and ALS, each condition possesses its own unique molecular foundation. One potential treatment approach would be targeting shared signaling pathways relevant to myelination and remyelination. Nonetheless, disease variability and specific pathogenic characteristics demand a targeted therapy approach.

CONCLUSION: Myelin integrity and oligodendrocyte function are central to the progression of demyelinating and neurodegenerative diseases. Targeting molecular pathways involved in myelination offers significant potential for improving disease outcomes and developing advanced therapeutic strategies.},
}

@article {pmid42613775,
year = {2026},
author = {Nalicho, JC and Mabeyo, PE and Paluch, AS and Paul, L},
title = {Integrated In Silico Discovery of Thymoquinone Analogs Targeting the Keap1-Nrf2 Pathway for Amyotrophic Lateral Sclerosis Therapy.},
journal = {ChemistryOpen},
volume = {15},
number = {9},
pages = {e70286},
doi = {10.1002/open.70286},
pmid = {42613775},
issn = {2191-1363},
mesh = {*NF-E2-Related Factor 2/metabolism/antagonists & inhibitors/chemistry ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Benzoquinones/chemistry/pharmacology/metabolism/therapeutic use ; *Kelch-Like ECH-Associated Protein 1/metabolism/antagonists & inhibitors/chemistry ; Humans ; Quantitative Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Signal Transduction/drug effects ; Drug Discovery ; Oxidative Stress/drug effects ; },
abstract = {Oxidative stress drives neuronal vulnerability in amyotrophic lateral sclerosis (ALS), making the Keap1-Nrf2 pathway a vital therapeutic target. While thymoquinone (TQ) modulates this axis, its efficacy is limited by low potency and poor drug-likeness. We utilized an integrated in silico workflow-including validated QSAR modeling (R[2] = 0.68, Q[2] ext = 0.66), ADMET profiling, docking, 200 ns molecular dynamics, and MM-PBSA analysis-to identify improved TQ-derived Keap1 inhibitors. Screening 64 analogs prioritized three leads (CHEMBL3416163, CHEMBL4636830, and CHEMBL221598) with favorable safety and blood-brain barrier permeability. Docking and dynamics confirmed these analogs form stable interactions with Kelch domain hotspots. MM-PBSA calculations revealed significantly enhanced binding free energies (-75.10 to -93.79 kJ mol[-1]) compared to parent TQ (-21.05 kJ mol[-1]), driven primarily by van der Waals and hydrophobic forces. This study identifies structurally tractable TQ analogs with improved predicted potency and establishes a robust computational framework for neuroprotective discovery. The prioritized leads are compelling candidates for in vitro and in vivo validation as redox-modulating agents in ALS.},
}

*NF-E2-Related Factor 2/metabolism/antagonists & inhibitors/chemistry
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism
*Benzoquinones/chemistry/pharmacology/metabolism/therapeutic use
*Kelch-Like ECH-Associated Protein 1/metabolism/antagonists & inhibitors/chemistry
Humans
Quantitative Structure-Activity Relationship
Molecular Docking Simulation
Molecular Dynamics Simulation
Signal Transduction/drug effects
Drug Discovery
Oxidative Stress/drug effects

@article {pmid42614000,
year = {2026},
author = {Wei, LC and Lee, CH},
title = {Healthcare Resilience Should Include the Worker-Patient Safety Loop: A Taiwan Psychiatric Hospital Perspective.},
journal = {The International journal of health planning and management},
volume = {},
number = {},
pages = {},
doi = {10.1002/hpm.70130},
pmid = {42614000},
issn = {1099-1751},
abstract = {Research before and during COVID-19 has framed health-system resilience as the capacity to absorb shocks, adapt, transform and learn while sustaining essential functions. Building on this broader literature, including Meredith et al.'s account of local public-health adaptation under political and resource constraints, we propose a worker-patient safety loop from a Taiwan psychiatric hospital perspective: workforce strain can weaken safety-critical care; near misses, adverse events and continuity failures should trigger reporting, organisational learning and corrective action; and the resulting changes should protect workers, patients and care continuity. The loop can be monitored through indicators of workforce wellbeing and safety, safety-event learning, and continuity across settings, supported by digital incident, staffing and handoff systems with safeguards for privacy and data quality. Informed by professional experience and published evidence, this conceptual framework applies to acute shocks and continuing operational pressures. Its proposed domains require prospective empirical validation before they can be treated as established measures of hospital resilience.},
}

@article {pmid42614182,
year = {2026},
author = {Shevchuk, DV and Nuzhnyi, EP and Fedotova, EY and Ershova, MV and Minaev, IV and Anikin, GA and Protsenko, AR and Abramycheva, NY and Zakharova, MN and Illarioshkin, SN},
title = {Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1889931},
pmid = {42614182},
issn = {1664-2295},
mesh = {Humans ; *Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/complications/diagnostic imaging ; *Cerebellar Ataxia/genetics/physiopathology/diagnostic imaging ; Phenotype ; Male ; Middle Aged ; Female ; Adult ; Mutation/genetics ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) associated with mutations in the superoxide dismutase 1 (SOD1) gene is recognized for phenotypic variability, yet cerebellar ataxia as a presenting feature has been reported only in isolated cases.

METHODS: We describe four unrelated patients: three men and one woman, aged 35 to 49 years at symptom onset, who carried the SOD1 D91A (p.Asp91Ala) mutation. Two patients were heterozygous and two homozygous for the D91A variant. Clinical, neuroimaging, electrophysiological and genetic data were reviewed.

RESULTS: All patients presented with progressive gait ataxia as their initial and predominant symptom, with upper and lower motor neuron signs emerging months to years later and ultimately meeting criteria for ALS. Diagnostic latencies from ataxia onset to recognition of ALS ranged from 3 to 9 years. Cerebellar signs included gait and limb ataxia, dysmetria, intention tremor, and oculomotor abnormalities; neuroimaging revealed mild cerebellar atrophy only in one case, and electrophysiological evidence of lower motor neuron involvement was often limited at initial assessment. To our knowledge, this is the largest reported case series of patients homogeneous for a single SOD1 mutation and a shared cerebellar ataxia-onset ALS phenotype.

CONCLUSION: The findings expand the clinical spectrum of SOD1-associated ALS and underscore the importance of SOD1 genetic testing in patients with progressive adult-onset ataxia of undetermined origin, particularly given the emerging availability of SOD1-targeted therapies.},
}

Humans
*Superoxide Dismutase-1/genetics
*Amyotrophic Lateral Sclerosis/genetics/physiopathology/complications/diagnostic imaging
*Cerebellar Ataxia/genetics/physiopathology/diagnostic imaging
Phenotype
Male
Middle Aged
Female
Adult
Mutation/genetics

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

@article {pmid42614372,
year = {2026},
author = {Watanabe, N and Kawahori, Y and Ta, V and Wang, D and Ohgi, KA and Wang, H and Kleschevnikova, N and Ishikawa, E and Head, BP},
title = {i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1[G93A] mice.},
journal = {Molecular therapy. Advances},
volume = {34},
number = {3},
pages = {201820},
pmid = {42614372},
issn = {3117-387X},
abstract = {Practical and broad biodistributable gene delivery interventions are essential for advancing therapeutic strategies targeting neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously demonstrated that subpial delivery of AAV9-synapsin-promoted caveolin-1 (SynCav1) afforded significant neuroprotective effects in mutant superoxide dismutase (SOD)-1-induced ALS pathology. However, subpial delivery is regionally restricted, technically challenging, and highly invasive. This study evaluated whether the intracerebroventricular (i.c.v.) route of administration (ROA), an alternative CNS delivery strategy less invasive than direct spinal cord injections, could achieve broader CNS biodistribution and produce functional or histological benefits in hSOD1[G93A] mice. i.c.v. administration of AAV9-SynCav1 achieved widespread Cav-1 overexpression in the motor cortex and spinal cord. SynCav1-treated male mice exhibited improved running wheel (RW) performance and better motor-evoked potentials. Immunofluorescence revealed attenuated degeneration of cholinergic motor neurons (MNs) in the cervical and lumbar ventral horn, as well as preserved diaphragm neuromuscular junction (NMJ) innervation in SynCav1-treated mice. These findings serve as preclinical proof of concept that i.c.v. delivery of AAV9-SynCav1 can achieve CNS target engagement and produce selective functional and anatomical benefits in hSOD1[G93A] mice.},
}

@article {pmid42614391,
year = {2026},
author = {Gomes-Duarte, A and Wong, JK and Moro, A and Pasteuning-Vuhman, S and Pos, W and Haselberg, R and Sogorb-González, M and Pascoal, S and Borst, L and Chatterjee, M and Giera, M and Tsimikas, S and Sadiq, SA and van Deventer, S},
title = {Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.},
journal = {Molecular therapy. Advances},
volume = {34},
number = {3},
pages = {201822},
pmid = {42614391},
issn = {3117-387X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder defined by progressive motor neuron loss and TDP-43 proteinopathy, yet the upstream drivers of this pathology remain unclear. Oxidized phosphatidylcholines (PC-OxPL) have emerged as potent inducers of proteinopathy in the central nervous system (CNS), but their role in ALS has not been systematically explored. We identify a distinct PC-OxPL signature in the cerebrospinal fluid (CSF) of patients with sporadic ALS (sALS) and show that apolipoprotein E (apoE)-containing particles are the primary PC-OxPL carriers in this compartment. In human iPSC-derived motor neurons, PC-OxPL exposure triggered disease-relevant transcriptional alterations and TDP-43 pathology, establishing PC-OxPL as a mediator of ALS-like neurodegeneration in vitro. To counteract this toxicity, we engineered an Adeno-Associated Virus (AAV)-delivered single-chain antibody fragment (scFv), PC-OxPL-VecTab, targeting PC-OxPL neoepitopes. PC-OxPL-VecTab neutralized PC-OxPL-induced neurotoxicity, reduced TDP-43 aggregation, and prevented motor neuron death and behavioral deficits in a sALS CSF transfer mouse model. Intrathecal delivery of PC-OxPL-VecTab in minipigs achieved broad CNS biodistribution and transgene expression, supporting the feasibility of CNS delivery. These findings position PC-OxPL as a mechanistic contributor to ALS pathogenesis and establish PC-OxPL-VecTab as a therapeutic strategy for ALS with potential broader applicability to disorders associated with PC-OxPL accumulation.},
}

@article {pmid42615765,
year = {2026},
author = {Khazaal, M and Stretavská, P and Kuźma-Kozakiewicz, M and Nieporęcki, K and Betík, A and Vlčková, E and Koprušáková, MT and Petrovic, R and Cetin, H and Keritam, O and Löscher, W and Eggers, C and Iglseder, S and Orenčák, R and Molnár, MJ and Grosz, Z and Szlepák, T and Koritnik, B and Koszewicz, MA and Baumgartner, D and Slachtova, L},
title = {SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy.},
journal = {European journal of neurology},
volume = {33},
number = {8},
pages = {e70717},
doi = {10.1111/ene.70717},
pmid = {42615765},
issn = {1468-1331},
support = {PRIMUS UK 21/MED/012//Univerzita Karlova v Praze/ ; OP JAK MSCA GOALS//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; 65269705//Fakultni nemocnice Brno/ ; MUNI/A/1728/2025//Masarykova Univerzita/ ; TKP2021 NVA-15//Nemzeti Kutatási Fejlesztési és Innovációs Hivatal/ ; OTKA139010//Nemzeti Kutatási Fejlesztési és Innovációs Hivatal/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/therapy/drug therapy ; *Superoxide Dismutase-1/genetics ; Female ; Middle Aged ; Male ; Genetic Testing ; Adult ; Europe, Eastern/epidemiology ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is one of the most devastating fatal motor neuron diseases, characterized by progressive degeneration of motor neurons in the brain and spinal cord. A significant advance in ALS therapy was achieved with the recent European Medicines Agency approval of Tofersen, the first antisense oligonucleotide (ASO) specifically targeting SOD1 mRNA, a key genetic determinant of the disease. Yet, despite its clinical relevance, data on SOD1-ALS in Central Eastern Europe remain scarce.

METHODS: Here, we present a multicentric study across six countries-Austria, Czechia, Poland, Hungary, Slovakia, and Slovenia-representing approximately 16% of the European Union's population. We report all pathogenic, likely pathogenic, and uncertain SOD1 variants, along with the phenotypic features, including heritability, age, site of onset, and survival. We also assessed the availability of genetic testing, counseling, and access to Tofersen therapy across the region.

RESULTS: Out of 1200 patients with confirmed ALS, we identified 24 distinct pathogenic SOD1 variants in a total of 67 patients (median age at onset 47 [40-55] years), of whom 65.7% had familial ALS (fALS) and 34.3% had sporadic ALS (sALS). We characterized the associated phenotypes and reported that 42 patients are currently receiving Tofersen therapy.

CONCLUSION: This study provides the first comprehensive overview of SOD1-ALS in Central Eastern Europe. Our findings underscore the importance of genetic testing and counseling, as well as equitable access to targeted therapies such as Tofersen to advance patient-specific care in this region.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/epidemiology/therapy/drug therapy
*Superoxide Dismutase-1/genetics
Female
Middle Aged
Male
Genetic Testing
Adult
Europe, Eastern/epidemiology

@article {pmid42615866,
year = {2026},
author = {Horton, DK and Raymond, J and Larson, T and Goutman, SA and Mehta, P},
title = {Multidisciplinary clinic attendance and patterns of care in the U.S. National ALS Registry, 2013-2023.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2026.2717968},
pmid = {42615866},
issn = {2167-9223},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) multidisciplinary clinics (MDCs) are the standard model of care, but national-level data on utilization and outcomes in the United States are lacking.

OBJECTIVE: To compare baseline characteristics and symptoms, clinical interventions and specialized care processes, and healthcare utilization among U.S. National ALS Registry (Registry) participants by MDC attendance.

METHODS: Registry data from 2013 to 2023 were analyzed for participants completing demographic and clinical surveys, stratified by MDC attendance (attendance vs. no attendance by survey completion).

RESULTS: Among 4764 participants, 77.0% reported attending an MDC. Baseline characteristics were similar between groups, including sex, age at diagnosis, and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. MDC attendees reported lower prevalence of dysphagia (23.6% vs. 27.5%, p = 0.007) and bowel/bladder issues (10.7% vs. 14.3%, p = 0.001). Attendees were more likely to use evidence-based interventions, including wheelchairs/scooters, noninvasive ventilation, percutaneous endoscopic gastrostomy (PEG), communication devices, and ALS disease-modifying therapies, specifically riluzole (72.7% vs. 48.1%) and edaravone (10.5% vs. 2.6%) (all p < 0.001). MDC attendees also demonstrated higher rates of specialized care processes, including advance directive completion, genetic testing, and prior research participation (all p < 0.001). For healthcare utilization, MDC attendance was associated with fewer emergency department visits among those with any use (RR 0.90, 95% confidence interval (CI) 0.82-0.99) and shorter hospital stays (β = -2.67 days, 95% CI -4.56 to -0.78).

CONCLUSION: MDC attendance was associated with greater uptake of evidence-based interventions, higher rates of specialized care processes, and reduced healthcare utilization intensity, consistent with previously reported multidisciplinary ALS care outcomes.},
}

@article {pmid42606140,
year = {2026},
author = {Flores, SV and Lillo, P and Briceño-Moya, J},
title = {Population-Level Nucleotide Diversity and Genetic Differentiation at SOD1 Across Global Human Populations.},
journal = {Annals of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1111/ahg.70052},
pmid = {42606140},
issn = {1469-1809},
abstract = {BACKGROUND: The SOD1 gene encodes superoxide dismutase 1, an antioxidant enzyme in which pathogenic variants cause a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although the clinical and molecular consequences of SOD1 variants are well established, its locus-wide population genetic architecture has not been systematically characterized across global populations.

OBJECTIVE: To characterize patterns of genetic diversity, population differentiation, and evolutionary constraint across the SOD1 locus in worldwide human populations.

METHODS: We analyzed genomic variation spanning the SOD1 region in the five continental populations of the 1000 Genomes Project. Nucleotide diversity (π), fixation index (FST), and allele frequency distributions were estimated using sliding-window analyses. Bootstrap resampling was used to compare diversity within and outside the coding region. Recent positive selection was assessed using XP-nSL, and codon-based evolutionary analyses were performed using primate SOD1 orthologs.

RESULTS: The coding region consistently exhibited a twofold to threefold reduction in nucleotide diversity relative to adjacent genomic sequences across all populations. Bootstrap analyses confirmed significantly lower diversity within the locus than in flanking regions (p < 0.05 in all populations). Population differentiation was low (mean FST ≈ 0.03) and showed no pronounced peaks within the coding interval, whereas allele frequency distributions were broadly similar across continental populations. XP-nSL analyses detected no evidence of population-specific recent selective sweeps. Codon-based analyses identified only 31 variable codons among 155 analyzed positions, six codons under negative selection, and no evidence of positive selection.

CONCLUSION: The SOD1 locus exhibits reduced standing genetic variation, limited continental differentiation, and strong evolutionary conservation, consistent with sustained functional constraint. These findings provide a comprehensive population genetic framework for interpreting genetic variation at this medically important locus.},
}

@article {pmid42606797,
year = {2026},
author = {Raghunathan, T and Parthasarathy, B and Prabhu, P and Mahesh, P and Dhanushkodi, A},
title = {Regenerative strategies for ALS: stem cells and extracellular vesicles.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {42606797},
issn = {2731-9229},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is caused by progressive degeneration of upper and lower motor neurons. The disease is late onset, and to date, no early diagnosis is possible. Patients with ALS have a 5-year survival rate since diagnosis. Though recent studies highlighted the possible mechanisms of motor neuron degeneration in ALS, the treatment options are extremely limited. This underscores the urgent need to develop effective therapeutic strategies that can prolong patient survival and ultimately slow/halt ALS progression. Extracellular vesicles released from the degenerative milieu contribute to ALS propagation and progression by shuttling misfolded proteins, proinflammatory cytokines, and neurotoxins; thus, they could serve as a biomarker for diagnosis and prognosis. The advancement of stem cell-based therapies for neurodegenerative diseases and the evolving understanding of extracellular vesicles as potential biotherapeutics provide a ray of hope for millions of patients suffering from neurological disorders/neurodegenerative diseases like ALS.},
}

@article {pmid42607915,
year = {2026},
author = {Zhang, Y and Dong, X and Shai, Y and Alam, M and Han, D and Hu, Y and He, Z and Zhou, Z and Jiang, H},
title = {Annexin A1 inhibits neuronal apoptosis in amyotrophic lateral sclerosis by restraining the Hippo pathway.},
journal = {Brain research},
volume = {1891},
number = {},
pages = {150510},
doi = {10.1016/j.brainres.2026.150510},
pmid = {42607915},
issn = {1872-6240},
abstract = {Annexin A1 (ANXA1) is a multifunctional regulatory protein involved in neuroinflammation and cellular homeostasis, but its role in amyotrophic lateral sclerosis (ALS) remains unclear. In this study, we investigated the relationship between ANXA1 and Hippo pathway signaling in ALS. Bioinformatic analysis of transcriptomic data from iPSC-derived motor neurons showed that ANXA1 expression was reduced in ALS and associated with apoptosis and Hippo pathway-related changes. Decreased ANXA1 expression was confirmed in hSOD1^G93A transgenic mice and NSC34 motor neuron-like cells. Phosphorylation levels of MST1/2, LATS1/2, and YAP1 were elevated, indicates activation of the Hippo pathway. Functional experiments showed that ANXA1 overexpression reduced Hippo pathway activation, enhanced cell viability, and decreased apoptosis, as increased Bcl-2 expression and reduced Bax and cleaved caspase-9 levels. In contrast, ANXA1 knockdown further activated Hippo pathway and aggravated apoptotic changes. These findings identify ANXA1 as an upstream regulator associated with Hippo pathway activation in ALS and suggest that the ANXA1/Hippo axis may represent a potential therapeutic target.},
}

@article {pmid42607955,
year = {2026},
author = {Wang, SY and Hunter, ER and Valdes Morales, KL and Perry, NJ and Feldman, E and Sobanko, JF and Etzkorn, JR and Higgins, HW and Zhang, J and Walker, JL and Miller, CJ},
title = {Response to Guan et al.'s, "Letter to the Editor 'Rethinking Routine Cartilage Grafting for Alar Defects'".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.08.037},
pmid = {42607955},
issn = {1097-6787},
}

@article {pmid42608759,
year = {2026},
author = {Talukdar, G and Cvetanovic, M},
title = {Relationship of polyglutamine expansion and loss of ataxin-1 function in neurological diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01950},
pmid = {42608759},
issn = {1673-5374},
abstract = {Ataxin-1 (ATXN1) was originally identified as a gene in which abnormal expansion of glutamine encoding CAG repeats causes inherited neurodegenerative disease spinocerebellar ataxia type 1. Spinocerebellar ataxia type 1 is characterized by alterations in movement, cognition, and mood, with severe pathology in the cerebellum and brain stem. Studies in spinocerebellar ataxia type 1 mouse models indicated that CAG expansion predominantly causes pathogenic ATXN1 gain-of-function in the cerebellum. Conversely, mice lacking ATXN1 are severely impaired in cognitive tests and exhibit abnormalities in cortical functions. Subsequent genetic and functional studies have associated ATXN1 with intelligence and several neurological conditions, including Alzheimer's disease, amyotrophic lateral sclerosis, schizophrenia, and multiple sclerosis. In some conditions, association is found with CAG expansions in ATXN1 and in others with the loss of ATXN1 expression. Additionally, recent studies indicate the role of ATXN1 in glial cells. Here, we review current genetic and functional evidence of how ATXN1 CAG expansion and loss of ATXN1 function contribute to brain dysfunction in spinocerebellar ataxia type 1, Alzheimer's disease, and multiple sclerosis, with an emphasis on glial cells.},
}

@article {pmid42608803,
year = {2026},
author = {Xiao, Y and Yao, X and Mao, H and Xu, Y and Liu, Z and Li, Y and Yang, X and Liu, X},
title = {Annual monitoring reveals spatiotemporal dynamics of multiple herbicide resistance in Echinochloa crus-galli populations across Zhejiang Province, China.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71186},
pmid = {42608803},
issn = {1526-4998},
support = {//"Three Rural Areas-Nine Parties" Science and Technology Collaboration Program of Zhejiang Province/ ; //National Key Research and Development Program of China/ ; //National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Echinochloa crus-galli is a damaging weed in global rice production with rapidly evolving herbicide resistance. This study investigated resistance dynamics to six major herbicides across Zhejiang Province, China (2022-2024), to inform region-specific management.

RESULTS: A 3-year systematic monitoring covering 356 populations from 27 counties revealed that the annual resistance frequency of quinclorac consistently exceeded 50.00%. Cyhalofop-butyl resistance ranged from 32.18% to 61.18%. Penoxsulam resistance ranged from 24.14% to 50.59%. Resistance to bispyribac-sodium was detected in 25.00% of populations in 2023 and 81.18% in 2024. Resistance to the newly introduced florpyrauxifen-benzyl was detected in 49.41% of populations in its first monitoring year (2024). Metamifop remains largely effective due to low resistance frequency (6.90%-16.47%). In 2023, four populations resistant to all tested herbicides were detected, increasing to seven in 2024. Molecular analysis identified acetyl-CoA carboxylase (ACCase) target-site mutations I2041N and C2088R and the acetolactate synthase (ALS) mutation W574L as contributing factors, but the majority of cross-resistant populations lacked known target-site mutations, suggesting that non-target-site metabolic resistance is predominant. Under controlled conditions, propanil maintained complete control against all tested multiple-resistant populations.

CONCLUSION: Observed trends in E. crus-galli resistance include the widespread emergence of multiple resistance to ALS and ACCase inhibitors and regional variation linked to cropping intensity. Reported resistance frequencies are conditional estimates from problem fields, not unbiased provincial rates. Non-target-site resistance predominates among cross-resistant populations. Propanil is a promising alternative pending field validation. These findings support developing region-specific resistance management strategies for rice production in Zhejiang. © 2026 Society of Chemical Industry.},
}

@article {pmid42609140,
year = {2026},
author = {Wedgwood, HE and Tuxworth, RI and Ahmed, Z},
title = {Exploring Genetic Therapies Targeting Amyotrophic Lateral Sclerosis in Animal Models: A Systematic Review and Meta-Analysis.},
journal = {The journal of gene medicine},
volume = {28},
number = {8},
pages = {e70106},
pmid = {42609140},
issn = {1521-2254},
support = {//LifeArc/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Animals ; Disease Models, Animal ; *Genetic Therapy/methods ; Humans ; Motor Neurons/pathology/metabolism ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disease, for which there is currently no known cure. ALS primarily affects motor neurons, with rapid deterioration, meaning symptoms develop quickly, from problems with speech and muscle weakness to breathing issues and paralysis. This systematic review aimed to explore the preclinical efficacy of various genetic therapies used to target ALS using in vivo rodent models.

METHODS: In vivo studies of genetic therapies targeting ALS and its symptoms published between January 2015 and December 2025 were included in this review. The following databases were used: Web of Science, Scopus and PubMed. The primary outcome investigated was the total number of motor neurons, with secondary outcomes of rodent survival and muscle function by observing rotarod performance also being analysed. The SYRCLE tool was used to assess risk of bias in included studies.

RESULTS: Of the 451 studies identified by searching the databases, 53 studies were found to be eligible for this systematic review. The articles were divided into subcategories depending on the gene target of each therapy. Meta-analysis of outcomes within appropriate studies showed significant improvements for the majority of selected outcomes (p < 0.05), favouring genetic therapy intervention.

CONCLUSIONS: Results suggest that genetic therapies in rodent models targeting ALS are effective. However, due to a high risk of bias in preclinical studies, further high-quality studies are warranted to support this conclusion and onward translation into the clinic.},
}

*Amyotrophic Lateral Sclerosis/therapy/genetics
Animals
Disease Models, Animal
*Genetic Therapy/methods
Humans
Motor Neurons/pathology/metabolism

@article {pmid42609516,
year = {2026},
author = {Li, T and Zhang, Q and Wu, Y and Huang, R},
title = {Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {9},
pages = {e70915},
pmid = {42609516},
issn = {2688-2663},
abstract = {Neurodegenerative diseases (NDs) are marked by selective neuronal vulnerability and progressive failure of neural circuits. Increasing evidence indicates that neuronal loss is not driven by a single terminal event, but emerges from interacting regulated cell death (RCD) programs. These programs are closely coupled to mitochondrial injury, proteostatic collapse, lysosomal stress, metabolic imbalance, glial state transitions, and chronic neuroinflammation. Yet, how distinct death pathways are organized across cell types, disease stages, and disease-specific microenvironments remains unresolved. This review examines RCD as an integrated pathogenic network in major NDs. Caspase and B-cell lymphoma 2 (BCL2) family signaling, receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein activation, NOD-like receptor family pyrin domain containing 3 and gasdermin signaling, GPX4-linked lipid peroxidation control, and autophagy lysosomal failure are discussed as convergent stress response modules rather than isolated pathways. Across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, these modules shape neuronal fate through disease-specific interactions with mitochondrial dysfunction, iron dyshomeostasis, inflammasome activation, and microglial metabolic remodeling. We further evaluate emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system, highlighting the importance of molecular selectivity, cellular context, disease stage, and translational feasibility.},
}

@article {pmid42609692,
year = {2026},
author = {Lazinkaitė, M and Avery, M and Olley, R and Stankūnienė, A and Czabanowska, K and Stankūnas, M},
title = {Authentic Leadership in Lithuanian Healthcare: A Qualitative Exploratory Study of Health Managers' Views and Experiences.},
journal = {Acta medica Lituanica},
volume = {33},
number = {1},
pages = {74-85},
pmid = {42609692},
issn = {1392-0138},
abstract = {Authentic Leadership (AL) is a value-based approach to leadership that focuses on self-awareness, relational transparency, balanced processing, and an internalized moral perspective. AL nurtures a supportive, high-trust work environment that boosts team cohesion, productivity, and ethical standards. In the healthcare workforce, the challenges and demands of person-centred care are significant, making AL a valuable opportunity to enhance the effectiveness of leadership and management. This study explored the key constructs and opportunities of AL within the context of the Lithuanian health system. A qualitative interpretative phenomenological approach was used to conduct semi-structured interviews with senior healthcare managers in Lithuania. The goal was to explore how these leaders understood and practiced AL. Thematic analysis was performed on the transcriptions of study participants' semi-structured interviews about perceptions of AL's four theoretical dimensions. The findings identified that Lithuanian healthcare leaders view self-awareness, moral integrity, and adaptability as central to effective leadership. Leaders emphasized self-reflection, openness to feedback, and moral consistency as crucial to their roles, enabling them to manage complex ethical responsibilities and strengthen organizational trust. AL has been shown to promote resilience in dynamic healthcare settings, thereby enabling adaptability and innovation. Leaders valued transparency and inclusive decision-making to ensure that diverse perspectives informed the team strategies. This study indicates that AL is an effective leadership approach for healthcare management in Lithuania. Our findings suggest that healthcare organizations could benefit from AL-based training programs, which may improve leaders' self-reflective practices, ethical decision-making, and collaboration skills.},
}

@article {pmid42609882,
year = {2026},
author = {Bottale, I and Spinelli, EG and Basaia, S and Ghirelli, A and Gardoni, A and Russo, T and Canu, E and Castelnovo, V and Schito, P and Falzone, Y and Filippi, M and Agosta, F},
title = {Altered perivascular space diffusivity dynamics in motor neuron disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag307},
pmid = {42609882},
issn = {2632-1297},
abstract = {Converging evidence supports a key pathogenic role of the glymphatic system in the accumulation of pathological aggregates in several central nervous system proteinopathies, including amyotrophic lateral sclerosis and other motor neuron diseases. This study aimed to investigate potential glymphatic impairment using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) across motor neuron disease phenotypes, to examine its clinical correlates, and to assess its relationship with white matter damage. Fifty-seven patients with motor neuron disease and 32 age- and sex-matched healthy controls underwent a 3 Tesla brain MRI scan, including diffusion tensor imaging sequences. We obtained the DTI-ALPS index from each individual, evaluating its relationship with measures of motor and cognitive disability, site of symptom onset, cognitive status, genetic status and fractional anisotropy of white matter tracts. Comparisons between groups were evaluated using analysis of covariance adjusting for age, sex, local fractional anisotropy and white matter hyperintensity burden. Partial correlations with clinical and cognitive measures were also tested. Patients with motor neuron disease exhibited significantly lower DTI-ALPS index values relative to healthy controls (P = 0.05). Patients with bulbar onset had lower DTI-ALPS values than those with spinal onset (P = 0.017). Comparable DTI-ALPS values were found across patients with classical amyotrophic lateral sclerosis clinical presentation and predominant upper or lower motor neuron clinical presentations, with no effect of cognitive diagnosis or genetic status. DTI-ALPS exhibited a significant correlation with disease duration (r = -0.38, P = 0.01). Motor neuron disease patients presenting insomnia had significantly lower DTI-ALPS values compared to those without sleep disturbances (P = 0.002). Significant positive correlations were found between ALPS index and fractional anisotropy values across major white matter tracts, including the internal and external capsules, superior longitudinal fasciculi, anterior, posterior and superior corona radiata, posterior thalamic radiation, fornix and the genu and body of the corpus callosum. This study confirms the presence of altered interstitial fluid diffusivity dynamics across motor neuron disease phenotypes, with greater impairment observed in bulbar-onset cases, patients with longer disease duration, and those experiencing more pronounced sleep disturbances. These findings may support a potential pathogenic role of glymphatic failure in the accumulation of TAR DNA-binding protein 43 proteinopathy and widespread microstructural axonal damage in motor neuron diseases.},
}