@article {pmid42780196,
year = {2026},
author = {Okuda, M and Okinaka, Y and Saino, O and Taguchi, A},
title = {Case Report: Autologous bone marrow mononuclear cell transplantation improved motor function in a patient with amyotrophic lateral sclerosis.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1940826},
pmid = {42780196},
issn = {2296-858X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, and no established treatment restores impaired motor function. In mouse models of ALS, bone marrow mononuclear cell (BM-MNC) injection improved motor function. In patients with ALS, direct spinal cord injection of BM-MNCs has also been reported to improve motor function. Here, we report the case of a 52-year-old male patient with ALS who underwent intravenous autologous BM-MNC transplantation and demonstrated improved motor function. His revised ALS Functional Rating Scale score increased from 17 before treatment to 18 at 24 weeks after transplantation. The score of Manual Muscle Testing of fifth finger metacarpophalangeal joint flexion improved from 0 before treatment to 2(-) at 24 weeks after transplantation. No serious adverse events were observed. As this is a single case report, additional case series and subsequent randomized clinical trials are essential to clarify the effect of BM-MNC transplantation on ALS outcomes. This case suggests, however, that motor dysfunction in patients with ALS might be reversible. These findings encourage future studies investigating motor function improvement, rather than disease progression slowing, by elucidating the mechanisms underlying BM-MNC transplantation and optimizing treatment.},
}

@article {pmid42780961,
year = {2026},
author = {Standal, B and Kenter, RMF and Gullslett, MK and Nordgreen, T and Teig, IL},
title = {The perceived fit of guided iCBT in specialised mental healthcare services: a qualitative study of healthcare professionals' perspectives.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1955151},
pmid = {42780961},
issn = {2673-253X},
abstract = {BACKGROUND: Therapist-guided internet-delivered cognitive behavioural therapy (guided iCBT) is an effective treatment for common mental disorders and has the potential to improve access to care. However, its integration into routine practice remains limited. This study explored healthcare professionals' perceptions of the suitability of guided iCBT in specialised mental healthcare and examined how perceived fit influences implementation across clinical and organisational contexts.

METHODS: Semi-structured interviews and participatory observations were conducted at three specialised mental health clinics in Norway that offered guided iCBT to adults with anxiety and depression. Thirty-one healthcare professionals were recruited through purposive and snowball sampling. Data were analysed using a combination of inductive and deductive approaches. The deductive analysis was informed by Lau et al.'s framework of contextual fit, which conceptualises fit as alignment between an intervention and professional, organisational, and external contexts.

RESULTS: Healthcare professionals' perceptions of fit varied across contextual levels and influenced the implementation of guided iCBT. At the intervention level, participants identified a perceived mismatch between the evidence base for guided iCBT and limitations in its technological design, which was viewed as insufficiently aligned with contemporary therapeutic practices. At the professional level, differing professional values and therapeutic norms shaped perceptions of appropriateness and acceptability. At the organisational level, limited readiness for implementation and concerns about patient complexity in specialised care settings contributed to doubts about the intervention's suitability. At the external level, tensions emerged between evidence-based expectations and prevailing clinical assumptions favouring face-to-face care, further affecting perceptions of fit and legitimacy.

CONCLUSIONS: The findings suggest that implementing guided iCBT in specialised mental healthcare depends on aligning the intervention with the clinical, organisational, and broader system contexts in which it is introduced. Efforts to improve technological usability, strengthen organisational readiness, engage clinicians, and address assumptions about legitimate forms of therapy may enhance perceived fit and support sustained implementation of guided iCBT.},
}

@article {pmid42781313,
year = {2026},
author = {Zhu, JX and Xia, Y and Liu, J and Cao, L and Hou, SX and Wang, Y},
title = {Protecting Against Cytoplasmic Protein Aggregates With Cytoplasmic PML Variants.},
journal = {Bio-protocol},
volume = {16},
number = {18},
pages = {e5815},
pmid = {42781313},
issn = {2331-8325},
abstract = {Cytoplasmic protein aggregation is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and certain forms of motor neuron disease. Recent evidence indicates that promyelocytic leukemia protein (PML) and engineered PML-derived variants can act as versatile aggregate-remodeling factors. In particular, cytoplasmically redirected PML variants recognize pathological cytoplasmic inclusions and promote their clearance. Here, we describe a protocol to generate and validate two engineered cytoplasmic PML variants: full-length mPML, which is redirected to the cytoplasm by disruption of its nuclear localization sequence, and the truncated mPML[ΔRBC] variant, which lacks the RING, B-box, and coiled-coil domain but retains aggregate-reducing activity. The protocol integrates fluorescence-based imaging, bimolecular fluorescence complementation, detergent-soluble/insoluble fractionation, and validation in primary rat cortical neurons. This workflow provides a practical platform for assessing cytoplasmic aggregate burden and for comparing the aggregate-remodeling activities of PML-derived constructs. It can also be adapted to other disease-associated aggregation-prone proteins, including TDP-43, SOD1, FUS, tau, polyGA, and polyQ-expanded proteins. Key features • Describes the generation and validation of two complementary cytoplasmic PML variants: full-length mPML and truncated mPML[ΔRBC]. • Provides fluorescence-based and BiFC-based assays to visualize pathological cytoplasmic protein assemblies. • Includes detergent-soluble/insoluble fractionation for biochemical assessment of aggregate burden. • Establishes a primary rat cortical neuron workflow to evaluate the effect of mPML on TDP-43-CTF aggregates. • Can be adapted to other aggregation-prone proteins and additional PML-derived aggregate-remodeling candidates.},
}

@article {pmid42781630,
year = {2026},
author = {Freidling, T and Piccininni, M},
title = {The Cornfield Condition and Principle: A Critical Appraisal.},
journal = {Observational studies},
volume = {12},
number = {2},
pages = {179-192},
pmid = {42781630},
issn = {2767-3324},
abstract = {Cornfield, Haenszel, Hammond, Lilienfeld, Shimkin, and Wynder (1959)'s seminal work made two major contributions that shape causal inference and epidemiology to this day. First, Cornfield et al. provided the first example of quantitative sensitivity analysis for unmeasured confounding; a result that became subsequently known as the Cornfield condition. Second, they advocated for the use of relative effect measures for causal inference and absolute effect measures in public health. This recommendation is also referred to as the Cornfield principle. This commentary critically re-examines Cornfield et al.'s landmark contributions. With the benefit of hindsight, we formalize their arguments, identify shortcomings, and contextualize their claims in the light of recent research.},
}

@article {pmid42781640,
year = {2026},
author = {Eisenhauer, EW and Han, D and Edwards, B and Brick, JM},
title = {Toward a Total Causal Error Framework: Extending Cornfield's Insights Across Causal Identification, Representation, and Measurement.},
journal = {Observational studies},
volume = {12},
number = {2},
pages = {311-322},
pmid = {42781640},
issn = {2767-3324},
abstract = {Cornfield et al.'s (1959) analysis of smoking and lung cancer showed how explicit assumptions about unobserved confounding and selection mechanisms shape the boundary between statistical association and causal conclusions. Today, causal inference spans diverse fields including economics, statistics, psychology, epidemiology, and evaluation, with distinct traditions and tools. Without a shared framework, it can be difficult to accumulate evidence across studies or to diagnose why results differ when similar questions are studied independently, particularly when differences arise from upstream design and data-generation choices rather than analytic methods alone. While tools for causal identification such as Directed Acyclic Graphs (DAGs) have become widely used across disciplines, they do not naturally foreground threats arising from representation and measurement errors. In contrast, the Total Survey Error (TSE) framework enumerates representation and measurement errors across the survey life cycle and is routinely used to evaluate tradeoffs in survey design and data collection. We propose a Total Causal Error (TCE) framework that integrates causal inference with the TSE perspective to organize risks to causal conclusions along parallel paths of causal identification, representation, and measurement, across the stages of the theoretical estimand, empirical estimand, data collection, data processing, and estimation and interpretation. We propose a version of this framework, provide explicit definitions for its components, illustrate a small number of use cases, and invite further development and coordination across fields.},
}

@article {pmid42781650,
year = {2026},
author = {Lun, Z},
title = {The Journey of Cornfield's Inequalities and How They Shaped Modern Sensitivity Analysis.},
journal = {Observational studies},
volume = {12},
number = {2},
pages = {155-162},
pmid = {42781650},
issn = {2767-3324},
abstract = {Cornfield et al.'s 1959 paper introduced a seminal framework for evaluating the impact of unmeasured confounding by quantifying the strength an unobserved factor would need to overturn an observed association. This commentary revisits Cornfield's original inequalities, clarifying their interpretation, and highlighting the reverse-reasoning principle that underlies modern sensitivity analysis. We summarize key methodological extensions developed by later researchers-ranging from conditional independence formulations and multiplicative bounds to the sharpened limits that led to the E-value, and illustrate how these refinements broadened the applicability of Cornfield's logic. Finally, we discuss the continued influence of Cornfield-type reasoning across epidemiology and related fields, where sensitivity analysis has become an essential component of study design and causal interpretation. More than six decades later, Cornfield's insight remains a foundational pillar of causal inference, guiding researchers in assessing the robustness of empirical findings to unmeasured confounding.},
}

@article {pmid42781667,
year = {2026},
author = {Frank, KA and Lin, Q and Maroulis, SJ},
title = {Cornfield's Pragmatic Contribution to Policy Discourse: Continued.},
journal = {Observational studies},
volume = {12},
number = {2},
pages = {163-178},
pmid = {42781667},
issn = {2767-3324},
abstract = {Cornfield et al.'s contributions included documenting epidemiological and policy debates regarding the effects of smoking on lung cancer. It was in the context of those debates that Cornfield et al. expressed sensitivity of the estimated effect of smoking to the dual components of confounding-relationship of a potential confounder (e.g., genes) to smoking (the focal predictor) and to lung cancer (the outcome). Current advancements have used various graphical and tabular representations to similarly express sensitivity to the dual components of confounding. As a representative of these advancements, we present Frank's Impact Threshold for a Confounding (ITCV), which resolves the dual components of confounding into a single term based on the product of the confounder's correlations with the focal predictor and with the outcome. We calculate the ITCV for an inference of an effect of kindergarten retention on achievement and provide benchmarks based on observed covariates to interpret the ITCV. Ultimately, any sensitivity analysis should only be applied after one has estimated the best possible model. The value of the sensitivity analysis is then to inform policy-oriented discourse among as wide a range of stakeholders as possible.},
}

@article {pmid42782389,
year = {2026},
author = {Walden, F and Reihani, Y and Peters, A and Sepehrimanesh, M},
title = {Dysregulation of mitochondrial bioenergetics, RNA processing, and cellular stress responses in FUS-ALS: a multi-dataset transcriptomic perspective.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42782389},
issn = {1590-3478},
support = {NASA EPSCoR RID-RAP grant//NASA EPSCoR RID-RAP grant/ ; SBS Start-up budget//SBS Start-up budget/ ; ANS Faculty mini-grant//ANS Faculty mini-grant/ ; },
mesh = {Humans ; *RNA-Binding Protein FUS/genetics/metabolism ; *Astrocytes/metabolism ; *Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Motor Neurons/metabolism ; *Transcriptome ; *Energy Metabolism/physiology/genetics ; Induced Pluripotent Stem Cells/metabolism ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron (MN) degeneration. Mutations in the FUS gene, particularly the aggressive P525L variant, disrupt nuclear localization of the FUS RNA-binding protein, resulting in cytoplasmic accumulation, altered RNA metabolism, and toxic aggregation. Astrocytes also contribute to disease progression through non-cell-autonomous mechanisms.

OBJECTIVE: To identify shared and cell-type-specific molecular mechanisms underlying FUS-associated ALS through integrated transcriptomic analysis of human induced pluripotent stem cell (hiPSC)-derived motor neurons and astrocytes.

METHODS: Five publicly available RNA-sequencing datasets from hiPSC-derived motor neurons and astrocytes carrying FUS mutations were analyzed. Differential gene expression and Gene Ontology enrichment analyses were performed to identify dysregulated genes and pathways.

RESULTS: Both cell types showed convergent dysregulation of mitochondrial/bioenergetic pathways (oxidative phosphorylation, ATP metabolism, translation, membrane potential). Pathway analysis across motor neuron datasets identified largely MN-specific enrichment in cell-cycle regulation, intracellular trafficking, and stimulus response, while only four pathways were shared with astrocytes, most notably NADH dehydrogenase complex assembly, enriched across all datasets and both cell types, marking mitochondrial complex I as the strongest convergent signature. RNA processing/splicing pathways were also enriched, consistent with FUS function. Shared DEGs included upregulated COMT, TXNRD2, and PCDHGB4, and downregulated PCDH17 and C11orf87, implicating neurotransmitter metabolism, antioxidant defenses, and adhesion. Stress pathways (oxidative stress, autophagy, heat-shock, ER stress/UPR) were broadly altered, with UPR genes mainly upregulated and inflammatory genes downregulated.

CONCLUSION: FUS-ALS involves shared mitochondrial complex I and stress-response disturbances layered onto MN-intrinsic cell-cycle and trafficking dysregulation, reflecting convergent and cell-type-specific mechanisms.},
}

Humans
*RNA-Binding Protein FUS/genetics/metabolism
*Astrocytes/metabolism
*Mitochondria/metabolism
*Amyotrophic Lateral Sclerosis/metabolism/genetics
*Motor Neurons/metabolism
*Transcriptome
*Energy Metabolism/physiology/genetics
Induced Pluripotent Stem Cells/metabolism

@article {pmid42782554,
year = {2026},
author = {Padhiyar, DP and Butani, S and Vyas, T and Mukharya, A and Rajput, A},
title = {Recent Innovations in Drug Delivery Systems for Amyotrophic Lateral Sclerosis: Past, Present and Future.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {5},
pages = {},
pmid = {42782554},
issn = {1530-9932},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; Animals ; Nanoparticles/chemistry ; Drug Carriers/chemistry ; Polymers/chemistry ; Delayed-Action Preparations ; Biological Availability ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder characterized by degeneration of upper and lower motor neurons, resulting in severe muscle weakness, respiratory failure, and death. Despite several pharmacological therapies having been approved, their clinical benefit remains limited due to poor central nervous system penetration, rapid metabolic clearance, and low patient compliance. Overcoming these pharmacokinetic and pharmacodynamic limitations remains a major challenge in ALS management. Recent advances in drug delivery have focused on brain-targeted strategies, improved bioavailability, and sustained or controlled-release systems. Nanocarriers, including lipid and polymeric nanoparticles, dendrimers, and mesoporous silica systems, facilitate blood-brain barrier traversal, protect labile drugs, and enable surface functionalization for receptor-mediated targeting. Biologically derived carriers such as exosomes and extracellular vesicles further enhance targeted delivery while minimizing immunogenicity. In parallel, noninvasive approaches such as mucoadhesive polymers, intranasal, and nose-to-brain delivery systems, including microneedle-based platforms, offer promising alternatives to bypass first-pass metabolism and improve patient adherence. Additionally, emerging therapeutic modalities, including gene therapy, stem cell-based interventions, and neuromodulation, are increasingly integrated with advanced delivery technologies. This article critically analyzes current ALS therapies, highlights recent breakthroughs in advanced drug delivery systems, and discusses future perspectives for achieving meaningful clinical outcomes.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/metabolism
Humans
*Drug Delivery Systems/methods
Blood-Brain Barrier/metabolism
Animals
Nanoparticles/chemistry
Drug Carriers/chemistry
Polymers/chemistry
Delayed-Action Preparations
Biological Availability

@article {pmid42782733,
year = {2026},
author = {Hou, X and Yu, W},
title = {The Role of cGAS-STING-Driven PANoptosis in Neurodegenerative Diseases and Therapeutic Prospects.},
journal = {Cells},
volume = {15},
number = {18},
pages = {},
pmid = {42782733},
issn = {2073-4409},
support = {31972623//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; Animals ; STING Protein ; *Membrane Proteins/metabolism ; Signal Transduction ; },
abstract = {Neurodegenerative diseases share features of neuronal loss, neuroinflammation, and protein aggregation. The cGAS-STING pathway, a key DNA sensor, mediates neuroinflammation via TBK1-IRF3 and IKK-NF-κB axes, inducing type I interferons and pro-inflammatory cytokines. This pathway upregulates ZBP1, promotes PANoptosome assembly, and triggers PANoptosis, releasing DAMPs and creating a self-amplifying "inflammation-death" cycle. In Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, pathological proteins (Aβ, Tau, α-synuclein, TDP-43) or genetic defects (e.g., C9orf72 repeats) cause mitochondrial DNA leakage or genomic instability, activating this axis. This review highlights the cGAS-STING-PANoptotic cascade as a shared pathogenic mechanism and discusses the current evidence and remaining challenges in confirming this hypothesis.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology/therapy
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
Animals
STING Protein
*Membrane Proteins/metabolism
Signal Transduction

@article {pmid42782801,
year = {2026},
author = {Almeida, S and Gu, Y and Kankel, MW},
title = {AUG-Dependent Translation of Antisense Repeat Transcripts Contributes to Dipeptide Repeat Protein Production in C9ORF72 Expansion Carriers.},
journal = {Cells},
volume = {15},
number = {18},
pages = {},
pmid = {42782801},
issn = {2073-4409},
support = {R21NS119952/NH/NIH HHS/United States ; 1R21NS112766-24/NH/NIH HHS/United States ; 1R21AG085076-25/NH/NIH HHS/United States ; },
mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Dipeptides/metabolism/genetics ; *Protein Biosynthesis/genetics ; *DNA Repeat Expansion/genetics ; Amyotrophic Lateral Sclerosis/genetics ; *RNA, Antisense/genetics/metabolism ; Frontotemporal Dementia/genetics ; Oligonucleotides, Antisense ; Motor Neurons/metabolism ; },
abstract = {A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Bidirectional transcription of the repeat expansion generates sense and antisense RNAs that are translated into dipeptide repeat (DPR) proteins, but the mechanisms of translation initiation remain incompletely understood. Here, we used CRISPR-Cas9 genome editing and steric-blocking antisense oligonucleotides (ASOs) to investigate the role of AUG codons within the antisense repeat RNA. Deletion of an AUG-containing region upstream of the antisense repeats markedly reduced poly(GP) production without affecting antisense RNA levels, demonstrating that this sequence is required for efficient poly(GP) synthesis. We further found that unspliced sense transcripts containing the repeat expansion likely serve as templates for poly(GA) and poly(GR) production in motor neurons. Finally, ASOs targeting the antisense AUG-containing region reduced poly(PR) and poly(GP) levels without altering repeat RNA abundance, supporting a role for AUG-dependent translation of the antisense repeat RNA. These findings provide new insights into the mechanisms of DPR production and suggest that translation-blocking ASOs may represent a therapeutic strategy for C9ORF72-associated ALS/FTD.},
}

*C9orf72 Protein/genetics/metabolism
Humans
*Dipeptides/metabolism/genetics
*Protein Biosynthesis/genetics
*DNA Repeat Expansion/genetics
Amyotrophic Lateral Sclerosis/genetics
*RNA, Antisense/genetics/metabolism
Frontotemporal Dementia/genetics
Oligonucleotides, Antisense
Motor Neurons/metabolism

@article {pmid42782811,
year = {2026},
author = {Bagyinszky, E and An, SSA},
title = {ERBB4 and Neurodegeneration: Association Between Hypothalamic-Pituitary-Adrenal (HPA) Axis: Associated Neurodegenerative Pathogenesis.},
journal = {Cells},
volume = {15},
number = {18},
pages = {},
pmid = {42782811},
issn = {2073-4409},
mesh = {Humans ; *Hypothalamo-Hypophyseal System/metabolism/pathology ; *Pituitary-Adrenal System/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Receptor, ErbB-4/metabolism/genetics ; Signal Transduction ; },
abstract = {The hypothalamic-pituitary-adrenal (HPA) axis is the central neuroendocrine system that controls physiological stress responses and maintains homeostasis through the coordinated interactions among the hypothalamus, pituitary gland, and adrenal cortex. Dysregulation of the HPA axis is associated with stress-related psychiatric conditions and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Chronic stress creates a detrimental environment in the brain, inducing structural changes and accelerating brain aging and the loss of neurons. Receptor tyrosine-protein kinase ERBB4 (ERBB4), a member of the epidermal growth factor receptor (EGFR) family, is activated primarily by neuregulin ligands and plays an essential role in neuronal development, synaptic plasticity, and cell survival. Emerging evidence suggests that ERBB4 signaling influences neuroendocrine regulation and stress responsivity. While further studies are needed to provide direct mechanistic evidence linking ERBB4-mediated HPA axis dysregulation to neurodegenerative cell death, this manuscript critically evaluated the preclinical models and proposes a possible feed-forward framework wherein ERBB4 served as a permissive homeostatic modulator at the intersection of stress endocrinology and neuroinflammation. Furthermore, the impact of ERBB4 dysregulation and its mutations on neurodegenerative diseases has been presented, focusing on potential mechanisms of oxidative stress, synaptic dysfunction, and neuronal apoptosis. Taken together, ERBB4 represents an important molecular interface between stress signaling and neurodegenerative pathology. Understanding the regulation of ERBB4 in the HPA axis has provided new insights into the mechanisms underlying neurodegenerative diseases and could identify novel therapeutic targets for stress-associated neurological disorders.},
}

Humans
*Hypothalamo-Hypophyseal System/metabolism/pathology
*Pituitary-Adrenal System/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Receptor, ErbB-4/metabolism/genetics
Signal Transduction

@article {pmid42783617,
year = {2026},
author = {Mitu, I and Caba, IC and Macovei, I},
title = {Cumulative and Interactive Effects of Heavy Metal Mixtures Across Neurodegenerative Diseases: A Comparative Review of Alzheimer, Parkinson, Amyotrophic Lateral Sclerosis and Multiple Sclerosis.},
journal = {Journal of xenobiotics},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/jox16050174},
pmid = {42783617},
issn = {2039-4713},
support = {7383/31.03.2026//Grigore T. Popa University of Medicine and Pharmacy/ ; },
abstract = {Heavy metals and metalloids are persistent environmental contaminants that accumulate in the central nervous system and interact with endogenous essential metals, yet most neurotoxicological research continues to treat metals as independent agents rather than as co-occurring mixtures. This review systematically compares the evidence for cumulative and interactive effects of heavy metal mixtures across four major neurodegenerative diseases-Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)-asking which metal combinations have been directly documented for each disease, and whether these patterns are disease-specific or shared. Following a PubMed search (January 2016-June 2026), 93 unique studies were included (AD: 49; PD: 38; ALS: 19; MS: 18; 31 shared across diseases). Combined exposure to lead, cadmium, arsenic, and mercury is linked to amyloid-beta accumulation and dementia risk in AD; manganese-vanadium co-exposure produces more severe dopaminergic damage in PD than either metal alone, with manganese activating the familial PD gene LRRK2; a multi-metal mixture in ALS was associated with a three-fold higher disease risk independent of genetic susceptibility; and MS showed almost no designed mixture studies despite considerable single-metal data, with conflicting findings across cohorts. Three general mechanisms were identified: competition at shared membrane transporters (notably DMT1), sequestration by metal-binding proteins, and direct synergistic or antagonistic interactions, in which essential elements can modulate toxic-metal handling. Mixture-statistics approaches (WQS, BKMR), already established for AD and PD, should be extended to MS to close this evidence gap.},
}

@article {pmid42783767,
year = {2026},
author = {Kang, Z and Meng, R and Nie, M and Wang, T},
title = {Gut Microbial Metabolism as a Dynamic Interface in Neurodegenerative Diseases.},
journal = {Metabolites},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/metabo16090642},
pmid = {42783767},
issn = {2218-1989},
support = {No.82405557//China National Natural Science Foundation of youth project/ ; KM202410025018//R&D Program of Beijing Municipal Education Commission 2024: Study on the improvement of clinical symptoms and mechanism of acupuncture in amyotrophic lateral sclerosis/ ; 20250639//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; 2024-QNRC2-B08//2024-2026 Chinese Association of Chinese Medicine young Talent lifting project/ ; },
abstract = {Gut microbial metabolism links intestinal ecology with systemic physiology and neural pathology, but its effects vary across disease stage, tissue compartment, and host background. This review uses Alzheimer's disease (AD) as the principal model and compares selected features with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Across the AD continuum, fermentation-related changes appear in prodromal cohorts, whereas broader alterations in amino acid products, host-microbial co-metabolites, bile acids, and lipids accompany mild cognitive impairment and dementia. These group-level patterns do not constitute a fixed patient trajectory. Microbial production, intestinal absorption, hepatic conversion, renal clearance, barrier integrity, and tissue-specific receptors jointly determine biological exposure. Experimental studies connect short-chain fatty acids and indole derivatives with epithelial and neuroimmune homeostasis, while imidazole propionate, trimethylamine N-oxide, selected kynurenine products, and remodeled bile acid pools engage vascular, inflammatory, amyloid, or tau-related pathways. Cerebral pathology can also remodel the intestinal ecosystem, creating reciprocal feedback. Apolipoprotein E4 modifies lipid handling, vascular permeability, and immune responses, helping to explain why comparable metabolic profiles may carry different consequences among individuals. Translation therefore requires more than a change in community composition. Trials must verify microbial function, metabolite target engagement, AD biomarker response, and clinical benefit in appropriately stratified participants. Shared pathways in PD and ALS provide comparison points, but disease-specific cells, proteinopathies, and treatment exposures constrain direct transfer of AD-derived targets.},
}

@article {pmid42784708,
year = {2026},
author = {Rajput, P and Jakhar, M and Kashyap, A and Rani, N and Singh, TG},
title = {The Intertwined Threat: How Diabetes Impacts Neurological Disorders - A Review Article.},
journal = {Acta neurologica Taiwanica},
volume = {35},
number = {3},
pages = {119-127},
pmid = {42784708},
issn = {1028-768X},
mesh = {Humans ; *Nervous System Diseases/etiology ; *Diabetes Complications ; *Diabetes Mellitus ; Oxidative Stress ; },
abstract = {The chronic illness known as diabetes mellitus (DM) is typified by persistently high blood glucose levels or hyperglycemia. Both type 1 and type 2 diabetes, the latter of which is frequently referred to as "adult-onset diabetes" or "insulin-dependent diabetes," are progressing conditions with complex and poorly understood etiologies. Often, patients show positive pancreatic beta-cell antibodies, signifying an autoimmune factor. The long-term complications of uncontrolled diabetes are numerous, not just physically based and encompassing everything from kidney failure to foot ulcers and damage to the cardiovascular system, but also with serious neurological disorders, including stroke, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease (AD), and epilepsy. The interplay between neurological disorders and diabetes is complex, and the association of these pathological states in their general description proposes common events, namely oxidative stress, mitochondrial damage, amyloid protein aggregation, glucagon-like peptide-1 secretion skewing, and inflammation. Learning about these interconnections will help us to develop effective strategies for managing both diabetes and its neurological complications.},
}

Humans
*Nervous System Diseases/etiology
*Diabetes Complications
*Diabetes Mellitus
Oxidative Stress

@article {pmid42785576,
year = {2026},
author = {Shameklis, J and Drutchas, A and Keeney, T and Rowland, M and Dow, L and Sawicki, D and Ho, D and Paladino, J and Lindenberger, E},
title = {A Qualitative Study of Team-Based Serious Illness Communication in ALS.},
journal = {Journal of pain and symptom management},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpainsymman.2026.09.025},
pmid = {42785576},
issn = {1873-6513},
abstract = {CONTEXT: Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease with an illness trajectory requiring repeated, high-stakes decisions and ongoing serious illness communication (SIC). While multidisciplinary team care is best practice in ALS, how interprofessional teams operationalize SIC, and how team culture shapes this work, remain poorly understood.

OBJECTIVE: To examine how team culture influences SIC delivery within an interprofessional ALS clinic.

METHODS: We conducted a qualitative study using semi-structured interviews and a focus group with interprofessional clinicians from a multidisciplinary ALS clinic at an academic medical center. Data explored clinicians' perceptions of interprofessional roles, team culture, facilitators, and barriers related to SIC. Transcripts were analyzed using thematic analysis with a combined deductive-inductive approach.

RESULTS: Analysis identified interpersonal facilitators, systems-level facilitators, and structural barriers shaping team-based SIC. Clinicians described shared responsibility for SIC, with conversations unfolding cumulatively over time across roles and clinical encounters. Interpersonal facilitators included mutual respect, psychological safety, role flexibility, and a shared commitment to reducing patient harm. Systems-level facilitators included frequent multimodal communication, structured documentation, leadership support, and use of adverse outcomes as opportunities for practice improvement. Structural barriers included time constraints, care transitions, regulatory limitations, and variability in comfort with SIC language.

CONCLUSIONS: In this multidisciplinary ALS clinic, strong team culture enabled SIC to function as a longitudinal, interprofessional process rather than a single clinician-led event. Findings highlight the importance of psychological safety, teamwork, and supportive systems in delivering high-quality SIC and inform future clinical practice, training, and research.},
}

@article {pmid42786692,
year = {2026},
author = {Poletaeva, MP and Gerasimov, AN and Sigalova, AE and Pigolkin, YI and Zolotenkova, GV},
title = {[Cameriere's European formula for age estimation: A study on the children in the Russian population].},
journal = {Sudebno-meditsinskaia ekspertiza},
volume = {69},
number = {5},
pages = {5-12},
doi = {10.17116/sudmed2026690515},
pmid = {42786692},
issn = {0039-4521},
mesh = {Humans ; *Age Determination by Teeth/methods ; Child ; Female ; Adolescent ; Male ; Russia ; *Radiography, Panoramic/methods ; Child, Preschool ; *Forensic Dentistry/methods ; *Tooth/diagnostic imaging ; },
abstract = {UNLABELLED: Determining the age of minors (children and adolescents) plays an important role in forensic medicine, justice and investigation, as it serves as the basis for making decisions on criminal and civil liability, forms an objective basis for the legal qualification of acts and determining the scope of legal capacity. Among all the existing methods of estimating the age of a living person, dental methods have become the most popular all over the world, as the most objective and least expensive. To assess dental age, an assessment of their development on radiographs is most often used, and the most popular method is the method of measuring the open tops of teeth (Cameriere).

OBJECTIVE: To verify the accuracy of the assessment of dental age according to the European Cameriere formula in a sample of Russian children. The method of determining dental age is based on the relationship between age and the size of the exposed tips of the roots of the teeth.

MATERIAL AND METHODS: Orthopantomograms from 300 children (146 boys and 154 girls) aged 5 to 15 years were analyzed. Seven left mandibular teeth were evaluated: the number of teeth with fully developed roots in this quadrant (with closed tips) was calculated, and in teeth with incomplete root development, the distance between the inner sides of the open apex was measured, which were later normalized by dividing by another metric indicator - tooth length.

RESULTS AND CONCLUSION: The Pearson correlation coefficients between age and the metric variables of teeth showed a significant negative relationship, while the variables sex and the number of teeth with the apical end of the root canals completely closed (N0) showed a significant positive correlation with chronological age. The use of the European Cameriere formula revealed an underestimation of the average age in the study sample for boys by 0.68 and for girls by 0.6 years, and the overall average forecasting error was 0.63 years. The error value varied and depended on the age group and gender: with increasing age and the number of teeth with closed apices, the error value increased. Statistical analysis showed that the selected morphological variables explain more than 65% of the variations in determining the chronological age according to the European formula. The positive results obtained provide space for improving the model and increasing the accuracy of age prediction by adapting the proposed formula to the regional characteristics of groups of children and subsequently creating a national age assessment formula for children and adolescents.},
}

Humans
*Age Determination by Teeth/methods
Child
Female
Adolescent
Male
Russia
*Radiography, Panoramic/methods
Child, Preschool
*Forensic Dentistry/methods
*Tooth/diagnostic imaging

@article {pmid42786852,
year = {2026},
author = {Yu, J and Xie, D and Zeng, X and Zhang, S and Xiao, B and Zhang, J and Fang, M and Zhu, Q and Yao, C},
title = {Therapeutic Implications of Cell Death Pathways Across the Course of Amyotrophic Lateral Sclerosis.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X500937260908042834},
pmid = {42786852},
issn = {1875-6190},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, resulting in paralysis and limited survival. Multiple regulated cell death pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis, lysosomal cell death, autophagy-dependent cell death, NETosis, and other emerging cell death modalities, have been implicated in ALS, but their mechanistic interactions and relative contributions remain poorly understood. This knowledge gap has hindered the development of effective therapies. Better experimental models are needed to dissect these pathways. This review summarizes current knowledge on the roles of cell death pathways in ALS. A tiered framework (M1-M4) is applied to critically evaluate data from human postmortem tissue, patient-derived cells, and animal models, ranking studies according to their relevance to human disease. Potential crosstalk among these pathways is further examined. It is also proposed that the relative contribution of specific cell death pathways may shift with disease progression, although this hypothesis requires longitudinal validation. To integrate this dynamic perspective, cell death pathway activities are hypothetically aligned with the King's clinical staging system. This stage-informed framework is presented as a conceptual model intended to generate hypotheses rather than to serve as a validated clinical algorithm. The model distinguishes established therapies from preclinical and exploratory strategies. Future research should prioritize the development of human-relevant model systems, the identification of longitudinal biomarkers of cell death, and the implementation of rigorously designed combination trials. These efforts may ultimately enable more precise, stage-appropriate therapeutic strategies for ALS.},
}

@article {pmid42788121,
year = {2026},
author = {Naruse, H and Mitsui, J and Ishiura, H and Okubo, S and Yoshida, C and Mitsutake, A and Maruta, K and Uchida, Y and Nobuhara, Y and Okabe, H and Nakamura, Y and Suzuki, R and Hotta, Y and Matsukawa, T and Tsukamoto, H and Kawamura, Y and Hara, K and Takado, Y and Kanzaki, M and Uesaka, Y and Ishii, A and Kitamura, A and Urushitani, M and Takahashi, Y and Kubota, A and Maeda, M and Shimizu, J and Shirota, Y and Hamada, M and Satake, W and Katagiri, T and Takahama, S and Yamamoto, T and Tsuji, S and Nakamura, Y and Toda, T},
title = {LRP12 CGG Repeat Expansions in Patients With Adult-Onset Non-5q Spinal Muscular Atrophy.},
journal = {Neurology. Genetics},
volume = {12},
number = {5},
pages = {e200440},
pmid = {42788121},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: Non-5q spinal muscular atrophy (SMA) is genetically heterogeneous, yet many adult-onset cases remain molecularly undiagnosed. CGG repeat expansions in the 5' untranslated region of LRP12, originally identified in oculopharyngodistal myopathy, have also been implicated in amyotrophic lateral sclerosis (ALS) and inherited peripheral neuropathy. The aim of this study was to determine whether LRP12 CGG repeat expansions occur in patients with adult-onset proximal-predominant non-5q SMA and characterize the associated clinical presentations.

METHODS: In this observational case series, we enrolled 8 consecutive, genetically unresolved families that met prespecified criteria for adult-onset non-5q SMA after exclusion of known genetic causes of SMA and familial ALS by comprehensive genetic evaluation, including whole-exome sequencing. LRP12 CGG repeat expansions were screened by repeat-primed PCR and then confirmed and sized by Oxford Nanopore long-read sequencing. LRP12 CGG repeat expansions were also screened in 496 unrelated ALS cases and 1,000 controls.

RESULTS: Monoallelic LRP12 CGG repeat expansions were identified in 6 of the 8 non-5q SMA probands (75%). Five of the 6 positive families were consistent with autosomal-dominant inheritance. Expanded alleles ranged from 58 to 92 repeat units. Affected individuals showed adult-onset, slowly progressive, proximal-predominant pure lower motor neuron weakness with preserved bulbar and sensory function and no upper motor neuron signs. Expansions were rare in ALS cases (2/496, 0.40%) and controls (2/1,000, 0.20%).

DISCUSSION: We identified LRP12 CGG repeat expansions in a substantial proportion of patients with slowly progressive, proximal-predominant pure lower motor neuron weakness not linked to 5q-SMA. These findings broaden the clinical spectrum of LRP12-related disease and support inclusion of LRP12 repeat-expansion analysis in the evaluation of genetically unresolved adult-onset lower motor neuron syndromes.},
}

@article {pmid42788147,
year = {2026},
author = {Baskurt, S and O'Donaghy, M and Babchishin, KM},
title = {Understanding Variations Among Individuals With Child Sexual Exploitation Material Offences: A Cumulative Meta-Analysis.},
journal = {Sexual offending (Trier, Germany)},
volume = {21},
number = {},
pages = {e16273},
pmid = {42788147},
issn = {2699-8440},
abstract = {Understanding the characteristics of individuals involved in child sexual exploitation material (CSEM) offences is crucial for policy, treatment, and case prioritization. This study examined the extent to which 238 men adjudicated for CSEM-exclusive offences (sexual history is limited to CSEM offences; Mage = 41.9, SD = 13.2) differ from 94 men with mixed offences (both CSEM and contact sexual offences; Mage = 43.4, SD = 13.9; median assessment year = 2009). We conducted a cumulative meta-analysis by integrating our findings with the latest meta-analysis on CSEM characteristics (i.e., Babchishin et al., 2015). Of the 10 characteristics examined, four showed significant deviation from the meta-analytical averages. Mixed offending individuals showed higher levels of prior offences (dweighted = .44, 95% CI [.34, .53], Q Δ = 18.35, p < .001), emotional identification with children (dweighted = .28, 95% CI [.15, .40], Q Δ = 18.35, p < .001), and empathy deficits (dweighted = .26, 95% CI [.13, .38], Q Δ = 29.05, p < .001) compared to CSEM-exclusive individuals, with differences increasing when incorporating our new sample. Conversely, the difference in prior violent offences decreased (dweighted = .78, 95% CI [.64, .92], Q Δ = 9.06, p = .028), with mixed individuals showing a greater reduction than the CSEM-exclusive group. No differences were noted for age, education, victim access, prior sexual offences, impulsivity, and substance use. This study highlights the distinct risk profiles of mixed versus CSEM-exclusive groups, underscoring the need for differentiated management approaches.},
}

@article {pmid42778113,
year = {2026},
author = {Kumari, P and Raval, A and Rana, P and Kaushik, RR and Sahi, AK and Gundu, S and Mahto, SK},
title = {Revisiting Culture Conditions of Satellite Cells In Vitro for Skeletal Muscle Regeneration and Therapeutic Applications.},
journal = {Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft},
volume = {},
number = {},
pages = {153381},
doi = {10.1016/j.aanat.2026.153381},
pmid = {42778113},
issn = {1618-0402},
abstract = {Skeletal muscle fibers are largely post-mitotic in adulthood yet retain robust regenerative capacity through satellite cells (SCs), quiescent muscle stem cells located beneath the basal lamina that are activated after injury, proliferate as myoblasts, differentiate, fuse into myotubes, and mature via tightly regulated cues. Given the burden of muscle-wasting and neuromuscular diseases, including Duchenne muscular dystrophy (DMD) (driven by dystrophin defects and impaired SC function), amyotrophic lateral sclerosis (ALS) (with progressive atrophy and evidence of SC perturbation), and myasthenia gravis (autoimmune neuromuscular junction failure), physiologically relevant and scalable in vitro SC systems are essential for mechanistic studies and future cell-therapy development. This review revisits culture conditions and workflows used to isolate, enrich, and differentiate rodent and human skeletal muscle progenitors, integrating key regenerative signalling (hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met), nitric oxide (NO), fibroblast growth factor (FGF)-mitogen-activated protein kinase (MAPK) modulated by Sprouty-1, insulin-like growth factor (IGF)-driven Akt/mechanistic target of rapamycin (mTOR) hypertrophy, inflammatory cytokines including interleukin-6 (IL-6) signal transducer and activator of transcription 3 (STAT3)-cyclin D1, and differentiation switches involving Notch/Wnt, glycogen synthase kinase 3 (GSK3), and mitogen-activated protein kinase (p38α MAPK)) with practical culture variables. Two principal isolation strategies are compared: explant outgrowth, which preserves tissue architecture and injury-mimicking activation but can be slow and yield-limited without matrix support, and enzymatic dissociation (e.g., collagenase, dispase, pronase, protease XIV), which accelerates release from the basal lamina and supports high-throughput needs but requires optimization to minimize trauma and fibroblast contamination. Across reported protocols, matrix choice (notably Matrigel or poly-L-lysine/Matrigel), differential pre-plating, and medium composition (serum levels, chick embryo extract (CEE), basic fibroblast growth factor (bFGF)) strongly influence SC quiescence, migration, survival, and myotube formation, with high purities achievable (e.g., ~97.6% Pax7+ after explant plus differential adherence; ~90% α7-integrin+/SCA-1-/CD31-/CD45-; up to ~98% after preplating; and ~95% in several optimized workflows) and differentiation occurring within ~1-7 days depending on conditions. The isolation of human SCs is constrained by the limited availability of tissue, inconsistent biopsy quality, and the absence of reliable markers to differentiate SCs from other mononuclear cells. Induced pluripotent stem cell (iPSC)-derived muscle organoids present a patient-specific alternative; however, they predominantly produce fetal-like PAX7+ progenitors instead of mature adult SCs. Overall, explant-based systems best retain physiological fidelity for niche and matrix studies, whereas enzymatic and hybrid approaches maximize efficiency and yield, underscoring that culture strategy should be selected based on the experimental objective rather than presumed universal superiority.},
}

@article {pmid42778416,
year = {2026},
author = {Fujino, Y and Nagai, Y},
title = {[Regulatory mechanisms of repeat-associated non-AUG translation: unveiling a novel molecular pathomechanism in repeat expansion diseases].},
journal = {Rinsho shinkeigaku = Clinical neurology},
volume = {},
number = {},
pages = {},
doi = {10.5692/clinicalneurol.cn-002278},
pmid = {42778416},
issn = {1882-0654},
abstract = {The expansion of genomic repeat sequences can cause more than 50 hereditary neuromuscular diseases, collectively referred to as repeat expansion diseases. In noncoding repeat expansion diseases caused by the expanded repeat sequences in the untranslated regions, repeat RNAs transcribed from the mutant genes can undergo repeat-associated non-AUG (RAN) translation despite lacking canonical AUG initiation codons, leading to the production of toxic repeat polypeptides that contribute to neurodegeneration. RAN translation has emerged as a promising therapeutic target for noncoding repeat expansion diseases; however, its regulatory mechanisms remain unclear. In this review, the characteristics of RAN translation and its roles in neuromuscular pathogenesis are overviewed. In addition, our research efforts for elucidating the regulatory mechanisms of RAN translation using Drosophila disease models are introduced.},
}

@article {pmid42778785,
year = {2026},
author = {Ding, J and Hu, N and Tian, H and Wang, Y and Shen, D and Yang, X and Niu, J and Liu, Q and Cui, L and Liu, M},
title = {Natural history of 441 cases of bulbar onset motor neuron disease (MND) in China: a single-center retrospective study.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42778785},
issn = {1590-3478},
support = {2026-PUMCH-C-008//National High Level Hospital Clinical Research Funding/ ; 2022ZD0118003//National Key R&D Program of China/ ; Z-2016-20-2402//China International Medical Foundation/ ; },
mesh = {Humans ; Female ; Retrospective Studies ; Male ; *Disease Progression ; Middle Aged ; *Motor Neuron Disease/physiopathology/diagnosis/mortality ; China/epidemiology ; Aged ; Prognosis ; Adult ; Age of Onset ; },
abstract = {OBJECTIVE: To describe the natural history and identify prognostic factors of bulbar onset motor neuron disease (MND).

METHODS: Bulbar onset MND patients with regular follow-up between January 2014 and December 2023 were included. Clinical features at initial evaluation, duration from onset to next region and time to death or tracheotomy were retrospectively collected. Survival analysis was performed by Kaplan-Meier method and Cox regression model.

RESULTS: A total of 441 patients were included. Disease progression occurred most frequently from bulbar region to upper limbs (77.1%), followed by lower limbs (16.4%) and respiratory muscles (6.5%), with a median time interval of 6.0 (1.0, 48.0) months. 215 patients died or underwent tracheotomy. The median duration to death or tracheotomy was 43.0 (95% CI 39.1-46.9) months, the 1-year, 2-year, 3-year, 4-year and 5-year survival rates (95%CI) were 96.6% (94.9-98.3), 79.9% (76.0-83.9%), 59.1% (54.0-64.7), 42.2% (36.6-48.6) and 29.9% (24.3-36.7), respectively. Younger onset age, slower ALSFRS-R decreasing rate, longer diagnostic delay, longer duration to next region and pure upper motor neuron involvement at initial evaluation were associated with favorable prognosis. Upper limbs involvement secondly to bulbar region was independently associated with better outcomes compared with respiratory muscles spreading.

CONCLUSIONS: The natural history of bulbar-onset ALS exhibits substantial heterogeneity. Patients with only upper motor neuron involvement in bulbar region at onset and subsequent upper limbs involvement as the second region tend to have a favorable prognosis.},
}

Humans
Female
Retrospective Studies
Male
*Disease Progression
Middle Aged
*Motor Neuron Disease/physiopathology/diagnosis/mortality
China/epidemiology
Aged
Prognosis
Adult
Age of Onset

@article {pmid42778939,
year = {2026},
author = {Zhou, X and Han, J and Cui, X and Wu, S and Lu, Z and Zong, S},
title = {Roles of lactate and protein lactylation in neurogenesis and neurodegenerative disease.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42778939},
issn = {1479-5876},
support = {82272414//National Natural Science Foundation of China/ ; 82572653//National Natural Science Foundation of China/ ; 2022CXGC010507//Key Technology Research and Development Program of Shandong Province/ ; ZR2023QH258//Natural Science Foundation of Shandong Province/ ; },
mesh = {Humans ; *Neurogenesis ; *Neurodegenerative Diseases/metabolism/pathology ; *Lactic Acid/metabolism ; Animals ; },
abstract = {BACKGROUND: Neurodegenerative diseases are characterized by the gradual deterioration and impaired functionality of neuronal cells, which in turn results in the progressive decline of both cognitive capabilities and motor performance. Over the past few years, accumulating evidence has demonstrated that neurogenesis participates in pathogenesis of various neurodegenerative conditions. In the adult brain, neurogenesis involves the proliferation and differentiation of neural stem cells into functional neurons, a process that serves a critical function in sustaining neuroplasticity and repairing neural damage. Additionally, studies conducted recently show that lactate and the protein lactylation modification it induces can regulate neurogenesis and influence the progression of neurodegenerative diseases.

MAIN BODY: We elaborate on how lactate, as an energy substrate and signaling molecule, supports neuronal survival and synaptic plasticity, and discuss the mechanisms by which histone lactylation regulates neural stem cell proliferation and differentiation via epigenetic pathways, as well as the regulation of specific protein functions by non‑histone lactylation. We further integrate the dual effects of lactate and lactylation in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). They can be neuroprotective by improving energy metabolism, promoting neurotrophic signals, and reducing inflammation, but they can also be neurotoxic via inflammation, oxidative damage, and protein aggregation under certain conditions. Key factors that determine this switch include concentration, cell type, pathological context, and lactylation site. We also evaluate therapeutic strategies targeting lactate metabolism and lactylation, and the challenges for clinical translation.

CONCLUSIONS: Lactate and protein lactylation exhibit a regulatory duality in neurogenesis and neurodegenerative diseases, encompassing both neuroprotective and neurotoxic effects. This finding provides a new perspective for understanding disease mechanisms and reveals potential intervention targets.},
}

Humans
*Neurogenesis
*Neurodegenerative Diseases/metabolism/pathology
*Lactic Acid/metabolism
Animals

@article {pmid42779169,
year = {2026},
author = {Yang, X and Yuan, J and Huang, S and Yao, X},
title = {Identifying Modifiable Factors and Their Joint Effect on Amyotrophic Lateral Sclerosis: A Prospective Cohort Study in the UK Biobank.},
journal = {Brain and behavior},
volume = {16},
number = {9},
pages = {e71771},
pmid = {42779169},
issn = {2162-3279},
support = {82271448//National Natural Science Foundation of China/ ; 2020B1111170002//Guangdong Provincial Clinical Research Centre for Neurological Diseases/ ; 2020A0505020004//Guangdong Province International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2024MDRD02//Guangzhou Major Difficult and Rare Diseases Project/ ; //Guangdong Provincial Engineering Centre for Major Neurological Disease Treatment/ ; //Guangzhou Clinical Research and Translational Centre for Major Neurological Diseases/ ; //Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Female ; United Kingdom/epidemiology ; Prospective Studies ; Male ; Risk Factors ; Middle Aged ; Aged ; Biological Specimen Banks ; UK Biobank ; Exposome ; },
abstract = {BACKGROUND: Hypothesis-driven studies have linked numerous risk factors to amyotrophic lateral sclerosis (ALS). However, the full extent of their diversity and co-occurrence has not been adequately appreciated. This study aims to comprehensively explore the modifiable risk factors for ALS and to evaluate the potential benefit of controlling these factors.

METHODS: This prospective cohort study utilized data from UK Biobank participants enrolled between 2006 and 2010 for whom complete data were available. An exposome-wide association study (EWAS) was employed to screen for modifiable risk factors, adjusted for sex and age. The main outcome was the first recorded diagnosis of ALS. The associations of modifiable risk factors with ALS risk were assessed using hazard ratios and 95% confidence intervals. The population attributable fraction (PAF) was used to estimate the joint effects of modifiable factors.

RESULTS: This study included a total of 326,050 participants and assessed 184 modifiable risk factors. During follow-up, 744 participants were diagnosed with ALS for the first time. EWAS, adjusted for sex and age, identified 45 modifiable factors associated with ALS incidence across six domains (excluding early life), including varicella, lower education, and peak expiratory flow. Analysis using the PAF indicated that 25.94%-87.40% of ALS cases could potentially be prevented.

CONCLUSIONS: In this study, newly identified risk factors for ALS through the EWAS may serve as targets for future studies. Interventions targeting modifiable risk factors, particularly those related to lifestyle and socioeconomic status, may help reduce the incidence of ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology
Female
United Kingdom/epidemiology
Prospective Studies
Male
Risk Factors
Middle Aged
Aged
Biological Specimen Banks
UK Biobank
Exposome

@article {pmid42779195,
year = {2026},
author = {Xu, W and Zhou, W and Xie, X},
title = {CUD-PRS: Predicting Cannabis Use and Neurostructural Impacts in Adolescents.},
journal = {Developmental psychobiology},
volume = {68},
number = {5},
pages = {e70206},
doi = {10.1002/dev.70206},
pmid = {42779195},
issn = {1098-2302},
support = {2022030410//Ningbo Top Medical and Health Research Program/ ; },
mesh = {Humans ; *Marijuana Abuse/genetics ; Adolescent ; Genetic Risk Score ; *White Matter/pathology/diagnostic imaging ; *Genetic Predisposition to Disease ; *Impulsive Behavior/physiology ; },
abstract = {With recreational cannabis use rising globally, understanding and preventing cannabis use disorders (CUD) has become increasingly important. Cupertino et al.'s recent study (2025) sheds light on the development mechanism of CUD. Our commentary briefly highlights their key findings and the clinical significance of their work: genetic vulnerability influences early cannabis use, and adolescence is a crucial period when this risk is most likely to emerge. We believe their work suggests that identifying individuals with high genetic risk early on could help shape targeted prevention strategies. Notably, white matter integrity and impulsive behavior appear to mediate the link between genetic risk and cannabis use. Based on this, we propose screening of adolescents for genetic susceptibility or white matter abnormalities in the future, followed by targeted behavioral, cognitive, or neuromodulation interventions to strengthen white matter integrity and potentially reduce the risk of CUD development.},
}

Humans
*Marijuana Abuse/genetics
Adolescent
Genetic Risk Score
*White Matter/pathology/diagnostic imaging
*Genetic Predisposition to Disease
*Impulsive Behavior/physiology

@article {pmid42779622,
year = {2026},
author = {Peethambaran Mallika, A and Baghel, MS and Sitzman, O and Yu, JG and Cao, T and Renganathan, S and Sinha, IR and Melnikova, T and Ling, JP and Wong, PC},
title = {Restoring multiple TDP-43 cryptic targets, but not solely Unc13a , rescues motor neuron disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.11.751082},
pmid = {42779622},
issn = {2692-8205},
abstract = {Dysfunction of TAR DNA-binding protein 43kDa (TDP-43) underlies amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder with limited therapeutic options. While current therapeutic approaches are designed to individually target unique cryptic exons of TDP-43 such as UNC13A , the sufficiency of such a strategy to mitigate motor neuron disease remains unclear. Using a mouse model lacking TDP-43 in spinal motor neurons which mimics early stages of ALS, we show that the exclusion of Unc13a cryptic exon fails to mitigate motor neuron disease. In contrast, the restoration of multiple TDP-43 cryptic targets, including Unc13a , attenuated motor neuron loss, and rescued motor neuron disease. Additionally, compared to brain neurons, spinal motor neurons accumulate markedly lower amounts of Unc13a cryptic exons in mice and humans, suggesting that the contribution of this TDP-43 cryptic target to spinal motor neuron loss may be limited. Together, these results strongly support ALS therapeutic strategies designed to simultaneously restore multiple TDP-43 cryptic targets to attenuate spinal motor neuron loss.},
}

@article {pmid42779744,
year = {2026},
author = {Weerakkody, JS and Bokstaller, F and Sthanu, U and Pitt, D},
title = {Paired RNA profiling of circulating small extracellular vesicles links survival in ALS to reactive glial - vascular programs.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.08.749915},
pmid = {42779744},
issn = {2692-8205},
abstract = {Circulating RNA can capture molecular variation associated with amyotrophic lateral sclerosis (ALS) progression, but biofluid heterogeneity makes biologically organized signals difficult to recover. Here, we paired microRNA (miRNA) and messenger RNA (mRNA) profiles from glutamate-aspartate transporter (GLAST)-positive small extracellular-vesicles (sEVs) to estimate survival time and identify survival-associated programs. In 45 participants with ALS and 15 controls, biologically constrained multi-omic factor analysis identified a program in which reciprocal miRNA-mRNA states among target-supported pairs tracked survival. The miRNA arm was then evaluated in an independent total-plasma cohort of 248 participants with ALS, refining a five-miRNA panel that added prognostic information beyond functional decline and neurofilament light chain, particularly over longer survival horizons. The mRNA arm was evaluated across 586 cortical profiles from 308 donors and 527,261 nuclei from 69 donors, identifying a five-gene core associated with glial reactivity, vascular programs and reduced myelinating identity. Together, these findings establish a framework for integrating regulatory RNA layers in circulation to identify clinically relevant programs and relate them to disease-relevant cellular states.},
}

@article {pmid42779765,
year = {2026},
author = {Dattilo, D and Pellegrini, F and Barattucci, S and Brown, AL and Vargas, JNS and Gatt, A and Morrie, R and Miller, G and Bachmutsky, I and McEachin, Z and Chung, M and Keuss, MJ and Ryadnov, E and Zanovello, M and Mehta, PR and Mattedi, F and Barioglio, M and Kamath, S and Kargbo-Hill, SE and Palade, J and Kowal, I and Glass, J and Gearing, M and Lee, EB and Murray, ME and Dickson, DW and , and Green, EM and Seyfried, NT and Chandriani, S and Ward, M and Fratta, P},
title = {TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.17.752342},
pmid = {42779765},
issn = {2692-8205},
abstract = {Nuclear depletion of TDP-43 is a defining pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to widespread RNA misprocessing, including the formation of cryptic exons. Here, we identified TDP-43 as a regulator of circular RNA (circRNA) biogenesis in multiple human neuronal cell models, and showed that its dysfunction induces the de novo formation of cryptic circular RNAs (c-circRNAs). Analysis of post-mortem brain transcriptomic data identified a subset of c-circRNAs which are specific for ALS and FTD cases with TDP-43 pathology. Further, we developed highly sensitive rolling-circle amplification-based circRNA detection assays that allow to distinguish TDP-43 pathology in human CNS tissues with a 0.99 AUC. We found that c-circRNAs can co-occur with cryptic linear splicing events, uncovering complex RNA misprocessing hotspots that induce loss of disease-relevant proteins, including RPTOR and EHMT1. Notably, one of these c-circRNAs originates from UNC13A, a gene whose cryptic exon has previously been linked to one of the major GWAS hits in ALS/FTD and that is being pursued as a therapeutic target through splice-switching ASOs. We showed that c-circUNC13A is co-regulated with the linear cryptic transcript and suppression of UNC13A cryptic exon results in c-circUNC13A reduction in cultured neurons and in vivo, highlighting its potential as a target engagement biomarker for emerging UNC13A-directed therapies. Overall, this work identifies a novel molecular mechanism for TDP-43 dysfunction, opening novel avenues for understanding disease pathogenesis and developing much needed pathology biomarkers.},
}

@article {pmid42780028,
year = {2026},
author = {Zhao, T and Hoffman, MM and Wu, G and Belzil, VV},
title = {Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.17.26363319},
pmid = {42780028},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose genetic architecture and underlying molecular mechanisms remain incompletely understood, particularly in sporadic disease. To investigate whether genetically regulated DNA methylation may help interpret ALS susceptibility, we conducted a methylome-wide association study (MWAS) of genetically predicted blood DNA methylation using the PrediXcan framework. CpG-specific prediction models developed in the ARIES and Understanding Society cohorts were applied to ALS genome-wide association study (GWAS) summary statistics from 27,205 cases and 110,881 controls of European ancestry. In total, genetically predicted methylation at 192,378 unique CpG sites was evaluated using S-PrediXcan. At a nominal threshold of p < 0.05, 3,741 CpGs were associated with ALS risk using ARIES models and 13,127 using Understanding Society models. After Bonferroni correction, 25 CpGs across eight genomic regions remained significantly associated with ALS risk. These included signals near established ALS and ALS-frontotemporal dementia genes and loci, including C9orf72, TBK1, SCFD1, and MOB3B, as well as three CpGs mapping to WHAMM at 15q25.2, a region not previously implicated in ALS by GWAS. Predicted methylation was positively associated with ALS risk at 18 CpGs and inversely associated at seven. Complementary transcriptome-wide association analyses using GTEx v8 whole-blood gene-expression prediction models identified 11 genes associated with ALS risk after Bonferroni correction, including convergent methylation and expression signals at C9orf72. These findings add a regulatory dimension to ALS genetic studies by prioritizing CpG sites, genes, and genomic regions through which inherited variation may influence disease susceptibility. PrediXcan-based MWAS therefore provides a complementary strategy for refining genetic association signals into biologically testable candidates and identifying regulatory mechanisms for further functional investigation.},
}

@article {pmid42780048,
year = {2026},
author = {Zhu, C and Zhao, Z and Song, B and Chen, YM and Xiao, Y and Zhang, Z and Ye, Y and Xu, N and Zhang, R and Huang, Y and Troncoso, JC and He, C and Sun, S},
title = {Loss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.17.752169},
pmid = {42780048},
issn = {2692-8205},
abstract = {TAR DNA-binding protein 43 (TDP-43) is a key pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and a critical regulator of RNA splicing. While loss of TDP-43 induces aberrant splicing in linear transcripts, its impact on circular RNA (circRNA) biogenesis remains unexplored. Here, we show that TDP-43 depletion in human neurons induces widespread circRNA changes, especially upregulation of a distinct class of cryptic circRNAs that arise specifically upon loss of TDP-43. Some of these cryptic circRNAs incorporate cryptic exons derived from intronic sequences. Notably, these cryptic circRNAs exhibit greater stability than their corresponding linear RNA isoforms and accumulate progressively in neurons. Moreover, cryptic circRNAs are elevated in postmortem brain tissues from ALS, FTD and Alzheimer's disease (AD) patients. These findings reveal a previously unrecognized role for TDP-43 in repressing cryptic circRNA formation and establish these circRNAs as stable molecular signatures of TDP-43 dysfunction.},
}

@article {pmid42764825,
year = {2026},
author = {Chen, HW},
title = {Operator-Driven Active Craniospinal Tensioning (ACT) Device for Non-ambulatory Application.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114854},
pmid = {42764825},
issn = {2168-8184},
abstract = {Active craniospinal tensioning (ACT) is an upright-posture axial spinal traction maneuver hypothesized to couple two mechanisms: dural pull-recoil, a cerebrospinal fluid (CSF) pressure-gradient effect shared with the supine technique pelvis-stabilized axial spinal traction (PSAST), and suboccipital venous occlusion-rebound, proposed to promote central nervous system (CNS) venous and lymphatic drainage, and as a distinct modality for cerebral venous preconditioning (CVPC). The CVPC mechanism depends on upright posture. In the upright position, cerebral venous return preferentially routes through the suboccipital venous plexus rather than the internal jugular veins, allowing the ACT strap to transiently occlude this outflow pathway during the hold and produce a hemodynamic rebound upon release. This CVPC-based rationale for choosing ACT over PSAST, along with the full biomechanical model, was developed in prior papers and is not re-derived here. In its originally described form, ACT is participant-driven: the participant voluntarily squats against a fixed overhead strap secured by a simple anchor, and the participant's own hands close the strap loop as a fail-safe. This report refers to that form, and the strap-and-anchor apparatus that delivers it, as active craniospinal tensioning, self-administered (ACT-SA). ACT-SA's delivered craniocervical junction (CCJ) tension depends on the participant fully relaxing into the maneuver. It categorically excludes non-ambulatory participants with advanced neurodegenerative disease, e.g., Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), who cannot generate or safely control a voluntary squat, yet who may stand to benefit most from craniospinal tensioning and CVPC given their disease-associated glymphatic impairment. This report describes active craniospinal tensioning, operator-driven (ACT-OD), a device that reproduces ACT-SA's anchor geometry, target force range, and hold duration while substituting the source of tensioning force. Rather than gravity acting on a squatting participant's own body mass, tension is generated by a practitioner operating a pulley-and-lever mechanism against a stationary, seated participant, with the strap confined near the forehead by a polyvinyl chloride (PVC) pipe rather than closed by the participant's own hands. Because the participant does nothing and the seated default state carries no CCJ tension, the fail-safe ACT-SA requirement becomes unnecessary; disengagement, not engagement, is ACT-OD's default. Freed from managing the strap, the practitioner can devote full attention to the lever and to continuous observation of the participant's response, a substitution that matters because non-verbal or cognitively impaired participants cannot reliably self-report the presyncopal symptoms that serve as ACT-SA's real-time safety signal. The design is offered without patent restrictions for research and clinical replication. This report presents device design and mechanism only, with no clinical outcome or efficacy data.},
}

@article {pmid42764995,
year = {2026},
author = {Rhymes, ER and Fetkowitz, C and Schiavo, G and Sleigh, JN and Tosolini, AP},
title = {Ciliary neurotrophic factor slows axonal transport of signalling endosomes.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag339},
pmid = {42764995},
issn = {2632-1297},
support = {/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Efficient axonal transport is essential for maintaining neuronal function, enabling the bidirectional delivery of diverse cargoes between the cell body and distal compartments. In the neuromuscular system, neurotrophic factors regulate motor neuron survival, function and synaptic connectivity, in part, through retrograde trafficking of activated neurotrophic factor-receptor complexes from the neuromuscular junction to the cell body. We recently demonstrated that brain-derived neurotrophic factor stimulation to muscles selectively enhances retrograde transport of signalling endosomes in fast, but not slow, motor neurons in vivo. Moreover, both axonal endosome transport and its brain-derived neurotrophic factor-mediated regulation are disrupted in mouse models of diseases impacting motor neurons, including amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. Here, we examined whether additional neurotrophic factors, when applied to distal axon terminals, share this transport-modulating property. Through imaging sciatic nerves in anaesthetised mice, we tracked the in vivo dynamics of signalling endosomes in fast and slow motor neurons via intramuscular injections of a fluorescent atoxic fragment of tetanus neurotoxin. These injections were co-administered with ciliary neurotrophic factor, hepatocyte growth factor, neurturin, or cleavage-resistant pro-brain-derived neurotrophic factor-four growth factors with known effects on motor neurons. Compared to vehicle-treated controls, pro-brain-derived neurotrophic factor, hepatocyte growth factor and neurturin produced no detectable change in transport dynamics. In contrast, ciliary neurotrophic factor markedly reduced endosome speeds in both fast and slow motor neurons, indicating remarkable selectivity of specific neurotrophic factors in the regulation of signalling endosome transport in motor neurons. Understanding this selectivity may aid the development of muscle-targeted neurotrophic factor-based therapeutic strategies aimed at restoring axonal transport in neurodegenerative disease, peripheral neuropathy and nerve injury.},
}

@article {pmid42765595,
year = {2026},
author = {Lang, C and Guillot, SJ and Knehr, A and Weydt, P and Dorst, J and Tumani, H and Ludolph, AC and Dupuis, L and Bolborea, M},
title = {Genetic ALS-Progressive Sleep Defects Precede the Onset of Clinical Disease.},
journal = {European journal of neurology},
volume = {33},
number = {9},
pages = {e70755},
pmid = {42765595},
issn = {1468-1331},
support = {ANR-24-CE37-4064//Agence Nationale de la Recherche/ ; ANR-10-IDEX-0002//Agence Nationale de la Recherche/ ; ANR-20-SFRI-0012//Agence Nationale de la Recherche/ ; JPND HiCALS//Agence Nationale de la Recherche/ ; DORALS//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone/ ; Institut Charcot//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone/ ; 28944//French Muscular Dystrophy Association/ ; //Target ALS/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/complications ; Female ; Male ; Polysomnography ; Disease Progression ; Middle Aged ; *Sleep Wake Disorders/genetics/physiopathology/etiology ; Electroencephalography ; Longitudinal Studies ; Adult ; Superoxide Dismutase-1/genetics ; Mutation ; C9orf72 Protein/genetics ; Aged ; Cohort Studies ; },
abstract = {BACKGROUND: The onset of amyotrophic lateral sclerosis (ALS) is preceded by non-motor signs detectable many years before motor symptom onset. We recently showed that early ALS patients and presymptomatic carriers of ALS-associated gene mutations display altered sleep macroarchitecture, characterised by increased wakefulness and decreased non-REM sleep, together with altered microarchitecture, particularly reduced slow oscillations and sleep spindles. Here we aimed at determining whether sleep alterations are progressive in premanifest carriers of ALS-associated gene mutations.

METHODS: This longitudinal observational cohort study included presymptomatic first-degree relatives of ALS patients carrying pathogenic gene mutations (n = 18) and noncarrier family members (n = 3). Sleep macroarchitecture and sleep microarchitecture were assessed using standardised polysomnography and electroencephalographic analyses at baseline and in a follow-up examination after 2.3 ± 1.5 years.

RESULTS: In all carriers, sleep alterations were more severe at follow-up compared to the initial examination, for both macro- and microarchitecture. The progression of sleep alterations was seemingly independent of proximity to motor onset, whether evaluated by increased neurofilament levels or phenoconversion during the study period.

CONCLUSIONS: Sleep macro- and microarchitectural abnormalities progressively worsen during the premanifest phase of ALS. These findings suggest that polysomnography-derived sleep measures and their neurochemical correlates may serve as sensitive, noninvasive surrogate biomarkers of disease progression in clinically silent ALS. This could support disease prevention, for example, by the antisense oligonucleotide tofersen in patients carrying SOD1 mutations.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/physiopathology/complications
Female
Male
Polysomnography
Disease Progression
Middle Aged
*Sleep Wake Disorders/genetics/physiopathology/etiology
Electroencephalography
Longitudinal Studies
Adult
Superoxide Dismutase-1/genetics
Mutation
C9orf72 Protein/genetics
Aged
Cohort Studies

@article {pmid42767135,
year = {2026},
author = {Alemdağ, B and Siyah, B and Alemdağ, İN and Berber, T and Güdük, ÖF},
title = {Elucidating the molecular nexus between dental developmental anomalies and chronic inflammatory diseases: A computational systems biology analysis of genomic sequence homology using matrix factorization.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109395},
doi = {10.1016/j.compbiolchem.2026.109395},
pmid = {42767135},
issn = {1476-928X},
abstract = {This entirely in silico, exploratory study investigates potential sequence-level links between periodontal disease, developmental dental anomalies such as molar-incisor hypomineralization (MIH), and selected systemic conditions including leukemias, amyotrophic lateral sclerosis, and Alzheimer's disease. To identify annotation-independent signatures, we applied Non-negative Matrix Tri-Factorization (NMTF) to k-mer/tf-idf representations of disease-associated gene and protein sequences compiled from OMIM, GeneCards, and PubMed for eleven curated disease groups; similarity values denote the proportion of the total between-cluster interaction (S-matrix) captured by a cluster. To guard against trivial explanations, we applied a composition-preserving sequence-shuffling test of the similarity magnitude and a degree-preserving (curveball) permutation test of the disease co-clustering that accounts for the dependence introduced by isoform records and shared genes, repeating the latter across a 1890-configuration parameter grid. At the gene level the dominant cluster was governed by the largest disease group (MIH) rather than by disease identity, whereas at the protein level periodontitis, dental anomalies, and leukemia subtypes co-clustered. The magnitude of the shares did not exceed a composition-preserving null (gene p=0.66; protein p=0.082), and under the degree-preserving null co-clustering was not significant at the gene level (p=0.36) but was significant, modest, and grid-robust at the protein level (p=0.033); canonical k-mer and coding-sequence controls confirmed that the gene-level weakness is intrinsic to nucleotide k-mers. These results delineate the protein level as the informative scale for annotation-independent cross-disease screening and identify the dental-leukemia axis as the candidate relationship for targeted follow-up. The findings are hypothesis-generating: the disease-associated gene sets were compiled with a non-systematic, literature-guided procedure, magnitudes do not exceed composition baselines, neither experimental or clinical validation nor quantitative benchmarking against alternative computational frameworks was performed, and any translational implication requires future validation.},
}

@article {pmid42768102,
year = {2026},
author = {Qi, Z and Liu, X and Geng, L and Liu, X and Dong, S and Li, J and Hua, W and Deng, Y and Lai, S and Wang, Y and Xia, Y and Han, Y and Zhu, D and Zhang, X and Li, J and Li, J and Chen, X},
title = {Convergent TBK1 loss of function drives gasdermin E dependent pyroptosis and motor neuron degeneration across ALS genotypes.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
pmid = {42768102},
issn = {1476-5403},
support = {82572011//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82371431//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons, yet it is unknown whether diverse genetic risks converge on a shared pathogenic pathway. Here we identify a common mechanism linking TBK1 insufficiency to inflammatory cell death across distinct ALS genotypes. Whole-exome sequencing of 8 familial ALS patients revealed that 3 of them carried pathogenic variants, namely TBK1 (R573H), TDP-43 (G298V)/GARS (I44M)/SETX (L1304W), or SOD1 (G94R)/SQSTM1 (G262R). Motor neurons differentiated from patient iPSCs, despite their different mutations, consistently exhibited axonal and neurite shortening, reduced TBK1 activity, increased phosphorylated TDP-43 with cytoplasmic aggregation, and co-assembly of caspase-8/7 with the pyroptosis executor gasdermin E (GSDME). Neuroinflammatory stimulation further enhanced caspase-8/7 and GSDME cleavage, increased RIPK1 phosphorylation and suppressed TBK1 activation in patient-derived motor neurons, whereas TBK1 knockdown in SH-SY5Y cells recapitulated these phenotypes. Furthermore, a generated humanized TBK1 R573H knock-in mouse developed progressive motor deficits accompanied by spinal motor-neuron loss, neuroinflammation, and TDP-43 pathology. In these mice, LPS challenge produced increased cleavage of GSDME and caspase-7, along with a marked upregulation of p-TDP-43 expression in vulnerable neurons. Together, these data identify TBK1 loss of function as an upstream driver of a caspase-8/7-GSDME pyroptotic program in motor neurons and provide a mechanistic bridge between neuroinflammation, TDP-43 proteinopathy, and neurodegeneration. Targeting the TBK1-caspase-GSDME axis may offer a tractable strategy for disease modification in ALS.},
}

@article {pmid42769109,
year = {2026},
author = {Jin, T and Yang, B and Cai, Z and Zhang, H and Wang, T},
title = {The Dual Role of Exosome-Mediated Central-Peripheral Immune Dialogue in Amyotrophic Lateral Sclerosis-Associated Neuroinflammation.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {622530},
pmid = {42769109},
issn = {1178-7031},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is increasingly viewed as a multisystem disorder in which central-peripheral immune communication may modify neuroinflammation. Exosomes, an endosome-derived subset of extracellular vesicles (EVs), have been proposed as mediators of this communication, but the strength and disease specificity of the evidence require critical evaluation.

METHODS: PubMed/MEDLINE, Web of Science Core Collection, and Scopus were searched from database inception to July 20, 2026, with supplementary citation tracking through Google Scholar and reference lists. Evidence was categorized as human ALS evidence, ALS-specific cellular or animal evidence, evidence from non-ALS neuroinflammatory models, or review-level background evidence.

RESULTS: Human studies have identified ALS-associated proteins and altered miRNA profiles in circulating EV-containing preparations, but their cellular origin, direction of transfer, and causal relevance remain uncertain. ALS-specific cellular and animal models support the possibility that EVs participate in intercellular protein transfer and modify glial inflammatory, phagocytic, antioxidant, and trophic responses. Some proposed mechanisms, including miR-216a-5p-mediated microglial regulation, are derived mainly from other neurological injury models and should be considered hypothesis-generating. Single-cell studies further indicate that ALS microglia occupy heterogeneous and overlapping states; therefore, M1/M2 terminology is used only as a simplified descriptive framework. Circulating EV cargo remains under investigation as a biomarker source, whereas the additional value of EV-associated neurofilament light chain and the diagnostic utility of TDP-43, SOD1, or miRNAs require independent validation. Therapeutic evidence remains predominantly preclinical, with only small, early, non-confirmatory human studies.

CONCLUSION: EVs may participate in central-peripheral immune communication in ALS, but their causal role, cellular origin, in vivo trafficking, and clinical utility remain incompletely established. Standardized methods and rigorous mechanistic and clinical validation are required before EV-based biomarkers or therapies can be translated into practice.},
}

@article {pmid42769571,
year = {2026},
author = {Toda, Y and Masumoto, S and Kimura, Y and Aramaki, M and Hamano, J},
title = {Autonomic Storm in a Patient With Amyotrophic Lateral Sclerosis in a Home-Care Setting.},
journal = {Journal of general and family medicine},
volume = {27},
number = {5},
pages = {e70182},
pmid = {42769571},
issn = {2189-7948},
abstract = {Amyotrophic lateral sclerosis (ALS) can cause autonomic storms characterized by blood pressure fluctuations, particularly in the advanced stages of the disease and among ventilator-dependent patients. Although benzodiazepines are used to manage these symptoms, the optimal agent is unclear. We present the case of a 78-year-old home-care patient with ventilator-dependent ALS who developed autonomic storms. Clotiazepam did not adequately control the episodes; however, diazepam was associated with resolution of the episodes, followed by improved sleep and nutritional intake. This report highlights the importance of recognizing an autonomic storm in advanced ALS patients and the potential benefit of diazepam in home-care settings.},
}

@article {pmid42769968,
year = {2026},
author = {Zambetti, E and Baronchelli, I and Belli, S and Mucci, C and Greco, A},
title = {Caregivers in amyotrophic lateral sclerosis (ALS): preliminary results between paid care and family care.},
journal = {Health psychology and behavioral medicine},
volume = {14},
number = {1},
pages = {2709184},
pmid = {42769968},
issn = {2164-2850},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease affecting about 6,000 people in Italy. Caring for ALS impacts the quality of life and mental health of formal and informal caregivers, but few studies have explored this.

METHODS: This research analyzes experiences of 9 formal caregivers (FC; 8 women) with an average age of 49.29 years (SD = 3.861) and 6.58 years of average length of service (SD = 5.975), and 11 informal caregivers (iFC; 9 women) with an average age of 48.30 years (SD = 13.500) and who have been caring for relatives for 3.29 years (SD = 2.500). All participants were recruited from an Italian healthcare residence. We assessed psychological well-being, burnout (for FC), and burden (for iFC), and included testimonies retrieved from online sources. Data were analyzed using mixed-methods analysis, including nonparametric tests, Emotional Text Mining, and discourse analysis.

RESULTS: The results showed both groups had high psychological well-being (Mfc = 85.86; SDfc = 9.026; Mifc = 83.10; SDifc = 11.435). FC had low emotional exhaustion (M = 16.67; SD = 10.087) and depersonalization (M = 2.56; SD = 2.186), and a moderate level of personal gratification (M = 29.11; SD = 11.667; M = 27.43; SD = 11.238). iFC experienced a higher burden when the patient is in a healthcare residence than when he/she was at home. FC discussed patient and family challenges, emphasizing the necessity of research and new therapies; iFC focused on social and emotional needs, seeing themselves as adaptors out of necessity.

CONCLUSIONS: The study highlights the psychological impact of caregiving and preliminary qualitative differences between paid and family caregivers. Further analysis could explore these distinctions, aiding the development of targeted interventions to promote caregivers' well-being.},
}

@article {pmid42770300,
year = {2026},
author = {Oikawa, Y and Luo, Y and Suzuki, N and Kasahara, T and Tongu, Y and Yoshida, Y and Tominari, T and Tanabe, S and Suto, Y and Kashiwagi, H and Saito, S and Ikeda, K and Suzuki, C and Kuranaga, A and Akiyama, T and Morimoto, S and Aoki, Y and Muramatsu, R and Soga, T and Aoki, M and Okano, H and Tanaka, T and Abe, T and Kuranaga, E and Toyohara, T},
title = {Mitochonic acid 5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation.},
journal = {JCI insight},
volume = {11},
number = {18},
pages = {},
pmid = {42770300},
issn = {2379-3708},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Animals ; Humans ; *Mitochondria/drug effects/metabolism ; Disease Models, Animal ; Phenotype ; Superoxide Dismutase-1/genetics/metabolism ; Fibroblasts/drug effects/metabolism ; Motor Neurons/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Drosophila ; Induced Pluripotent Stem Cells ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that urgently requires effective treatment. Mitochondrial dysfunction underlies ALS pathology and represents a potential therapeutic target. Here, we demonstrated the therapeutic potential of mitochonic acid 5 (MA-5), a novel mitochondria-targeted compound that ameliorated ALS phenotypes by enhancing mitochondrial function. In a Drosophila ALS model expressing a mutant human SOD1 (G85R), MA-5 significantly improved locomotor activity, with a trend toward restoration of mitochondrial integrity. In skin fibroblasts derived from ALS patients and motor neurons derived from induced pluripotent stem cells, MA-5 restored ATP production and increased mitochondrial motility. Multiomics analyses suggested that MA-5 modulated mitochondria-linked gene expression and downregulated the glycerophosphate shuttle, contributing to mitochondrial reactive oxygen species production. Transcriptomic analysis identified C7orf31 as a potential marker for monitoring the therapeutic effects of MA-5 and diagnosing ALS subtypes. These findings support MA-5 as a promising therapeutic candidate for ALS and propose C7orf31 as a potential biomarker for treatment monitoring and for disease subtyping.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology
Animals
Humans
*Mitochondria/drug effects/metabolism
Disease Models, Animal
Phenotype
Superoxide Dismutase-1/genetics/metabolism
Fibroblasts/drug effects/metabolism
Motor Neurons/drug effects/metabolism
Reactive Oxygen Species/metabolism
Drosophila
Induced Pluripotent Stem Cells

@article {pmid42770357,
year = {2026},
author = {Sahu, K and Sahu, R and Mishra, M and Chhabra, N and Tiwari, S and Kaur, K and Rathore, H and Lodhi, R and Sulakhiya, K},
title = {Designing Multi-functional Antioxidants for Neurodegenerative Disorders.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575494157260901095536},
pmid = {42770357},
issn = {1875-5607},
abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease, Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS), pose a major global health threat due to complex pathology, increased prevalence, and lack of effective therapies. Numerous findings have indicated that oxidative stress (OS) is a central and unifying pathological mechanism driving neuronal dysfunction and degeneration across these disorders. Excessive reactive oxygen species (ROS) and nitrogen species (RNS) generation, coupled with impaired endogenous antioxidant defenses, leads to lipid peroxidation, protein misfolding, nucleic acid damage, mitochondrial dysfunction, neuroinflammation, metal dyshomeostasis, and disruption of the blood-brain barrier (BBB). These interconnected processes form self-perpetuating pathogenic cycles that accelerate synaptic failure and neuronal loss. This review is a compilation of thoroughly searched literature from the last 20 years (2006-2026) on OS-mediated neurodegeneration and emerging antioxidant-based therapeutic strategies for neurodegenerative disorders, sourced from PubMed, Scopus, ScienceDirect, Google Scholar, and Web of Science. Relevant articles were selected using specific keywords "Neurodegenerative Disorders", Neurodegenerative disorders and antioxidants", "Alzheimer's Disease and Oxidative Stress", "Parkinson's Disease and Oxidative Stress", "Alzheimer's Disease and Multi-functional Antioxidants", "Parkinson's Disease and Multifunctional Antioxidants", "Neurodegenerative Disorders and Antioxidant therapies". Despite strong mechanistic support, conventional antioxidant-based therapies have demonstrated limited clinical success, largely due to poor bioavailability, inadequate BBB penetration, and failure to address the multifactorial nature of neurodegeneration. Consequently, there is a paradigm shift toward the development of multi-functional antioxidants capable of simultaneously targeting multiple redoxdriven pathways. Such agents are designed to combine free-radical scavenging, metal chelation, mitochondrial protection, modulation of redox-sensitive signaling pathways, and regulation of neuroinflammatory responses within a single therapeutic framework. By restoring redox homeostasis while preserving physiological redox signaling, multi-functional antioxidants offer a rational and promising disease-modifying strategy. This review critically examines OS-mediated mechanisms underlying major NDs and emphasizes the therapeutic potential of designed multi-functional antioxidants as next-generation neuroprotective agents.},
}

@article {pmid42770359,
year = {2026},
author = {Kumari, N and Dwivedi, S and Yadav, S and Kosey, S},
title = {Ferroptosis in Neurodegenerative Diseases: Iron Dysregulation, GPX4/FSP1 Signaling, and Emerging Neuroprotective Strategies.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026502165260904054005},
pmid = {42770359},
issn = {1875-5739},
abstract = {INTRODUCTION: Neurodegenerative Diseases (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), are increasingly associated with ferroptosis, a regulated irondependent form of cell death characterised by the excessive accumulation of lipid peroxides.

METHODS: This review examines the molecular underpinnings of ferroptosis, focusing on dysregulation in iron homeostasis, increased vulnerability of polyunsaturated fatty acids in neuronal membranes, and impairment of antioxidant defence systems, particularly the Glutathione-GPX4 and FSP1-CoQ10-NADPH pathways. Relevant literature was critically analysed to explore mechanistic insights and therapeutic implications.

RESULTS: Pathological hallmarks such as amyloid-β, tau, and α-synuclein were found to disrupt iron metabolism, thereby exacerbating oxidative stress and mitochondrial dysfunction across various NDDs. These alterations significantly contribute to neuronal damage and disease progression through ferroptosis-related mechanisms.

DISCUSSION: Emerging therapeutic strategies, including radical-trapping antioxidants, iron chelators, and nanotechnology-based delivery systems, show potential in targeting ferroptosis. However, challenges in clinical translation persist. Artificial intelligence and personalised medicine approaches may address these issues by enabling patient stratification, biomarker discovery, and optimisation of therapeutic interventions.

CONCLUSION: Ferroptosis represents a promising therapeutic target for mitigating oxidative and metal-induced neurotoxicity in neurodegenerative disorders. Future research integrating multiomics profiling, longitudinal clinical data, and advanced computational modelling is essential to validate the efficacy of ferroptosis-targeted interventions and facilitate their successful translation into precision neurotherapeutics.},
}

@article {pmid42770444,
year = {2026},
author = {Duan, X and Li, Y and Zhao, R and Jiang, X and Xia, C and Xie, F},
title = {Cell Therapy Targeting Pathological Networks in Neurodegenerative Diseases: Mechanisms and Translation from Stem Cells to Extracellular Vesicles.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026476083260903180127},
pmid = {42770444},
issn = {1875-5739},
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are characterized by interacting pathological processes such as protein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired proteostasis. This narrative review examines how embryonic/ induced pluripotent stem cells, neural stem cells, mesenchymal stem/stromal cells, immune cells, and extracellular vesicles may intervene across these pathological networks. A targeted PubMed search and reference-list screening through 5 July 2026 identified relevant mechanistic, preclinical, clinical, manufacturing, and regulatory evidence. The reviewed strategies act through cell replacement, paracrine support, immunomodulation, metabolic stabilization, and pathological- protein clearance. Evidence maturity differs substantially by disease and product: pluripotent stem cell-derived dopaminergic progenitors have entered early clinical evaluation in Parkinson's disease, whereas most mesenchymal stem/stromal cell studies remain small and exploratory, and immune-cell and extracellular-vesicle approaches are predominantly preclinical or early translational. Major barriers include product heterogeneity, mechanism-linked potency testing, longterm safety, delivery and dose optimization, disease-stage selection, clinically meaningful endpoints, and regulatory comparability. Future development should emphasize standardized manufacturing, biomarker-guided trial design, transparent reporting of negative findings, and rational combinations with pharmacological or gene-based therapies. Cell-based interventions remain promising, but durable clinical benefit has not yet been established.},
}

@article {pmid42770452,
year = {2026},
author = {Maleksabet, H and Movahed, MA and Zarghi, A},
title = {Integrative Perspectives on COX-2 Signaling and Selective Inhibitors in Central Nervous System Disorders: A Narrative Review.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673496586260831110156},
pmid = {42770452},
issn = {1875-533X},
abstract = {INTRODUCTION: Central nervous system disorders include various neurodegenerative and psychiatric conditions characterized by progressive neuronal damage, synaptic dysfunction, and chronic neuroinflammation, affecting millions worldwide. This group includes Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Multiple Sclerosis (MS), Major Depressive Disorder (MDD), and epilepsy, among others. Recent studies have emphasized the significant role of Cyclooxygenase-2 (COX-2), an inducible enzyme in the arachidonic acid pathway, in maintaining neuroinflammatory cascades that worsen these conditions.

METHODS: For this review, we gathered and carefully analyzed published literature related to COX-2 signaling in CNS disorders. We reviewed preclinical studies, animal models, and clinical trials to understand how COX-2 contributes to disease mechanisms and whether selective inhibitors show real therapeutic promise.

RESULTS: Inflammatory cytokines or excitotoxic insults upregulate COX-2 and promote the formation of prostaglandins, including PGE2. These mediators subsequently trigger the activation of microglia and astrocytes, cytokine release, oxidative stress, disruption of the blood-brain barrier, and neuronal apoptosis. Despite variations in disease-specific features, the mechanisms dependent on COX-2 are generally consistent across these disorders.

DISCUSSION: The consistent involvement of COX-2-driven neuroinflammation across multiple CNS disorders suggests it could be a promising therapeutic target. However, failures in some clinical trials highlight the complexity of translating preclinical findings into patient care. This may be due to the stage-dependent expression of COX-2, the multifunctional roles of the enzyme in normal brain function, and the cardiovascular risks associated with long-term COX-2 inhibition. These factors must be carefully considered in future research and drug development.

CONCLUSION: COX-2 plays a central role in driving neuroinflammation and disease progression in AD, PD, ALS, schizophrenia, MS, MDD, and epilepsy. Selective COX-2 inhibitors show promising neuroprotective potential, especially in early stages or in combination therapies, but inconsistent efficacy and cardiovascular risks necessitate safer next- generation inhibitors.},
}

@article {pmid42771220,
year = {2026},
author = {Li, K and Si, Q and Zhang, C and Zhang, C and Wang, M and Liu, J and Zhao, J and Xing, H and Liu, J},
title = {Dysregulated polyamine metabolism in neurological disorders: molecular mechanisms and therapeutic opportunities.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42771220},
issn = {1573-4978},
support = {No. YJSCX202502Z//The Graduate Research Innovation Support Program of Henan Medical University/ ; No. GCC2026048//the Henan High-level Talent International Training Project/ ; No. LHGJ20190457//the Henan Provincial Health Commission/ ; No. HNMOTO2025081//the Henan Medical Researcher Overseas Training Program/ ; No. 25A320037//the Key Scientific Research Project Plan of Higher Education Institutions in Henan Province/ ; No. 262300420548//the Henan Natural Science Foundation Project/ ; },
mesh = {Humans ; *Polyamines/metabolism ; *Nervous System Diseases/metabolism ; Oxidative Stress ; Animals ; Autophagy ; Spermidine/metabolism ; },
abstract = {Polyamines (PAs), principally putrescine (Put), spermidine (Spd), and spermine (Spm), are ubiquitous aliphatic polycations that regulate nucleic-acid interactions, ion-channel activity, autophagy, redox balance, proteostasis, and immune signaling. Growing genetic, multi-omics, and experimental evidence indicates that disruption of PA biosynthesis, catabolism, acetylation, and transport contributes to neurological disease. In Alzheimer's disease (AD), altered PA flux intersects with Tau and amyloid-β (Aβ) pathology, methylation imbalance, oxidative stress, and impaired autophagic clearance. In Parkinson's disease (PD), PA transport and interconversion are linked to lysosomal dysfunction, mitochondrial stress, and α-synuclein toxicity; ATP13A2-associated Kufor-Rakeb syndrome further illustrates the neurological consequences of defective lysosomal PA transport. PA dysregulation is also implicated in amyotrophic lateral sclerosis (ALS), diabetic retinopathy, Snyder-Robinson syndrome, epilepsy, Bachmann-Bupp syndrome, and cerebral ischemia. This review integrates disease-specific evidence with four interconnected mechanisms-autophagy, oxidative stress, proteostasis, and neuroinflammation-and discusses therapeutic approaches including direct Spd administration, modulation of PA-metabolic enzymes and transporters, and combination strategies. Because PAs can exert both protective and toxic effects depending on concentration, cellular compartment, and disease context, translation will require CNS-relevant biomarkers, dose and route optimization, and explicit consideration of blood-brain barrier constraints.},
}

Humans
*Polyamines/metabolism
*Nervous System Diseases/metabolism
Oxidative Stress
Animals
Autophagy
Spermidine/metabolism

@article {pmid42771346,
year = {2026},
author = {Paganoni, S and Chibnik, LB and Quintana, M and Macklin, EA and Detry, MA and Vestrucci, M and Paulon, G and McGlothlin, A and Wang, J and Walk, D and Elman, L and Chase, M and Heyd, L and Harkey, B and Sherman, AV and Shefner, J and Berry, JD and Scirocco, E and Giacomelli, E and Yu, H and Kittle, G and Hall, M and Ho, D and Jawdat, O and Ladha, S and Locatelli, E and Rivner, M and Felice, K and Katz, J and Ajroud-Driss, S and Fee, D and Miller, T and Rosow, L and Quick, A and Heitzman, D and Foster, LA and Maragakis, NJ and Goutman, SA and Rosenfeld, J and Benatar, M and Swenson, A and Connors, RD and Shroff, S and Bedlack, R and McIlduff, CE and Chen, IA and Fernandes, JAM and Walsh, A and Peltier, A and Ilieva, H and Diaz, F and Kushlaf, H and Beydoun, SR and Myers, B and Arcila-Londono, X and Heiman-Patterson, T and Elliott, M and Whitesell, J and Al-Lahham, T and Elliott, M and Olney, N and Baer, M and Jackson, C and Young, E and Caress, J and Weiss, MD and Kuenzler, R and Nayar, S and Kasarskis, EJ and Simmons, Z and Gibson, S and Owegi, MA and Goyal, NA and Wymer, JP and Gwathmey, KG and Erickson, A and Gursoy, N and Alameda, G and Bodkin, C and Wu, A and Martinez-Thompson, J and Twydell, PT and Andrews, J and Bayat, E and Rezania, K and Usman, U and McCluskey, L and Kovvuru, S and Jennings, D and Garza-Meilandt, A and Maciuca, R and Cohen, IV and Tamuly, D and Eren, E and Cudkowicz, ME and Babu, S and , },
title = {DNL343 and Disease Progression in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {9},
number = {9},
pages = {e2634809},
pmid = {42771346},
issn = {2574-3805},
mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Double-Blind Method ; Treatment Outcome ; },
abstract = {IMPORTANCE: DNL343 is a brain-penetrant small molecule that acts as an activator of eukaryotic translation initiation factor 2B (eIF2b), designed to inhibit the integrated stress response. A prior phase 1B trial of DNL343 in amyotrophic lateral sclerosis (ALS) provided evidence of a favorable safety profile, central nervous system penetrance, and target engagement based on integrated stress response biomarkers in blood and cerebrospinal fluid.

OBJECTIVES: To evaluate the safety and efficacy of a 200-mg formulation of DNL343 given once daily in individuals living with ALS.

DNL343 was evaluated as a regimen of the HEALEY ALS Platform Trial, a double-blind, multiregimen, placebo-controlled randomized clinical trial conducted at 74 centers in the US between May 24, 2023, and May 22, 2025. Eligible participants were randomized in a 3:1 ratio to receive DNL343 or matching placebo, with both groups enrolling concurrently. The analysis included shared randomized participants receiving placebo from an additional regimen.

INTERVENTION: The study drug was administered for a placebo-controlled duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary analysis was a bayesian shared parameter model of function and survival that provided an integrated estimate of the relative rate of disease progression among participants receiving DNL343 relative to placebo. The model had components for function and survival linked through an integrated estimate of disease slowing in treatment relative to controls across the 2 outcomes (denoted as the disease rate ratio [DRR]). Several safety, secondary, and exploratory end points were also evaluated.

RESULTS: A total of 259 screenings were completed in this regimen; 249 participants met eligibility and were randomized to DNL343 (n = 186) and regimen-specific placebo (n = 63), with an additional 76 participants from a concurrent regimen receiving placebo included for a total of 139 shared placebo participants (325 participants, with 196 (60.3%) male and mean [SD] age of 59.3 [11.5] years). The estimated median DRR common to the ALS Functional Rating Scale-Revised and survival was 1.04 (95% credible interval, 0.83-1.32; probability of DRR <1, 0.37). Secondary outcome measures were not statistically different between the DNL343 and placebo groups. Overall, the incidence rates of adverse events were similar in participants receiving DNL343 and placebo.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, despite the relevance of the eIF2b activation pathway in ALS disease biology and supporting evidence of proof of mechanism and optimal dose selection in a prior phase 1B ALS clinical trial, 200-mg/d DNL343 did not show evidence of slowing disease progression in ALS, highlighting the need for alternative therapeutic approaches.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05842941.},
}

Aged
Female
Humans
Male
Middle Aged
*Amyotrophic Lateral Sclerosis/drug therapy
*Disease Progression
Double-Blind Method
Treatment Outcome

@article {pmid42771573,
year = {2026},
author = {Hu, N and Su, N and Zhang, D and Zhang, J and Wang, K and Xu, Y and Li, Z and Wang, L and Wu, B and Chu, L and Wang, Y and Jiang, H and Lu, Z and Wu, J and Fan, X and Han, F and Yuan, J and Zhu, Y and Liu, M},
title = {Gait Characteristics and Fall Risk in Amyotrophic Lateral Sclerosis: A 12-Month Prospective Cohort Study.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ndd/aduag003},
pmid = {42771573},
issn = {1660-2862},
abstract = {BACKGROUND: Gait impairment in amyotrophic lateral sclerosis (ALS) substantially increases fall risk and accelerates functional decline. However, prospective data linking quantitative gait parameters to fall outcomes remain scarce. We aimed to identify gait parameters associated with falls and functional decline in ALS.

METHODS: In this single-center prospective cohort study, we enrolled 256 ALS patients and 256 matched healthy controls. Nineteen spatiotemporal gait parameters were captured using a 3D vision-based system at baseline. Falls, time to wheelchair use, and ALSFRS-R decline were recorded over 12 months. Multivariable logistic regression was used to identify independent fall predictors.

RESULTS: During follow-up, 129 of 224 patients (57.6%) experienced at least one fall. Prolonged Timed Up and Go (TUG) time (OR=1.083 per second, 95%CI 1.036-1.133, p<0.001), younger age (OR=0.968 per year, 95%CI 0.940-0.996, p=0.024), and lower MRC sum score (OR=0.976 per point, 95%CI 0.954-0.998, p=0.035) independently predicted falls. The model showed moderate discrimination (AUC=0.665, 95%CI 0.594-0.736). Gait speed (rₛ=0.366) and TUG time (rₛ=-0.381) correlated most strongly with time to wheelchair use (both p<0.001), whereas no gait parameters correlated with ALSFRS-R decline rate.

CONCLUSIONS: TUG time, younger age, and lower MRC score independently predict falls in ALS, though with modest predictive accuracy. The modest model performance underscores the multifactorial nature of falls and the need for multi-domain risk assessment. Gait speed and TUG time may warrant further investigation as candidate surrogate markers for functional decline. Future studies integrating cognitive evaluation, continuous monitoring, and attention to psychosocial factors may improve prediction and fall prevention strategies.},
}

@article {pmid42771575,
year = {2026},
author = {Tsujisawa, Y and Takahashi-Iwata, I and Yabe, I and Mukaino, M and Shibamoto, I},
title = {Phenotype-Related Characteristics of Tongue Motor Function in Amyotrophic Lateral Sclerosis: A Retrospective Comparative Study of Static and Dynamic Acoustic Measures.},
journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)},
volume = {},
number = {},
pages = {1},
doi = {10.1159/fpl/acvag012},
pmid = {42771575},
issn = {1421-9972},
abstract = {This study aimed to characterize lingual motor function in patients with amyotrophic lateral sclerosis (ALS) by analyzing static acoustic indices obtained from sustained vowels and dynamic indices derived from sentence reading. The following aspects were examined: (1) the independence of static and dynamic indices, (2) the relationship between F2 transition duration and F2 excursion, (3) differences in vowel formant frequencies across ALS phenotypes, (4) associations between static indices and speech intelligibility, and (5) acoustic elements contributing to static indices. Sixty-eight patients with ALS were enrolled (42 men and 26 women). The main analyses focused on the men (n = 42), categorized as spinal-onset (n = 21), spinal onset with bulbar involvement (spinal + bulbar) (n = 9), and bulbar-onset (n = 12). From sustained vowels (/a/-/o/), F1 and F2 values were extracted. The triangular vowel space area (tVSA) and formant centralization ratio (FCR) were calculated using F1 and F2 of /a/, /i/, and /u/. Dynamic measures were obtained from the diphthong /ai/ within /taiyo/ during sentence reading, yielding F2 transition duration and excursion. Static indices (tVSA and FCR) correlated with F2 excursion only in the spinal-onset group (r = 0.458, p = 0.049), whereas no associations were observed in the other phenotypes or in the overall sample. This finding suggests that static and dynamic indices may reflect partially distinct aspects of lingual motor control. tVSA and FCR showed a negative correlation across all phenotypes, confirming that they are complementary indicators of vowel space expansion and centralization. Regarding time-space control, bulbar-onset ALS showed no relationship between F2 transition duration and excursion, suggesting that spatial limitations of tongue movement may not necessarily parallel changes in articulatory speed. Phenotype comparisons revealed significant differences in F1 of /e/ and F2 of /a/, /i/, /u/, and /o/. These findings indicate phenotype-related differences in vertical and anterior-posterior tongue movement characteristics. In bulbar-onset ALS, tVSA correlated with speech intelligibility (visual analogue scale: VAS), and FCR showed a trend-level association (p=0.075). Acoustic element analysis indicated that tVSA was primarily associated with F1 of /a/ and F2 of /i/, whereas FCR was closely associated with F2 of /i/. These findings suggest that combining static (articulatory position) and dynamic (articulatory transition) acoustic indices enables multifaceted evaluation of phenotype-related characteristics of lingual motor dysfunction in ALS. Bulbar-onset ALS is characterized by restricted anterior-posterior movement and impaired vertical tongue adjustment, both of which may contribute to reduced intelligibility.},
}

@article {pmid42771582,
year = {2026},
author = {Chen, J and Wan, X and Zhou, Y},
title = {Reconstructing the professional identity of rural pre-service teachers via an English pedagogy course: A case study.},
journal = {PloS one},
volume = {21},
number = {9},
pages = {e0358864},
pmid = {42771582},
issn = {1932-6203},
mesh = {Humans ; China ; *School Teachers/psychology ; Rural Population ; *Teaching ; Longitudinal Studies ; *Social Identification ; },
abstract = {Teacher Professional Identity is critical for rural teacher recruitment and retention, but effective pathways for its construction remain limited. This study examines whether and how a holistically designed English pedagogy course, integrating theoretical learning and micro-teaching practices with guided reflective discourses, shapes the professional identities of rural pre-service teachers. A longitudinal study spanning one academic year was conducted with three rural pre-service teachers enrolled in the Excellent Teacher Program at a normal university in western China. Data were collected through semi-structured interviews and reflective journals. Drawing on Varghese et al.'s identity-in-practice and identity-in-discourse as a conceptual lens, and Wenger's three modes of belonging as explanatory tools, our dual-layered framework reveals two key transformations. First, the course significantly transformed participants' initially underdeveloped Teacher Professional Identity (self-doubt, narrow grammar and vocabulary focus) into a broader, more confident and committed identity. Two patterns of change were identified: broadening of pedagogical vision from discrete skills to holistic design, and affective repositioning from fear and doubt to confidence and clarity. Second, the course functioned as a discourse-rich community of practice wherein three mechanisms operated to facilitate identity (re)formation: engagement through micro-teaching and peer collaboration, imagination through exposure to contemporary theories, and alignment through guided reflections linking practice to professional standards. The study demonstrates that a campus-based, holistically designed pedagogy course can serve as an effective pathway for the professional identity construction of rural pre-service teachers, particularly in contexts where quality field placements are not feasible. It also highlights the need to integrate such on-campus training with authentic rural experiences (e.g., short-term placements) to translate identity gains into sustained commitment to rural teaching. These findings offer insights for teacher education policy and practice, with implications for addressing global challenges in rural teacher retention.},
}

Humans
China
*School Teachers/psychology
Rural Population
*Teaching
Longitudinal Studies
*Social Identification

@article {pmid42772334,
year = {2026},
author = {Kaczmarek, PM and Wiegand-Grefe, S and Pawils, S},
title = {[Structural Barriers to Implementation: Clinic-Initiated Dissemination Activities and Awareness of a Family-Centered Care Model Among Outpatient Professionals].},
journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2935-5938},
pmid = {42772334},
issn = {1439-4421},
abstract = {INTRODUCTION: Evidence-based care models frequently fail to reach outpatient professionals as potential referrers. Previous analyses of CHIMPS-NET, a new family-centered care model implemented in German psychiatric clinics, showed that centrally organized information campaigns had no measurable effect on awareness among this group. The present study examines whether decentralized, clinic-initiated public relations efforts are associated with greater awareness of the care model.

METHODS: Data are drawn from a postal and electronic survey of outpatient professionals across 18 psychiatric clinic sites in Germany at follow-up. Following Proctor et al.'s taxonomy of implementation outcomes, reach/penetration was operationalized as binary awareness of the care among outpatient professionals. Clinic-initiated activities were categorized into three intensity levels (low, medium, high) by two blinded raters based on internal project documentation. Associations were examined using binary logistic regression.

RESULTS: Of 2,828 professionals contacted, 203 returned evaluable questionnaires (response rate 7.2%). Only 9.4% of respondents (19/203) reported awareness of CHIMPS-NET. Logistic regression revealed no significant association between public relations intensity and awareness (χ[2](2)=0.411; p=0.814; Nagelkerke R[2]=0.003).

CONCLUSION: Neither centrally nor decentrally organized dissemination efforts measurably increased awareness of the care model among outpatient professionals. The findings suggest that sustainable implementation requires structural approaches, such as embedding relevant criteria in clinical guidelines or creating billing-relevant incentives within the statutory health insurance system.},
}

@article {pmid42772840,
year = {2026},
author = {Frank, M and Barthélémy, C and Dufour, A and Rivera, S and Baranger, K},
title = {Matrix metalloproteinases (MMPs) in neurodegenerative diseases, an updated overview of the role of MT1-MMP and MT5-MMP in Alzheimer's disease.},
journal = {The Enzymes},
volume = {60},
number = {},
pages = {209-241},
doi = {10.1016/bs.enz.2026.07.004},
pmid = {42772840},
issn = {0423-2607},
mesh = {Humans ; *Alzheimer Disease/enzymology/metabolism ; Animals ; *Neurodegenerative Diseases/enzymology/metabolism ; *Matrix Metalloproteinases/metabolism ; Amyloid beta-Peptides/metabolism ; *Matrix Metalloproteinase 14/metabolism ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, pose an increasing threat to global health due to ageing populations and the lack of effective treatments. Matrix metalloproteinases (MMPs), which are proteases that belong to the metzincin superfamily, are critical regulators of neuroinflammation, blood-brain barrier integrity, protein misfolding, synaptic dysfunction and neuronal death. This chapter provides a comprehensive overview of the roles of MMPs at the intersection of the molecular and cellular mechanisms that underpin neurodegenerative processes. The focus is on their pathophysiological mechanisms, therapeutic potential, and recent advances. We highlight novel mechanistic insights in Alzheimer's disease, such as the roles of MT1-MMP and MT5-MMP in amyloid-beta peptide production and the dual functions of MMPs in both neuroprotection and neurotoxicity. This review emphasizes the need for further mechanistic research into the different MMPs involved in neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/enzymology/metabolism
Animals
*Neurodegenerative Diseases/enzymology/metabolism
*Matrix Metalloproteinases/metabolism
Amyloid beta-Peptides/metabolism
*Matrix Metalloproteinase 14/metabolism

@article {pmid42772919,
year = {2026},
author = {Kernaghan, A and Harvey, A and Currie, H and McAlister, O and Walker, R and Chapman, F and McEneaney, D and Adgey, J},
title = {Incidence of refibrillation and shock-resistant ventricular fibrillation during OHCA when treated with a public access defibrillator: implications for CPR timing in lay rescuer-treated OHCA.},
journal = {Open heart},
volume = {13},
number = {2},
pages = {},
pmid = {42772919},
issn = {2053-3624},
mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/physiopathology/diagnosis ; *Ventricular Fibrillation/therapy/physiopathology/diagnosis/epidemiology/etiology ; *Electric Countershock/instrumentation/adverse effects ; *Defibrillators ; *Cardiopulmonary Resuscitation/methods/adverse effects ; Time Factors ; Retrospective Studies ; Incidence ; Female ; Male ; Aged ; Middle Aged ; Electrocardiography ; Emergency Medical Services ; Treatment Outcome ; },
abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) treatment often requires multiple defibrillatory shocks due to failed defibrillation or refibrillation. The complete nature of refractory ventricular fibrillation (VF) is unknown, as many studies do not consider shocks delivered by lay rescuers prior to the arrival of basic life support (BLS)/advanced life support (ALS) when quantifying refractory VF. ERC guidelines define refractory VF as continuous VF after three consecutive shocks, not differentiating between patients who refibrillate and those with shock-resistant VF (three consecutive failed shocks) which may contribute to this variation in reported incidence. There are some differences in treatment recommendations for patients who refibrillate and those with shock-resistant VF. Therefore, understanding the number of shocks delivered by lay-rescuers with public access defibrillators (PADs) and the patient's response to them prior to BLS/ALS arrival may inform treatment strategies.

METHODS: ECG data collected retrospectively from OHCAs treated by lay-rescuers using PADs were analysed. Cardiac rhythm, shock success, refibrillation, time to refibrillation and presence of shock-resistant VF (three consecutive failed shocks) were determined by two investigators.

RESULTS: Data were available for 1459 patients receiving at least one shock. Refibrillation occurred in 498 (34.1%) patients. The median number of refibrillations per patient was 1 (IQR 1, 2). Median time to refibrillation was 29.8 s. Three consecutive shocks were observed in 231 of the 1459 (15.8%) patients, 11 patients (4.8% of 231 patients) had shock-resistant VF.

CONCLUSION: When treated by lay-rescuers with PADs, refibrillation occurrence is lower than that reported for patients treated by BLS/ALS. However, aligned with BLS/ALS studies, in lay-rescuer treated OHCA, refibrillation typically occurs within the first 30 s following a successful shock. Therefore, patients who refibrillate are typically in VF for an additional 1.5 min before receiving a subsequent shock for PADs with a 2 min cardiopulmonary resuscitation (CPR) cycle. This finding emphasises the need for investigation into optimal CPR duration for patients requiring multiple shocks.},
}

Humans
*Out-of-Hospital Cardiac Arrest/therapy/physiopathology/diagnosis
*Ventricular Fibrillation/therapy/physiopathology/diagnosis/epidemiology/etiology
*Electric Countershock/instrumentation/adverse effects
*Defibrillators
*Cardiopulmonary Resuscitation/methods/adverse effects
Time Factors
Retrospective Studies
Incidence
Female
Male
Aged
Middle Aged
Electrocardiography
Emergency Medical Services
Treatment Outcome

@article {pmid42773049,
year = {2026},
author = {McKee, NW and Jing, Y and Serdah, R and Thulasingam, S and Lopez, XS and Tan, EP},
title = {Lipophagy and lipid droplets in neurodegeneration.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2026.08.004},
pmid = {42773049},
issn = {1873-3735},
abstract = {Lipid droplet (LD) accumulation in neurons and glia is a feature of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) and is associated with oxidative stress and neuroinflammation. Although protein-targeted monotherapies have achieved partial clinical success, continued disease progression in many patients suggests that additional cellular mechanisms contribute to pathogenesis. Lipophagy, the selective autophagic degradation of LDs, provides a potential clearance route but has been studied primarily in hepatocytes under nutrient deprivation. Recent studies have begun to map noncanonical regulatory mechanisms of lipophagy, identify disease-associated points of failure in AD, PD, and ALS, and report compounds that enhance LD clearance through mechanisms distinct from canonical nutrient sensing. In this article, we review these advances and discuss the emerging rationale for exploring neuron- and context-specific approaches to modulate lipophagy as a complementary strategy in neurodegeneration.},
}

@article {pmid42773922,
year = {2026},
author = {Krane, NA},
title = {Invited Commentary on: Kandathil et al.'s "Postoperative Pain Management in Rhinoplasty: A Double Blind Randomized Controlled Trial".},
journal = {Facial plastic surgery & aesthetic medicine},
volume = {},
number = {},
pages = {26893614261485079},
doi = {10.1177/26893614261485079},
pmid = {42773922},
issn = {2689-3622},
}

@article {pmid42775169,
year = {2026},
author = {Xue, F and Bao, L and He, A and Liang, S},
title = {CRISPR-based functional genomic screening in neurodegeneration: mechanistic insights into AD, PD, and ALS.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1831375},
pmid = {42775169},
issn = {1663-4365},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by pronounced clinical and molecular heterogeneity, as well as highly interconnected pathogenic pathways. This biological complexity has long hindered efforts to systematically define disease mechanisms and to develop effective, targeted therapies. In recent years, clustered regularly interspaced short palindromic repeats (CRISPR) based functional genomic screening technologies have emerged as powerful tools for large-scale genetic perturbation in cellular, organoid, and in vivo models, enabling unbiased interrogation of disease relevant genetic networks and the identification of potential therapeutic targets. In this review, we summarize CRISPR knockout, CRISPR interference, CRISPR activation, and in vivo screening studies in AD, PD, and ALS, with emphasis on pathological phenotypes, experimental models, cell types, validation strategies, and evidence strength. In AD, these screens have identified regulators of amyloid-β (Aβ) production, Tau homeostasis and propagation, microglial states, neuronal aging, and stress responses. In PD, they have provided insights into α-synuclein (α-syn) homeostasis, mitochondrial quality control, lysosomal trafficking, and transplanted dopaminergic neuron survival. In ALS, they have identified modifiers of C9orf72-associated toxicity, repeat-associated non-AUG translation, TAR DNA-binding protein 43 (TDP-43) inclusion formation, and ATXN2 homeostasis. Cross-disease comparison indicates recurring involvement of proteostasis, endolysosomal function, mitochondrial regulation, and cellular stress responses, although individual screening hits show limited overlap and remain strongly influenced by experimental context. Overall, CRISPR-based screening provides a useful framework for identifying candidate disease modifiers, but further validation across complementary human-relevant and in vivo models is required before therapeutic translation.},
}

@article {pmid42777814,
year = {2026},
author = {Ren, EM and Branscom, GA and Srinivasan, KK and Lemonick, MB and Nguyen, K and Carr, M and Judy, BF and Choudhri, TF},
title = {The Top 100 Most Cited Articles on Posterior Cervical Foraminotomies: A Bibliometric Analysis.},
journal = {World neurosurgery},
volume = {},
number = {},
pages = {125360},
doi = {10.1016/j.wneu.2026.125360},
pmid = {42777814},
issn = {1878-8769},
abstract = {BACKGROUND: Posterior cervical foraminotomy (PCF) is a procedure used for treating refractory cervical radiculopathy. Although anterior cervical discectomy and fusion (ACDF) remains the historical standard, growing evidence supports the noninferiority of PCF while preserving physiological cervical stability. While ACDF has extensive publications and associated bibliometric analyses, similar analyses are nonexistent for PCF. This study aims to identify the most influential studies related to PCF and investigate emerging trends and themes in the field.

METHODS: The 100 most-cited articles related to PCF were identified through Web of Science. Title, publication year, journal, authorship, affiliation, country, and citation count were extracted. Keyword co-occurrence and co-authorship network analyses were performed using VOSviewer and Bibliometrix in RStudio.

RESULTS: The earliest article among the top 100 was published in 1990, with publications steadily increasing after. The most-cited article was Ruetten et al.'s 2008 article describing the efficacy of full-endoscopic PCF relative to ACDF for cervical disc herniations. Fessler R.G. was the most productive author, World Neurosurgery the most productive journal, and Seoul National University the most productive institution. The United States contributed the most articles (47), followed by South Korea (24), and then China (14). Network analysis identified comparative outcomes (ACDF versus PCF), minimally invasive surgery, and surgical technique as prevalent themes. Furthermore, small collaboration groups were observed with limited collaboration between groups.

CONCLUSION: This work analyzes the most influential papers related to PCF and demonstrates its continued advancement, especially with the emergence of minimally invasive techniques and trials demonstrating its efficacy compared to ACDF.},
}

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

@article {pmid42763025,
year = {2026},
author = {Wang, S and Dolce, MA and Burkett, AM and Collis, VL and Fuller, PE and Blanco, GA and Le, NTT and Fingert, JH and Monteiro, MJ},
title = {TBK1 overexpression reduces neuronal loss in the P497S UBQLN2 mouse model of ALS/FTD.},
journal = {Neurobiology of disease},
volume = {229},
number = {},
pages = {107611},
doi = {10.1016/j.nbd.2026.107611},
pmid = {42763025},
issn = {1095-953X},
support = {R01 NS098243/NS/NINDS NIH HHS/United States ; },
abstract = {Missense mutations in UBQLN2 are linked to dominant inheritance of amyotrophic lateral sclerosis (ALS) which is frequently accompanied by frontotemporal dementia (FTD). The encoded UBQLN2 protein functions to maintain proteostasis, collapse of which is increasingly being realized as the cause of many neurodegenerative diseases. During investigations of our UBQLN2 mouse models of ALS/FTD, we observed a significant decline in Tank-binding kinase 1 (TBK1) protein in end-stage mice. The decline could be significant, as haploinsufficiency of TBK1 expression is linked to ALS/FTD. To determine whether the reduction in TBK1 levels is responsible for driving pathogenesis, we crossed P497S UBQLN2 transgenic (Tg) mice with BacTBK1 Tg mice that overexpress TBK1 and analyzed the progeny for signs of pathology. The analysis revealed that double transgenic mice had a significant reduction in neurodegeneration in both the brain and spinal cord (SC) compared to P497S single-Tg mice. Double immunofluorescence staining of P497S mouse tissue revealed TBK1 colocalizes with UBQLN2 aggregates in spinal motor neurons. Biochemical extraction studies of mouse brain tissue revealed increased enrichment of TBK1 along with wild type and mutant UBQLN2 proteins in detergent-insoluble material, suggesting TBK1 gets sequestered by UBQLN2 aggregates. GST-pulldown assays revealed that UBQLN2 binds directly with TBK1, but paradoxically the P497S mutation was found to reduce TBK1 binding. Turnover studies indicated that loss of UBQLN2 destabilizes TBK1, providing another route for its reduction. These findings lead us to propose that efforts directed toward increasing TBK1 expression may provide a therapeutic approach for treating ALS/FTD caused by UBQLN2 mutations.},
}

@article {pmid42763209,
year = {2026},
author = {Liu, YW and Fan, DS and Chen, L},
title = {[Evaluation value of NRS2002 and MNA-SF on nutritional status and prognosis in adult patients with amyotrophic lateral sclerosis].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {35},
pages = {3746-3753},
doi = {10.3760/cma.j.cn112137-20251225-03422},
pmid = {42763209},
issn = {0376-2491},
support = {81873784, 82071426//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; 2024//The Special Fund of the National Clinical Key Specialty Construction Program, P. R.China/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Prognosis ; *Nutritional Status ; *Nutrition Assessment ; Female ; Male ; Middle Aged ; Prospective Studies ; Body Mass Index ; Malnutrition ; Aged ; Adult ; },
abstract = {Objective: To evaluate the value of the Nutritional Risk Screening 2002 (NRS2002) and the Mini-Nutritional Assessment Short-Form (MNA-SF) in assessing nutritional status, disease progression, and prognosis in adult patients with amyotrophic lateral sclerosis (ALS). Methods: Baseline data of 148 ALS patients who visited Peking University Third Hospital from January to December 2024 were prospectively collected. Patients were divided into malnutrition group and normal group based on the presence of nutritional risk. Assessments were conducted every 3 months over a 1-year follow-up period, during which ALSFRS-R scores, body mass index (BMI), and nutritional scale scores were recorded. The rates of ALSFRS-R score decline (δFS) and BMI change (δBMI) were calculated as (baseline ALSFRS-R score-follow-up ALSFRS-R score)/follow-up months and (baseline BMI-follow-up BMI)/follow-up months, respectively. The primary endpoint events were death or tracheostomy. Clinical data were compared between patients with different nutritional statuses. Spearman and Pearson correlation analyses were used to explore the correlations between scale scores and various indicators. Cohen's Kappa coefficient was used to evaluate the inter-rater consistency between the two scales. Linear mixed-effects models were applied to assess the relationships between nutritional risk and changes in δFS and δBMI. Results: A total of 148 ALS patients were collected in this study, including 96 males and 52 females, with the age [M(Q1, Q3)] of 56.0 (49.0, 61.0) years. A total of 4 enrolled patients were excluded from the NRS2002 assessment owing to missing BMI data, which resulted from the inability to measure height and weight in these bedridden individuals. Based on the NRS2002 and MNA-SF, patients were classified into the malnutrition group (NRS2002 malnutrition group, n=45; MNA-SF malnutrition group, n=59) and the normal group (NRS2002 normal group, n=99; MNA-SF normal group, n=89). The Kappa values for the consistency between NRS2002 and MNA-SF at baseline, 3, 6, 9, and 12 months were 0.726, 0.713, 0.698, 0.648, and 0.769, respectively (all P<0.001). NRS2002 was negatively correlated with BMI (r=-0.413, P<0.001), body weight (r=-0.442, P<0.001), prealbumin (r=-0.253, P<0.001), creatinine (r=-0.139, P=0.049), and triglycerides (r=-0.228, P=0.003); MNA-SF was positively correlated with BMI (r=0.573, P<0.001), body weight (r=0.514, P<0.001), prealbumin (r=0.277, P<0.001), creatinine (r=0.233, P=0.002), and triglycerides (r=0.289, P<0.001). After adjusting for confounders using linear mixed-effects models, a higher NRS2002 score was identified as a risk factor for increases in δFS (β = 0.127, 95%CI: 0.065-0.189, P<0.001) and δBMI (β=0.150, 95%CI: 0.104-0.197, P<0.001), whereas a higher MNA-SF score served as a protective factor against increases in δFS (β=-0.090, 95%CI:-0.116 to -0.064, P<0.001) and δBMI (β=-0.092, 95%CI:-0.113 to -0.071, P<0.001). Conclusions: NRS2002 and MNA-SF demonstrate good consistency in nutritional risk assessment among ALS patients. The scores of both scales are correlated with traditional nutritional indicators including BMI, body weight, prealbumin, creatinine, and triglycerides, and are associated with the rates of ALSFRS-R and BMI changes in these patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis
Prognosis
*Nutritional Status
*Nutrition Assessment
Female
Male
Middle Aged
Prospective Studies
Body Mass Index
Malnutrition
Aged
Adult

@article {pmid42763500,
year = {2026},
author = {Mew, L and Rosser, E and Heron, E and Mezzetti, C and Baron, S and Cronin, C},
title = {Evaluating the impact of a Sigma Action Learning Set on leadership development among nurse leaders.},
journal = {Journal of research in nursing : JRN},
volume = {},
number = {},
pages = {17449871261477335},
pmid = {42763500},
issn = {1744-988X},
abstract = {BACKGROUND: Leadership capability is essential for nursing practice, influencing patient care, staff well-being and organisational effectiveness. Inclusive leadership valuing diversity, equity and shared learning are increasingly recognised as vital in complex healthcare systems. Action Learning Sets (ALSs) are an established approach to leadership development through structured peer reflection, questioning and collaboration.

AIM: To evaluate the effectiveness of a nationally delivered, inclusive ALS programme in developing nurse leadership over 12 months.

METHOD: Kirkpatrick's model was used to evaluate the programme, examining participants' preparedness, learning, behavioural change and organisational impact. Participants (n = 5) were purposefully selected from diverse healthcare organisations across England and Wales. Data were collected through an online group evaluation and analysed across four levels: reaction, learning, behaviour and results.

FINDINGS: All domains were positively evaluated. The ALS provided a safe space for reflection and collaborative learning. Participants reported increased leadership confidence, enhanced self-awareness and improved inclusive leadership. Behavioural changes included greater engagement with diverse perspectives and application of reflective practices. Policy-focused sessions were highly valued.

CONCLUSION: The ALS offered a supportive and effective approach to leadership development, enabling nurses to address real-world challenges through reflection and peer learning. Wider adoption across practice settings is recommended.},
}

@article {pmid42764383,
year = {2026},
author = {Pasho, E and Catanese, A and Kabashi, E and Ciura, S},
title = {What can we learn on ALS pathophysiology from iPSC-derived motor neurons harbouring TARBDP mutations: a systematic review.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42764383},
issn = {2047-9158},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology ; Humans ; *Motor Neurons/pathology/metabolism ; *Induced Pluripotent Stem Cells/pathology/metabolism ; *DNA-Binding Proteins/genetics ; *Mutation/genetics ; Animals ; },
abstract = {The degenerating motor neurons of amyotrophic lateral sclerosis (ALS) patients are characterized by the accumulation of cytoplasmic aggregates, specifically enriched in ubiquitinated TDP-43. Expressed mainly in the nucleus and partially in the cytoplasm to execute its role in RNA metabolism, the exact mechanisms that bring TDP-43 to aggregate in disease have yet to be described. Unfolding these processes could bring us closer to effective drug development that is drastically lacking in the ALS research field. Induced pluripotent stem cells (iPSCs) offer a promising platform for studying ALS pathogenesis directly in the relevant human genetic backgrounds of ALS patients. Since 2012, more than 30 published studies have investigated altered cellular and subcellular features in iPSC-derived motor neurons from ALS patients harbouring mutations in the TARDBP gene (encoding for TDP-43 protein). However, there are discrepancies in the obtained results, which call into question the relevance of this model for ALS disease modelling and its use for drug development efforts. Thus, there is a need in the field for a clear and detailed layout and summary of all the published data on ALS modelling using TARDBP mutant iPSC-derived motor neurons. In this systematic review, we analyse all phenotypic assessments that have been done on iPSC-derived motor neurons derived from TARDBP ALS patients on the morphology, functionality and the viability of these cells. We also analyse if this model recapitulates ALS pathology in vitro by comparing studies that looked at TDP-43 and neurofilament aggregation, as well as stress granule dynamics. Importantly, we compare the technical details of all the discussed studies, such as differentiation protocol, age and purity of the used motor neurons and quantification method, in order to discuss how all of these parameters affect the observed phenotypes. Lastly, we also expand our review to all other different cell types that have been differentiated from TARDBP iPSCs, highlighting non-cell autonomous mechanisms of TDP-43-ALS pathophysiology. By integrating findings across studies, this review identifies commonalities and discrepancies, discusses methodological advancements and limitations, and highlights potential therapeutic targets revealed through TARDBP iPSC-derived models.},
}

*Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology
Humans
*Motor Neurons/pathology/metabolism
*Induced Pluripotent Stem Cells/pathology/metabolism
*DNA-Binding Proteins/genetics
*Mutation/genetics
Animals

@article {pmid42756835,
year = {2026},
author = {Lemos, JP and Stockholm, D and Dinatale, B and Chaves, AS and Pezet, S and Frias Carvalho, V and Pérez, AR and Mendes-da-Cruz, DA and Savino, W and Smeriglio, P},
title = {The thymus gland is a target and maintainer of amyotrophic lateral sclerosis pathophysiology.},
journal = {Brain, behavior, & immunity - health},
volume = {57},
number = {},
pages = {101323},
pmid = {42756835},
issn = {2666-3546},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the brain and spinal cord with evidence of local neuroinflammation. Regulatory T cells (Treg) exert neuroprotective effects and correlate with disease progression, but central mechanisms governing Treg development during ALS remain unclear. We investigated the thymic architecture and T cell differentiation in SOD1-G93A (mSOD1) ALS mice at multiple disease stages. Thymocyte and thymic epithelial cells (TEC) subpopulations, as well as stages of Treg differentiation and suppressive capacity, were analyzed by flow cytometry, in situ immunofluorescence, and functional assays. At late disease stage (120 days-old), mSOD1 mice displayed thymic atrophy, reduced thymocyte numbers, and decreased double-positive (DP), CD4 single-positive (SP), and Treg populations. Foxp3 expression per cell was preserved, but Treg progenitors and mature Treg numbers declined, paralleled by reduced suppressive function in vitro. TEC analysis revealed reduced total and mature medullary TEC (CD80[high]MHCII[high]), despite preserved Aire expression. Foxp3[+] cells were abnormally localized at cortical sites, away from mTEC, associated with migratory abnormalities and increased apoptosis. TREC evaluation revealed reduced intrathymic sjTREC, consistent with impaired proliferation and differentiation between DN and DP stages, although peripheral sj/βTREC ratios remained stable. Reduced Treg numbers were also observed in lymph nodes draining affected hindlimbs. Our findings identify the thymus as a target organ in ALS, where thymic involution, TEC loss, and Treg dysfunction may compromise immune tolerance. These alterations likely reinforce the role of the thymus in peripheral immune dysregulation and neuroinflammation observed in ALS.},
}

@article {pmid42757528,
year = {2026},
author = {Stibbard-Hawkes, DNE},
title = {A lobbying theory of cultural evolution: Rhetoric, expediency, and self-interest promote inequality in the prescriptive grammar of complex institutions.},
journal = {The Behavioral and brain sciences},
volume = {49},
number = {},
pages = {e412},
doi = {10.1017/S0140525X26106487},
pmid = {42757528},
issn = {1469-1825},
mesh = {Humans ; *Cultural Evolution ; },
abstract = {Anthropologists have noted, time and again, that cultural norms and institutions often (1) are "functional," providing context-relevant benefits, (2) convergently evolve, and (3) benefit certain individuals over others. In this commentary, I consider inequality, self-interest, and coercion in complex cultural institutions. I extend Chater and Christiansen's theory of social tinkering, taking cues from Mercier and Sperber's argumentative theory of human reason and Singh et al.'s self-interested enforcement hypothesis, to argue that humans are well-adapted "cultural lobbyists."},
}

Humans
*Cultural Evolution

@article {pmid42758107,
year = {2026},
author = {Abdanipour, A and Nikfar, A and Feizi, H},
title = {Selegiline induces neuroprotection via PGC-1α/Nrf2 gene upregulation in H2O2 -treated hippocampal-derived neural stem/progenitor cells.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {72},
number = {5},
pages = {47-53},
doi = {10.14715/cmb/2026.72.5.7},
pmid = {42758107},
issn = {1165-158X},
mesh = {*Selegiline/pharmacology ; *Hydrogen Peroxide/pharmacology/toxicity ; Animals ; *NF-E2-Related Factor 2/genetics/metabolism ; *Hippocampus/cytology ; *Neural Stem Cells/drug effects/metabolism/cytology ; *Up-Regulation/drug effects ; Apoptosis/drug effects ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; Oxidative Stress/drug effects ; Rats ; Cells, Cultured ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Neuroprotection/drug effects ; },
abstract = {Oxidative stress mediated by reactive oxygen species (ROS) is a major contributor to the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and amyotrophic lateral sclerosis. Selegiline, a monoamine oxidase B inhibitor, has been reported to exert neuroprotective effects, although its precise cytoprotective mechanisms remain unclear. In this study, we investigated the effects of selegiline on apoptosis, necrosis, and cell survival in hydrogen peroxide (H2O2)-treated hippocampal-derived neural stem/progenitor cells (HD-NSPCs) in vitro. Passage 3 HD-NSPCs were treated with varying concentrations of selegiline (10[-3] to 10[-9] M) prior to exposure to 125 μM H2O2. Cell viability was assessed using the MTT assay, while apoptosis and necrosis were evaluated using TUNEL and acridine orange/ethidium bromide staining, respectively. Real-time RT-PCR was performed to quantify mRNA levels of PGC-1α, Nrf2, and Bcl-2. Treatment with 10[-7] M selegiline significantly enhanced HD-NSC viability, reduced apoptotic and necrotic cell fractions, and upregulated PGC-1α, Nrf2, and Bcl-2 expression compared to untreated cells (P < 0.05). These findings suggest that selegiline mitigates oxidative stress-induced cytotoxicity by activating Nrf2/PGC-1α signaling and promoting anti-apoptotic gene expression, thereby preserving mitochondrial function and enhancing cell survival. Overall, selegiline may represent a promising therapeutic agent for protecting neural progenitor cells and alleviating neuronal damage in neurodegenerative disorders.},
}

*Selegiline/pharmacology
*Hydrogen Peroxide/pharmacology/toxicity
Animals
*NF-E2-Related Factor 2/genetics/metabolism
*Hippocampus/cytology
*Neural Stem Cells/drug effects/metabolism/cytology
*Up-Regulation/drug effects
Apoptosis/drug effects
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism
*Neuroprotective Agents/pharmacology
Cell Survival/drug effects
Oxidative Stress/drug effects
Rats
Cells, Cultured
Proto-Oncogene Proteins c-bcl-2/metabolism/genetics
*Neuroprotection/drug effects

@article {pmid42758317,
year = {2026},
author = {Calvo, A and Moglia, C and Callegaro, S and Canosa, A and Manera, U and Mora, G and Cabras, S and Palumbo, F and Matteoni, E and Maccabeo, A and Pellegrino, G and Minerva, E and Pascariu, D and D'Ovidio, F and Vasta, R and Mazzini, L and De Marchi, F and Chiò, A},
title = {What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42758317},
issn = {1432-1459},
support = {PNRR-MAD-2022-12375731//Ministero della Salute/ ; RF-2016-02362405//Ministero della Salute/ ; 101017598//Horizon 2020 Framework Programme/ ; 259867//FP7 Ideas: European Research Council/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Female ; Prognosis ; Phenotype ; Male ; Middle Aged ; Aged ; Registries ; *Motor Neurons/pathology ; Prospective Studies ; },
abstract = {BACKGROUND: The ALS-OPM 3.3 classification stratifies incident ALS through three axes: onset region (O), propagation time (P) and motor-neuron pattern (M). We assessed whether OPM 3.3 improves prognostic discrimination over established classifications and characterised how it decomposes their prognostic signal in a population-based cohort.

METHODS: In the prospective Piedmont and Aosta Valley ALS Register (2000-2022), patients were classified on the three axes; M was operationalised as M_3class (M0 balanced, M1d UMN-predominant, M2d LMN-predominant), with the PLS-spectrum M1p analysed separately. Outcome was survival (death or tracheostomy) from onset. Multivariable Cox models (O, P1(n), M_3class, age, sex) underwent bootstrap optimism-correction and fivefold cross-validation, and were compared against alternative taxonomies and clinical staging systems.

RESULTS: Amongst 2,738 non-PLS patients (2,561 events, 93.5%), median survival differed across M classes (M0 27.0, M2d 36.0, M1d 41.9 months). OPM 3.3 outperformed the bulbar/spinal dichotomy but matched the classical phenotype (optimism-corrected C-index 0.703, 95% CI 0.685-0.719 vs 0.701). In the arm-proximal cell (95.7% M2d), the O2p protective effect vanished after M adjustment (HR 0.99, 95% CI 0.79-1.24), whilst M2d retained HR 0.83 (95% CI 0.72-0.95), showing prognosis reflects motor-neuron pattern, not anatomy. Adding King's, Milano-Torino (MiToS), or Fine'til 9 (FT9) clinical staging further improved discrimination.

CONCLUSIONS: OPM 3.3 did not improve discrimination over established phenotypes but decomposed their prognostic signal into independently interpretable dimensions. Favourable prognosis of arm-proximal/flail-arm onset reflects the underlying LMN-predominant phenotype, not onset site. The motor-neuron axis is robust to the treatment of the propagation axis and independent of clinical staging.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology
Female
Prognosis
Phenotype
Male
Middle Aged
Aged
Registries
*Motor Neurons/pathology
Prospective Studies

@article {pmid42758660,
year = {2026},
author = {Salas, C and Rodríguez, F and Bingman, VP and Striedter, GF},
title = {Investigating map-like navigation and hippocampus homologs in teleost fish: Comment on Givon et al., 2023 "Lateral and medial telencephalic pallium lesions impair spatial memory in goldfish".},
journal = {Brain, behavior and evolution},
volume = {},
number = {},
pages = {1},
doi = {10.1159/bbe/abqag007},
pmid = {42758660},
issn = {1421-9743},
abstract = {This commentary critically examines the article by Givon et al. (2023), which reports that lesions to the lateral or medial regions telencephalic pallium (Dl or Dm) both impair allocentric spatial navigation in goldfish and concludes that both regions are necessary for this function. This interpretation challenges the extensive body of evidence supporting the functional dissociation between Dl and Dm. In particular, Dl's ventral subdivision (Dlv) has been shown to be essential for map-like spatial memory. In contrast, Dm has been associated primarily with emotional and motivational processes rather than spatial cognition. This commentary focuses on the fact that Givon et al's behavioral tasks (a plus-maze and a breadboard maze) lacked essential controls, such as systematic maze rotations and probe trials, that are necessary to rule out non-allocentric behavioral strategies. Moreover, the lesions are poorly localized, including some that extend well beyond the pallium and affect subpallial telencephalic regions and even the mesencephalic optic tectum - structures whose damage produces widespread sensorimotor and regulatory disturbances. Furthermore, the relatively high post-surgical mortality indicates nonspecific surgical effects. Overall, we conclude that Givon et al. (2023) does not provide convincing evidence for a role of Dm in allocentric navigation and does not undermine previous findings of a functional dissociation between Dl and Dm. We briefly discuss how these findings impact the ongoing search for a hippocampus homolog in teleosts and the larger effort to elucidate the neural mechanisms underlying spatial navigation in teleosts.},
}

@article {pmid42758722,
year = {2026},
author = {Yamakawa, I and Tamura, R and Yabata, H and Tsukamoto, T and Kobashi, S and Tamaki, Y and Ogawa, N and Kitamura, A and Urushitani, M},
title = {Serum Na-Cl value from routine blood tests reflects CO2 retention in amyotrophic lateral sclerosis.},
journal = {PloS one},
volume = {21},
number = {9},
pages = {e0358772},
pmid = {42758722},
issn = {1932-6203},
mesh = {Humans ; *Carbon Dioxide/blood ; *Amyotrophic Lateral Sclerosis/blood ; Female ; *Sodium/blood ; Retrospective Studies ; Male ; Blood Gas Analysis ; Middle Aged ; Aged ; *Chlorides/blood ; ROC Curve ; Respiratory Insufficiency/blood ; Biomarkers/blood ; Adult ; },
abstract = {BACKGROUND: Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Early detection of CO2 retention is crucial for assessing respiratory failure severity and guiding noninvasive positive pressure ventilation (NPPV) management. However, arterial blood gas analysis is invasive and uncomfortable for routine monitoring.

OBJECTIVE: We investigated whether the serum sodium-chloride difference (Na-Cl value), calculated from routine blood tests, could serve as a screening marker for CO2 retention in ALS patients.

METHODS: This retrospective study included 88 ALS patients with 116 paired samples of arterial blood gas and serum electrolyte data. We analyzed correlations between Na-Cl value and blood gas parameters (HCO3-, PCO2), performed receiver operating characteristic (ROC) analysis for detecting CO2 retention (PCO2 ≥ 45 mmHg), and examined relationships with respiratory function (%FVC).

RESULTS: Na-Cl value showed strong correlation with HCO3- (r = 0.78, p < 0.001) and PCO2 (r = 0.71, p < 0.001). Na-Cl ≥ 37 mEq/L demonstrated sensitivity of 85.11% and specificity of 69.57% for detecting PCO2 ≥ 45 mmHg, with negative predictive value of 87.27% (AUC = 0.842). Na-Cl ≥ 39 mEq/L achieved specificity of 92.75%. Patients with %FVC < 50% had significantly higher Na-Cl, PCO2, and HCO3- values.

CONCLUSIONS: Serum Na-Cl value serves as a simple, noninvasive screening marker for CO2 retention in ALS. Na-Cl ≥ 37 mEq/L warrants blood gas analysis, while Na-Cl ≥ 39 mEq/L provides specificity >90%. This marker can be calculated from routine blood tests without additional cost, making it suitable for frequent monitoring and reducing the risk of missing intervention timing.},
}

Humans
*Carbon Dioxide/blood
*Amyotrophic Lateral Sclerosis/blood
Female
*Sodium/blood
Retrospective Studies
Male
Blood Gas Analysis
Middle Aged
Aged
*Chlorides/blood
ROC Curve
Respiratory Insufficiency/blood
Biomarkers/blood
Adult

@article {pmid42759101,
year = {2026},
author = {Santangelo, S and Casarotto, V and Campelli, L and Leoni, S and Cabras, S and Matteoni, E and Marco, G and Canosa, A and Basso, M and Bonetto, V and Trojisi, F and Bossolasco, P and Silani, V and Chiò, A and Ticozzi, N and Calvo, A and Ratti, A},
title = {Establishment of two iPSC lines from ALS patients carrying mutations in SQSTM1 and TBK1 genes.},
journal = {Stem cell research},
volume = {96},
number = {},
pages = {104105},
doi = {10.1016/j.scr.2026.104105},
pmid = {42759101},
issn = {1876-7753},
abstract = {We describe the generation and characterization of two induced pluripotent stem cell (iPSC) lines: one derived from an ALS patient carrying the heterozygous SQSTM1 c.1175C > T (p.Pro392Leu) mutation, identified as cell line 047, and another one (cell line 053) derived from a patient carrying the heterozygous TBK1 c.1760 + 4_1760 + 7delAGTA likely pathogenic variant, predicted to result in a premature stop codon +, together with the ERBB4 c.2402A > T (p.His801Leu) variant of unknown significance (VUS).},
}

@article {pmid42759848,
year = {2026},
author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HJ and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Nishimune, H and Arnold, WD},
title = {Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43[Q331K] mice.},
journal = {Neurobiology of disease},
volume = {229},
number = {},
pages = {107610},
doi = {10.1016/j.nbd.2026.107610},
pmid = {42759848},
issn = {1095-953X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration in the motor cortex and spinal cord. Aging is a key risk factor for ALS, and cellular senescence - a hallmark of aging marked by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype - has been implicated in neurodegeneration, yet its role in ALS progression remains incompletely understood. Here, we show that molecular markers of cellular senescence emerge in the motor cortex and spinal cord alongside declines in neural and neuromuscular function in TDP-43[Q331K] ALS mice, supporting senescence as an early feature of ALS pathology. To test whether reduced senescence ameliorates ALS pathology, we evaluated longitudinal senolytic treatment with dasatinib and quercetin (D&Q) in TDP-43[Q331K] mice. D&Q treatment improved motor behavior, neuromuscular function, and reduced axonal damage as measured by plasma neurofilament light chain, accompanied by robust improvements in motor cortex excitability and preservation of layer V neuron counts. At the cellular level, cortical microglia were implicated as a potential mediator of senolytic benefits based on reduced microglial TDP-43 burden and senescence markers. Together, these findings identify cellular senescence as an early, disease-relevant, and modifiable feature of ALS pathology.},
}

@article {pmid42760265,
year = {2026},
author = {Huang, W and Wan, XY and Wang, YX and Hu, YH and Jing, SH and Zhang, Y and Ke, P and Li, DK and Zhang, C and Leng, RX and Wang, Q and Di, DS},
title = {Early-life tobacco smoke exposure and incident rheumatoid arthritis: mediated by allostatic load and joint effects with polygenic risk.},
journal = {Rheumatology (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/rheumatology/keag519},
pmid = {42760265},
issn = {1462-0332},
abstract = {OBJECTIVES: Rheumatoid arthritis (RA) is a widespread autoimmune disorder. Early-life environmental exposures may contribute to RA, and tobacco smoke represents an important modifiable factor. This study aimed to examine whether early-life tobacco smoke exposure affects incident RA risk, and to clarify the potential mediating role of allostatic load (AL) and interactive effects with genetic susceptibility.

METHODS: Using questionnaire, biomarker, genetic, and linked health-record data from UK Biobank, we examined intrauterine tobacco smoke exposure (IUTSE; n = 427,037), age at tobacco use initiation (ATUI; n = 414,318) and RA cases. Cox models evaluated associations between early-life tobacco exposure and RA risk. Mediation analysis quantified AL's mediating effect. Additive and multiplicative interaction examined genetic susceptibility interactions.

RESULTS: IUTSE was associated with higher RA risk (HR = 1.15, 95% CI: 1.08, 1.21). Compared with never-smokers, individuals who started tobacco smoking in childhood, adolescence, and adulthood exhibited elevated RA risk, with corresponding HRs of 1.74 (95% CI: 1.39, 2.17), 1.56 (95% CI: 1.29, 1.88), and 1.47 (95% CI: 1.22, 1.76). Mediation analyses indicated statistically significant but small indirect effects of AL. The indirect effect for IUTSE was 1.001 (95% CI: 1.001, 1.002) and for tobacco use during childhood, adolescence, and adulthood were 1.009 (95% CI: 1.005, 1.013), 1.006 (95% CI: 1.003, 1.009), and 1.006 (95% CI: 1.003, 1.009). High genetic risk with IUTSE (HR = 1.93, 95% CI: 1.75, 2.13) or childhood initiation (HR = 2.89, 95% CI: 2.17, 3.86) increased RA risk.

CONCLUSION: Early-life tobacco smoke exposure elevates RA risk in adulthood, with limited mediation by AL and modification by genetic predisposition.},
}

@article {pmid42760536,
year = {2026},
author = {Garg, L and Chaplot, K and Kuppili, G and Tendulkar, S and Joseph, J and Kamat, S and Ratnaparkhi, G},
title = {Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42760536},
issn = {2051-5960},
support = {SL03//EMSTAR/ ; SB/SJF/2021-22/01//ANRF, India/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Neuroglia/metabolism/pathology ; Disease Models, Animal ; *Lipid Metabolism/physiology ; Humans ; Drosophila Proteins/genetics/metabolism ; *Brain/metabolism/pathology ; Drosophila ; Animals, Genetically Modified ; Vesicular Transport Proteins/genetics/metabolism ; },
abstract = {Membrane Contact sites (MCS) have emerged as physiologically relevant zones that coordinate inter-organelle communication and cellular function. VAPB, an ER-resident MCS tethering protein, plays a central role in regulating MCSs through its numerous protein interactors, thereby influencing cellular homeostasis. A pathogenic missense VAPB[P56S] mutation causes familial Amyotrophic Lateral Sclerosis 8 (ALS8) in humans, with progressive degeneration of motor neurons. The precise mechanisms underlying the motor neurodegeneration remain poorly understood. In this study, we examine lipid imbalance in the brain of a Drosophila model of ALS8 (VAPB[P58S]). Specifically, we find that lipid homeostasis is disrupted in an age-dependent manner. Strikingly, cholesterol esters and sphingolipids show an age-dependent increase, while cholesterol shows a decrease. Intriguingly, from a cellular perspective, despite the accumulation of triacylglycerols (TAGs) in the brains of VAPB[P58S] animals, the increased neutral lipid species do not correlate with lipid droplets (LDs), which are fewer in density and smaller in size. Lipid imbalance and progressive motor dysfunction in VAPB[P58S] animals can be reversed by expressing VAPB[WT], suggesting a relationship between VAPB activity and lipid flux. To uncover VAPB's role in lipid homeostasis, we modulate VAPB activity in neurons and glia to dissect out tissue-specific roles. We find that both cell types contribute to lipid homeostasis in differential ways. In glia, LD flux is strongly dependent on VAPB activity, a dependence further recapitulated in cultured human cell lines, suggesting evolutionary conservation of the regulatory mechanism. Thus, we hypothesize that lipid dysregulation constitutes a critical pathogenic feature of ALS8, with the VAPB[P56S] allele disrupting lipid homeostasis in the neuro-glial axis.},
}

Animals
*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
*Neuroglia/metabolism/pathology
Disease Models, Animal
*Lipid Metabolism/physiology
Humans
Drosophila Proteins/genetics/metabolism
*Brain/metabolism/pathology
Drosophila
Animals, Genetically Modified
Vesicular Transport Proteins/genetics/metabolism

@article {pmid42760704,
year = {2026},
author = {Liu, Y and Chen, S and Wu, Y and Zhou, W and Shang, H and Ou, R},
title = {Causal relationship between metabolites, cerebral volume, and amyotrophic lateral sclerosis: A 2-step Mendelian randomization analysis.},
journal = {Medicine},
volume = {105},
number = {38},
pages = {e50769},
pmid = {42760704},
issn = {1536-5964},
support = {82271272//the National Science Fund of China/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood/metabolism/pathology ; Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Organ Size ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration. Although metabolic abnormalities have been implicated in ALS, the causal relationships between circulating metabolites and ALS remain unclear. This study aimed to investigate the potential causal associations between plasma metabolites and ALS risk and to explore the mediating role of cerebral volume. A 2-sample Mendelian randomization (MR) study was conducted using publicly available genome-wide association study summary statistics. Genetic instruments for plasma metabolites were obtained from metabolomic GWAS datasets, and ALS-associated genetic data were used as the outcome. The inverse-variance weighted method was used as the primary analysis, with sensitivity analyses performed using MR-Egger regression, weighted median analysis, MR-PRESSO, heterogeneity testing, and leave-one-out analysis. A 2-step MR analysis was further conducted to evaluate whether cerebral volume mediated the associations between metabolites and ALS. Six metabolites showed significant associations with ALS risk. Genetically predicted higher levels of N,N-dimethylalanine, Behenylcarnitine (C22), and deoxycarnitine were associated with increased ALS risk, whereas higher levels of (N(1) + N(8))-acetylspermidine, Betaine, and tetradecadienedioate (C14:2-DC) were associated with decreased ALS risk. Sensitivity analyses supported the robustness of the findings. Two-step MR analysis suggested that cerebral volume did not significantly mediate the associations between these metabolites and ALS risk. This study identified 6 circulating metabolites genetically associated with ALS risk. These findings provide insights into the potential metabolic pathways involved in ALS and suggest that the observed associations are unlikely to be mediated through cerebral volume changes.},
}

*Amyotrophic Lateral Sclerosis/genetics/blood/metabolism/pathology
Humans
*Mendelian Randomization Analysis
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Organ Size

@article {pmid42760853,
year = {2026},
author = {Wenz, L and Scholl, LS and Reinhardt, N and Heynitz, RV and Gmeiner, V and Rau, P and Müller, PJ and Wolff, AW and Feneberg, E and Demleitner, AF and Lingor, P},
title = {Chitinases in Tear Fluid of Patients With Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {33},
number = {9},
pages = {e70757},
pmid = {42760853},
issn = {1468-1331},
support = {EXC 2145 SyNergy - ID 390857198//Deutsche Forschungsgemeinschaft/ ; project H-13//Technische Universität München/ ; },
mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Male ; *Hexosaminidases/genetics/metabolism ; *Tears/enzymology ; *Chitinase-3-Like Protein 1/metabolism ; Middle Aged ; *Chitinases/metabolism/genetics ; Aged ; Biomarkers/metabolism/blood ; Adult ; },
abstract = {BACKGROUND: Chitinases, including chitotriosidase (CHIT1) and chitinase-3-like protein 1 (CHI3L1), are markers of neuroinflammation, a key process in amyotrophic lateral sclerosis (ALS). Tear fluid (TF) can be collected non-invasively and may represent a promising alternative to CSF or blood to study chitinases.

METHODS: TF was collected from 50 ALS patients and 50 control subjects using Schirmer strips. CHIT1 and CHI3L1 levels in TF, serum, and CSF were quantified using ELISA. Serum NfL was measured using SIMOA. The frequency of a 24 bp-duplication polymorphism in the CHIT1 gene influencing CHIT1 expression was assessed by PCR.

RESULTS: No group differences in the distribution of the CHIT1 polymorphism were detected. Carriers of the polymorphism in both ALS and controls showed lower CHIT1 levels in serum and TF. CHI3L1 levels in TF were higher in ALS patients compared to controls (p = 0.007), consistent with changes in CSF but not serum. In ALS, males showed higher TF CHIT1 values compared to females (p = 0.009). Combining TF chitinase values with serum NfL values improved discrimination between ALS and controls.

CONCLUSIONS: Chitinases are detectable in TF, and CHI3L1 levels recapitulate changes observed in CSF, highlighting its potential for non-invasive longitudinal assessment. Furthermore, chitinase values in TF, together with serum NfL, may act complementarily by capturing distinct aspects of the disease, neuroinflammation and axonal damage. These results suggest TF chitinases and serum NfL could complementarily contribute to the diagnosis and monitoring of the disease, and call for further evaluation of TF as a biomarker source in ALS.},
}

Humans
Female
*Amyotrophic Lateral Sclerosis/genetics/metabolism
Male
*Hexosaminidases/genetics/metabolism
*Tears/enzymology
*Chitinase-3-Like Protein 1/metabolism
Middle Aged
*Chitinases/metabolism/genetics
Aged
Biomarkers/metabolism/blood
Adult

@article {pmid42760861,
year = {2026},
author = {De Nardi, A and Paris, A and Lauria, M and Martinelli, I and Zucchi, E and Simonini, C and Mandrioli, J and Marchetti, L},
title = {Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers.},
journal = {European journal of neurology},
volume = {33},
number = {9},
pages = {e70756},
pmid = {42760861},
issn = {1468-1331},
support = {FGCR02/2015//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; GPG/2022/1343//Emilia Romagna Regional Health Authority/ ; 53232941//Pfizer/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/mortality/diagnosis ; *C9orf72 Protein/genetics ; Female ; Male ; Prognosis ; *Sirolimus/therapeutic use ; Middle Aged ; Survival Analysis ; Retrospective Studies ; Multivariate Analysis ; Aged ; Mutation ; Heterozygote ; Adult ; *Immunosuppressive Agents/therapeutic use ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by considerable variability in survival times. This retrospective study aims to evaluate the prognostic value of a broad range of variables by conducting a comprehensive survival analysis on longitudinal data from RAP-ALS, a clinical trial investigating the effects of rapamycin in ALS patients (n = 63).

METHODS: Covariates were classified as risk or protective factors according to their hazard ratios. Regularized Cox regression was utilized to select the best-performing multivariate models in cross-validation. Longitudinal measures were incorporated by modeling covariates as time-dependent. Survival times of treated C9orf72 mutation carriers (n = 6) were further investigated through log-rank tests and restricted mean survival time analysis.

RESULTS: Univariate analyses confirmed several previously established prognostic factors. Multivariate regularized Cox models incorporated neurofilaments, creatinine, clinical scores, and markers of immune activation. Moreover, the inclusion of time-varying covariates allowed us to investigate late-stage risk factors, such as the neutrophil-to-lymphocyte ratio. Additionally, the analysis indicated a protective effect in treated C9orf72 mutation carriers (log-rank test, p = 0.026), which was confirmed after comparing this treatment subgroup with an independent C9orf72+ cohort (n = 40; RMST test, p = 0.04).

CONCLUSIONS: The survival analysis confirmed the role of previously identified prognostic factors, while suggesting that high-performing multivariate models should integrate multiple ALS pathological hallmarks. Moreover, the observed longer survival among C9orf72 mutation carriers contrasts with prior reports. Due to the small sample size and potential confounding factors, the observed benefits in treated C9orf72 patients should be considered exploratory, supporting evaluation in a larger, genetically stratified trial.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/mortality/diagnosis
*C9orf72 Protein/genetics
Female
Male
Prognosis
*Sirolimus/therapeutic use
Middle Aged
Survival Analysis
Retrospective Studies
Multivariate Analysis
Aged
Mutation
Heterozygote
Adult
*Immunosuppressive Agents/therapeutic use

@article {pmid42761194,
year = {2026},
author = {Akouri-Shan, L and Leathem, L and Fletcher, EH and Calderon, R and Friedlander, S and Kalofonos, I},
title = {A qualitative analysis of experiences in veteran voices and visions groups: developing a participant-informed model of connection, acceptance, and social integration.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1717311},
pmid = {42761194},
issn = {1664-0640},
support = {T32 MH122395/MH/NIMH NIH HHS/United States ; },
abstract = {PURPOSE/AIMS: This study applied a model of transformation for Hearing Voices Groups in the US developed by Hornstein et al. to Veteran Voices and Visions (VVV) groups adapted for a Veterans Affairs healthcare system. The aims were twofold: (1) identify instances of Discovery, Reframing, and Change and empirically confirm the salience of this model for our groups; and (2) identify the specific dynamics of change in our groups, thus refining and elaborating upon the existing model.

METHOD: This study used a qualitative design with in-depth semi-structured interviews that were assessed pre-intervention, at 8 weeks, and at 16 weeks with 24 participants within five groups. Interviews were recorded and transcribed. Abductive analysis of the interview transcripts was conducted, first drawing theoretical insights from Hornstein et al.'s framework to organize and synthesize qualitative data deductively then using inductive rapid qualitative analysis to enrich and develop a theory of change specific to this study population.

FINDINGS: While data from this study mostly align with the Hornstein et al. model of transformation, in our data, findings from each phase seemed to emphasize a different theme than that foregrounded in the Hornstein et al. model. We articulate these differences in a refined model of transformation. Our model makes an additional refinement by delineating two distinct tracks: an inner track reflecting how the group influences participants' relationships with themselves and their own experiences, and an outer track reflecting how participants relate to fellow group members. We also consider barriers and facilitators within each phase.

IMPLICATIONS: Our findings indicate that the Hearing Voices approach can be successfully adapted to a large public mental healthcare system. They also provide a model for engagement with groups during the initial weeks and months of group attendance. VVV groups provided a valuable setting for connection, acceptance, and community that led to a greater sense of belonging and social integration.},
}

@article {pmid42761537,
year = {2026},
author = {Bruning, K and Heidrick, L and Rong, P},
title = {A mechanistically informed framework of hierarchical temporal speech organization for objective differential assessment of motor speech disorders in neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1907826},
pmid = {42761537},
issn = {1662-4548},
support = {UL1 TR002366/TR/NCATS NIH HHS/United States ; },
abstract = {INTRODUCTION: Speech is organized into discrete utterances and pauses in accordance with underlying linguistic structure, temporal coordination, prosodic organization, and respiratory demands. Temporal speech characteristics, including rhythmic and pausing patterns, are governed by multiple neurophysiological mechanisms and provide valuable insights for the assessment and management of motor speech disorders. This study employed a mechanistically informed analytic framework of hierarchical temporal speech organization to derive interpretable, objective measures for assessing rhythmic and pausing disturbances in neurodegenerative diseases.

METHODS: Orofacial kinematic and acoustic recordings were obtained from two neurodegenerative disease groups-amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD)-along with a neurologically healthy control (HC) group, during a passage reading task. Using automated analytic procedures, kinematic rhythm measures (movement-based) and acoustic rhythm measures (sound-based) were derived to characterize hierarchical rhythmic modulation of articulatory movements and critical-band acoustic modulation envelopes at prosodic, syllabic, and sub-syllabic levels. Pause measures were derived to characterize within- and between-sentence pausing patterns. Rhythmic and pausing patterns were compared across groups. The acoustically derived rhythm and pause measures were subsequently subjected to (1) discriminant analyses for multiclass classification among the ALS, PD, and HC groups, and (2) regularized regression models to evaluate their associations with functional outcomes.

RESULTS: Both neurodegenerative disease cohorts exhibited a reorganization of hierarchical rhythmic modulation characterized by reduced prosodic-level modulation and increased syllabic-level modulation. Such changes were, however, driven primarily by articulatory impairment in ALS and by respiratory-laryngeal impairment in PD. In addition, both cohorts showed reduced regularity of intra-syllabic temporal organization and altered within-sentence pausing patterns, whereas the ALS cohort exhibited additional changes in between-sentence pausing. Measures capturing these rhythmic and pausing disturbances demonstrated promising classification performance (mean accuracy = 0.77; mean area under the curve [AUC] = 0.84) and meaningful associations with functional speech decline across diseases.

DISCUSSION: The rhythm and pause measures captured disease-specific subclinical changes in the physiological substrates underlying rhythmic and pausing disturbances in ALS and PD, demonstrating potential as clinically applicable, objective markers to enable more accurate differential diagnosis, targeted intervention, and measurement-based care for neurodegenerative motor speech disorders.},
}

@article {pmid42762093,
year = {2026},
author = {Wang, PS and Zou, SM and Wei, Q and Wu, ZY and Li, HF},
title = {Weak association of pathogenic ERBB4 variants with amyotrophic lateral sclerosis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17582024.2026.2736021},
pmid = {42762093},
issn = {1758-2032},
abstract = {INTRODUCTION: ERBB4 variants were reported to cause amyotrophic lateral sclerosis (ALS). However, gene burden analyses did not find an enrichment of rare variants in patients, leaving the pathogenic role of ERBB4 in ALS unclear. Therefore, this study aimed to reassess the association of ERBB4 variants with ALS.

METHODS: Next-generation sequencing was performed in 250 ALS and 714 non-ALS patients. Low-frequency, deleterious non-synonymous ERBB4 variants were filtered, and their allele frequencies were compared between groups.

RESULTS: In total, 42 low-frequency and deleterious ERBB4 variants were identified in patients and normal controls, with three variants in all groups. There was no significant difference in allele frequencies between ALS and non-ALS groups. Additionally, four reported pathogenic variants (c.158A > G, c.284G > A, c.965T > A, and c.1624G > A) were observed in patients with neuromuscular disease or leukoencephalopathy, as well as normal controls. Based on the evidence from this study, c.284G > A was reclassified as a likely benign variant, while the others were reclassified as uncertain significance according to the American College of Medical Genetics and Genomics Guidelines.

DISCUSSION: These results suggest a modest association between ERBB4 variants and ALS, underscoring the need for clinicians to conduct more careful molecular diagnosis and genetic consultations for ALS patients with ERBB4 variants.},
}

@article {pmid42762623,
year = {2026},
author = {Uppal, G and Singh, A and Parasuraman, RN and Kumar, A and Jena, KC and Kumar, R},
title = {Label-free analysis of grade-specific molecular alterations in osteoarthritic subchondral bone using Raman spectroscopy coupled with MCR-ALS.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {365},
number = {},
pages = {128743},
doi = {10.1016/j.saa.2026.128743},
pmid = {42762623},
issn = {1873-3557},
abstract = {Changes in subchondral bone metabolism are central to osteoarthritis (OA) progression, highlighting the need for sensitive, label-free analytical approaches capable of resolving molecular-level alterations in complex biological tissue matrices. Raman spectroscopy is a powerful, non-destructive tool for detecting molecular changes in intact pathological tissues; however, overlapping spectral bands obscure accurate interpretation. In this study, Raman spectroscopy combined with multivariate curve resolution-alternating least squares (MCR-ALS) was applied to human subchondral bone at different stages of osteoarthritic degeneration to identify grade-specific molecular changes. The MCR-ALS approach enabled decomposition of overlapping Raman spectra into distinct biochemical components attributed to mineral, lipid, and collagen. Comparative statistical analysis revealed grade-dependent biochemical alterations in osteoarthritic subchondral bone. No significant changes occurred in mineral or lipid content at the early stage; however, significant mineral reduction and enhanced lipid accumulation were observed in advanced-stage degeneration. Collagen content exhibited an initial increase in the early stage, followed by a substantial decline in the advanced stage, accompanied by progressive disruption of its structural organization. Deconvolution of the amide I band further enabled improved characterization of collagen structural changes in intact tissue. These findings demonstrate that the Raman-MCR approach effectively resolves complex biological spectra, sensitively detects stage-specific molecular alterations in osteoarthritic subchondral bone, and offers a robust analytical framework for the label-free characterization of intact tissues.},
}

@article {pmid42762936,
year = {2026},
author = {Luo, L and Chen, W and Luo, S and Ma, S and Liu, K and Gong, Q and Huang, B and Chen, Z and He, Y and Wang, D},
title = {Defective ATP13A2-ITCH-ALIX signaling impairs intraluminal vesicle biogenesis and increases neuronal vulnerability.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112897},
doi = {10.1016/j.cellsig.2026.112897},
pmid = {42762936},
issn = {1873-3913},
abstract = {ATP13A2 is a lysosomal P5B-type ATPase whose loss-of-function mutations are associated with a spectrum of neurodegenerative disorders, including early-onset Parkinson's disease, Kufor-Rakeb syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. Although ATP13A2 is known to contribute to lysosomal homeostasis and, thereby, to neuronal degeneration, emerging evidence suggests that it may also influence exosome biology. However, the mechanisms by which endogenous ATP13A2 regulates exosome biogenesis and the relevance of this process to neuronal vulnerability remain unclear. In the present study, using multiple ATP13A2-deficient human cell models, we demonstrated that ATP13A2 deficiency impairs intraluminal vesicle (ILV) biogenesis and reduces exosome secretion across diverse cellular contexts. Loss of ATP13A2 did not markedly affect endocytosis, early endosome abundance, or multivesicular body formation, but it consistently reduced ILV density within multivesicular bodies. Mechanistically, ATP13A2 deficiency promoted lysosome-associated accumulation of the E3 ubiquitin ligase ITCH, which enhanced ubiquitin-proteasome-dependent degradation of ALG-2-interacting protein X (ALIX), a critical adaptor of the endosomal sorting complex required for transport machinery that mediates ILV membrane remodeling. Restoration of ALIX expression or reduction of Itchy E3 ubiquitin-protein ligase (ITCH) activity rescued the ILV biogenesis defects in ATP13A2-deficient neuronal cells. Furthermore, dysregulation of the ATP13A2-ITCH-ALIX pathway increased neuronal susceptibility to mitochondrial stress, whereas restoration of ALIX or reduction of ITCH activity markedly improved neuronal survival. Together, these results identify an ATP13A2-ITCH-ALIX signaling axis linking lysosomal dysfunction to impaired ILV biogenesis and exosome regulation. Our study suggests that defective ILV biogenesis contributes to neuronal vulnerability and that modulation of the ATP13A2-ITCH-ALIX pathway may represent a therapeutic strategy for ATP13A2-associated neurodegeneration.},
}

@article {pmid42485274,
year = {2026},
author = {Shakeri, N and Yadegari, F and Alipour, S and Teymouri, R},
title = {A Secondary Analysis of Time Reference in the Discourse of Persian-Speaking Individuals with Fluent and Non-Fluent Aphasia.},
journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)},
volume = {},
number = {},
pages = {1-10},
doi = {10.1159/000553206},
pmid = {42485274},
issn = {1421-9972},
abstract = {INTRODUCTION: According to the Past Discourse Linking Hypothesis (PADILIH), people with agrammatic aphasia have difficulty referring to the past tense. Yet, the account is challenged by task-dependent arguments, i.e., unlike spontaneous speech tasks, structured tests require predictable answers from people with aphasia (PWA), keeping them far from free retrieval of tense forms. The current study was aimed at examining time reference in the discourse of fluent and non-fluent Persian-speaking PWAs using secondary data.

METHODS: We used the transcribed discourse samples of Alipour et al.'s (2024) study, which were elicited through a picture description task, open-ended questions, and narrative speech of their PWA and non-brain-damaged (NBD) participants. We counted the present imperfect (or present), past tense, simple past, past perfect, past imperfect, present perfect and future imperfect (or future). Time reference categories were compared between and within groups. PWA tense/aspect errors were evaluated quantitatively and qualitatively.

RESULTS: The fluent group used the past imperfect more than NBDs; NBDs used the present and imperfect aspect more than the fluent group (p < 0.01). NBDs used the present imperfect, simple past, present perfect, future imperfect, past tense, perfect aspect and imperfect aspect more than the non-fluent group (p < 001). Both PWA groups made errors in referring to past, present and future tenses, but in most cases were able to use the appropriate time reference.

CONCLUSION: The presence of a deficit in past tense marking was not confirmed in the present study. The finding does not support PADILIH; yet, further research is needed across tasks and languages.},
}

@article {pmid42752431,
year = {2026},
author = {Cedric, W and Uli, L},
title = {Development and Chemical Stability Assessment of a Methyl-β-Cyclodextrin-Containing Dextromethorphan/ Quinidine Oral Solution for Extemporaneous Compounding.},
journal = {International journal of pharmaceutical compounding},
volume = {30},
number = {4},
pages = {393-399},
pmid = {42752431},
issn = {1092-4221},
mesh = {*Dextromethorphan/chemistry/administration & dosage ; *Quinidine/chemistry/administration & dosage ; *beta-Cyclodextrins/chemistry ; Drug Stability ; *Drug Compounding ; Solubility ; Drug Combinations ; Drug Storage ; Administration, Oral ; Excipients/chemistry ; Pharmaceutical Solutions ; Bulk Drugs ; },
abstract = {Pseudobulbar affect is a distressing condition frequently observed in patients with amyotrophic lateral sclerosis (ALS), for which a fixed-dose combination of dextromethorphan and quinidine is approved in the United States. In Europe, no commercial product is available, and compounded capsules or suspensions are used; however, capsules may be unsuitable for patients with dysphagia, and suspensions require shaking before administration. The aim of this study was to develop simple fully water-soluble formulation of dextromethorphan hydrobromide and quinidine sulfate using methyl-ß-cyclodextrin as a solubilizing agent and to evaluate its stability under different storage conditions, enabling pharmacies to compound the preparation without complex infrastructure. Preliminary qualitative solubility experiments showed that the dextromethorphan hydrobromide/ quinidine sulfate powder mixture did not dissolve in water without methyl-ß-cyclodextrin. Addition of methyl-ß-cyclodextrin improved dissolution; however, the initial preparation targeting 20 mg/mL dextromethorphan hydrobromide and 10 mg/mL quinidine sulfate in a final volume of 100 mL remained incompletely dissolved. Increasing the final volume to 250 mL yielded a clear formulation containing nominal concentrations of 8.4 mg/mL dextromethorphan hydrobromide and 4.2 mg/mL quinidine sulfate. Three independently prepared batches were stored in amber PET bottles providing light protection and fitted with child-resistant closure at 2-8°C, 15-25°C, and 40°C and analyzed by HPLC for four weeks. HPLC assay values remained within 10% of the corresponding baseline values at each storage condition, and no visible precipitation was observed. The results support the physical clarity and chemical consistency of the tested methyl-ß-cyclodextrin- containing formulation over four weeks under the evaluated storage conditions. Microbiological stability, preservative effectiveness, formal method validation in the author's laboratory, and the extent of cyclodextrin inclusion complexation were not assessed. This formulation may serve as a basis for further pharmaceutical, microbiological, and clinical evaluation of an extemporaneously compounded oral liquid.},
}

*Dextromethorphan/chemistry/administration & dosage
*Quinidine/chemistry/administration & dosage
*beta-Cyclodextrins/chemistry
Drug Stability
*Drug Compounding
Solubility
Drug Combinations
Drug Storage
Administration, Oral
Excipients/chemistry
Pharmaceutical Solutions
Bulk Drugs

@article {pmid42753291,
year = {2026},
author = {Tamiz, AP and Baran, SW and Hartung, T and Wu, WW},
title = {New approach methodologies in neurotherapeutics development.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01056},
doi = {10.1016/j.neurot.2026.e01056},
pmid = {42753291},
issn = {1878-7479},
abstract = {New Approach Methodologies (NAMs) offer substantial opportunities to transform neurotherapeutics discovery, optimization, and development, reducing the timeline to translate central nervous system (CNS) innovations to patients. Strategically deployed, NAMs enhance the predictive value of preclinical studies for human outcomes while reducing reliance on animal models. Current scientific community interest focuses particularly on human-based and -derived systems, in silico and AI-driven models, and advanced microphysiological platforms, reflecting a shift toward human-centric drug development paradigms. Despite this momentum, significant challenges remain, including NAM reproducibility and validation, the establishment of standardized performance criteria, data sharing, and the evolution of regulatory frameworks needed to enable consistent adoption across the neurotherapeutics continuum. Nevertheless, there is a rich history of developing and adopting methodologies, particularly for improving the prediction of neurotherapeutic safety profiles while reducing animal use, and for advancing understanding of drug delivery across the blood-brain barrier, and the assessment of adverse neurological effects. These advances have begun to influence regulatory decision-making and are increasingly reflected in guidance and review practices. Furthermore, NAMs are showing concrete impact in neurological disorders, including Epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, where human-relevant models and computational approaches support more precise characterization of disease mechanisms and therapeutic responses. In this paper, we examine the current and emerging roles of NAMs in neurotherapeutics development from government, academia, and industry perspectives, highlight key opportunities and limitations, and discuss the scientific, technical, and regulatory steps required to fully realize their potential in accelerating safe and effective CNS therapies.},
}

@article {pmid42753929,
year = {2026},
author = {Hawkes, BA and Goodrich, JM and Beitel, SC and Porter, C and Burgess, JL and Jung, AM and Furlong, MA},
title = {Associations of per- and polyfluoroalkyl substances (PFAS) exposures and firefighting experience with microRNA signatures previously linked to Amyotrophic Lateral Sclerosis (ALS): a cross-sectional analysis of active-duty municipal and airport firefighters.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103577},
doi = {10.1016/j.neuro.2026.103577},
pmid = {42753929},
issn = {1872-9711},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear etiology in sporadic cases. Blood microRNA (miRNA) expression varies between individuals with and without ALS. Firefighters may face elevated ALS risks due to occupational exposures, including elevated serum per- and polyfluoroalkyl substances (PFAS) concentrations.

METHODS: This study investigates the association between occupational firefighter characteristics (years of experience, incumbent status (binary; 1=incumbent, 0=recruit), serum PFAS) and ALS-relevant miRNA expression in U.S. firefighters across 10 states. MiRNA expression was quantified from blood collected from 608 firefighters. Serum PFAS concentrations were available for a subset of 302 participants. We identified 19 ALS-related miRNAs using miRWalk's Disease Ontology. Adjusted linear regression models estimated associations between exposures and miRNA expression, controlling for demographic and occupational factors.

RESULTS: In analyses of firefighter occupational characteristics (n=608), incumbent firefighters had significantly altered expression in ten ALS-related miRNAs compared to new recruits (p<0.05) and all remained significant after false discovery rate (FDR) adjustment for multiple testing (q<0.20). Years of firefighting was associated with lower expression of multiple miRNAs, including hsa-miR-23a-3p (β = -11.276, 95% CI: -18.870, -3.682), and this association remained significant after FDR correction. In PFAS analyses (n=302), higher serum PFAS concentrations were associated with 13 significant PFAS-miRNA associations (p<0.05) involving ALS-related miRNAs, including Sm-PFOS and hsa-let-7i-5p (β = -0.169, 95% CI: -0.287, -0.052), hsa-let-7c-5p (β = -0.128, 95% CI: -0.218, -0.037), and hsa-let-7e-5p (β = -0.113, 95% CI: -0.210, -0.017); PFNA and hsa-let-7c-5p (β = -0.126, 95% CI: -0.214, -0.037); and PFHxS and hsa-let-7i-5p (β = -0.126, 95% CI: -0.223, -0.029). Six remained significant after FDR adjustment (q < 0.20). Hsa-let-7e-5p was significantly lower in firefighters with higher Sm-PFOS, n-PFOS, and in incumbent firefighters.

CONCLUSIONS: Significant associations between PFAS exposure, firefighting status, and ALS-related miRNAs suggest that PFAS exposure and firefighting characteristics are associated with miRNA expression patterns previously linked to ALS, warranting further investigation into potential biological pathways.},
}

@article {pmid42754548,
year = {2026},
author = {Peters, GA and Bongiorno, DM and Misra, AJ and Chang, W and Allerhand, T and Kennedy, M and Dorsett, M and Rosen, T and Goldberg, SA and Cash, RE},
title = {Prehospital Sedation and Physical Restraint of Older Adults Presenting With Behavioral Health Emergencies: A Nationwide Cross-Sectional Study.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70731},
pmid = {42754548},
issn = {1532-5415},
abstract = {BACKGROUND: Management of behavioral health emergencies (BHE) such as acute agitation by emergency medical services (EMS) is associated with significant patient safety risks, particularly among older adults. However, the unique considerations for BHE among older adults may not be adequately addressed in prehospital BHE protocols and training. We aimed to provide the first nationwide description of EMS use of physical restraint and sedation for older adults with BHE in the United States.

METHODS: We conducted a cross-sectional evaluation of a nationwide convenience sample of 9-1-1 EMS encounters during 2023. We included EMS encounters for BHE that were managed by advanced life support (ALS) units. Outcomes of interest included physical restraint or administration of chemical sedation. Descriptive statistics were computed and stratified by patient age group. Differences in proportions with 95% confidence intervals were used to compare older (age ≥ 65 years) versus younger adults (age 18-64 years).

RESULTS: A total of 1,468,697 EMS encounters for BHE were included, of which 238,754 (16.3%) involved an older adult. Among 65,088 BHE encounters in which chemical sedation and/or physical restraint was used (older adults: n = 5915, 9.1%), older adults were more likely than younger adults to be sedated (69.2% vs. 61.3%) and less likely to be restrained (39.7% vs. 52.7%). Among those requiring sedation and/or restraint, benzodiazepines were more often used in older adults compared to younger adults (52.8% vs. 45.3%), antipsychotic agents were used at similar rates (15.4% vs. 14.9%), and ketamine was used slightly less often in older adults (5.5% vs. 6.6%).

CONCLUSIONS: Thousands of older adults presenting with BHE are restrained and/or sedated by EMS each year in the United States. Further work to improve evidence-based recommendations, protocols, and training specific to older adults is needed to help support EMS in these high-risk encounters.},
}

@article {pmid42756552,
year = {2026},
author = {Thompson, D and Williams, C and Price, G and Tosolini, AP and Falker-Gieske, C and Gilthorpe, JD and Schiavo, G and Fisher, EMC and Cunningham, TJ},
title = {Metabolic alterations in the absence of a neuromuscular phenotype in humanized SOD1[A5V] mice.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag302},
pmid = {42756552},
issn = {2632-1297},
support = {/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Amyotrophic lateral sclerosis caused by mutations in superoxide dismutase 1 (SOD1) accounts for 15-30% of familial cases and is typically autosomal dominant. How single amino acid changes in this small protein cause neurodegeneration is unknown. In North America, SOD1[A5V] is the most common familial SOD1 mutation and results in an aggressive form of amyotrophic lateral sclerosis. Here, we present a novel genomically humanized mouse model of SOD1[A5V] , in which the mouse Sod1 locus has been replaced by the human SOD1 gene, with intact genomic architecture of exons and introns, but bearing an A5 V mutation. In agreement with previously reported human genomic knock-in mice, the phenotype is mild; however, transcriptomic and metabolomic profiling reveal significant dysregulation of glycolysis, the tricarboxylic acid cycle, and lipid metabolism. These changes suggest an early bioenergetic imbalance that precedes neuromuscular impairment. Our findings support metabolic dysfunction as an early event in amyotrophic lateral sclerosis pathogenesis. This freely available SOD1[A5V] model provides a valuable tool for studying amyotrophic lateral sclerosis progression and identifying therapeutic targets for pre-symptomatic treatment.},
}

@article {pmid42752158,
year = {2026},
author = {Jambon, M and Smetana, JG and Battaglia, N and Di Biase, J},
title = {Children's and young adults' evaluations of distributional fairness in relation to other norms.},
journal = {Developmental psychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/dev0002261},
pmid = {42752158},
issn = {1939-0599},
abstract = {Although developmental theories have long conceptualized fairness in resource distribution contexts as a component of morality, this view has been challenged recently. Based on findings from two studies, Yucel et al. (2022) concluded that children-and perhaps adults-do not perceive fairness as a moral norm. Using social domain theory as a framework, this article considers (mis)conceptions in Yucel et al.'s definitions and measurement of morality and empirically reevaluates their claims regarding children's and adults' perceptions of fairness. Study 1 used an online survey to examine university students' (N = 306; 18-24 years) judgments and justifications in response to hypothetical scenarios involving straightforward moral and nonmoral norm violations. Participants' reasoning about harm and resource inequality centered on concerns for others' welfare and fairness. Judgments of harm and resource inequality were also less dependent on the existence of norms/expectations than were conventional violations (nonmoral transgressions). Study 2 used interviews to examine whether children (N = 50; 4-8 years) also treat resource inequality as a moral concern. Children judged unequal resource distribution, like harm, as more norm-independent than conventions and provided justifications focused on fairness. In Study 3, a partial reanalysis of data from Yucel et al.'s Study 1 suggested that their failure to detect a significant difference in norm independence judgments of resource inequality and conventional transgressions was likely due to insufficient statistical power. Together these findings suggest that children and adults do perceive distributional fairness as a moral norm as conceptualized within social domain theory. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42746532,
year = {2026},
author = {Zhang, E and Oh, P and Shamas, T and Patwa, HS and Johung, KL},
title = {Radiation Therapy for Sialorrhea in Patients With Amyotrophic Lateral Sclerosis: A Case Series and Critical Review.},
journal = {Advances in radiation oncology},
volume = {11},
number = {9},
pages = {102135},
pmid = {42746532},
issn = {2452-1094},
abstract = {PURPOSE: Radiation therapy (RT) for sialorrhea has historically used 3-dimensional techniques that broadly irradiate both major and minor salivary glands. However, some reports indicate that treatment of minor salivary glands may contribute to excessive xerostomia. In this retrospective case series, we assessed the efficacy and tolerability of oral-cavity-sparing volumetric modulated arc therapy (VMAT) and bilateral electron field radiation for sialorrhea in patients with amyotrophic lateral sclerosis (ALS) and reviewed the relevant literature.

METHODS AND MATERIALS: From 2014 to 2025, 6 patients with bulbar-onset ALS and medically refractory sialorrhea were treated with RT to the parotid and submandibular glands (20 Gy in 5 fractions) at a single institution. Five patients received VMAT with 6 MV photons, and one received bilateral 16 MeV electrons. Clinical response, medication use, toxicity, and dosimetry were assessed. A PubMed search using "sialorrhea," "RT," and "amyotrophic lateral sclerosis" was performed for the literature review.

RESULTS: At a median follow-up of 15.05 months (range, 3.0-61.7 months), 5 of 6 patients (83.3%) achieved symptomatic improvement, with an average 60% patient-reported reduction in salivation and ≥2 point improvement in ALS Functional Rating Scale saliva subscore. Two discontinued anticholinergics, and 1 achieved complete resolution for 3 years. Acute toxicities with VMAT were mild and self-limiting, most commonly parotitis and thickened secretions. The patient treated with electrons developed grade 2 mucositis, not observed with VMAT. Late toxicities, including xerostomia, were minimal and transient. Dosimetry showed higher larynx and oral cavity doses with electrons, whereas VMAT delivered slightly higher spinal cord doses. Critical literature review supported RT as an effective and well-tolerated intervention.

CONCLUSIONS: RT provides durable relief of refractory sialorrhea in ALS with manageable toxicity. VMAT response is comparable with historical outcomes and may offer dosimetric advantages that correlate with reduced acute toxicities, although its clinical benefit and cost-effectiveness warrant further validation.},
}

@article {pmid42746632,
year = {2026},
author = {Artigas, R and Menchaca, C and Jara, E and Mondino, A and Vázquez, N and Branda Sica, A and Llambí, S},
title = {SOD1:c.118G>A mutation in the Cimarrón Uruguayo dog: prevalence, drift dynamics, and structural effects.},
journal = {Brazilian journal of veterinary medicine},
volume = {48},
number = {},
pages = {e005526},
pmid = {42746632},
issn = {2527-2179},
abstract = {Canine degenerative myelopathy (DM) is associated with a missense mutation in the SOD1 gene (c.118G>A), which results in the E40K amino acid substitution and promotes protein aggregation mechanisms similar to those described in human amyotrophic lateral sclerosis. The present study estimated the frequency of the SOD1:c.118G>A mutation in the Cimarrón Uruguayo dog and evaluated its structural and population implications. A total of 82 dogs were genotyped. The mutant allele was detected at a frequency within the range of common variants (q = 0.177), and genotype distribution did not deviate from Hardy-Weinberg equilibrium. Wright-Fisher simulations showed that stochastic processes alone may substantially influence allele-frequency trajectories over time. Additionally, a high-resolution melting (HRM) assay was optimized and enabled clear discrimination of the three genotypes, supporting its use as a rapid genotyping approach. Sanger sequencing of SOD1 exons 2-5 was performed in a subset of individuals to identify additional coding variants. Sequencing revealed no additional non-synonymous variants, except for a synonymous substitution in exon 4. Structural inspection indicated that the E40K substitution does not alter the local hydrogen-bonding pattern but produces a charge inversion that modifies the electrostatic environment surrounding residues 40 and 91. These findings support the hypothesis that electrostatic alterations in this region may contribute to an increased aggregation propensity of mutant SOD1 and provide new insights into the molecular and population context of this mutation in the Cimarrón Uruguayo breed.},
}

@article {pmid42747163,
year = {2026},
author = {Sanna, C and Sanna, M and Borghero, G and Redolfi, S},
title = {Noninvasive ventilation in patients with amyotrophic lateral sclerosis: Is home sleep apnea testing a useful tool for initiating noninvasive ventilation?.},
journal = {Multidisciplinary respiratory medicine},
volume = {21},
number = {},
pages = {1088},
doi = {10.5826/mrm.2026.1088},
pmid = {42747163},
issn = {1828-695X},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration and eventual respiratory failure, often first manifesting during sleep. Timely detection of nocturnal respiratory impairment is critical for initiating noninvasive ventilation (NIV), one of the few therapies proven to improve survival. Although polysomnography (PSG) is the reference standard, it is not always readily available in clinical practice.

CASE PRESENTATION: We describe a 62-year-old man with spinal-onset ALS who underwent home sleep apnea testing (HSAT) for respiratory assessment. Although standard metrics were within normal limits, careful manual analysis of respiratory signals revealed diaphragmatic dysfunction through position-dependent desaturation and paradoxical breathing. NIV was initiated, resulting in improvements in sleep quality and daytime functioning.

CONCLUSIONS: This case illustrates the value of HSAT as a pragmatic and accessible tool for early detection of respiratory involvement in ALS, particularly when combined with detailed waveform inspection in setting where PSG is unavailable. Additionally, it emphasizes the importance of individualized NIV titration and interface optimization to ensure adherence and therapeutic benefit.},
}

@article {pmid42747562,
year = {2026},
author = {Zhang, Y and Wei, K and Lin, H and Guo, Z and Lu, Y and Ma, T},
title = {Unraveling the regulatory nexus of aggrephagy in ALS: identification of novel candidate biomarkers and molecular triggers.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42747562},
issn = {1573-7365},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Autophagy/genetics/physiology ; Mice ; Biomarkers/metabolism ; Superoxide Dismutase-1/genetics ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Motor Neurons/metabolism ; Humans ; Transcriptome ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder involving multiple systems, with motor neuron degeneration as its primary feature. This disease can be classified into sporadic and familial types. Genes such as SOD1, C9orf72, FUS, and TDP-43 have been identified as the main causative genes for familial ALS. Multiple bioinformatics tools combined with an experimental verification strategy have helped in understanding the association of a selective autophagy pathway called aggrephagy with the disease.

RESULTS: The transcriptome data of spinal cord tissue from SOD1-G93A mice was obtained from the Gene Expression Omnibus (GEO) database. Based on the GSE281064 dataset, we investigated aggrephagy-related transcriptional alterations in the SOD1-G93A mouse model of ALS. After comparison with the aggrephagy-related genes (AGGRGs) set included in the GeneCards database, 49 candidate genes closely related to the autophagy process were obtained. Functional enrichment analysis showed these genes participate in extracellular matrix remodeling, hyaluronic acid and glycosaminoglycan metabolism, tumor necrosis factor regulation, and lysosomal function, indicating central roles in inflammation, apoptosis, and metabolic disorders. Based on feature selection algorithms, this study employed machine learning methods such as random forest (RF), extreme gradient boosting (XGBoost), and Boruta to conduct multi-angle screening of candidate genes. The intersection of the results ultimately identified three key genes: Ctsb, Kif11, and S100a6.

CONCLUSIONS: In both the training data and external validation data, Ctsb and S100a6 showed significant upregulation and demonstrated excellent discriminatory capabilities. The nomogram constructed based on Ctsb and S100a6 expression showed potential for distinguishing SOD1-G93A model samples from nontransgenic controls. The predicted probability demonstrated the potential of these two as candidate biomarkers. Meanwhile, further validation is needed in larger independent population cohorts in the future. The SOD1-G93A mouse model and SOD1-G93A-expressing NSC34 cell model showed expression patterns of Ctsb and S100a6 consistent with the bioinformatics findings. Through S100a6 overexpression and knockdown experiments in an NSC34 motor neuron-like ALS model, we found that S100a6 impaired autophagy and promoted SOD1 aggregation. These findings further validate its potential as a biomarker and provide new insights into the pathogenesis of ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
Animals
*Autophagy/genetics/physiology
Mice
Biomarkers/metabolism
Superoxide Dismutase-1/genetics
Mice, Transgenic
Spinal Cord/metabolism/pathology
Motor Neurons/metabolism
Humans
Transcriptome

@article {pmid42748981,
year = {2026},
author = {Zhang, C and Yang, Z},
title = {The double-edged sentinel: cGAS-STING as a context-dependent regulator of microglial senescence and neuronal genotoxic stress in neurodegeneration.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112118},
doi = {10.1016/j.brainresbull.2026.112118},
pmid = {42748981},
issn = {1873-2747},
abstract = {BACKGROUND: Neurodegenerative diseases may continue to progress even when a pathogenic protein aggregate is reduced, suggesting that downstream inflammatory and genotoxic circuits can become partly autonomous. This narrative review examines cGAS-STING as a context-dependent regulator of DNA-stress responses in the ageing and proteinopathic brain.

METHODS: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for mechanistic, translational, and human-tissue studies of cGAS-STING, DNA damage, mitochondrial quality control, neuroinflammation, and major neurodegenerative diseases. Evidence was separated into biochemical or cellular, animal, and human observations, and contradictory findings were retained.

RESULTS: Mitochondrial DNA leakage is a recurrent candidate trigger, while activity-induced nuclear DNA breaks, defective repair, retrotransposon-derived cDNA, and micronuclear rupture provide conditional inputs. Microglial evidence is currently more extensive and causally developed than neuron-specific evidence; neuronal STING is most firmly supported in selected contexts such as excitotoxic or ischemic stress. Across Alzheimer disease, Parkinson disease, ALS/FTD, multiple sclerosis, and Huntington disease, cGAS-STING-associated inflammation is plausible but not uniform, and human validation remains limited. Therapeutic strategies therefore require cell-, source-, and stage-aware modulation rather than indiscriminate pathway ablation.

CONCLUSION: cGAS-STING is best regarded as a testable kinetic-bottleneck model, not a universal driver of neurodegeneration. Longitudinal human studies and cell-resolved biomarkers are needed to determine when recalibration can suppress pathological inflammation while preserving antiviral and homeostatic functions.},
}

@article {pmid42749235,
year = {2026},
author = {Knezovic, A and Krsnik, A and Homolak, J and Babic Perhoc, A and Deskin, A and Virag, D and Salkovic-Petrisic, M and Osmanovic Barilar, J},
title = {From systems to cells: Metabolic mechanisms underlying risk divergence in Alzheimer's disease and amyotrophic lateral sclerosis.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {106982},
doi = {10.1016/j.neubiorev.2026.106982},
pmid = {42749235},
issn = {1873-7528},
abstract = {Epidemiological studies show an inverse relationship between metabolic disorders and two major neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Obesity, type 2 diabetes (T2DM), and reduced physical activity increase AD risk, whereas in ALS cardiometabolic factors, particularly T2DM, show inverse, age-dependent associations with disease risk. This review integrates epidemiological, clinical, and experimental evidence to suggest that cell-type-specific energy metabolism underlies these contrasting risk profiles. Neurons and skeletal muscle differ in metabolic organization, substrate use, and redox capacity. Neurons rely mainly on glucose and lactate and have limited fatty acid oxidation, making them vulnerable to lipid overload, insulin resistance, and oxidative stress, hallmarks of AD. In contrast, skeletal muscle is metabolically flexible, efficiently oxidizes fatty acids, and has strong antioxidant defenses, which may protect against ALS. These cell-type-specific metabolic profiles are proposed to causally shape disease susceptibility: neuronal lipid overload and impaired redox homeostasis promote amyloid and tau pathology in AD, whereas preserved muscle fatty acid oxidation and antioxidant capacity support neuromuscular junction stability and delay motor neuron degeneration in ALS. Hypermetabolism, hypothalamic dysfunction, glial-neuronal coupling and lactate shuttling may further shape disease susceptibility. Overall, these patterns likely reflect distinct cellular responses to metabolic stress.},
}

@article {pmid42749372,
year = {2026},
author = {Yaghobi, M and Ahmadi, F and Mohammad Khan Kermanshahi, S and Kazemnejad, A and Vaismoradi, M},
title = {Design and psychometric properties of an instrument to evaluate nursing students' perceptions of discrimination by nurse educators: a protocol for a mixed-method study.},
journal = {BMJ open},
volume = {16},
number = {9},
pages = {e120281},
pmid = {42749372},
issn = {2044-6055},
mesh = {Humans ; Psychometrics ; *Students, Nursing/psychology ; *Faculty, Nursing/psychology ; Qualitative Research ; Reproducibility of Results ; Research Design ; },
abstract = {INTRODUCTION: Perceived discrimination by nurse educators is a harmful phenomenon in nursing education that influences nursing students in both classroom and clinical settings. It is associated with psychological distress, reduced learning outcomes, feelings of hopelessness and higher rates of attrition. There is a need to identify the dimensions of discrimination for developing strategies to promote educational justice. This research aims to develop and test the psychometric properties of an instrument to evaluate nursing students' perceptions and experiences of discrimination by nurse educators.

METHODS AND ANALYSIS: A sequential exploratory mixed-methods design (QUAL → QUAN) will be used in this research. Phase 1 involves a qualitative descriptive study using semistructured interviews with nursing students chosen through purposive sampling with the consideration of maximum variation. Data will be analysed using conventional qualitative content analysis and trustworthiness will be addressed according to Lincoln and Guba's criteria. In phase 2, the qualitative findings will guide item generation and preliminary scale development based on Waltz et al's framework. In phase 3, psychometric properties of the scale will be evaluated in terms of content, face, construct validity and reliability. This study provides preliminary evidence supporting the validity, reliability and cultural appropriateness of an instrument for systematic assessment of perceived discrimination among nursing students.

ETHICS AND DISSEMINATION: This protocol describes a mixed-method study conducted as part of a doctoral thesis that explores nursing students' perceptions of discrimination by nurse educators. The study has received ethical approval from the Research Ethics Committees of Tarbiat Modares University, Iran (decree code: IR.MODARES.REC.1404.068). The findings will provide educational experts and policymakers with evidence-based insights to inform the development of interventions aimed at reducing discrimination and promoting justice and equity in nursing education.},
}

Humans
Psychometrics
*Students, Nursing/psychology
*Faculty, Nursing/psychology
Qualitative Research
Reproducibility of Results
Research Design

@article {pmid42749468,
year = {2026},
author = {Mercadante, S},
title = {Non-invasive ventilation (NIV) and high-flow nasal therapy (HFNT) in palliative care: a critical narrative review.},
journal = {BMJ supportive & palliative care},
volume = {},
number = {},
pages = {},
doi = {10.1136/spcare-2026-006580},
pmid = {42749468},
issn = {2045-4368},
abstract = {BACKGROUND: Dyspnoea is a prevalent, debilitating symptom in advanced life-limiting illnesses. While opioids and non-pharmacological measures remain foundational, refractory breathlessness presents a major palliative challenge.

OBJECTIVES: To critically appraise the evidence regarding patient selection, comparative tolerability, adverse effects and ethical considerations of non-invasive ventilation (NIV) and high-flow nasal therapy (HFNT) in palliative care.

METHODS: A comprehensive narrative review of literature from PubMed, Embase and Cochrane Library (from inception to June 2026) and major clinical guidelines was conducted.

RESULTS: NIV is best supported in hypercapnic respiratory failure (PaCO >45 mm Hg), showing benefits in chronic obstructive pulmonary disease exacerbations, pulmonary oedema and amyotrophic lateral sclerosis (ALS). In advanced cancer, NIV reduces dyspnoea primarily in hypercapnic patients but mask discomfort and communication barriers limit tolerability. Conversely, HFNT has emerged as a superiorly tolerated option in hypoxemic failure-particularly in end-stage interstitial lung disease (ILD) and advanced cancer-providing significant dyspnoea relief while preserving oral intake and verbal communication until the end of life. Time-limited trials (<1 hour for NIV; 2 hours for HFNT) help identify early responders. Ethical challenges include potential overtreatment and support withdrawal complexities.

CONCLUSIONS: Respiratory support selection should be guided by respiratory physiology (hypercapnic vs hypoxemic), explicit goals of care and tolerability. NIV remains optimal for hypercapnic failure, whereas HFNT offers superior comfort and preserves communication in hypoxaemic patients. Robust randomised trials are needed.},
}

@article {pmid42750159,
year = {2026},
author = {Torabi, SJ and Humphrey, CD and Kriet, JD and Tollefson, TT},
title = {Invited Commentary on: Xiao and Hadlock et al.'s "Rapid Restoration: Suture Stabilization of the Central Facial Landmarks": Patient Selection for Bridging Before Reanimation.},
journal = {Facial plastic surgery & aesthetic medicine},
volume = {},
number = {},
pages = {26893614261486968},
doi = {10.1177/26893614261486968},
pmid = {42750159},
issn = {2689-3622},
}

@article {pmid42750182,
year = {2026},
author = {Xiao, R and Hadlock, TA},
title = {Response to: "Commentary on Xiao and Hadlock et al.'s 'Rapid Restoration: Suture Stabilization of the Central Facial Landmarks': Patient Selection for Bridging Before Reanimation".},
journal = {Facial plastic surgery & aesthetic medicine},
volume = {},
number = {},
pages = {26893614261486969},
doi = {10.1177/26893614261486969},
pmid = {42750182},
issn = {2689-3622},
}

@article {pmid42750660,
year = {2026},
author = {Chetty, N and Bennett, J and Schone, HR and Fry, A and Yoo, PE and Lacomis, D and Oxley, TJ and Collinger, JL and Putrino, DF and Weber, DJ},
title = {Measuring motor intent for BCI control-A comparative analysis of signal quality of simultaneously recorded vECoG and scalp EEG.},
journal = {Journal of neural engineering},
volume = {23},
number = {5},
pages = {},
pmid = {42750660},
issn = {1741-2552},
support = {F32 MH139145/MH/NIMH NIH HHS/United States ; UH3 NS120191/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Brain-Computer Interfaces/standards ; *Electroencephalography/methods/standards/instrumentation ; *Scalp/physiology ; Male ; *Electrocorticography/methods/standards/instrumentation ; *Intention ; Female ; Movement/physiology ; },
abstract = {Objective.Stent-electrode arrays enable endovascular brain-computer interfaces (BCI) by recording cortical neural activity from within the superior sagittal sinus and have recently been evaluated in an early feasibility clinical trial in the United States (ClinicalTrials.gov: NCT05035823). For a BCI to be viable, the signals need to be high quality to enable accurate decoding of user intent. Compared to electrodes placed on the scalp for electroencephalography (EEG), stent-electrode arrays lie closer to the cortical surface and would presumably offer higher signal quality yet a direct comparison of intravascular and scalp-based neural recordings in humans has not yet been investigated.Approach.We directly compared the signal quality of vascular electrocorticography (vECoG) versus scalp EEG signals in one participant with severe upper limb paralysis due to ALS. During two experimental sessions, the participant underwent simultaneous recording with the stent-electrode array and a scalp EEG using a gel cap. The participant was visually cued to attempt motor tasks, such as repeated flexion and extension of the ankles. Signal quality was assessed by quantifying motor modulation strength, differentiation of movement effort, and spatial lateralization. Noise metrics evaluated the relative impact of artifacts including 60 Hz line noise, electrocardiogram contamination, eye blinks, jaw clenching, and vocalization.Main results.Both recording modalities exhibited significant modulation during attempted movement relative to rest, with vECoG generally demonstrating significantly stronger modulation per channel in some frequency bands and conditions. Motor modulation was significantly reduced during motor imagery compared to overt movement in both modalities. Spatial source localization between left and right ankle movement did not reach significance for either modality. Each modality was vulnerable to some artifacts while generally unaffected by others. Scalp EEG showed large susceptibility to ocular artifacts and cranial muscle activity due to its proximity to superficial physiological sources, whereas vECoG exhibited prominent cardiac activity.Significance.Within this participant, the large modulation during attempted movement recorded with vECoG, unaffected by the attenuating effects of the skull, coupled with fewer artifacts in the frequency bands of interest, provides preliminary evidence that the stent-electrode arrays can acquire high quality neural signals that could support BCI control.},
}

Humans
*Brain-Computer Interfaces/standards
*Electroencephalography/methods/standards/instrumentation
*Scalp/physiology
Male
*Electrocorticography/methods/standards/instrumentation
*Intention
Female
Movement/physiology

@article {pmid42751043,
year = {2026},
author = {Oskarsson, B and Heckman, MG},
title = {From Vision to Validation: The Journey of Tofersen in Superoxide Dismutase 1 Gene-Associated Amyotrophic Lateral Sclerosis.},
journal = {Mayo Clinic proceedings. Innovations, quality & outcomes},
volume = {10},
number = {5},
pages = {100755},
pmid = {42751043},
issn = {2542-4548},
}

@article {pmid42751965,
year = {2026},
author = {van Eijk, RPA and Lu, Y},
title = {Comparing Missing Data Strategies for Generalized Pairwise Comparisons in Randomized Clinical Trials: A Simulation Study.},
journal = {Statistics in medicine},
volume = {45},
number = {20-22},
pages = {e70737},
doi = {10.1002/sim.70737},
pmid = {42751965},
issn = {1097-0258},
support = {VENI 09150162210036//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; AL230152//U.S. Department of Defense/ ; },
mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Computer Simulation ; Bias ; Amyotrophic Lateral Sclerosis/therapy ; Data Interpretation, Statistical ; Models, Statistical ; Longitudinal Studies ; Survival Analysis ; Endpoint Determination ; },
abstract = {Generalized pairwise comparisons are increasingly being used in randomized clinical trials. This study evaluates how missing data strategies impact the operating characteristics of endpoints combining overall survival and a longitudinal outcome. A simulation study was conducted to evaluate the impact of censoring and missing longitudinal data on the Type I error, power, and bias of a hierarchical composite endpoint. Seven missing data strategies were identified from the literature, including assigning ties to missing patient pairs, comparing patients at their last common visit, and applying multiple imputation. Conditional longitudinal and survival data were generated based on the natural history of amyotrophic lateral sclerosis. Simulation scenarios varied in censoring rates, extent of missing longitudinal data, differential attrition between treatment arms, and the dependency of missingness on disease severity. All methods were unbiased and maintained nominal Type I error when censoring and missingness were balanced across treatment arms. Under imbalance, however, Type I error increased-reaching up to 0.378 for some strategies. The last common visit strategy was the only approach that consistently preserved nominal error rates (0.025 ± 0.002). Regarding statistical power, all methods exhibited a loss of precision and increased bias under the alternative hypothesis as missingness increased. Multiple imputation partially recovered power and reduced bias but inflated the Type I error rate in scenarios with differential attrition. As generalized pairwise comparisons are increasingly used in pivotal clinical trials-and therefore in regulatory contexts-our findings provide practical guidance for selecting a robust primary analysis strategy and minimizing bias arising from incomplete data.},
}

Humans
*Randomized Controlled Trials as Topic/methods/statistics & numerical data
Computer Simulation
Bias
Amyotrophic Lateral Sclerosis/therapy
Data Interpretation, Statistical
Models, Statistical
Longitudinal Studies
Survival Analysis
Endpoint Determination

@article {pmid42742283,
year = {2026},
author = {Jacobson, R and Babu, S and Hurley, J and Zawar, I},
title = {ALS Research and Healey ALS MyMatch.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78364},
pmid = {42742283},
issn = {1531-8249},
}