@article {pmid42568821,
year = {2026},
author = {Okano, H},
title = {From neural development to regenerative medicine: A research journey in stem cell biology, spinal cord repair, and iPSC-based drug discovery.},
journal = {Regenerative therapy},
volume = {33},
number = {},
pages = {101157},
pmid = {42568821},
issn = {2352-3204},
abstract = {This commemorative article reflects on a research journey spanning neural development, stem cell biology, regenerative medicine, and iPSC-based drug discovery. My early work focused on RNA-mediated regulation in the nervous system, including studies on myelin basic protein gene regulation and the identification and functional characterization of the RNA-binding protein Musashi. These studies contributed to the conceptual foundation of neural stem cell biology and helped establish methods for identifying and isolating neural stem/progenitor cells, including those present in the adult human brain. Building on this foundation, my colleagues and I pursued translational research in spinal cord injury, ranging from analyses of injury pathophysiology and molecular interventions to preclinical studies using rodent and non-human primate models. These efforts ultimately led to the first-in-human clinical study of induced pluripotent stem cell-derived neural stem/progenitor cell transplantation for subacute spinal cord injury. In parallel, we developed patient-derived iPSC platforms for neurological disease modeling and drug discovery, particularly for amyotrophic lateral sclerosis, where iPSC-based screening identified Ropinirole as a therapeutic candidate and enabled reverse translational research linking cellular phenotypes with clinical responses. Looking ahead, I argue that the future of regenerative therapy will depend on the continued integration of developmental biology, stem cell science, disease modeling, rehabilitation, and clinical translation to address unmet medical needs in disorders of the central nervous system.},
}

@article {pmid42568823,
year = {2026},
author = {Ding, M and Lu, J},
title = {The Influence of Applied Voltage on Drying Kinetics, Quality, and Mathematical Modeling of Ginger During Electrohydrodynamic (EHD) Drying.},
journal = {Food science & nutrition},
volume = {14},
number = {8},
pages = {e72218},
pmid = {42568823},
issn = {2048-7177},
abstract = {This paper systematically evaluated the effects of electrohydrodynamic (EHD) on the drying characteristics, color, texture, moisture state, volatile components, and drying kinetics model of ginger. The results showed that EHD significantly increased the drying rate, rehydration rate, and effective moisture diffusion coefficient (D eff) of ginger. Among all the evaluated parameters, a voltage of 17 kV can produce the highest quality ginger. The drying rate of the 21 kV treatment group was 4.48 times higher than that of the control group (CG). ln[MR] showed a highly linear relationship with time (R [2] > 0.9). Among the ten thin-layer drying kinetics models, Midilli et al.'s model performed the best. Under 17 kV conditions, the best color retention was achieved for dried ginger. EHD drying significantly improved the texture of ginger. LF-NMR results showed a significant decrease in free water and an increase in bound water. Compared with the CG group, EHD showed good retention of most terpenoid compounds in dry ginger. SwissADME predicted six volatile compounds with good drug-like properties. Based on this study, it has been confirmed that the EHD technology has a good application in the ginger industry, providing theoretical support and experimental basis for the further expansion of EHD technology in the field of food drying.},
}

@article {pmid42569815,
year = {2026},
author = {Kondo, A and Hokkoku, K and Kanbayashi, T and Nakayama, T and Sasaki, T and Matsuno, H and Iguchi, Y and Fukutake, T and Ando, T and Kamiyama, T and Kim, P and Hasegawa, T and Hatanaka, Y and Kobayashi, S and Sonoo, M},
title = {"Abductor Sparing": A New Selective Involvement in ALS.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70374},
pmid = {42569815},
issn = {1097-4598},
support = {JP22K15738//Japan Society for the Promotion of Science/ ; 22K07524//Ministry of Education, Science, Sports and Culture of Japan/ ; 26K10419//Ministry of Education, Science, Sports and Culture of Japan/ ; 20FC1030//Ministry of Health, Labour and Welfare of Japan/ ; },
abstract = {INTRODUCTION/AIMS: Various signs of selective muscle involvement have been reported in amyotrophic lateral sclerosis (ALS) but such studies for the lower limbs are scarce. We formed a preliminary impression that hip abductors (Ab) are often preserved in ALS. We named this phenomenon "abductor sparing", and this study aimed to verify our findings.

METHODS: Patients with a confirmed diagnosis of ALS (ALS group) and patients with pyramidal weakness other than ALS (pyramidal group) were retrospectively identified. Medical Research Council (MRC) scores of 10 muscle groups in the lower limbs were evaluated. The proportion of patients with weakness (MRC score 4 or less) was compared between different groups.

RESULTS: We enrolled 61 patients in the ALS group and 27 patients in the pyramidal group. The most frequently weak muscle groups in both groups were big toe extensors and hip flexors. Ab was the third (70%) in the pyramidal group, whereas it was weak only in 30% of patients with ALS. This held true also for patients with ALS with shorter duration or less severity. "The lower limb flexor pattern", i.e., flexor muscles being weaker than extensor muscles, was observed both in ALS and pyramidal groups.

DISCUSSION: Patients with ALS generally showed similar muscle weakness patterns to those with pyramidal syndrome, except for abductor sparing. The reason for the latter phenomenon is unclear. Abductor sparing may be useful for early diagnosis of ALS, although larger studies with blinded evaluators are needed to confirm these findings.},
}

@article {pmid42570648,
year = {2026},
author = {Ye, P and Guo, B},
title = {Identification of Glycolysis-Related Diagnostic Biomarkers for Amyotrophic Lateral Sclerosis Using Machine Learning.},
journal = {Clinical laboratory},
volume = {72},
number = {8},
pages = {},
doi = {10.7754/Clin.Lab.2025.250766},
pmid = {42570648},
issn = {1433-6510},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism/blood ; *Biomarkers/metabolism/blood ; *Glycolysis/genetics ; *Machine Learning ; Predictive Learning Models ; Boosting Machine Learning Algorithms ; Blood Glucose/analysis/metabolism ; },
abstract = {BACKGROUND: Glycometabolism has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), yet the precise molecular mechanisms underlying this association remain poorly understood. The identification of reliable biomarkers for ALS diagnosis represents a critical unmet need in clinical practice, as early detection and intervention could significantly improve patient outcomes.

METHODS: We employed a comprehensive analytical approach combining two-sample Mendelian randomization analysis to investigate the causal relationship between blood glucose levels and ALS. Additionally, we integrated differential expression analysis, multiple machine learning algorithms, and correlation analyses to identify potential diagnostic biomarkers for ALS. The machine learning framework utilized gradient boosting tree methodology to construct predictive models, with performance evaluation conducted through cross-validation procedures.

RESULTS: Mendelian randomization analysis demonstrated a significant negative causal relationship between blood glucose levels and ALS risk. Through bioinformatic analysis and machine learning approaches, we successfully identified candidate genes and constructed a high-performance predictive model using gradient boosting tree methodology, achieving an average area under the curve (AUC) of 0.8782 in cross-validation. Validation studies utilizing both bulk and single-cell RNA sequencing datasets revealed that COL5A1 and VCAN genes play significant roles in ALS pathogenesis, likely through their involvement in glycolytic pathways.

CONCLUSIONS: Our findings provide novel insights into the molecular mechanisms linking glycometabolism and ALS, while identifying potential diagnostic biomarkers for the disease. The identified genes, COL5A1 and VCAN, represent promising targets for further investigation in ALS pathogenesis. However, the clinical translation of these findings requires validation through additional datasets and prospective clinical trials to establish their diagnostic utility and therapeutic potential.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism/blood
*Biomarkers/metabolism/blood
*Glycolysis/genetics
*Machine Learning
Predictive Learning Models
Boosting Machine Learning Algorithms
Blood Glucose/analysis/metabolism

@article {pmid42572287,
year = {2026},
author = {Okunomiya, T and Sakasai, T and Tsukita, K and Shimizu, R and Okusa, A and Adachi, M and Tomita, S and Tanaka, A and Kondo, T and Imamura, K and Inoue, H},
title = {Generation of mutant human SOD1 knock-in mouse lines at the Rosa26 locus as a platform for developing genome-editing therapies for amyotrophic lateral sclerosis.},
journal = {Experimental animals},
volume = {},
number = {},
pages = {},
doi = {10.1538/expanim.26-0040},
pmid = {42572287},
issn = {1881-7122},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, resulting in progressive paralysis and death within a few years of symptom onset. Although current treatments modestly slow the disease progression, effective disease-modifying and curative therapies remain an urgent unmet need. SOD1 mutations are one of the major genetic causes of familial ALS. The p.Leu127Ser (L126S) and p.Gly94Ser (G93S) variants are clinically relevant pathogenic variants for which appropriate animal models are needed for preclinical evaluation of gene-editing therapies. However, most existing SOD1 models rely on high copy overexpression of mutant SOD1. Therefore, animal models carrying a single copy mutant human SOD1 allele are required for evaluating the in vivo efficacy of genome editing therapies. Here, we used CRISPR/Cas9-mediated homology-directed repair to generate a knock-in mouse line at the Gt(ROSA)26Sor (Rosa26) locus carrying a single-copy, 11-kb human SOD1 genomic fragment, including all exons and introns, with the L126S mutation. The Rosa26-hSOD1[L126S] mice did not develop ALS-like phenotypes during the limited observation period. However, they faithfully retained a single-copy mutant human SOD1 genomic allele, providing a valuable preclinical platform for evaluating genome-editing therapies. We also generated Rosa26-hSOD1[G93S] mice carrying the SOD1 G93S mutation with comparable efficiency. Together, these mutant human SOD1 knock-in mouse lines provide a versatile and clinically relevant platform for the preclinical evaluation of genome-editing therapies targeting heterozygous SOD1 mutations.},
}

@article {pmid42572464,
year = {2026},
author = {Cannedy, S and Lesser, R and Yano, EM and Hamilton, AB and Fenwick, KM},
title = {Staff Perspectives on Optimising Organisational Responses to Patient-Initiated Workplace Violence.},
journal = {Journal of advanced nursing},
volume = {},
number = {},
pages = {},
doi = {10.1111/jan.70713},
pmid = {42572464},
issn = {1365-2648},
support = {PPO 21-272//US Department of Veterans Affairs/ ; RCS 05-195//US Department of Veterans Affairs/ ; RCS 21-135//US Department of Veterans Affairs/ ; },
abstract = {AIMS: To identify existing and ideal practices for responding to patient-initiated workplace violence in the US Veterans Health Administration.

DESIGN: Cross-sectional, descriptive qualitative design.

METHODS: Qualitative interviews with staff (n = 31) in eight veteran healthcare facilities located in the western United States (2023-2024). Guided by Spelten et al.'s model of strategies to reduce patient-initiated workplace violence, thematic analysis examined post-incident interventions with patients and identified recommendations for improvement.

RESULTS: Educating and setting limits with patients varied by facility. Most respondents were unaware of patient education/support that occurred post-incident. Respondents disagreed about the role that patients' clinical status should play; some wanted more leeway for certain patients (e.g., those diagnosed with dementia) and others wanted a consistent response (regardless of clinical status) to create a culture of respect.

CONCLUSION: Patient education and limit-setting are important elements in addressing patient-initiated workplace violence, but they are inconsistently used. Offering resources to patients is underutilised. Staff have differing perspectives on what constitutes ideal post-incident interventions for medically complex patients.

When responding to patient violence, healthcare systems may benefit from clear and consistently implemented protocols and tailored educational interventions and support for different patient populations (e.g., dementia). Staff may benefit from guidance on balancing patient care with limit-setting during encounters with medically complex patients.

IMPACT: We examined existing practices for responding to patient-initiated workplace violence and staff suggestions for improvement in a large healthcare system. Participants wanted additional and consistent patient interventions; opinions varied on how patient clinical status and intent should shape organisational responses. Staff can benefit from consistently implemented protocols for responding to patient violence. Healthcare systems may need to provide staff guidance on balancing patient care with limit-setting.

REPORTING METHOD: SRQR guidelines for qualitative studies.

No patient or public contribution.},
}

@article {pmid42572514,
year = {2026},
author = {Sheehy, TP and Sia, T and Morgan, PE and Zhao, Y and Mathieson, SR and Gibb, RM and Smith, AA and Wools, CA},
title = {Relationship between neck weakness in motor neurone disease and respiratory function: a retrospective study.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/17582024.2026.2705867},
pmid = {42572514},
issn = {1758-2032},
abstract = {AIMS: The primary aim was to explore the relationship between neck weakness in people with motor neurone disease (MND) and their respiratory function. The secondary aim was to identify whether neck weakness can be a prognostic factor.

METHODS: This was a retrospective observational cohort study. Data was collected from patient records on MND characteristics, neck weakness, respiratory function, and noninvasive ventilation (NIV) use. Multivariate modeling explored the effect of neck weakness on respiratory variables.

RESULTS: MND-related neck weakness was evident in 41% of 324 participants. Fifty-four percent used NIV and 17% became dependent on NIV during disease progression. The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC <50% and NIV use) as well as having an effect on time to death. Median time from neck weakness onset to death was 8 months (IQR 10 months; range 0 to 60 months) with bulbar onset the quickest, median of 7 months (IQR 7 months, range 0 to 43 months).

CONCLUSIONS: The presence of neck weakness is associated with a more rapid respiratory function decline in MND. In addition, neck weakness can be considered a prognostic factor in MND survival.},
}

@article {pmid42573583,
year = {2026},
author = {Yeow, A and Cleland, J and Soh, C and Balete, C},
title = {Sociotechnical Misalignments in Hospital AI System Implementation: Qualitative Case Study.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e87534},
pmid = {42573583},
issn = {1438-8871},
mesh = {Humans ; *Artificial Intelligence ; Qualitative Research ; },
abstract = {BACKGROUND: Implementing AI into real-world health care settings is known to be challenging, particularly regarding how well AI is embedded into the existing knowledge, practices, and procedures of a context. Understanding this process is critical for maximizing the successful implementation of AI tools and planning the time, costs, and resources needed for their successful implementation.

OBJECTIVE: This study sought to examine the contextual challenges of implementing an AI chatbot, ChatAI (which provided quick access to clinical and operational information without relying on the intranet), in a large tertiary government hospital by analyzing the impact of sociotechnical factors on its sustained use.

METHODS: We used an instrumental case study approach, utilizing interviews and meeting minutes. A total of 16 semistructured interviews were conducted with the implementation team and hospital staff who interacted with ChatAI. Interviews were audio-recorded and transcribed. Sociotechnical systems (STS) theory, specifically Davis et al's (2014) framework, was adopted to examine ChatAI's implementation and use.

RESULTS: Multiple misalignments among 5 of Davis et al's sociotechnical elements (goals, people, processes, technology, and infrastructure) limited ChatAI's user adoption and sustainability. Although the hospital's innovation center team attempted to address these initial misalignments, contextual changes such as new regulatory mandates, infrastructure changes, and evolving stakeholder practices introduced further misalignments between ChatAI and the hospital-eventually leading to its discontinuation.

CONCLUSIONS: This study highlights how sociotechnical misalignments can undermine the use and sustainability of large-scale implementation of AI systems. These findings will inform future efforts to implement AI tools in real-world health care settings, increasing awareness of the need to align sociotechnical dimensions of goals, people, processes, technology, and infrastructure. It highlights the particularly challenging aspect of aligning continually evolving infrastructure with regulatory requirements. Future research should focus on how infrastructure and infrastructure changes, as well as external regulatory requirements, influence AI implementation and use.},
}

Humans
*Artificial Intelligence
Qualitative Research

@article {pmid42573824,
year = {2026},
author = {Su, B and Li, L and Zheng, X and Ma, H and Li, X and Feng, X},
title = {Clinical significance of SQSTM1 variants in ALS: report of p.Arg119Cys and literature review.},
journal = {Neurogenetics},
volume = {27},
number = {1},
pages = {},
pmid = {42573824},
issn = {1364-6753},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Sequestosome-1 Protein/genetics ; Male ; Middle Aged ; Pedigree ; Mutation, Missense ; Genetic Association Studies ; Adaptor Proteins, Signal Transducing/genetics ; },
abstract = {We analyzed the clinical features of a patient with amyotrophic lateral sclerosis (ALS) carrying a novel variant in the sequestosome 1 (SQSTM1) gene and explored the genotype-phenotype association of SQSTM1 gene variants in combination with previous literature. Clinical data and genetic testing results of an ALS patient treated at our hospital were collected. Whole-exome sequencing was used to screen for ALS-related genes, and candidate variants were validated by Sanger sequencing and family analysis. A systematic search was conducted in the PubMed database using the keywords ("amyotrophic lateral sclerosis") OR ("motor neuron disease") AND ("SQSTM1") to summarize the clinical and genetic characteristics of previously reported ALS patients with SQSTM1 variants. The patient was a 49-year-old male with progressive weakness in both lower limbs for one year and weakness in the left upper limb for the past three months. Electromyography showed extensive neurogenic damage. Genetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene. Family verification revealed that his phenotypically normal mother carried the same variant. The literature search identified 58 cases of ALS associated with SQSTM1 variants. Missense variants were the most common type. We identified a novel SQSTM1 variant, c.355 C > T (p.Arg119Cys), in a ALS patient. Although this finding expands the variant spectrum, its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation. Our literature review further shows that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget's disease.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Sequestosome-1 Protein/genetics
Male
Middle Aged
Pedigree
Mutation, Missense
Genetic Association Studies
Adaptor Proteins, Signal Transducing/genetics

@article {pmid42561511,
year = {2026},
author = {Al Ojaimi, Y and Dupuis, A and Palla, M and Lanznaster, D and Hergesheimer, R and Galineau, L and Serriere, S and Chami, AA and Martineau, P and Alouane, T and Marouillat, S and Dupuy, C and Schneider, BL and Veyrat-Durebex, C and Masse, F and Trovero, F and Andres, CR and Corcia, P and Vourcʼh, P and Blasco, H},
title = {Intrabody B1 targeting TDP-43 modulates neuroinflammatory and metabolic pathways in a preclinical ALS model.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {5},
pages = {e01032},
doi = {10.1016/j.neurot.2026.e01032},
pmid = {42561511},
issn = {1878-7479},
abstract = {TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS), yet no therapeutic strategy effectively targets its upstream molecular consequences. Here, we investigated whether the anti-TDP-43 intrabody scFv B1 modulates neuroinflammatory and metabolic pathways in a preclinical ALS model, and whether these effects translate into functional benefit after symptom onset. Using phage display, we previously identified single-chain variable fragments (scFvs) binding TDP-43, including the candidate therapeutic scFv B1. In NSC-34 motor neuron-like cells overexpressing human wildtype TDP-43, B1 reduced NF-κB activation, consistent with disruption of TDP-43-driven inflammatory signaling. For in vivo assessment, B1 was delivered via AAV-CAP.B10 after symptom onset in the hTDP-43(WTxA315T) transgenic mouse model, enabling neuro-specific expression. Two cohorts were analyzed - longitudinal (nine months) and terminal (six months post-treatment) - through behavioral testing, PET imaging, metabolomics, transcriptomics, and plasma biomarker analyses. B1 achieved robust CNS expression and modulated several disease-relevant molecular pathways. RNA-sequencing revealed attenuation of NF-κB-related inflammatory signatures and partial normalization of metabolic and trophic gene expression. Metabolomic profiling identified shifts toward wild-type-like levels in oxidative stress, mitochondrial, and membrane phospholipid metabolites. Despite these molecular effects, symptomatic B1 administration did not improve motor behavior or reduce plasma neurofilament light chain (NfL) concentrations. Notably, plasma TDP-43 levels were stabilized, indicating systemic target engagement. Collectively, scFv B1 modulates upstream pathogenic processes associated with TDP-43 proteinopathy but is insufficient to reverse established neurodegeneration after symptom onset, underscoring the need for earlier and likely combinatorial intervention strategies in ALS.},
}

@article {pmid42561943,
year = {2026},
author = {Rostalski, H and Hietanen, T and Hoffmann, D and Heikkinen, S and Huber, N and Dhingra, A and Rodriguez-Nieto, S and Kuulasmaa, T and Ohtonen, S and Jäntti, H and Pekkala, V and Leskelä, S and Mäkinen, P and Katisko, K and Hartikainen, P and Lehtonen, Š and Solje, E and Koistinaho, J and Malm, T and Portaankorva, AM and Natunen, T and Martiskainen, H and Takalo, M and Hiltunen, M and Haapasalo, A},
title = {C9orf72-associated and sporadic FTD patient iPSC-microglia show differences in phagocytosis and gene expression.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {103026},
doi = {10.1016/j.stemcr.2026.103026},
pmid = {42561943},
issn = {2213-6711},
abstract = {C9orf72 hexanucleotide repeat expansion (C9-HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). However, approximately half of the FTD patients are sporadic without a clear genetic background. To compare characteristics of microglia from different FTD subtypes, we generated induced pluripotent stem cell-derived microglia (iMG) from sporadic and C9-HRE-carrying behavioral variant FTD (bvFTD) patients and healthy controls. C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins. All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG. Additionally, C9-HRE iMG showed significantly increased LC3BII/I conversion after bafilomycin A1 treatment and altered phagocytic activity. The gene expression profile of C9-HRE iMG only modestly differed from the control iMG, but was greatly different from the sporadic bvFTD patient iMG. Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time.},
}

@article {pmid42561977,
year = {2026},
author = {Helmold, B and Armon, C and Benatar, M and Bertorini, T and Bromberg, M and Brown, A and Cadavid, JM and Carbunar, O and Carter, GT and Crayle, J and Feldman, E and Foucher, J and Glass, J and Greenstein, E and Jhooty, S and Jiang, N and Kochen, NN and McDermott, C and Olby, N and Pattee, G and Porter, D and Premasari, A and Rao, A and Ratner, D and Staats, K and Tito, E and Vieira, F and Wicks, P and Bedlack, R},
title = {ALSUntangled #84 - ivermectin.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/21678421.2026.2714724},
pmid = {42561977},
issn = {2167-9223},
abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we explore the possibility of using ivermectin to slow ALS progression. Ivermectin's ability to modulate neuroinflammation and excitotoxicity give it plausible mechanisms for treating ALS, though it does not get into the brain very well. One preclinical study demonstrated that ivermectin lengthened lifespan within a mouse model of mSOD1 genetic ALS. This finding has not been replicated. The 2 PALS we found who had data comparing ALSFRS-R progression on and off ivermectin appeared to have no benefit from it. We found no trials of ivermectin in PALS. Ivermectin is low cost and generally well tolerated with most adverse effects being mild and transient, but serious side effects can rarely occur, and it has not been carefully studied in PALS. We cannot at present endorse ivermectin as an ALS treatment.},
}

@article {pmid42562736,
year = {2026},
author = {Chan, SC and Tung, CW and Chang, CY and Su, CC and Chen, YC and Wu, PM and Tung, CY and Chen, SF and Kuo, HY and Cheng, PH and Chen, CM and Yang, SH},
title = {Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00970},
doi = {10.1016/j.neurot.2026.e00970},
pmid = {42562736},
issn = {1878-7479},
abstract = {Mutant C9orf72 has been extensively studied as a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, and is also known to generate Huntington's disease (HD)-like phenocopies. However, despite this strong disease association, the role of wild-type C9orf72 (wt-C9orf72) in neurodegeneration remains largely unexplored. HD is a neurodegenerative disease, and characterized by the accumulation of misfolded mutant Huntingtin (mHTT) and impaired proteostasis, yet the upstream mechanisms driving ubiquitin-proteasome system (UPS) dysfunction are not fully understood. Here, we identify a previously unrecognized modulatory role of wt-C9orf72 in regulating mHTT aggregation in experimental HD models. Analysis of public transcriptomic datasets reveal context-dependent C9ORF72 expression changes across HD-related human datasets, while C9orf72 levels are increased in R6/2 mouse brain lysates. Functional analyses reveal that overexpression of wt-C9orf72 increases mHTT aggregation and is accompanied by increased apoptotic signaling and reduced cell viability. Unbiased proteomic profiling identifies Stat1 as a key downstream effector. Mechanistically, wt-C9orf72 promotes Stat1 activation and nuclear translocation, leading to transcriptional upregulation of Isg15, a ubiquitin-like modifier. Elevated Isg15 disrupts UPS function, resulting in accumulation of polyubiquitinated proteins and impaired proteasomal degradation. Importantly, genetic suppression of Stat1 or Isg15 significantly attenuates C9orf72-associated mHTT aggregation, supporting a functional C9orf72-Stat1-Isg15 axis. Consistent with these cell-based findings, Stat1, phosphorylated Stat1 and Isg15 levels are elevated in the cortex and striatum of R6/2 HD mouse brains. Collectively, our findings identify a novel wt-C9orf72-Stat1-Isg15 axis that promotes proteasomal dysfunction and mHTT aggregation, providing new insights into wt-C9orf72-associated protein homeostasis.},
}

@article {pmid42562773,
year = {2026},
author = {Zheng, X and Zhang, N and Wang, L and Zhao, H and Liu, C and Wang, J and Zhao, W and Zhao, J and Yang, P and Robinson, L and Hunt, L and Lokken, A and Lin, L and Nelson, PT and Kofler, J and Xie, H and Xia, H and Mao, Q},
title = {A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag085},
pmid = {42562773},
issn = {1554-6578},
support = {GC-202008-2020689//Alzheimer's Drug Discovery Foundation/ ; R21AG080502/AG/NIA NIH HHS/United States ; R21AG088509/AG/NIA NIH HHS/United States ; R01AG097508/AG/NIA NIH HHS/United States ; },
abstract = {TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.},
}

@article {pmid42562776,
year = {2026},
author = {Wan, Y and Gao, C and Li, J and Luan, M and Lu, Y and Wang, J and Yang, B and Zheng, J and Yuan, Y and Wei, J and Wang, Z and Deng, J},
title = {Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag013},
pmid = {42562776},
issn = {1554-6578},
support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons leading to muscle weakness, paralysis, and ultimately, respiratory failure. Extracellular vesicles (EVs) facilitate intercellular communication by mimicking the functions of their parent cells. In this study, we found that repeated administration of neural stem cell-derived extracellular vesicles (NSC-derived EVs) improved motor performance and provided protection to lumbar motor neurons, the neuromuscular junctions, and muscle morphology in the SOD1 G93A transgenic mouse model of ALS. Furthermore, by analyzing the RNA-sequencing of muscle specimens from ALS-SOD1 patients, we demonstrated that the rescue effects of NSC-derived EVs might be linked to the p53 pathway. Compared to the PBS control treatment group, both TP53 and the p53 upregulated modulator of apoptosis (PUMA) were downregulated in the spinal cord of mice treated with NSC-derived EVs. These data provide additional knowledge for the promising use of NSC-derived EVs as a potential therapy for ALS.},
}

@article {pmid42564086,
year = {2026},
author = {Zhang, G and Li, Z and Yao, X and Ding, M and Liu, X},
title = {Observed changes in clinical proxy measures of airway protection after cervical epidural spinal cord stimulation in neurological disorders: a preliminary retrospective case series.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1875581},
pmid = {42564086},
issn = {1664-2295},
abstract = {OBJECTIVES: Although spinal cord stimulation (SCS) has been investigated for cough and respiratory motor output after neurological injury, its relationship with clinical proxy measures of airway protection remains unclear. We explored observed changes in aspects of airway protection after cervical SCS in patients with neurological disorders.

MATERIALS AND METHODS: We retrospectively analyzed six patients who underwent cervical SCS for spinal cord injury, amyotrophic lateral sclerosis, or disorders of consciousness. Clinical proxy measures included the Semi-quantitative Cough Strength Score (SCSS), Functional Oral Intake Scale (FOIS), Water Swallow Test (WST), and Chinese Swallowing Quality of Life Questionnaire (cSWAL-QoL). SCSS was available for all six patients, whereas FOIS, WST, and cSWAL-QoL were limited to the four conscious patients. SCSS, FOIS, and WST were descriptively compared across preoperative, stimulation ON, and stimulation OFF conditions when clinically permissible. cSWAL-QoL was compared between preoperative and postoperative follow-up.

RESULTS: During active stimulation, SCSS scores were higher in all six patients, with the median score changing from 3.0 preoperatively to 4.0 during stimulation ON (nominal p = 0.031). SCSS was also higher during stimulation ON than OFF (4.0 vs. 3.0; nominal p = 0.031). Among the four conscious patients, FOIS changed from 4.0 to 5.0 and WST changed from 3.5 to 2.5 during stimulation ON, while cSWAL-QoL changed from 91.0 to 151.5 postoperatively. No stimulation-related adverse events occurred.

CONCLUSION: Clinical proxy measures related to airway protection showed exploratory state-associated changes during cervical epidural SCS, particularly in cough-strength scores. These preliminary findings do not establish efficacy or mechanism.},
}

@article {pmid42564438,
year = {2026},
author = {Diovu, EO and Nnadi, CO and Paul-Chima, UO},
title = {Pharmaceutical wastewater irrigation and metabolite-based environmental pharmacognosy: a perspective on quality and safety risks for medicinal plants.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1878168},
pmid = {42564438},
issn = {1663-9812},
abstract = {Medicinal plants are increasingly cultivated in agroecosystems irrigated with treated or untreated wastewater, biosolids and contaminated surface water. Pharmaceutical residues are recognised contaminants of emerging concern, but their implications for botanical-drug quality, therapeutic consistency and safety remain insufficiently characterised. This Perspective argues that pharmaceutical wastewater irrigation is a plausible yet underexamined driver of metabolite reprogramming in medicinal plants. Chronic exposure to antibiotics, non-steroidal anti-inflammatory drugs, antiepileptics, antidepressants, hormones and transformation products may alter secondary metabolism through oxidative stress, xenobiotic detoxification, rhizosphere microbiome disturbance and modified nutrient signalling. These processes may change phenolic, flavonoid, alkaloid, terpenoid, glycoside and volatile metabolites that underpin pharmacognostic quality and ethnopharmacological reliability. Medicinal plants may also accumulate parent pharmaceuticals, transformation products and, under some conditions, microbial signatures associated with antibiotic resistance. Building on Carter et al.'s source-pathway-receptor framework and Helmecke et al.'s regulatory risk synthesis, we shift attention from residue burden to how exposure history alters the medicinal metabolome. Evidence from antibiotic-induced metabolite changes in Pinellia ternata supports this proposition, while indicating compound- and context-specific effects. We advance a balanced position: metabolite reprogramming is biologically credible, but food-crop studies often report de minimis residue risks and inconsistent rhizosphere-resistome effects. Future work should integrate wastewater profiling, matched controls, targeted and untargeted metabolomics, transformation-product discovery, microbiome analysis, digestion and bioaccessibility testing, bioactivity assays and probabilistic mixture-risk assessment.},
}

@article {pmid42565285,
year = {2026},
author = {Semendric, I and Munn, Z and Jenkins, T and Edwards, A and Tull, V and Travlos, V and Hutchinson, K and Krikheli, L and Sheers, N and Hall, LA and Chua, P and Hatch, N and Allcroft, P and Werth, B and Saffrett, A and Yoong, J and Cooper, L and Signorelli, M and Farrugia, E and Devenney, E and Douglas, A and Gibb, A and Macshane, M and Gardiner, M and Collins, A and Yang, J and Rogerson, B and Schultz, D and Lim, D and Fisher, F and Herz, H and Puckering, H and Swain, I and Cameron, J and Donnelly, L and Davis, L and Anderson, L and Acampora, M and Heatley, R and Taubert, S and Sheehy, T and Sia, T and Aiyappan, V and Huynh, W and Stern, C and , },
title = {Issues in the clinical assessment and management of people living with motor neurone disease (MND): a survey of Australian healthcare professionals.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2026.2710550},
pmid = {42565285},
issn = {2167-9223},
abstract = {Objective: To inform the development of the Australian MND Guideline, this study aimed to identify challenges Australian healthcare professionals (HCPs) face in the clinical assessment and management of people living with MND (plwMND) including where practice varies from evidence or is underrepresented in the literature and challenges that arise when supporting non-MND specialists. Methods: An anonymous online survey was developed on Qualtrics (Provo, UT) and distributed in July 2025 to members of the Australian MND Guideline Clinical and Content Advisory Group. Demographic data were analyzed using descriptive statistics and verbatim responses were analyzed thematically to a pre-defined framework of guideline scopes and topics. Results: Fifty HCPs, predominantly allied health professionals, completed the survey (55% response rate). HCPs reported diagnostic delays, difficulties accessing timely multidisciplinary support, and challenges coordinating care, particularly outside MND clinic catchment areas. HCPs perceived uncertainty in respiratory support, nutrition, saliva management, and psychological and cognitive care. Variations from guidance reflected gaps and inconsistencies in the evidence base, the need for individualized care, and systemic constraints including funding, workforce shortages, and inequities in access. Non-MND specialists sought guidance on prognosis, referral pathways, symptom management, and end-of-life care. Conclusion: This survey identified areas of clinical practice uncertainty and variability in the clinical assessment and management of plwMND from the perspective of Australian HCPs. These findings will inform the development of the Australian MND Guideline, including prioritization of topics and questions, and consideration of areas where expert consensus is required.},
}

@article {pmid42566133,
year = {2026},
author = {Thompson, JC and Kobylecki, C and Jones, M and Haigh, J and Larbey, M and Langheinrich, TC and Thomasson, R and Richardson, AMT and Snowden, JS},
title = {Frontotemporal dementia with right temporal predominance: a clinical comparison with left-predominant FTD.},
journal = {Journal of neurology},
volume = {273},
number = {9},
pages = {},
pmid = {42566133},
issn = {1432-1459},
mesh = {Humans ; *Frontotemporal Dementia/physiopathology/diagnostic imaging/pathology/psychology/classification ; Female ; Male ; *Temporal Lobe/pathology/diagnostic imaging ; Middle Aged ; Aged ; Retrospective Studies ; Neuropsychological Tests ; Magnetic Resonance Imaging ; *Functional Laterality/physiology ; Atrophy ; },
abstract = {BACKGROUND: The right-temporal variant of frontotemporal dementia (FTD) is well characterised. Whether it should be considered a distinct clinical entity, separate from other syndromes of FTD, remains an open question. The study addressed the issue through a retrospective comparison of clinical characteristics of patients with predominant atrophy in right or left anterior temporal lobe (R-ATL vs. L-ATL).

METHODS: Patients were identified from a clinical database, diagnosed with FTD, and reported to show temporal lobe atrophy on imaging. Fifty-one patients were selected in whom independent ratings of atrophy were greatest in right or left anterior temporal lobe. Presenting symptoms, cognitive and behavioural characteristics, neuropsychological findings, and diagnostic classification were recorded.

RESULTS: Difficulty recognising people, impaired decision-making, perseverative preoccupations, disinhibition, and loss of empathy characterised the R-ATL group, in keeping with the previous reports. There was, however, overlap in cognitive and behavioural symptomatology in R-ATL and L-ATL, and sensitivity and specificity values were modest. Group differences diminished with disease progression. The most common clinical classification at first assessment in both groups was semantic dementia (SD), with other patients being classified as behavioural-variant FTD (bvFTD), FTD with amyotrophic lateral sclerosis or mixed FTD/SD. Not all patients with L-ATL met criteria for semantic variant primary progressive aphasia (svPPA).

CONCLUSIONS: The data question the notion that R-ATL and L-ATL presentations are separate entities. We argue that a common diagnostic framework for the two is warranted, with classification being based on cognitive/behavioural characteristics rather than neuroradiological grounds.},
}

Humans
*Frontotemporal Dementia/physiopathology/diagnostic imaging/pathology/psychology/classification
Female
Male
*Temporal Lobe/pathology/diagnostic imaging
Middle Aged
Aged
Retrospective Studies
Neuropsychological Tests
Magnetic Resonance Imaging
*Functional Laterality/physiology
Atrophy

@article {pmid42567782,
year = {2026},
author = {Risby-Jones, G and Lee, JD and Fung, JN},
title = {Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.07.002},
pmid = {42567782},
issn = {1878-108X},
abstract = {Interleukin-6 (IL-6) exerts protective and pathogenic effects in the central nervous system through distinct receptor-signalling modes. Classical signalling via membrane-bound IL-6 receptor (IL-6R) is often associated with homeostatic and reparative functions, whereas trans-signalling, mediated by soluble IL-6R, expands IL-6 responsiveness to gp130-expressing cells and may promote chronic inflammation. Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Here, we review mechanisms linking IL-6 trans-signalling to immune, glial, neuronal, and vascular dysfunction in neurodegeneration. We highlight key knowledge gaps and discuss whether selective targeting of trans-signalling can limit inflammatory pathology while preserving beneficial classical IL-6 functions.},
}

@article {pmid42559804,
year = {2026},
author = {Bonde, JP and Skaaby, S and Flachs, EM and Dollard, M and Keyes, K and Rosengren, A and Mehlum, IAS and Mikkelsen, S},
title = {Lavigne-Robichaud et al: Job strain and ischemic heart disease: the balance of methodological bias and implications for prevention. Author reply.},
journal = {Scandinavian journal of work, environment & health},
volume = {},
number = {},
pages = {},
doi = {10.5271/sjweh.4324},
pmid = {42559804},
issn = {1795-990X},
abstract = {We appreciate Lavigne-Robichaud et al`s critical remarks (1) to our systematic review addressing the epidemiological evidence for causal relations between job strain and the risk of ischemic heart disease (IHD) (2). Their main concern relates to the strength of the hypothesized association between job strain and IHD and, by extension, the magnitude of the population attributable fraction. They argue that our overall conclusion places too much emphasis on biases that inflate risk estimates and underrates biases that attenuate estimates towards the null. However, we believe it is premature to discuss in detail the strength of associations before a causal link is established with reasonable confidence. The main objective of our review was to evaluate the epidemiological evidence that observed associations are indeed causal. We concluded that the current evidence neither substantiates nor excludes a causal association for several reasons, including, but not limited to, the presence of inflating or deflating biases (2). That said, we appreciate the opportunity to discuss the sources of bias raised by Lavigne-Robichaud et al (1). First, it is argued that dichotomizing exposure into "high" and "no-high" job strain deflates risk estimates because a subgroup of the no-high job strain group (passive jobs with low demands and low control) might also be associated with increased risk. However, others have found that results are broadly similar when different non-strain groups are used as reference (3). Thus, at present, the evidence for effects of passive jobs is not strong enough to deviate from the parsimonious use of "all others" as reference. Second, the notion that the pooled risk estimate may be attenuated by sex because women develop IHD at older ages than men is supported by our review indicating slightly lower risk estimates among women. However, the confidence intervals substantially overlap [(2), table 4] and the small difference, if valid, may be due to several other factors and thus considered of minor importance. Third, the use of job-exposure matrices (JEM) is not associated with attenuated risk estimates if the average exposure in the job groups is close to the true average (4). This condition is probably violated in most instances and may lead to attenuated risk estimates if the exposure misclassification is non-differential. However, misclassification may depend on potential confounders (eg, sex, socioeconomic status and psychosocial and lifestyle factors) in ways that inflate or deflate risk estimates. Note also that the JEM studies do not provide the independent assessment of exposure that is needed for stronger conclusions to be drawn. This is because most studies are based on JEM established by population-based questionnaire studies. We consider the lack of independent exposure assessment a major obstacle for causal inference. Fourth, we agree that the prospective cohort study design in principle eliminates recall bias caused by later occurring manifest disease. But it is not obvious that subclinical or early stages of the disease cannot confound the association, potentially leading to inflated risk estimates even in prospective studies (3). Fifth, self-reported psychosocial work exposures are inherently vulnerable to respondents` individual interpretations, particularly when they are asked to rate the intensity or frequency of subjective experiences. We acknowledge the references provided by Lavigne-Robichaud et al, but these studies do not rule out potential confounding by personality (5, 6). The influence of social context, attitudes, life experiences and personality traits remains unresolved and likely constitute bias regardless of study design (7). We are aware that our review may be misused to discourage sound efforts to improve the psychosocial work environment. While this unfortunate risk is inherent to all critical appraisals of the literature, we believe it remains incumbent on researchers to provide the most evidence-based assessments possible so that we can collectively endeavor to improve science. References 1. Lavigne-Robichaud M, Landsbergis P, Brisson C, Sembajwe G, Gilbert-Ouimet M, Li J, Milot A, Trudel X. Job strain and ischemic heart disease: the balance of methodological bias and implications for prevention. Response to: Bonde JP et al. The demands-control-support work stress model and risk of ischemic heart disease: causal inference based on observational epidemiology. Scand J Work Environ Health - online first. https://doi.org/10.5271/sjweh.4315. 2. Bonde JP, Skaaby S, Flachs EM, Dollard M, Keyes K, Rosengren A et al. The demands-control-support work stress model and risk of ischemic heart disease: causal inference based on observational epidemiology. Scand J Work Environ Health 2026 Jul;52(4):360-70. https://doi.org/10.5271/sjweh.4299. 3. Kivimäki M, Nyberg ST, Batty GD, Fransson EI, Heikkilä K, Alfredsson L et al.; IPD-Work Consortium. Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data. Lancet 2012 Oct;380(9852):1491-7. https://doi.org/10.1016/S0140-6736(12)60994-5. 4. Armstrong BG. Effect of measurement error on epidemiological studies of environmental and occupational exposures. Occup Environ Med 1998 Oct;55(10):651-6. https://doi.org/10.1136/oem.55.10.651. 5. Spector PE, O'Connell BJ. The contribution of personality traits, negative affectivity, locus of control and Type A to the subsequent reports of job stressors and job strains. J Occup Organ Psychol 1994;67:1-2. https://doi.org/10.1111/j.2044-8325.1994.tb00545.x. 6. Shipley BA, Weiss A, Der G, Taylor MD, Deary IJ. Neuroticism, extraversion, and mortality in the UK Health and Lifestyle Survey: a 21-year prospective cohort study. Psychosom Med 2007 Dec;69(9):923-31. https://doi.org/10.1097/PSY.0b013e31815abf83. 7. Kasl SV. Measuring job stressors and studying the health impact of the work environment: an epidemiologic commentary. J Occup Health Psychol 1998 Oct;3(4):390-401. https://doi.org/10.1037/1076-8998.3.4.390.},
}

@article {pmid42560011,
year = {2026},
author = {Abrar, F and Martin, DDO},
title = {Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/15548627.2026.2711593},
pmid = {42560011},
issn = {1554-8635},
abstract = {SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.},
}

@article {pmid42560418,
year = {2026},
author = {León-Ruiz, M and Castañeda-Cabrero, C and Benito-León, J},
title = {Response to "Palpebral ptosis as the initial symptom of amyotrophic lateral sclerosis": the potential usefulness of cortical excitability and motor band sign as biomarkers of upper motor neuron degeneration.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {9},
pages = {},
pmid = {42560418},
issn = {1590-3478},
}

@article {pmid42561134,
year = {2026},
author = {Ehn, E and Thonberg, H and Nennesmo, I and Lindstrand, A and Kvarnung, M and Graff, C},
title = {Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.},
journal = {Human molecular genetics},
volume = {35},
number = {16},
pages = {},
doi = {10.1093/hmg/ddag072},
pmid = {42561134},
issn = {1460-2083},
mesh = {Humans ; *Whole Genome Sequencing/methods ; *Neurodegenerative Diseases/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Female ; C9orf72 Protein/genetics ; DNA Copy Number Variations/genetics ; Male ; Middle Aged ; Alzheimer Disease/genetics/diagnosis ; Genetic Predisposition to Disease ; Frontotemporal Dementia/genetics/diagnosis ; Aged ; DNA Repeat Expansion/genetics ; Adult ; Polymorphism, Single Nucleotide ; Phenotype ; },
abstract = {Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP/P cases (57%); most of which were C9orf72 expansions (31/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype-phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.},
}

Humans
*Whole Genome Sequencing/methods
*Neurodegenerative Diseases/genetics/diagnosis
Amyotrophic Lateral Sclerosis/genetics/diagnosis
Female
C9orf72 Protein/genetics
DNA Copy Number Variations/genetics
Male
Middle Aged
Alzheimer Disease/genetics/diagnosis
Genetic Predisposition to Disease
Frontotemporal Dementia/genetics/diagnosis
Aged
DNA Repeat Expansion/genetics
Adult
Polymorphism, Single Nucleotide
Phenotype

@article {pmid42557952,
year = {2026},
author = {Acharya, A and Thurman, M and Sutar, D and Olasunkanmi, OI and Malik, JR and Dyavar, SR and Végvári, Á and Byrareddy, SN},
title = {In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.},
journal = {Journal of medical virology},
volume = {98},
number = {8},
pages = {e71086},
pmid = {42557952},
issn = {1096-9071},
support = {R01DA05284/NH/NIH HHS/United States ; R01DA061678/NH/NIH HHS/United States ; },
mesh = {*Pericytes/virology/metabolism ; *Astrocytes/virology/metabolism ; Humans ; *Signal Transduction ; *HIV Infections/metabolism/complications/virology ; *SARS-CoV-2/physiology ; *Coinfection/virology/metabolism ; *Neurodegenerative Diseases/metabolism/virology ; *COVID-19/metabolism/complications/virology ; Proteomics ; Microglia/virology/metabolism ; Post-Acute COVID-19 Syndrome ; Virus Replication ; Proteome ; },
abstract = {Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.},
}

*Pericytes/virology/metabolism
*Astrocytes/virology/metabolism
Humans
*Signal Transduction
*HIV Infections/metabolism/complications/virology
*SARS-CoV-2/physiology
*Coinfection/virology/metabolism
*Neurodegenerative Diseases/metabolism/virology
*COVID-19/metabolism/complications/virology
Proteomics
Microglia/virology/metabolism
Post-Acute COVID-19 Syndrome
Virus Replication
Proteome

@article {pmid42558399,
year = {2026},
author = {Okethwangu, D and Venkateswaran, M and Ario, AR and Nabatanzi, S and Asio, E and Ocom, F and Okot, CL and Nyisomeh, A and Nankabirwa, V and Rutebemberwa, E and Mayega, RW and Kiwanuka, SN},
title = {Resilience as recovery: stakeholder perspectives on Uganda's health system response to infectious disease shocks.},
journal = {Frontiers in health services},
volume = {6},
number = {},
pages = {1888814},
pmid = {42558399},
issn = {2813-0146},
abstract = {BACKGROUND: The conceptualization, definition, and measurement of health system resilience remain contested, hindering policy integration. Country-specific empirical evidence from sub-Saharan Africa, where infectious disease shocks recur, is limited. This study explored how national-level Ugandan stakeholders conceptualize health system resilience to infectious disease shocks and its attributes.

METHODS: We conducted a descriptive exploratory qualitative study using semi-structured key informant interviews with 15 purposively selected national-level stakeholders from the Ministry of Health, academia, and development and implementing partners between May and July 2025. Data were analyzed using a hybrid deductive-inductive (abductive) thematic analysis approach, drawing on Kruk et al.'s and the WHO's resilience frameworks while remaining open to emergent themes. Reporting follows the Consolidated Criteria for Reporting Qualitative Research (COREQ).

RESULTS: Participants conceptualized resilience across five capacities: preparedness, absorptive, adaptive, transformative, and recovery. Recovery-dominated narratives prevailed, while transformative capacity was least articulated, indicating a system oriented toward "bouncing back" rather than reform: A resilient system in Uganda is one that anticipates and prepares for infectious disease shocks; absorbs them while sustaining essential services; adapts through innovation and operational adjustment; recovers core functioning; and institutionalizes learning to transform structures, financing, and service delivery models in preparation for future shocks. Seven interconnected attributes were identified: (1) governance and leadership, (2) preparedness, (3) service delivery, (4) community involvement, (5) adaptability, (6) collaboration and partnerships, and (7) soft skills. Governance and leadership emerged as foundational; preparedness, service delivery, community involvement, adaptability, and collaboration as structural; and soft skills (trust, communication, cultural sensitivity) as relational enablers.

CONCLUSIONS: From the perspective of national-level actors, Uganda's health system is predominantly reactive, with recovery prioritized over transformation. Strengthening resilience requires institutionalizing learning, anticipatory financing, empowered subnational structures, and multisectoral partnerships. Future research should triangulate these perspectives with subnational, frontline, and community voices.},
}

@article {pmid42558527,
year = {2026},
author = {Li, S and Cao, T and Zhang, Q},
title = {Oxidative stress as a driver of organelle cascade damage in neurological diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1892923},
pmid = {42558527},
issn = {1663-4365},
abstract = {As a core driver in the pathological progression of neurological diseases, oxidative stress contributes to the onset and development of multiple disorders, including traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), by inducing interconnected and bidirectional damage among mitochondria, endoplasmic reticulum, lysosomes, and the nucleus. This review systematically summarizes the oxidative stress-mediated inter-organelle crosstalk network: Mitochondria act as one of the earliest and central hubs, and their dysfunction (e.g., reactive oxygen species burst, calcium overload, and respiratory chain impairment) induces endoplasmic reticulum stress via ROS diffusion and calcium signaling disturbance. The disruption of endoplasmic reticulum calcium homeostasis further exacerbates mitochondrial damage, forming a vicious cycle. Lysosomes exhibit reduced membrane stability and impaired autophagic flux under oxidative stress, failing to clear damaged organelles and aggravating oxidative stress accumulation. Ultimately, oxidative stress signals are transmitted to the nucleus, resulting in DNA damage, aberrant epigenetic modifications, and activation of pro-inflammatory/pro-apoptotic genes, thereby accelerating disease progression. Notably, this organelle injury transmission is not a rigid unidirectional linear cascade; primary lysosomal or MAM defects can independently initiate the full organelle damage loop without preceding mitochondrial dysfunction. This review integrates current studies, clarifies context-dependent and disease-specific characteristics of organelle interactions, and discusses potential therapeutic strategies with critical consideration of translational challenges and limitations, providing a theoretical foundation for mechanistic research and clinical intervention of neurological diseases.},
}

@article {pmid42558984,
year = {2026},
author = {Pourasghari, M and Babaie, S and Markazi-Movaghar, R and Salehpour, S and Eftekharsadat, B and Farshbaf-Khalili, A},
title = {The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.},
journal = {Stem cells international},
volume = {2026},
number = {},
pages = {4122493},
pmid = {42558984},
issn = {1687-966X},
abstract = {BACKGROUND: This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products.

METHODS: The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I [2] statistics, and subgroup analyses were conducted based on treatment duration and dosing.

RESULTS: A pooled analysis (treatment group: n = 93; control group: n = 90) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the ≥10 × 10[6] and <10 × 10[6] dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n = 88) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups.

CONCLUSION: Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.},
}

@article {pmid42559389,
year = {2026},
author = {Murray, G and Dupuis, M and Hagan, J and Laroche, M and Peters, J},
title = {Arbeitnehmer:innen als Klima-Akteure: Was können Gewerkschaften gegen den Klimawandel unternehmen? Einleitung.},
journal = {Transfer (Brussels, Belgium)},
volume = {32},
number = {2},
pages = {141-151},
doi = {10.1177/10242589261467970},
pmid = {42559389},
issn = {1024-2589},
}

@article {pmid42314945,
year = {2026},
author = {Goldberg, MS and Lebwohl, MG},
title = {Response to Baharuddin et al.'s Comment on ''The 487-gene expression profile test guides systemic therapy selection to improve outcomes for patients with atopic dermatitis: Results from a prospective trial''.},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.06.061},
pmid = {42314945},
issn = {1097-6787},
}

@article {pmid42551425,
year = {2026},
author = {Petrescu, J and Gouveia Roque, C and Jackson, CA and Daly, AC and Butti, Z and Kang, K and Casel, O and Leung, M and Reilly, L and Eschbach, J and Gebremedhin, B and McDade, K and Gregory, JM and Bonneau, R and Smith, C and Phatnani, H},
title = {Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.07.008},
pmid = {42551425},
issn = {1097-4172},
abstract = {Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.},
}

@article {pmid42551655,
year = {2026},
author = {Toyama, G and Koide, S and Yamagishi, T and Washida, A and Hanyu, R and Onodera, O and Sugai, A},
title = {Persistent export bias of TDP-43 under native autoregulation links insoluble accumulation to nuclear dysfunction.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107560},
doi = {10.1016/j.nbd.2026.107560},
pmid = {42551655},
issn = {1095-953X},
abstract = {Nuclear depletion and cytoplasmic mislocalization of TDP-43 are central pathological features of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 protein levels are normally maintained by autoregulation through its native 3' untranslated region (3' UTR), but whether this feedback remains protective during chronic cytoplasmic bias is unclear. To address this, we engineered full-length human TDP-43 carrying an N-terminal nuclear export signal (NES) while retaining the native 3' UTR autoregulatory module. In HEK293T cells, NES insertion imposed cytoplasmic bias and promoted detergent-insoluble TDP-43 species. In differentiated SH-SY5Y cells, nuclear splicing defects and autoregulatory changes scaled with export-biased load; detergent-insoluble accumulation was already detectable within a low-load range, defined by whole-cell RIPA-soluble exogenous TDP-43 ≤ 30% of endogenous levels. Human iPSC-derived neurons showed a comparable cytoplasmic shift, discrete TDP-43-immunoreactive foci, and TDP-43-dependent splicing defects. Endogenous TARDBP depletion provided a functional rescue test: nuclear-competent WT-TDP-43-3' UTR restored TDP-43-dependent nuclear readouts, whereas NES-TDP-43-3' UTR did not. In the NES condition, weakened autorepression increased transgene-derived TARDBP transcripts, but the added output failed to expand the soluble, splice-competent pool and instead partitioned into insoluble fractions. Increasing soluble NES-TDP-43 to endogenous-equivalent levels likewise did not normalize splicing, indicating that abundance alone is insufficient when output remains export-biased. These findings support a model in which persistent export bias converts native TARDBP autoregulation into maladaptive feedback: compensatory output is uncoupled from productive nuclear recovery and diverted toward cytoplasmic insoluble/fragmented species.},
}

@article {pmid42551865,
year = {2026},
author = {Dalle, S and Vanderbeke, K and Burg, T and Schouten, M and Lauriks, W and Hersmus, N and Van Den Bosch, L and Koppo, K},
title = {Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1[G93A] Mice.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {4},
pages = {e70357},
pmid = {42551865},
issn = {2190-6009},
support = {G086823N//Fonds Wetenschappelijk Onderzoek/ ; 12Z8622N//Fonds Wetenschappelijk Onderzoek/ ; 11PRA24N//Fonds Wetenschappelijk Onderzoek/ ; PDMt1/24/001//Onderzoeksraad, KU Leuven or KU Leuven Research Council/ ; },
mesh = {Animals ; Female ; Mice ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Endocannabinoids/metabolism ; Disease Models, Animal ; *Superoxide Dismutase-1/genetics ; *Lipid Metabolism ; *Muscle Fibers, Slow-Twitch/metabolism ; },
abstract = {BACKGROUND: Skeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type-specific ECS changes in ALS.

METHODS: Female hSOD1[G93A] transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56-138 days of age; n = 7-8/group). Endocannabinoids, N-acyl-ethanolamine congeners and inflammatory lipid mediators were quantified using targeted LC-MS/MS in the tibialis anterior (TA) and soleus (SOL) muscles. ECS-related enzymes and receptors were assessed by immunoblotting and integrated with transcriptomic analyses of skeletal muscle biopsies from ALS patients (n = 5/group; ~63 years). To evaluate therapeutic relevance, ALS mice were treated with the fatty acid amide hydrolase (FAAH) inhibitor URB937 or vehicle (n = 10-11/group), and survival, body weight, welfare and motor function were assessed longitudinally.

RESULTS: ALS caused severe atrophy in the predominantly fast-twitch TA muscle (-76.5%; p < 0.01), while the slow-twitch soleus was largely preserved (-14.4%; p < 0.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy- and epoxy-fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%; p = 0.03) and multiple N-acyl-ethanolamine congeners (+76-102%; p < 0.05), reduced 2-arachidonoylglycerol (-28%; p = 0.06), increased CB1 receptor expression (+93%; p < 0.01) and dynamic, age-dependent regulation of FAAH (presymptomatic: -68%; p = 0.04, symptomatic: +21%; p = 0.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%; p = 0.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH; pFDR = 0.010). Despite evidence for a therapeutic potential, chronic peripheral FAAH inhibition with URB937 did not improve weight loss, motor functions and survival of ALS mice (all p > 0.05).

CONCLUSIONS: Muscle type-specific endocannabinoid system remodelling in ALS precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation. Although peripheral FAAH inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of ALS muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.},
}

Animals
Female
Mice
Mice, Transgenic
*Amyotrophic Lateral Sclerosis/metabolism/pathology
Humans
*Muscle, Skeletal/metabolism/pathology
Endocannabinoids/metabolism
Disease Models, Animal
*Superoxide Dismutase-1/genetics
*Lipid Metabolism
*Muscle Fibers, Slow-Twitch/metabolism

@article {pmid42552039,
year = {2026},
author = {Venu, G and A, VP and Justin, A},
title = {Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {113-143},
doi = {10.1016/bs.irn.2026.05.014},
pmid = {42552039},
issn = {2162-5514},
mesh = {Humans ; *PPAR gamma/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Signal Transduction/physiology ; Animals ; *Huntington Disease/metabolism ; },
abstract = {Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.},
}

Humans
*PPAR gamma/metabolism
*Amyotrophic Lateral Sclerosis/metabolism
*Signal Transduction/physiology
Animals
*Huntington Disease/metabolism

@article {pmid42552041,
year = {2026},
author = {Khodve, G and Raval, S and Banerjee, S},
title = {Intestinal microbiota in neurodegeneration and ageing: Mechanisms, pathways, and therapeutic interventions.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {199-229},
doi = {10.1016/bs.irn.2026.05.015},
pmid = {42552041},
issn = {2162-5514},
mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy ; *Aging/metabolism/immunology ; *Gastrointestinal Microbiome/physiology ; Animals ; *Dysbiosis/metabolism/immunology ; *Brain-Gut Axis/physiology ; Probiotics ; Brain/metabolism ; },
abstract = {The human gut microbiota represents a complex ecosystem of trillions of microorganisms with profound implications for neurological health. Emerging evidence demonstrates that dysbiosis, an imbalance in microbial composition and function, plays a crucial role in the pathogenesis of neurodegenerative diseases and age-related cognitive decline. This chapter summarizes current knowledge of the microbiota-gut-brain axis (MGBA) and elucidates how intestinal microbes and their metabolites communicate with the central nervous system via neural, immune, endocrine, and metabolic pathways. We examine the mechanistic links between gut dysbiosis and specific neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Multiple sclerosis (MS). Furthermore, we explore age-related changes in the microbiota and their contributions to neuroinflammation, immunosenescence, and cognitive decline. Finally, we evaluate therapeutic interventions targeting the microbiota, including probiotics, prebiotics, synbiotics, and dietary modulation as promising strategies to prevent and ameliorate neurodegenerative pathology. The chapter provides a comprehensive summary of how microbiota-targeted approaches may delay ageing and neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy
*Aging/metabolism/immunology
*Gastrointestinal Microbiome/physiology
Animals
*Dysbiosis/metabolism/immunology
*Brain-Gut Axis/physiology
Probiotics
Brain/metabolism

@article {pmid42552132,
year = {2026},
author = {Labrèche, F and Prud'homme, P and Gagnon, M and Dupré, N and Gravel, S},
title = {Occupational exposure to pesticides increases the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Occupational and environmental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1136/oemed-2025-110662},
pmid = {42552132},
issn = {1470-7926},
abstract = {OBJECTIVE: To systematically review the evidence on the association between occupational exposure to pesticides and the risk of amyotrophic lateral sclerosis (ALS).

METHODS: A systematic search, conducted in eight bibliographic databases for publications between 1990 and 2025, identified observational studies estimating the risk of ALS after occupational pesticide exposure. Study quality was assessed using the WHO Risk of Bias (RoB) assessment instrument for systematic reviews, with the ROBINS-E (RoB in non-randomised studies of exposure) tool domains of bias. Pooled risk estimates were produced using random-effects models with restricted maximum likelihood, heterogeneity was assessed with I² statistics, and meta-regressions and publication bias explored with funnel plots and Egger's test.

RESULTS: Eight case-control studies (1734 cases) were retained for meta-analysis from 767 initially screened articles. 'Ever' occupational exposure to pesticides was associated with an increased risk of ALS (n=6 studies, pooled OR (pOR)=1.6; 95% CI 1.1, 2.2; I²=57%), for combined sexes. The risk for exposure to herbicides was slightly greater (pOR=1.7, I[2]=0.0%) than for exposure to insecticides or fungicides (pORs=1.6, I[2]=0.0%). Based on three studies, ever exposure to high levels of pesticides was associated with a higher risk (pOR=2.7; 95% CI=1.4, 5.0) than exposure to low levels (pOR=1.9; 95% CI=1.0, 3.7). Self-reported exposure assessment methods and older publication dates (<2015) were statistically significant predictors of the effect size.

CONCLUSION: Despite the small number of studies and some heterogeneity, our results add to the evidence suggesting that occupational exposure to pesticides may increase the risk of ALS.},
}

@article {pmid42552521,
year = {2026},
author = {Aradhya, L and Lath, V and Sirur, FM and Balakrishnan, JM and Hebbar, A and Shetty, AK},
title = {Evaluation of safety, comfort, and design ergonomics in ambulance retrieval vehicles: a survey in Southern India.},
journal = {International journal of emergency medicine},
volume = {19},
number = {1},
pages = {},
pmid = {42552521},
issn = {1865-1372},
abstract = {BACKGROUND: Ambulance interior design influences the safety, comfort, and operational efficiency of Emergency Medical Services (EMS) personnel. However, evidence regarding ergonomic challenges faced by EMS providers in the Indian prehospital setting remains limited.

OBJECTIVE: To evaluate EMS personnel perspectives on ambulance ergonomics, safety, comfort, and factors affecting patient care during transport.

METHODS: A multicentre, cross-sectional survey-based observational study was conducted among Emergency Medical Technologists (EMTs) and paramedics, recruited by convenience sampling, who were involved in patient transport using standard Advanced Life Support (ALS) ambulances across Southern India. Data on ergonomic challenges, safety concerns, occupational injuries, and patient-care factors were collected using a questionnaire developed from existing literature and refined through focused-group discussion and expert content review. Data were analysed using descriptive statistics and chi-square tests in jamovi.

RESULTS: A total of 130 EMS providers participated. Limited patient-cabin space (60%) and difficulty accessing equipment (50%) were the most frequently reported factors affecting safety and comfort. Half of the respondents reported concerns regarding EMT seat positioning during patient care. Uneven roads (49.23%) and sudden vehicle breakdowns (41.53%) were the leading causes of transport-related injuries. CPR was the procedure most commonly associated with injuries to the care giver (53.84%), while back pain was the predominant occupational health hazard (57.69%). Significant associations were observed between work experience and perceptions of ambulance ergonomics, injury mechanisms, patient safety concerns, and occupational health hazards (p < 0.05).

CONCLUSION: EMS personnel reported substantial concerns regarding ambulance ergonomics, particularly seat positioning, equipment accessibility, cabin workspace, and occupational safety. These findings emphasize the importance of further ergonomic research in ambulance design to enhance operational ease during in transit care while assuring provider and patient safety.},
}

@article {pmid42553257,
year = {2026},
author = {Ammar, FI and Aljahdali, E and Alshrif, A and Alshareef, A and Faidah, D and Almohammadi, M and Makkawi, S},
title = {Association of therapeutic plasma exchange with functional outcomes in selected neurological disorders: a retrospective cohort study from a single tertiary center in Saudi Arabia.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1876331},
pmid = {42553257},
issn = {1664-2295},
abstract = {BACKGROUND: Neurological disorders are associated with considerable morbidity and healthcare impact. Therapeutic plasma exchange (TPE) is an intervention that removes pathogenic antibodies, immune complexes, and other plasma constituents from circulation. Previous studies have suggested that TPE could be associated with improved outcomes in selected neurological disorders.

OBJECTIVES: To evaluate functional outcomes following therapeutic plasma exchange in patients with selected neurological disorders at National Guard Health Affairs (NGHA) in Jeddah, Saudi Arabia.

METHODS: This retrospective cohort study analyzes 133 patients diagnosed with various neurological disorders who received TPE between August 2015 and December 2022 at NGHA. Diagnoses included multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune encephalitis (AE), and other neurological conditions including amyotrophic lateral sclerosis (ALS), transverse myelitis, cerebellar ataxia, paraneoplastic neurologic syndrome, polymyositis, and central nervous system (CNS) infections. The effectiveness of TPE was assessed using the Modified Rankin Scale (mRS) before and 90 days following the final TPE session. Statistical analysis included Wilcoxon signed-rank tests and Mann-Whitney U test, with significance set at (p < 0.05).

RESULTS: Significant improvements in mRS scores were observed following TPE for MS, MG, and GBS (all p < 0.001), as well as for NMOSD (p = 0.008), CIDP (p = 0.007), and AE (p = 0.018), but not in other neurological disorders (p = 0.234). Overall mortality was 6.8%, with no TPE-related deaths. Comorbidities among deceased patients included hypertension, diabetes mellitus, malignancy, chronic kidney disease, and cardiovascular disease.

CONCLUSION: TPE was associated with improved functional outcomes in selected neurological disorders. Comorbidities were common among patients with poorer outcomes. Due to the retrospective design and potential confounding factors, causal inferences cannot be established. Further prospective studies are warranted to evaluate the role of TPE and optimize patient selection.},
}

@article {pmid42553297,
year = {2026},
author = {Li, Q and You, M},
title = {Targeting mitochondria for the treatment of neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1835506},
pmid = {42553297},
issn = {1662-4548},
abstract = {Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.},
}

@article {pmid42554090,
year = {2026},
author = {Silva, STD and de Souza, AA and de Melo, LP and de Oliveira Cacho, R and de Holanda, LJ and Ortiz, LDN and Dourado Júnior, MET and Farias, IB and Gonçalves, F and Nagem, DAP and de Medeiros Valentim, RA and Lindquist, ARR and Ribeiro, TS},
title = {Evidence-based physiotherapy recommendations for the management of motor aspects in amyotrophic lateral sclerosis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/17582024.2026.2713034},
pmid = {42554090},
issn = {1758-2032},
abstract = {AIM: To provide evidence-based recommendations for the physiotherapy management of Amyotrophic Lateral Sclerosis (ALS).

MATERIALS AND METHODS: Evidence-based recommendations were developed by a multidisciplinary team, including PhDs and master's-level researchers, physicians, and experienced physiotherapists specializing in neurological rehabilitation.

RESULTS: After the selection process, 23 studies were included. Eighteen recommendations addressing motor aspects in ALS were formulated.

CONCLUSIONS: Therapeutic exercise should be considered to improve or maintain ALSFRS-R scores in people with ALS. However, the effects of other interventions examined in this study remain uncertain with respect to motor aspects.},
}

@article {pmid42554285,
year = {2026},
author = {Benussi, A and Bracca, V and Premi, E and Cantoni, V and Palacino, F and Saccavini, A and Cotelli, MS and Binetti, G and Manenti, R and Alberici, A and Gasparotti, R and Ashton, NJ and Zetterberg, H and Blennow, K and Ghidoni, R and Borroni, B},
title = {Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71722},
pmid = {42554285},
issn = {1552-5279},
support = {//University of Brescia, Italy/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; },
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; Magnetic Resonance Imaging ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood ; Aged ; Middle Aged ; Neurofilament Proteins/blood ; Disease Progression ; Glial Fibrillary Acidic Protein/blood ; Atrophy/pathology ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Supranuclear Palsy, Progressive/pathology ; },
abstract = {BACKGROUND: The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)-associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking.

METHODS: We developed a data-driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD-ALS]; 1904 patient-visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate-adjusted longitudinal data.

RESULTS: Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT-B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT-B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA.

CONCLUSIONS: This first data-driven temporal cascade of multimodal biomarkers in sporadic FTLD-associated syndromes offers a framework for disease staging and stage-specific clinical trial design.},
}

Humans
Female
*Biomarkers/blood
Male
Magnetic Resonance Imaging
*Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood
Aged
Middle Aged
Neurofilament Proteins/blood
Disease Progression
Glial Fibrillary Acidic Protein/blood
Atrophy/pathology
Brain/pathology/diagnostic imaging
Neuropsychological Tests
Supranuclear Palsy, Progressive/pathology

@article {pmid42554695,
year = {2026},
author = {Krajewski, TJ and Koch, GG},
title = {Randomization-based covariance analysis for hypothesis testing of treatment comparisons based on restricted mean survival time with categorized time-to-event data.},
journal = {Journal of biopharmaceutical statistics},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/10543406.2026.2699854},
pmid = {42554695},
issn = {1520-5711},
abstract = {This paper introduces randomization-based analysis of covariance (RB-ANCOVA) for hypothesis testing of restricted mean survival time (RMST) differences between two randomized treatments in trials with categorized time-to-event data. RMST treatment differences over a prespecified time period are clinically meaningful and avoid assumptions like proportional hazards. The proposed method tests the strong null hypothesis that each participant's time-to-event would remain unchanged regardless of treatment assignment. Covariate adjustment is achieved by constraining baseline covariate means to be equal across arms, which reduces variance. The follow-up period is partitioned into mutually exclusive intervals, and RMST is approximated as the area under the survival curve. Under the strong null hypothesis, the joint asymptotic covariance structure of RMST and covariate means is known and used to construct a chi-squared test statistic for the covariate-adjusted RMST difference. The method accommodates stratified trial designs and supports hypothesis testing over single or several time intervals, enabling testing within internal intervals. The difference in RMSTs over an interval can be divided by its length to yield an average survival rate difference. Additionally, the approach allows the computation of essentially exact p-values via re-randomization. We illustrate the method with data from a randomized, placebo-controlled trial evaluating a test treatment for amyotrophic lateral sclerosis. This method provides a hypothesis testing approach for RMST treatment differences that leverages RB-ANCOVA to adjust for their correlations with baseline covariate differences. Under the strong null hypothesis, it enables hypothesis testing with clear control of Type I error and reduced variance without relying on model-based assumptions.},
}

@article {pmid42554905,
year = {2026},
author = {Colín-Martínez, E and Ramírez-Jarquín, UN and Tapia, R and Arias, C},
title = {Inhibition of Glutamate Decarboxylase in the Spinal Cord Induces Motor Deficits and Motor Neuron Degeneration.},
journal = {Neurotoxicity research},
volume = {44},
number = {4},
pages = {},
pmid = {42554905},
issn = {1476-3524},
support = {IN206719//Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México/ ; A1-S12135//Secretaría de Ciencia, Humanidades, Tecnología e Innovación/ ; },
mesh = {Animals ; *Glutamate Decarboxylase/metabolism/antagonists & inhibitors ; *Spinal Cord/drug effects/pathology/enzymology ; *Motor Neurons/drug effects/pathology/enzymology ; *Enzyme Inhibitors/toxicity/pharmacology ; *Nerve Degeneration/pathology/chemically induced/enzymology ; Male ; Rats ; gamma-Aminobutyric Acid/metabolism ; },
abstract = {Motor neuron (MN) diseases such as amyotrophic lateral sclerosis (ALS) are characterized by the loss of cortical and spinal MNs. Although the precise mechanisms of MN degeneration are still unknown, downregulation of GABAergic circuits has been identified in both ALS patients and transgenic models of the disease. GABA synthesis depends on the activity of the enzyme glutamate decarboxylase (GAD), of which two isoforms are known: GAD65 and GAD67. To study the effects of decreased GABA synthesis on spinal cord motor function, we analyzed the effects of administering three selective inhibitors of GAD: 3-mercaptopropionic acid (MPA), a competitive inhibitor of GAD, thiosemicarbazide (TSC), and pyridoxal phosphate γ-glutamyl hydrazone (PLPGH), two GAD cofactor blockers. A single dose of any of these inhibitors did not affect motor behavior or MN morphology. However, subchronic (3 days) and chronic (10 days) administration of MPA, TSC or PLPGH in rats caused motor alterations and cellular changes, including episodic myoclonus-like movements, flaccidity in the ipsilateral phalanges, loss of 35-50% of MNs, reactive astrogliosis and decreased GAD activity. These findings suggest that chronic inhibition of GAD can lead to MN degeneration and further suggest that GABA metabolism in the spinal cord may participate in the mechanisms that cause MN death in patients with neurodegenerative diseases such as ALS.},
}

Animals
*Glutamate Decarboxylase/metabolism/antagonists & inhibitors
*Spinal Cord/drug effects/pathology/enzymology
*Motor Neurons/drug effects/pathology/enzymology
*Enzyme Inhibitors/toxicity/pharmacology
*Nerve Degeneration/pathology/chemically induced/enzymology
Male
Rats
gamma-Aminobutyric Acid/metabolism

@article {pmid42555669,
year = {2026},
author = {Hubbard, I and Dubnau, J},
title = {Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model.},
journal = {PLoS genetics},
volume = {22},
number = {8},
pages = {e1011909},
doi = {10.1371/journal.pgen.1011909},
pmid = {42555669},
issn = {1553-7404},
abstract = {The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat in the first intron of the gene C9orf72. The C9orf72 repeat expansion is bidirectionally transcribed into sense and anti-sense RNA foci, and also produces dipeptide repeats (DPRs) via a non-canonical translation mechanism known as repeat-associated (RAN) translation. Each of these components of the G4C2 repeat expansion cause neurodegenerative effects in animal models when expressed in neurons, but impacts from glial expression are more poorly understood. Here, we use glial cell type-specific expression of individual DPRs, of RNA repeat-only, or of the G4C2 repeat, that produces both DPRs and RNA repeats, to systematically investigate glial toxicity of each component. We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia. Each of these transgenes are capable to produce the GR DPR, which also is the most toxic factor in neurons. We demonstrate that both the GR and G4C2 transgenes cause activation of mdg4, an endogenous retrovirus (ERV). Such ERV expression is a hallmark of TDP-43 dysfunction that is commonly observed in C9orf72 patients. We find that glial expression of either the GR or the G4C2 transgene is toxic to glial cells, but such expression does not cause loss nearby neurons. However, blocking apoptotic signaling within glia that express either GR or G4C2 via expression of the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects. Together, these results indicate that expression of toxic C9orf72 components in glia produces deleterious effects on lifespan, though potentially through different mechanisms than seen in TDP-43 models of ALS/FTD.},
}

@article {pmid42556002,
year = {2026},
author = {Tekan, ÜY and Aksoy, E and Kargın, F and Küçük, RS and Saltürk, C and Çiyiltepe, F and Yavuz, D and Güngör, G and Adıgüzel, N and Karakurt, Z},
title = {Chronic neurological diseases with acute respiratory failure in a real-life cohort: insights into ICU and long-term survival-A retrospective study.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {153},
number = {},
pages = {112228},
doi = {10.1016/j.jocn.2026.112228},
pmid = {42556002},
issn = {1532-2653},
abstract = {BACKGROUND: Patients with chronic neurological diseases (CND) are at increased risk of pulmonary complications that often require ICU admission. This study aimed to identify clinical factors associated with ICU mortality and long-term survival in patients with CND who developed acute respiratory failure (ARF).

METHODS: This retrospective cohort study was conducted in a level III respiratory ICU. Patients with pre-existing CND admitted to the ICU with ARF were included. ICU mortality was analyzed using multivariable logistic regression. Long-term survival after ICU discharge was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. Mortality timing was further characterized using hazard function analysis.

RESULTS: A total of 220 patients were included; the most common neurological diagnoses were dementia (37.3%), stroke (22.7%), and amyotrophic lateral sclerosis (14.1%). ICU mortality was 33.6%. Higher APACHE II scores were independently associated with increased ICU mortality (OR 1.076 per point increase; 95% CI 1.029-1.126; p < 0.001). Long-term survival differed significantly by post-discharge respiratory support strategy, with Kaplan-Meier analysis demonstrating more favorable survival patterns among patients receiving home non-invasive mechanical ventilation (NIMV) (p = 0.003). In Cox regression analysis, age, home NIMV, and feeding modality at discharge were independently associated with long-term outcomes. Survival analyses revealed an early clustering of deaths within the first months after ICU discharge, particularly among patients with dementia.

CONCLUSIONS: In patients with CND, acute physiological severity was the main determinant of ICU mortality, whereas long-term survival after ICU discharge was poor, with deaths clustering within the first months thereafter. Post-discharge respiratory support and nutritional management should be individualized according to the expected clinical trajectory and patient values.},
}

@article {pmid42556722,
year = {2026},
author = {Jiang, H and Ding, L and Yang, C and Guo, G and Zhong, C and Ma, Z and Zhu, H and Zhang, J and Luo, Y and Liu, Z and Liu, R and Ding, Y},
title = {Distinct competitive and allosteric binding modes of nanobodies targeting EphA4.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113394},
doi = {10.1016/j.jbc.2026.113394},
pmid = {42556722},
issn = {1083-351X},
abstract = {EphA4 signaling is a key negative regulator of axonal regeneration and a genetic modifier of amyotrophic lateral sclerosis (ALS), making EphA4 an attractive but mechanistically underexplored therapeutic target. Although EphA4-targeting nanobodies have shown inhibitory potential, the structural principles governing their binding and inhibitory mechanisms remain largely unknown. Here, we report high-resolution crystal structures of the EphA4 ligand-binding domain (LBD) in complex with four nanobodies (Nb50, Nb53, Nb57, and Nb60), resolved at 1.34-2.21 Å. Nb50, Nb53, and Nb57 competitively engage the canonical ephrin-binding pocket through deep CDR3 insertion, directly mimicking ephrin recognition. In contrast, Nb60 adopts a previously unrecognized binding mode, contacting two EphA4 molecules at noncanonical sites in the crystal structure through framework-dominated interactions and supporting a structural model for steric and allosteric restriction of ephrin access. Integrated biophysical analyses reveal distinct thermodynamic and kinetic signatures underlying these binding mechanisms. Together, our findings uncover unexpected structural diversity in nanobody-mediated EphA4 recognition and provide a framework for rational development of EphA4-targeted modulators for ALS and related neurodegenerative conditions.},
}

@article {pmid42556956,
year = {2026},
author = {Rahman, U and Yang, SC},
title = {Management of Anastomotic Leaks: Endoscopic, Interventional, and Surgical Strategies.},
journal = {Advances in surgery},
volume = {60},
number = {1},
pages = {259-270},
doi = {10.1016/j.yasu.2026.03.017},
pmid = {42556956},
issn = {1878-0555},
mesh = {Humans ; *Anastomotic Leak/therapy/surgery/etiology ; },
abstract = {Anastomotic leaks (ALs) are a significant source of morbidity and mortality. Every step should be implemented to prevent AL, including careful patient selection, optimizing patient's clinical and nutritional status, and ensuring proper technique. The appropriate management of an AL depends on several factors, such as patient's clinical status, the type of surgery, location of the AL, induction therapies, and the resources available. Surgeons should be familiar with the armamentarium of treatment modalities available to manage AL and use a patient-tailored approach when selecting the most appropriate treatment.},
}

Humans
*Anastomotic Leak/therapy/surgery/etiology

@article {pmid42548030,
year = {2026},
author = {Matsuki, Y and Bokuda, K and Morishima, R and Kawazoe, T and Kimura, H and Takahashi, K and Nakayama, Y and Shimizu, T},
title = {Sensory Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis Involves a Broad Hand Representation Within the Primary Somatosensory Cortex.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70371},
pmid = {42548030},
issn = {1097-4598},
support = {22H03398//JSPS KAKENHI/ ; },
abstract = {INTRODUCTION/AIMS: Sensory cortical hyperexcitability, reflected by enlarged median nerve somatosensory evoked potentials (SEPs), has been reported in amyotrophic lateral sclerosis (ALS) and is associated with shorter survival. This study investigated whether similar changes involve the ulnar nerve representation within the hand area of the primary somatosensory cortex and examined their relationship with survival.

METHODS: Ninety-nine patients with sporadic ALS and 42 healthy controls were retrospectively studied. Sensory nerve action potentials (SNAPs) and SEPs were recorded following median and ulnar nerve stimulation. SNAP amplitudes and the peak-to-peak amplitudes between N20 and P25 (N20p-P25p) were compared between groups. Patients were followed until death or tracheostomy, and associations between SEP amplitudes and survival were analyzed using Kaplan-Meier and Cox proportional hazards analyses.

RESULTS: SNAP amplitudes did not differ between patients and controls. In contrast, patients with ALS showed larger N20p-P25p amplitudes for both median and ulnar nerve SEPs. N20p-P25p amplitudes were positively correlated between the two nerves, and the ulnar-to-median amplitude ratio did not differ from controls. Patients with ulnar N20p-P25p ≥ 4.89 μV had significantly shorter survival than those with lower amplitude (log-rank test, p = 0.035). Multivariate Cox analysis identified increased N20p-P25p amplitude as an independent predictor of shorter survival for both nerves.

DISCUSSION: Sensory cortical hyperexcitability in ALS extends beyond the median nerve to the ulnar nerve hand area of the somatosensory cortex. Its association with survival supports the notion that sensory cortical dysfunction represents a fundamental pathophysiological feature of ALS and a potential electrophysiological prognostic marker.},
}

@article {pmid42548241,
year = {2026},
author = {Konarbayeva, Z},
title = {Rheological and Technological Design of Texture-Modified Food Systems for Dysphagia Management in Amyotrophic Lateral Sclerosis.},
journal = {Journal of texture studies},
volume = {57},
number = {4},
pages = {e70105},
pmid = {42548241},
issn = {1745-4603},
mesh = {*Deglutition Disorders/etiology/diet therapy ; *Amyotrophic Lateral Sclerosis/complications ; *Rheology ; Humans ; Viscosity ; *Food Technology ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is frequently accompanied by progressive dysphagia, weight loss, and hypermetabolism, which complicate the maintenance of adequate nutritional status. For these patients, food systems must not only provide sufficient energy and protein within a limited volume but also exhibit textural and rheological properties that support safe swallowing. This review analyzes technological and rheological approaches to the design of texture-modified food systems for nutritional support in ALS. Particular attention is given to apparent viscosity, shear-thinning behavior, yield stress, structural homogeneity, and storage stability as parameters affecting bolus formation, swallowing safety, and product performance. The relevance of the International Dysphagia Diet Standardization Initiative framework for classifying food textures and liquid consistencies is also considered. The review further examines the functional and technological roles of animal- and plant-based raw materials, including regional raw materials, in the formulation of energy-dense and structurally stable foods. Proteins, lipids, hydrocolloids, starch gels, and polysaccharide networks are discussed as key components for controlling texture, viscosity, gelation, emulsion stability, and nutritional density. Technological strategies such as homogenization, emulsification, protein-based structuring, hydrocolloid thickening, high-pressure homogenization, and 3D food printing are considered in relation to their potential for developing safe, acceptable, and locally adaptable products for patients with ALS-related dysphagia. The findings highlight the need to integrate food texture science, rheological control, nutritional adequacy, sensory acceptability, and regional availability in the development of clinically relevant texture-modified foods.},
}

*Deglutition Disorders/etiology/diet therapy
*Amyotrophic Lateral Sclerosis/complications
*Rheology
Humans
Viscosity
*Food Technology
Animals

@article {pmid42548317,
year = {2026},
author = {Hwang, JJ and Donnelly, TT and Davidson, S and Raffin Bouchal, S},
title = {Between Denial and Delay: Barriers to Accessing Nonpharmacological Interventions for Seniors With Mild-to-Moderate Dementia in Canada.},
journal = {Qualitative health research},
volume = {},
number = {},
pages = {10497323261468186},
doi = {10.1177/10497323261468186},
pmid = {42548317},
issn = {1552-7557},
abstract = {Dementia is a growing public health concern in Canada, yet timely access to nonpharmacological interventions (NPIs) for persons with dementia (PWDs) remains poorly understood. This critical ethnographic study explored factors influencing access to NPIs among private-dwelling seniors with mild-to-moderate dementia and their family/friend care partners (CPs) in Alberta, Canada. Guided by McLeroy et al.'s Ecological Perspective and Habermas' Critical Social Theory, we conducted 53 semi-structured interviews with eight PWDs and 21 CPs across 20 families. Reconstructive, thematic analysis revealed 10 interrelated factors across socioecological domains: intrapersonal (denial, acceptance, and perceived benefits), interpersonal (support from CPs, physicians, and case managers), organizational (program acceptability and accessibility), community (stigma), and policy (funding constraints). Findings illuminate how systemic conditions such as market-driven care models and fragmented care pathways intersect with lifeworld dynamics, including stigma and relational coping, to shape families' navigation of NPIs. While PWDs relied on their CPs for information and coordination of NPIs, CPs encountered significant informational and navigational barriers. Program invisibility, lengthy referrals, and limited capacity compounded inequities, often leaving families to cope in isolation or seek privatized alternatives. Stigma operated subtly yet systematically, reinforcing therapeutic nihilism, evidence-practice gaps, and policy stagnation. These findings highlight the need to reconceptualize two widely used and valued services, adult day programs and companion care, within a rehabilitative, nonpharmacological framework, strengthen anticipatory guidance, and invest in early, equitable care pathways. Addressing system-lifeworld tensions is essential for dementia care that promotes dignity, connection, and quality of life.},
}

@article {pmid42548517,
year = {2024},
author = {Palm, A and Grote, L and Einarsson, J and Hansson, D and Ljunggren, M and Sundh, J and Ekström, M},
title = {Evolution of Home Mechanical Ventilation in Sweden Over 27 Years: Changing Trends in Incidence, Prevalence, and Patient Characteristics - The Population-Based the Course of Disease in Patients Reported to the Swedish CPAP Oxygen and Ventilator Registry (DISCOVERY) Study.},
journal = {CHEST pulmonary},
volume = {2},
number = {4},
pages = {100108},
pmid = {42548517},
issn = {2949-7892},
abstract = {BACKGROUND: Home mechanical ventilation (HMV), noninvasive ventilation and invasive ventilation outside a hospital setting, is a key treatment to improve outcomes in chronic hypoventilation.

RESEARCH QUESTION: What are the temporal trends observed over 27 years in Sweden regarding the incidence, prevalence, diagnostic spectrum, and patient characteristics associated with HMV?

STUDY DESIGN AND METHODS: This was a national population-based longitudinal analysis of the Course of Disease in Patients Reported to the Swedish CPAP Oxygen and Ventilator Registry (DISCOVERY) study of patients initiating HMV between 1996 and 2022. Time trends stratified by the underlying diagnosis group (lung disease, predominantly COPD, restrictive thoracal diseases, obesity hypoventilation syndrome [OHS], neuromuscular diseases, amyotrophic lateral sclerosis, and other neurologic disorders) were analyzed using linear regression models.

RESULTS: We included 10,555 patients aged ≥ 16 years (mean age 63 [SD, 15] years; 50% women). Between 1996 and 1998 and 2020 and 2022, the HMV incidence increased threefold to 7 per 100,000 people, and the prevalence increased sixfold to 33 per 100,000 people. The most common indication for incident HMV shifted from restrictive thoracal diseases (35% in 1996-1998 to 3% in 2020-2022) to lung disease (14% to 31%), OHS (23% to 33%), and amyotrophic lateral sclerosis (4% to 14%) by 2020 to 2022 (P < .001). The proportion of women increased from 47% to 54% (P < .013) and the age at initiation of HMV increased from 58 [SD, 15] to 66 [SD, 14] years (P < .001). Lung function measured as vital capacity at treatment start increased significantly in all diagnosis groups except for OHS, where both vital capacity and FEV1 decreased. In the registry's first and last 3-year periods, the proportion of patients ventilated invasively decreased from 10% to 2% (P < .001).

INTERPRETATION: In the 27 years until 2022, the incidence and prevalence of HMV in Sweden have increased markedly, patient demographics have changed, and use of invasive ventilation has decreased. The average age of patients initiated on HMV has increased, but treatment is started earlier in the disease trajectory.},
}

@article {pmid42548788,
year = {2026},
author = {Erazo, D and Hesters, A and Bruneteau, G and De La Cruz, E and Bernard, E and Grapperon, AM and Le Masson, G and Cintas, P and Soriani, MH and Guy, N and Cassereau, J and Camdessanché, JP and Genestet, S and Corcia, P and Pittion, S and Danel, V and Filliatre, M and Choumert, A and Jacquin-Piques, A and Salachas, F and Esselin, F and Bohic, A and Lautrette, G and Attarian, S and Catteau, J and Guissart, C and Vincent, MC and Mouzat, K and Temple, M and Vourc'h, P and Couratier, P},
title = {Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).},
journal = {Mayo Clinic proceedings. Innovations, quality & outcomes},
volume = {10},
number = {5},
pages = {100739},
pmid = {42548788},
issn = {2542-4548},
abstract = {OBJECTIVE: To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort.

PATIENTS AND METHODS: Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline.

RESULTS: In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 ± 0.5 at baseline to 0.22 ± 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 ± 9.0 pg/ml at baseline to 29.2 ± 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03).

CONCLUSION: Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.},
}

@article {pmid42549498,
year = {2026},
author = {Iijima, N and Hagiwara, Y and Ishii, S and Kaneko, W and Araga, T and Yamano, Y},
title = {Quantitative Assessment of Tongue Atrophy in Amyotrophic Lateral Sclerosis Using Transoral Tongue Ultrasonography (TOTU): A Retrospective Single-Center Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70370},
pmid = {42549498},
issn = {1097-4598},
support = {25ek0109735//Japan Agency for Medical Research and Development/ ; 25fk0108733//Japan Agency for Medical Research and Development/ ; 25bm1423033//Japan Agency for Medical Research and Development/ ; 25ek0109617//Japan Agency for Medical Research and Development/ ; 25ek0109759//Japan Agency for Medical Research and Development/ ; 25FC1012//Ministry of Health, Labour and Welfare/ ; JP25K02584//Japan Society for the Promotion of Science/ ; JP24K10542//Japan Society for the Promotion of Science/ ; },
abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied by bulbar dysfunction, in which tongue atrophy contributes to dysarthria and dysphagia. Conventional tongue assessments rely on inspection, palpation, or electrophysiological testing but are limited by subjectivity and invasiveness. A rapid, objective, and repeatable imaging-based method for evaluating tongue size would be valuable. We quantified tongue atrophy in ALS using a standardized protocol for transoral tongue ultrasonography (TOTU) and assessed discrimination.

METHODS: This retrospective, cross-sectional study included 15 patients with ALS and 15 controls who underwent TOTU. Using standardized mid-sagittal images, tongue cross-sectional area (cm[2]) and tongue thickness (mm) were measured three times per subject and averaged. Associations with age, body mass index (BMI), disease duration, and ALS Functional Rating Scale-Revised (ALSFRS-R) scores were explored. Discrimination was evaluated using receiver operating characteristic (ROC) analyses.

RESULTS: Both tongue cross-sectional area (6.26 ± 1.37 vs. 9.44 ± 1.02 cm[2]) and tongue thickness (31.47 ± 3.0 vs. 39.44 ± 1.39 mm) were significantly lower in the ALS group than in controls (both p < 0.001). These indices showed no significant associations with age, BMI, disease duration, or ALSFRS-R scores. ROC analyses showed high discriminative ability, with an area under the curve of 0.982 for tongue cross-sectional area and 1.000 for tongue thickness.

DISCUSSION: Standardized TOTU enables rapid, quantitative, noninvasive assessment of tongue size and reliably detects tongue atrophy in ALS, supporting bedside evaluation of bulbar involvement.},
}

@article {pmid42549723,
year = {2026},
author = {Buthelezi, U and Lubuzo, B and Tingen, M and Chiya, H and Gigaba, SG and Goeieman, B and Ramotsela, S and Luvuno, Z},
title = {Adapting a United States cancer education programme for South Africa: A participatory, culturally tailored approach using Card's Seven-Step adaptation framework.},
journal = {African journal of primary health care & family medicine},
volume = {18},
number = {1},
pages = {e1-e10},
doi = {10.4102/phcfm.v18i1.5442},
pmid = {42549723},
issn = {2071-2936},
mesh = {Humans ; South Africa ; *Neoplasms/prevention & control ; Primary Health Care ; United States ; Community-Based Participatory Research ; *Health Education/methods/organization & administration ; Implementation Science ; Female ; },
abstract = {BACKGROUND: South Africa faces a growing cancer burden characterised by late-stage presentation, limited screening uptake and disparities in access to cancer education. While evidence-based cancer education programmes developed in high-income countries demonstrate effectiveness, direct transfer without contextual modification may compromise relevance and acceptability within resource-constrained health settings.

AIM:  To systematically adapt the United States (US)-based Cancer-Community Awareness Access Research Education (c-CARE) programme as a multi-cancer education intervention for implementation within the South African primary health care (PHC) context using Card et al.'s seven-step adaptation framework.

SETTING:  The adaptation was conducted in KwaZulu-Natal (iLembe District) and Gauteng (Johannesburg), South Africa, in collaboration with provincial Departments of Health, community health workers, traditional health practitioners and faith-based leaders.

METHODS:  This implementation science study employed Participatory Action Research integrated with Card's framework to guide a structured adaptation process (January 2023 - January 2024). Thirty-eight consultative meetings were conducted to review programme materials, identify linguistic, cultural and structural mismatches and implement iterative revisions while preserving core intervention components.

RESULTS:  Key adaptations included the addition of cervical cancer as a priority module; incorporation of South African epidemiological data and referral pathways; translation into isiZulu and Sesotho; integration of mental health, spirituality and palliative care content; and restructuring of delivery to align with the South African Health System. Core evidence-based content, modular design and interactive pedagogical strategies were retained.

CONCLUSION:  Framework-guided adaptation enabled contextual recalibration of c-CARE while maintaining fidelity to core components.Contribution: This study provides a transparent model for adapting evidence-based cancer education interventions for culturally diverse, resource-constrained PHC systems.},
}

Humans
South Africa
*Neoplasms/prevention & control
Primary Health Care
United States
Community-Based Participatory Research
*Health Education/methods/organization & administration
Implementation Science
Female

@article {pmid42549923,
year = {2026},
author = {Takahashi, M and Abe, T and Fujii, M},
title = {Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.},
journal = {Molecular and cellular biology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/10985549.2026.2705871},
pmid = {42549923},
issn = {1098-5549},
abstract = {Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.},
}

@article {pmid42550987,
year = {2026},
author = {Waters-Harvey, B and Kane, K and Griffiths, AW and Smith, G and Bartlett, CM and Sproson, L and Smith, S and Starkey, J and Clift, A and Stavroulakis, T and Hobson, E and Mayberry, E and O'Cathain, A and Bidder, C and Kennedy, K and Gibson, J and McDermott, C and Knox, L},
title = {Co-Designing a Care Coordination Intervention for People With Motor Neuron Disease: Protocol for a Mixed Methods Study.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e96327},
pmid = {42550987},
issn = {1929-0748},
mesh = {Humans ; *Motor Neuron Disease/therapy/psychology ; Amyotrophic Lateral Sclerosis/therapy ; England ; United Kingdom ; Wales ; },
abstract = {BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a rapidly progressive neurological condition that requires complex multidisciplinary care. Within the United Kingdom, specialist centers provide expert interventions, while day-to-day support often relies on local nonspecialist community health and social care professionals. This is due to the distance between people's homes and specialist centers, as well as the availability of specialist health and social care professionals. This can lead to fragmented communication and emotional, physical, and financial burdens, and it can be time-consuming for people living with MND, their carers, and the health care professionals involved in their care. Despite the recognized need for better care coordination, it remains inadequate in practice, with a current lack of specific evidence-based interventions for achieving this.

OBJECTIVE: The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales, (2) identifying barriers and facilitators to coordination within specialist and nonspecialist settings, and (3) co-designing a practical care coordination tool with key stakeholders.

METHODS: This protocol outlines the co-design of an intervention underpinned by the Behavior Change Wheel and the Socioecological Model. First, a mixed methods, multicenter study will be conducted to develop a national picture, comprising focus groups with people living with MND, carers, and health and social care professionals. Second, focused ethnography will be conducted in 5 MND specialist centers and their catchment areas, involving 25 people living with MND, to explore the barriers and facilitators to coordination in practice. Finally, a series of co-design workshops will be conducted to identify key priorities for care coordination and to develop a new intervention, the MND Together tool.

RESULTS: The project started in September 2025 and will run until October 2027. Workstream 1 started in December 2025, with recruitment beginning at the first site in February 2026. To date, we have recruited 23 people living with MND and carers as well as 16 health and social care professionals across 4 of the 9 sites. Workstream 1 will end in August 2026, with results published at the end of 2026. Workstream 2 began in May 2026 and will run until February 2027, with results published in the summer of 2027. Workstream 3 will begin in March 2027 and conclude with the co-design intervention developed by late 2027. This will then be piloted in practice.

CONCLUSIONS: By combining several methodologies with meaningful patient and public involvement and engagement, MND Together seeks to bridge the gap between specialist and community-based services. The MND Together tool aims to improve the quality of care and ensure that expert MND support is accessible as close as possible to every patient's home.},
}

Humans
*Motor Neuron Disease/therapy/psychology
Amyotrophic Lateral Sclerosis/therapy
England
United Kingdom
Wales

@article {pmid42539252,
year = {2026},
author = {Wieland, CM and Wright, SE and Willey, S and Purwar, I and Grudzien, SJ and Krans, A and Laimon, E and Asher, MJ and Isaacs, A and Garner, AL and Todd, PK},
title = {Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.16.739042},
pmid = {42539252},
issn = {2692-8205},
abstract = {Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks global cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global increase in start codon stringency in neurons as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with a cytoplasmic redistribution of eIF1 in neurons and is reversed with neuronal overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and selectively enhances cap-dependent RAN translation. Taken together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis and neuronal translational regulation.},
}

@article {pmid42539319,
year = {2026},
author = {Zhou, Y and Luster, CB and Pinto, SM and Feigel, ED and Paganoni, S and Izzy, S and Zafonte, RD and Giacino, JT and Hammond, FM and Daneshvar, DH},
title = {Traumatic Brain Injury and Risk of Amyotrophic Lateral Sclerosis Mortality: A Traumatic Brain Injury Model Systems Study.},
journal = {Neurotrauma reports},
volume = {7},
number = {},
pages = {2689288X261450846},
pmid = {42539319},
issn = {2689-288X},
abstract = {Emerging evidence suggests that amyotrophic lateral sclerosis (ALS) mortality is elevated following traumatic brain injury (TBI), reflecting a consequence of potential prodromal ALS, though the temporal patterns and underlying mechanisms remain unclear. We aimed to evaluate ALS mortality among individuals with TBI and examine temporal patterns. This study leveraged a retrospective cohort study of 20,250 individuals with complicated mild-to-severe TBI enrolled in the TBI Model Systems (TBIMS) from 1987 to 2024, with a cumulative 198,662 person-years (mean [standard deviation] = 9.8 [7.1] years) of follow-up. Standardized mortality ratios (SMRs) were calculated using the National Institute for Occupational Safety and Health Life Table Analysis System R package, adjusting for age, sex, race, and calendar year. Secondary analyses evaluated temporal patterns and injury severity differences in ALS mortality. Among 4,313 decedents in TBIMS, 11 died of ALS, representing significantly elevated mortality from ALS (SMR = 2.39; 95% confidence interval [CI]: 1.19-4.27) compared with the general population. Time-stratified analyses showed elevated ALS mortality within 2 years post-injury (SMR = 4.30; 95% CI: 1.17-11.01), but not after 2 years (SMR = 1.90; 95% CI: 0.76-3.92). Elevated ALS mortality was also observed within 2 years post-injury among those with severe TBI (SMR = 5.00; 95% CI: 1.03-14.61) and when including individuals with ALS at admission (SMR = 6.45; 95% CI: 2.37-14.04). ALS mortality was higher in the TBIMS cohort than in the general population, and this association was confined to within 2 years of injury. This pattern suggests potential reverse causality, whereby some TBIs in the cohort may have occurred in the setting of prodromal or pre-symptomatic ALS. Further investigation into TBI as a sign of subclinical ALS is warranted.},
}

@article {pmid42540536,
year = {2026},
author = {Wang, S and Lin, Y and Che, Y and Zhao, J and Xu, L and He, W and Zhang, W},
title = {Genetically inferred effects of brain structure and gene expression on neurodegenerative diseases: a Mendelian randomization study.},
journal = {Archives of medical science : AMS},
volume = {22},
number = {3},
pages = {1663-1677},
pmid = {42540536},
issn = {1734-1922},
abstract = {INTRODUCTION: Against the backdrop of accelerating population aging, the risk of neurodegenerative diseases (NDDs) has risen significantly. While brain structure plays a critical role in NDDs, the interplay between them remains unclear. This study employed Mendelian randomization (MR) to investigate potential causal relationships between brain structure, region-specific gene expression, and four NDDs - Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) - providing new directions and genetically informed hypotheses for disease research.

MATERIAL AND METHODS: MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and Wald ratio methods. Summary-data-based MR (SMR) was applied to identify brain genes influencing NDDs. We calculated F-statistics, 95% confidence intervals (CIs), odds ratios, and p-values. Sensitivity analyses included the heterogeneity I[2] statistic, Cochran's Q test, Egger intercept test, MR-PRESSO, and leave-one-out validation.

RESULTS: Data from 512 unsupervised deep-learning imaging phenotypes (UDIPs) were analyzed. Thirty-four UDIPs showed associations consistent with a potential causal role in AD, 56 in PD, 22 in ALS, and 92 in MS. After false discovery rate (FDR) correction, 4 remained significant for AD and PD, 3 for ALS, and 28 for MS (p < 0.05). Brain regions (excluding the cervical spinal cord C-1) exhibited shared causal genetic features across all four NDDs, primarily involving HLA-class genes.

CONCLUSIONS: This study provides genetic evidence suggestive of potential causal associations between UDIPs, brain gene expression, and NDDs. These findings offer genetically predicted evidence that may generate hypotheses and inform future mechanistic research into NDD pathogenesis.},
}

@article {pmid42541368,
year = {2026},
author = {Hirano, Y},
title = {Long-term trajectories of physical, psychological, and psychosocial experiences among people living with amyotrophic lateral sclerosis using tracheostomy invasive ventilation: An 18-year longitudinal study.},
journal = {Journal of health psychology},
volume = {},
number = {},
pages = {13591053261474390},
doi = {10.1177/13591053261474390},
pmid = {42541368},
issn = {1461-7277},
abstract = {Advances in respiratory care have enabled people living with amyotrophic lateral sclerosis (PALS) using tracheostomy invasive ventilation (TIV) to live for many years with the disease. However, longitudinal evidence describing their psychosocial trajectories remains limited. This study explored the long-term trajectories of three PALS using TIV through repeated face-to-face assessments over an approximately 18 year period. Psychological state, subjective physical symptoms, and hope followed similar patterns across participants, worsening after illness onset and reaching their lowest levels between diagnosis and TIV initiation before improving and becoming increasingly individual over time. Perceived psychological support and sources of joy peaked after TIV initiation before fluctuating, whereas perceived financial status remained relatively stable. These findings demonstrate a shared pattern of early adaptation followed by increasingly individual long-term trajectories, providing a foundation for trajectory-informed holistic care.},
}

@article {pmid42541567,
year = {2026},
author = {Estevez-Fraga, C and Alvarez-Velasco, R and Afroz, T and Costa, MR and Jovičić, A and Yeh, FL and McColgan, P and Malaspina, A and McCampbell, A},
title = {Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {8},
pages = {},
pmid = {42541567},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder characterized by motor neuron degeneration leading to early mortality. Despite advances in understanding genetic and molecular contributors, effective disease-modifying therapies for sporadic ALS are of limited utility. The identification of the accumulation of TAR DNA-binding protein 43 (TDP-43) in 97% of total ALS cases represents a critical pathogenic hallmark. This review examines key biological mechanisms underlying TDP-43 pathology, emerging therapeutic strategies, and evolving approaches to clinical trial design and biomarker development. TDP-43 loss of nuclear function, leading to widespread RNA missplicing, and inclusion of cryptic exons, represents an early and critical event in ALS pathogenesis causing downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction. Therapeutic strategies targeting these pathways are currently under investigation. Additional approaches aim to ameliorate TDP-43 gain-of-function through cytoplasmic TDP-43 aggregation or modulating processes such as stress responses and RNA metabolism, although clinical translation has been challenging. Advances in biomarkers, including neurofilament light chain and cryptic exon-derived peptides, provide tools for developing efficient clinical trials. However, heterogeneity in disease progression and limitations of available clinical endpoints complicate trial design. Integration of biological insights with biomarker-driven patient stratification and optimized trial methodologies is essential to improve clinical trial outcomes. Emerging biomarkers may enable earlier diagnosis, monitoring of therapeutic response, and personalized treatment approaches. Continued alignment of biological discovery with innovative clinical trial design holds promise for advancing effective therapies and transforming the future of ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology
*DNA-Binding Proteins/metabolism/genetics
Animals

@article {pmid42541645,
year = {2026},
author = {Chu, M and Tan, M and Gan, X and Cui, S and Shi, L},
title = {Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42541645},
issn = {1559-1182},
mesh = {*Microglia/metabolism/pathology/drug effects ; Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy ; *Mitochondria/metabolism/pathology/drug effects ; Animals ; },
abstract = {Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.},
}

*Microglia/metabolism/pathology/drug effects
Humans
*Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy
*Mitochondria/metabolism/pathology/drug effects
Animals

@article {pmid42542073,
year = {2026},
author = {Oriquat, G and Rizaev, J and Abdulqader, AF and Kadhim, AA and Jamuna, KV and Singhal, D and Bainsal, N and Mansurova, N},
title = {Gut microbiota and brain health: Disease-specific pathways and emerging therapeutic strategies.},
journal = {Multiple sclerosis and related disorders},
volume = {113},
number = {},
pages = {107407},
doi = {10.1016/j.msard.2026.107407},
pmid = {42542073},
issn = {2211-0356},
abstract = {The microbiota-gut-brain axis (MGBA) has emerged as a dynamic, bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS) through neural, immune, endocrine, and metabolic mechanisms. Increasing evidence indicates that alterations in gut microbial communities are associated with a wide range of neurological disorders; however, the strength of this association varies across diseases, and many mechanistic observations still rely predominantly on experimental models rather than human studies. This review provides an overview of current evidence regarding the role of the gut microbiota in maintaining CNS homeostasis, with particular emphasis on intestinal barrier function, immune modulation, vagal and enteric communication, and the generation of biologically active microbial metabolites, including short-chain fatty acids, bile acids, and neurotransmitter-related compounds. Studies in both clinical and experimental settings have reported disease-specific microbial signatures in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorders, and amyotrophic lateral sclerosis. In parallel, microbiota-directed interventions-including probiotics, prebiotics, dietary approaches, fecal microbiota transplantation, and strategies targeting microbial metabolites-have produced encouraging findings in preclinical studies and early-stage clinical investigations. Nevertheless, considerable heterogeneity in study populations, experimental methodologies, and therapeutic protocols continues to limit the translation of these findings into routine clinical practice. Collectively, current evidence supports the MGBA as a valuable framework for understanding neurological diseases while underscoring the need for rigorously designed longitudinal studies and well-controlled clinical trials to define its therapeutic relevance better.},
}

@article {pmid42543118,
year = {2026},
author = {Du, L and Yan, J},
title = {Lineage-calibrated peripheral monocyte-derived myeloid states in neurodegenerative disease: Recruitment, lesion decoding, and state persistence.},
journal = {Neurobiology of disease},
volume = {228},
number = {},
pages = {107556},
doi = {10.1016/j.nbd.2026.107556},
pmid = {42543118},
issn = {1095-953X},
abstract = {Peripheral monocytes and monocyte-derived macrophages are increasingly implicated in neurodegenerative disease, yet interpretation remains limited by phenotypic convergence with resident microglia, inconsistent lineage attribution, and strong dependence on experimental model and disease stage. We present a structured, lineage-calibrated framework that separates three linked processes: a recruitment gate controlling access to CNS borders and lesions; a lesion-decoding hub through which aggregate, lipid, cytokine, complement, antigenic, hypoxic, and danger-associated inputs are interpreted; and a state-persistence layer in which metabolic and epigenetic reinforcement stabilizes inflammatory, repair-supportive, or hybrid repair-restrictive programs. To make the framework operational, we first provide a cross-disease synthesis and then map representative models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis to their specific recruitment routes, lesion cues, lineage confidence, and functional outcomes. We also distinguish what single-cell or spatial data can infer from what only origin-resolving approaches can establish, and propose practical terminology for studies that cannot perform fate mapping or parabiosis. A worked therapeutic example illustrates why the same recruitment pathway may be harmful during lesion expansion but useful during debris clearance and recovery. The central question is therefore not whether monocytes are present, but which model, compartment, time point, evidentiary tier, and stabilized state justify a disease-modifying claim. This framework links mechanistic evidence to biomarkers, patient stratification, and stage-aware intervention while reducing over-attribution of peripheral origin.},
}

@article {pmid42543164,
year = {2026},
author = {Wang, CY and Taylor, S and Pandya, VA and Clarke, BE and Pal, K and Shelkovnikova, TA and Wang, Y and Luisier, R and Patani, R},
title = {Intron retention in health and amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {149},
number = {8},
pages = {2604-2618},
pmid = {42543164},
issn = {1460-2156},
support = {Patani/Dec22/957-793/MNDA_/Motor Neurone Disease Association/United Kingdom ; MN5DF/2022/003//My Name'5 Doddie Foundation/ ; BB-2024-c4-l4//Target ALS/ ; //Francis Crick Institute/ ; FC010110/CRUK_/Cancer Research UK/United Kingdom ; FC010110//UK Medical Research Council/ ; FC010110/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.},
}

@article {pmid42544409,
year = {2026},
author = {Tsang, LPM and Tan, MS and Foo, YY and Lee, CS},
title = {Professional identity formation of family medicine residents in Singapore: a qualitative study to identify influencing factors.},
journal = {Annals of medicine},
volume = {58},
number = {1},
pages = {2698271},
doi = {10.1080/07853890.2026.2698271},
pmid = {42544409},
issn = {1365-2060},
mesh = {Humans ; Singapore ; *Internship and Residency ; Qualitative Research ; *Social Identification ; Male ; *Family Practice/education ; Female ; *Burnout, Professional/psychology/prevention & control ; Job Satisfaction ; *Physicians, Family/psychology ; Adult ; Community of Practice ; },
abstract = {BACKGROUND: Physician burnout and retention are critical challenges in Family Medicine (FM). Professional Identity Formation (PIF) in family physicians (FP) fosters resilience and job satisfaction but is often overlooked in residency training, particularly in predominantly hospital-based programs where residents are disconnected from the primary care community.

AIM AND METHODS: This qualitative study explored FP PIF in a predominantly hospital-based FM residency program in Singapore and identified factors influencing its development. Individual in-depth semi-structured interviews were conducted with FM residents and post-residency FPs selected through maximum variation purposive sampling. Data was collected and analysed iteratively using Braun and Clarke's reflexive thematic analysis. Cruess et al.'s conceptual model for PIF was used as a sensitising framework, alongside Lankveld et al.'s framework describing psychological processes underlying identity formation.

RESULTS: Thirteen participants were interviewed. Three themes were constructed. First, FP PIF wasunderpinned by four psychological 'senses' of competence, connectedness, appreciation, and career trajectory. Second, reflection and socialization drove development of these senses by enabling meaning-making, learning and belonging within the FM community of practice (CoP). Third, residency program features both enabled and/or constrained PIF; while some components scaffolded PIF, more intentional support was needed.

DISCUSSION AND CONCLUSION: PIF is a dynamic, context-dependent psychological process shaped by reflective practice, social participation, and program structure. Intentional support through curriculum design and faculty practices may strengthen PIF. These findings extend existing PIF frameworks and have implications for curriculum design, faculty development, program evaluation, and future research on fostering PIF in hospital-based residency training.},
}

Humans
Singapore
*Internship and Residency
Qualitative Research
*Social Identification
Male
*Family Practice/education
Female
*Burnout, Professional/psychology/prevention & control
Job Satisfaction
*Physicians, Family/psychology
Adult
Community of Practice

@article {pmid42545188,
year = {2026},
author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Moreschi, A and Frisco, F and Bella, ED and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Cappa, SF and Calvo, A and Strong, MJ and Silani, V and Lauria, G and Chiò, A and Ticozzi, N},
title = {Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {33},
number = {8},
pages = {e70706},
pmid = {42545188},
issn = {1468-1331},
support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; RF-2016-02362405//Ricerca Sanitaria Finalizzata - Ministero della Salute/ ; 2017SNW5MB//"Progetti di Rilevante Interesse Nazionale" programme of the Ministry of Education, University and Research/ ; 101017598//Horizon 2020/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Female ; *Cognitive Dysfunction/etiology/diagnosis/epidemiology/psychology ; Neuropsychological Tests ; Male ; Aged ; Middle Aged ; Phenotype ; Retrospective Studies ; },
abstract = {BACKGROUND: This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks.

METHODS: We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures.

RESULTS: The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI).

CONCLUSIONS: This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/psychology
Female
*Cognitive Dysfunction/etiology/diagnosis/epidemiology/psychology
Neuropsychological Tests
Male
Aged
Middle Aged
Phenotype
Retrospective Studies

@article {pmid42546549,
year = {2026},
author = {Silvagi, R and Rodriguez-Fohn, E and Reece, RJ and Cranford, JA and Alangaden, K and Byrd, M and Klausner, H and Pravin, R and Li, J and Conn, C and Dunne, R and O'Neil, BJ},
title = {Advanced vs basic life support outcomes in treatment of out-of-hospital-cardiac-arrest: A registry-based cohort study.},
journal = {The American journal of emergency medicine},
volume = {109},
number = {},
pages = {263-267},
doi = {10.1016/j.ajem.2026.07.021},
pmid = {42546549},
issn = {1532-8171},
abstract = {IMPORTANCE: The absolute effect on outcomes with Advanced, (ALS) as compared to Basic Life Support, (BLS) care in Out of Hospital Cardiac Arrest, (OHCA) remains unclear.

OBJECTIVE: To assess the association of ALS compared to BLS alone prehospital care on return of spontaneous circulation, (ROSC), survival to hospital discharge, and neurological outcome in OHCA in Detroit, MI.

METHODS: Retrospective analysis of 6746 patients from the Cardiac Arrest Registry to Enhance Survival database from January 2016 to December 2021 who had non-traumatic OHCA and received cardiopulmonary resuscitation. Cohorts were grouped by ALS v BLS care then initial rhythm and then compared by chi-squared, multivariable logistic, and multinomial regression analysis for outcomes of sustained ROSC, survival to hospital discharge and favorable neurological outcome at hospital discharge. The BLS cohort is defined by units that provided manual CPR, automated rhythm and defibrillation, airway management, but no endotracheal intubation or parenteral medications. ALS care was defined as manual rhythm interpretation, manual defibrillation, intravenous or intraosseous drug administration or endotracheal intubation.

RESULTS: Mean age was 62.6 years (SD-16.7), with 56.3% male and 84.6% Black. Cohort breakdown: shockable ALS (S-ALS; n = 330, 4.9%); shockable BLS (S-BLS; n = 466, 6.9%); non-shockable ALS (NS-ALS; n = 2793, 41.4%); non-shockable BLS (NS-BLS; n = 3157, 46.8%). ROSC rates by cohort: S-ALS (37.9%); S-BLS (19.5%); NS-ALS (18.6%); NS-BLS (9.3%). ALS was associated with increased sustained ROSC for all initial rhythms (p < .001). S-ALS was associated with increased survival (p = .03), and neurologic outcome (p = .01) when compared to S-BLS.

CONCLUSION & RELEVANCE: Advanced Life Support, relative to Basic Life Support alone, was associated with improved sustained return of spontaneous circulation across all initial rhythms, and improved survival to discharge and favorable neurologic outcome in shockable initial rhythms.},
}

@article {pmid42546822,
year = {2026},
author = {Ghaderi, S and Mohammadi, S and Iturria-Medina, Y},
title = {Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110765},
doi = {10.1016/j.mri.2026.110765},
pmid = {42546822},
issn = {1873-5894},
abstract = {Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.},
}

@article {pmid42547743,
year = {2026},
author = {Tse, CS},
title = {Letter to the Editor Regarding Barkan et al.'s Article, "Randomized Trial of Intensive Nurse‑Led Follow‑up Versus Standard Care in Inflammatory Bowel Disease".},
journal = {Digestive diseases and sciences},
volume = {},
number = {},
pages = {},
pmid = {42547743},
issn = {1573-2568},
}

@article {pmid42547788,
year = {2026},
author = {Wo, XM and Zhang, GM},
title = {Interpreting the clinical utility and generalizability of a multitask perioperative prediction model.},
journal = {NPJ digital medicine},
volume = {9},
number = {1},
pages = {},
pmid = {42547788},
issn = {2398-6352},
abstract = {This Matters Arising comments on Yoon et al.'s multitask gradient boosting model for predicting acute kidney injury, postoperative respiratory failure and in-hospital mortality after non-cardiac surgery. We ask for clarification on the clinical decision context and threshold ranges in the decision curve analyses, the absolute impact of the model for rare outcomes, and calibration and potential recalibration in external cohorts to support implementation.},
}

@article {pmid42547898,
year = {2026},
author = {Domke, N and Geue, K and Schlichte, I and Ullsperger, M and Meyer, T and Petri, S and Schreiber, S and Vielhaber, S and Junne, F and Vogt, S},
title = {Depressive symptoms in amyotrophic lateral sclerosis: associations with quality of life, disease progression and perceived social support-a German multicenter study.},
journal = {BMC psychology},
volume = {14},
number = {1},
pages = {},
pmid = {42547898},
issn = {2050-7283},
mesh = {Humans ; *Social Support ; *Quality of Life/psychology ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Female ; Male ; Disease Progression ; Cross-Sectional Studies ; Middle Aged ; *Depression/psychology ; Aged ; Germany ; Adult ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease. Patients with ALS are at increased risk of developing depressive symptoms. A clearer understanding of the associations between depressive symptoms, disease progression, health-related quality of life and perceived social support is needed to advance intervention-oriented research and improve psychosocial care in ALS.

METHODS: In a multicenter cross-sectional study, patients with ALS were asked to complete patient-reported outcomes (PROs) to evaluate depressive symptoms (ALS-Depression-Inventory, ADI-12), health-related quality of life (ALS-Assessment-Questionnaire, ALSAQ-5/ALSAQ-40), physical functioning (ALS-Functional Rating Scale-Extension, ALSFRS-EX) and perceived social support (Multidimensional Scale of Perceived Social Support, MSPSS). To evaluate associations between demographic/clinical variables and PROs, we performed Pearson's, Spearman's, and partial correlation analyses. In addition, a multiple regression was run to identify predictors of depressive symptoms. Comparisons of patient groups were performed with chi-squared tests for categorical variables and Student t-tests or one-way analysis of variance (ANOVA) for continuous variables, followed by post-hoc tests.

RESULTS: Out of the 150 patients examined, 60% reported depressive symptoms, with half of them exhibiting clinically relevant depressive symptoms. Depressive symptoms were significantly associated with disease progression (r = .466, p < .001), various aspects of health-related quality of life (mobility: r = .394, activities of daily living: r = .268 and emotional well-being: r = .793, all p < .001), the MSPSS sum score (partial r = -.234, p  = .007), and the ALSFRS-EX sum score (r = -.352, p < .001). Patients with depressive symptoms reported significantly more physical impairments (p = .002) and less perceived social support by their families (p = .016) and friends (p < .001) compared to patients without depressive symptoms.

CONCLUSIONS: Depressive symptoms are prevalent in patients with ALS and are closely associated with faster disease progression, reduced physical functioning, poorer health-related quality of life, and lower perceived social support. Further studies, particularly using qualitative methods, are needed to elucidate protective factors, clarify psychosocial mechanisms, and support the conceptualization of specialized and integrated psychosocial care for patients with ALS in Germany.},
}

Humans
*Social Support
*Quality of Life/psychology
*Amyotrophic Lateral Sclerosis/psychology/complications
Female
Male
Disease Progression
Cross-Sectional Studies
Middle Aged
*Depression/psychology
Aged
Germany
Adult

@article {pmid42537332,
year = {2026},
author = {Silva Santos, M and Castro, J and de Carvalho, M},
title = {F-wave responses and recruitment at low intensities: Muscle-specific excitability profiles of intrinsic hand muscles.},
journal = {Neurophysiologie clinique = Clinical neurophysiology},
volume = {56},
number = {5},
pages = {103185},
doi = {10.1016/j.neucli.2026.103185},
pmid = {42537332},
issn = {1769-7131},
abstract = {OBJECTIVES: F-waves are late motor responses traditionally elicited via supramaximal stimulation. However, submaximal stimulation may offer a more sensitive probe for assessing spinal motoneuron excitability. This study characterizes F-wave recruitment curves using graded submaximal stimulation across various intrinsic hand muscles.

METHODS: F-waves were recorded from the abductor pollicis brevis (APB), abductor digiti minimi (ADM), and first dorsal interosseous (FDI) in 15 healthy subjects (ages 35-78). Four stimulus intensities were employed-10%, 20%, 30%, and 100% of the maximal compound muscle action potential (CMAP) amplitude-with 20 stimuli delivered per intensity. Analysis focused on F-wave frequency, amplitude, and matched F-wave/CMAP ratios (F-wave/CMAPm), where the F-wave and CMAP were recorded at identical stimulus intensities.

RESULTS: Most parameters correlated positively with stimulus intensity; however, F-wave/CMAPm consistently decreased as intensity increased. The ADM exhibited a distinct recruitment profile, with F-wave persistence rising steeply at low intensities and reaching near-saturation at 30%, while showing no significant amplitude differences between submaximal levels. In contrast, the APB and FDI displayed more linear recruitment patterns for both persistence and amplitude.

DISCUSSION: Submaximal stimulation reliably elicits F-waves and reveals muscle-specific excitability profiles. The ADM's high excitability suggests a more readily recruitable motoneuron pool. Furthermore, the inverse relationship between F-wave/CMAPm and stimulus intensity suggests the early recruitment of larger, highly excitable Type II motoneurons. This refined recruitment curve approach may provide valuable insights into the "split-hand" phenomenon observed in amyotrophic lateral sclerosis.},
}

@article {pmid42538529,
year = {2026},
author = {Marcus, B},
title = {Invited Commentary on: Azizzadeh et al.'s "The Multilevel Facial Anatomic Classification System: A Comprehensive Framework for Contemporary Facelift and Neck Rejuvenation Surgery".},
journal = {Facial plastic surgery & aesthetic medicine},
volume = {},
number = {},
pages = {26893614261466756},
doi = {10.1177/26893614261466756},
pmid = {42538529},
issn = {2689-3622},
}

@article {pmid42538750,
year = {2026},
author = {Krutovs, V and Grosmane, A and Kažmere, RR and Roddate, M and Ķauķe, G and Grosa, DP and Šetlere, S and Dīriks, M and Karelis, G and Ķēniņa, V},
title = {Nationwide Epidemiology of Motor Neuron Diseases in Latvia (2020-2024): Incidence, Prevalence, and Clinical Characteristics.},
journal = {European journal of neurology},
volume = {33},
number = {8},
pages = {e70710},
pmid = {42538750},
issn = {1468-1331},
mesh = {Humans ; Latvia/epidemiology ; Prevalence ; Female ; Incidence ; *Motor Neuron Disease/epidemiology/physiopathology ; Male ; Retrospective Studies ; Adult ; Middle Aged ; Aged ; Muscular Atrophy, Spinal/epidemiology ; Adolescent ; Young Adult ; Child ; Amyotrophic Lateral Sclerosis/epidemiology/physiopathology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA), are rare, progressive neurodegenerative conditions. Although well-studied in Western Europe, no nationwide epidemiological data have been published from Latvia. This study aimed to assess the incidence, prevalence, and clinical characteristics of MNDs in the Latvian population.

METHODS: A retrospective, hospital-based analysis was performed using records from Pauls Stradiņš Clinical University Hospital, Riga East University Hospital, and the Children's Clinical University Hospital between January 2020 and December 2024. Patients were identified through relevant ICD-10 codes. Incidence and prevalence rates were calculated per 100,000 population and age-standardized to the 2013 European Standard Population.

RESULTS: A total of 181 prevalent MND cases were identified: 131 with ALS or related phenotypes, 10 with adult-onset SMA, 33 with pediatric SMA, and 7 with SBMA. The age-standardized incidence of ALS was 1.22 per 100,000 person-years, and the prevalence was 4.69 per 100,000. Limb weakness or paresis was the most common initial symptom (48.1%). The mean diagnostic delay was 13.4 months for ALS, 43.8 months for PLS, 206.8 months for SBMA and 17.3 months for pediatric SMA. The prevalence of pediatric SMA was 9.91 per 100,000, with type II being the most frequent subtype. All SMA and SBMA cases were genetically confirmed.

CONCLUSION: This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA. Genetic testing, a national registry, and equitable therapy access should be prioritized.},
}

Humans
Latvia/epidemiology
Prevalence
Female
Incidence
*Motor Neuron Disease/epidemiology/physiopathology
Male
Retrospective Studies
Adult
Middle Aged
Aged
Muscular Atrophy, Spinal/epidemiology
Adolescent
Young Adult
Child
Amyotrophic Lateral Sclerosis/epidemiology/physiopathology
Aged, 80 and over

@article {pmid42538773,
year = {2026},
author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Vasta, R and Matteoni, E and Maccabeo, A and Cabras, S and Pellegrino, G and Minerva, E and Giudici, AD and Passidomo, V and Palumbo, F and Iazzolino, B and Mora, G and Chiò, A},
title = {Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.},
journal = {European journal of neurology},
volume = {33},
number = {8},
pages = {e70720},
pmid = {42538773},
issn = {1468-1331},
support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101137074//HORIZON EUROPE Framework Programme/ ; DIG-ALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; },
mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/complications/psychology/physiopathology ; Middle Aged ; Aged ; Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; *Cognitive Dysfunction/etiology/physiopathology ; Executive Function/physiology ; Neuropsychological Tests ; },
abstract = {OBJECTIVE: Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs).

METHODS: Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3 months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria.

RESULTS: Thirty-two PLS patients were included (mean disease duration, 25 months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia.

INTERPRETATION: Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement.},
}

Humans
Female
Male
*Motor Neuron Disease/complications/psychology/physiopathology
Middle Aged
Aged
Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology
*Cognitive Dysfunction/etiology/physiopathology
Executive Function/physiology
Neuropsychological Tests

@article {pmid42539086,
year = {2026},
author = {Lee, BH and Chan, J and Leung, YY and McMillan, CT and , and Song, Y and Amado, DA and Wang, K},
title = {Dissecting the relationship between haplotypes around ATXN2 CAG repeats and the number of CAA interruptions by long-read sequencing.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.11.26348169},
pmid = {42539086},
abstract = {BACKGROUND: CAG repeat expansions in ATXN2 are implicated as risk factors for several neurological diseases, including spinocerebellar ataxia type 2 (SCA2) when >=33 CAG repeats are present, and amyotrophic lateral sclerosis (ALS) when 27-33 CAG repeats are present. However, how haplotypes around the repeats and CAA interruptions within the repeats are associated with disease phenotypes remains poorly understood. Previous studies on haplotypes around ATXN2 were limited to SNPs very close to the repeats (<5kb) or were based on statistical inference only.

METHODS: Here, we used long-read sequencing on the Oxford Nanopore Technologies (ONT) platform to simultaneously infer haplotypes around ATXN2 , the number of CAG repeats, and the number of CAA interruptions, along with NYGC ALS Consortium NGS dataset. We further sequenced 41 individuals (EUR = 39) with neurological diseases with intermediate repeats by ONT.

RESULTS: We found that haplotypes around ATXN2 and the number of interruptions show ethnicity-specific and ALS-specific distribution. Three CAA interruptions are present at low prevalence (∼1%) in control populations in multiple ancestry groups, but high prevalence (∼55%) in ALS individuals with intermediate repeats. Furthermore, we examined 159 individuals with ALS (∼90% European ancestry) with intermediate ATXN2 repeats and found a unique haplotype in ALS individuals with three CAA interruptions, which can be tagged by an SNV, rs148019457. We also validated that the rs148019457-G allele is only present in haplotypes with three CAA interruptions.

CONCLUSIONS: In summary, our study shows that 3 CAA interruptions are rarely seen in healthy controls but are common in those with expanded ATXN2 CAG repeats who have neurological disorders, and that rs148019457 tags a specific haplotype with 3 CAA interruptions within expanded ATXN2 CAG repeats in individuals of European ancestry. These results have implications for the development of precision genomic medicine for neurological disorders, and the tag SNP may help identify those with interruptions from existing population genotyping data.},
}

@article {pmid42534468,
year = {2026},
author = {Luster, CB and Abdolmohammadi, B and Mastrodicasa, MJ and Nowinski, CJ and Feigel, ED and Finegan, B and White, AJ and Connors, EJ and Rovito, CA and Zafonte, RD and Alosco, ML and McKee, AC and Mez, J and Daneshvar, DH},
title = {Neurodegenerative mortality among National Football League Players.},
journal = {EClinicalMedicine},
volume = {97},
number = {},
pages = {104051},
pmid = {42534468},
issn = {2589-5370},
abstract = {BACKGROUND: Empirical research demonstrates elevated neurodegenerative mortality among individuals with repetitive head impact (RHI) exposure, including National Football League (NFL) players. This investigation addressed prior methodological limitations, including selection bias, subjective diagnoses, and retrospective reporting, by analyzing the relationship between RHI exposure and neurodegenerative mortality in a fully enumerated, 5.8-fold larger cohort of NFL players.

METHODS: A population-based retrospective cohort study was conducted comprising all current and former NFL athletes who debuted between 1960 and 2019 and played at least one regular or postseason NFL game, with National Death Index records (1979-2023) matched to Sports Reference, LLC data. Standardized mortality ratios (SMRs) were calculated from National Institute for Occupational Safety and Health data compared to an age-, sex-, race-, and calendar-year-standardized general population. Sensitivity analysis assessed whether the observed excess neurodegenerative mortality could be attributed to competing risks using a cause-specific hazard simulation.

FINDINGS: A total of 19,824 athletes had a cumulative 518,833 person-years (mean = 26.2 years, SD = 16.2), with 1994 decedents. NFL players exhibited lower all-cause mortality (SMR = 0.70; 95% CI: 0.67-0.74) but higher neurodegenerative mortality (SMR = 3.94; 95% CI: 3.38-4.56), including amyotrophic lateral sclerosis (SMR = 4.55; 95% CI = 3.13-6.38), all-cause dementia (SMR = 3.80; 95% CI = 3.11-4.60), and Parkinson's disease (SMR = 3.88; 95% CI: 2.76-5.30). Cause-specific hazard simulation indicated that competing risks alone would inflate the expected NDD SMR by a factor of 1.30, yielding a residual neurodegenerative SMR of 3.04 (95% CI: 2.63-3.50).

INTERPRETATION: Neurodegenerative mortality was nearly four times higher in NFL players compared to the general population and remained threefold higher after accounting for competing risks. Together, these findings strengthen the evidence for RHI exposure-related neurodegenerative mortality in NFL players that cannot be explained by differential survivorship.

FUNDING: The National Institute of Neurological Disorders and Stroke [U54NS115266; U01NS086659], the National Institute on Aging [P30AG13846; P30AG072978], and the Maloney/Carpenter Trauma-Related Neurodegenerative Disease Research Fund.},
}

@article {pmid42536230,
year = {2026},
author = {Naktinytė, E and Vilimienė, R and Valančius, D and Baronas, K and Zagorskienė, I and Utkus, A and Klimašauskienė, A and Burnytė, B},
title = {Genetic variants among patients with motor neuron disease in Lithuania - a retrospective single-center study.},
journal = {Neurogenetics},
volume = {27},
number = {1},
pages = {},
pmid = {42536230},
issn = {1364-6753},
mesh = {Humans ; *Motor Neuron Disease/genetics/epidemiology ; Female ; Retrospective Studies ; Lithuania/epidemiology ; Male ; Middle Aged ; *Genetic Variation ; C9orf72 Protein/genetics ; Aged ; Adult ; Phenotype ; Amyotrophic Lateral Sclerosis/genetics ; DNA Repeat Expansion ; },
abstract = {Motor neuron disease (MND) comprises several clinical phenotypes, with amyotrophic lateral sclerosis (ALS) being the most common. Despite the identification of over 40 ALS-associated genes, the pathogenesis remains complex and polygenic. This study evaluated the clinical phenotypes and prevalence of genetic causes in MND patients in Lithuania. We conducted a retrospective single-center study at a tertiary care clinic on patients with MND. Clinical and molecular genetic data were analyzed. The study included 53 patients with a mean age at symptom onset of 55 years. Most patients (43/53; 77.4%) were diagnosed with ALS, and the most common onset was spinal (39/53; 73.6%). The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51). C9orf72 hexanucleotide repeat expansion was detected in 5.9% (3/51) of patients. Next-generation sequencing was performed in 49 patients, of whom 5 (10.2%) had pathogenic or likely pathogenic variants, including pathogenic variants in the SOD1 and NEK1 genes and likely pathogenic variants in the FUS. The most common finding was C9orf72 hexanucleotide repeat expansion, followed by variants in SOD1 and FUS genes. The genetic spectrum was broadly similar to internationally recognized MND-associated genes, though formal comparisons were not performed due to the absence of a control group. These results emphasize the importance of systematic genetic testing in clinical practice and contribute to the limited data on the genetic spectrum of MND in the Baltic region.},
}

Humans
*Motor Neuron Disease/genetics/epidemiology
Female
Retrospective Studies
Lithuania/epidemiology
Male
Middle Aged
*Genetic Variation
C9orf72 Protein/genetics
Aged
Adult
Phenotype
Amyotrophic Lateral Sclerosis/genetics
DNA Repeat Expansion

@article {pmid42528478,
year = {2026},
author = {Palumbo, F and Iazzolino, B and Moglia, C and Manera, U and Matteoni, E and Cabras, S and Pellegrino, G and Minerva, E and Passidomo, V and Vasta, R and Mora, G and D'Ovidio, F and Canosa, A and Calvo, A and Chiò, A},
title = {Toward a Behavioral Reserve Model in Amyotrophic Lateral Sclerosis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78315},
pmid = {42528478},
issn = {1531-8249},
abstract = {OBJECTIVE: Behavioral impairment is common in amyotrophic lateral sclerosis (ALS) and strongly affects autonomy, caregiver burden, and outcomes, yet predictors of vulnerability remain unclear. We investigated whether premorbid regulatory traits and socio-educational exposures are associated with behavioral phenotypes in ALS within a behavioral reserve framework.

METHODS: We analyzed 965 consecutively assessed patients with ALS from a prospective tertiary-center cohort. Behavioral impairment was measured using the Frontal Systems Behavior Scale (FrSBe; family-rated before and after onset) and, in a subset (n = 633), the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). Theory-driven hierarchical logistic regression models tested associations between behavioral outcomes and premorbid behavioral regulation, education, occupation, and a Social Interaction Index, including interaction effects. Prespecified sensitivity analyses addressed potential bias in premorbid estimates.

RESULTS: Premorbid behavioral regulation showed the strongest associations with behavioral impairment across all FrSBe models. Higher combined educational attainment and social exposure were associated with lower odds of impairment, with a significant interaction across multiple behavioral domains. These patterns persisted in restricted sensitivity analyses. Reserve proxies were not significantly associated with ECAS-CI total impairment, although domain-specific effects were observed.

INTERPRETATION: These findings provide empirical support for a behavioral reserve framework in ALS, in which premorbid regulatory traits and socio-educational exposures are associated with behavioral vulnerability. Although causal inference is limited, reserve-related factors may contribute to non-motor heterogeneity in ALS and may inform future approaches to early behavioral risk stratification. ANN NEUROL 2026.},
}

@article {pmid42528798,
year = {2026},
author = {Gao, X and Chen, S and Mahabub, S and Cao, B and Deng, J and Ye, W and Yang, H and Zou, Z},
title = {A modified frailty index to identify high-risk groups for amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1879866},
pmid = {42528798},
issn = {1664-2295},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle weakness and poor prognosis, which requires early detection to optimize therapeutic outcomes. This study aims to develop a risk stratification tools for ALS and to assist in identifying high-risk groups.

METHODS: A prospective cohort study was conducted using the UK Biobank (500,033 participants), which were split into training sets and validation sets. We calculated the frailty index (FI) and modified frailty index (MFI) for the participants and estimated their association with ALS. Finally, two risk stratification tools were constructed and the time-dependent ROC curve was utilized to evaluate the discriminatory performance of each model.

RESULTS: Among the 49 deficits in FI, we identified five deficits that were significantly associated with ALS, including falls, whole-body pain, long-standing illness, disability or infirmity, self-rated health and tiredness or lethargy in last 2 weeks, which together constructed the MFI. Both the FI and MFI were associated with a higher risk of ALS (HRFI = 4.58, 95% CI = 1.31-16.07, HRMFI = 4.59, 95% CI = 2.79-7.53). Finally, a combination of MFI, gender, age and BMI demonstrated the best discriminative ability. Specifically, on the validation set, it achieved a C-index of 0.696.

CONCLUSION: By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease. It could therefore serve as a valuable screening tool for risk stratification in the general population.},
}

@article {pmid42529618,
year = {2026},
author = {Fiskum, V and Winter-Hjelm, N and Christiansen, N and Sandvig, A and Sandvig, I},
title = {Microscale dysfunction and mesoscale compensation in degenerating neuronal networks.},
journal = {Network neuroscience (Cambridge, Mass.)},
volume = {10},
number = {3},
pages = {594-612},
pmid = {42529618},
issn = {2472-1751},
abstract = {Progressive neurodegenerative diseases involve neuronal dysfunction across cellular, circuit, and whole-brain levels. Despite differences in anatomical origins, vulnerable neuronal subtypes, and specific misfolded proteins, these diseases share key features. In presymptomatic phases, neural networks engage compensatory processes to maintain function, including increased centralization and reliance on a rich-club of hub nodes. While such mechanisms have supporting evidence in some disorders, they remain less established in amyotrophic lateral sclerosis (ALS), limiting understanding of potential shared presymptomatic responses. To address this, we investigated structural and functional properties of ALS patient-derived motor neuron networks compared with healthy controls using longitudinal multielectrode array recordings and graph theory-based analysis. We observed microscale dysfunction marked by TAR DNA-binding protein 43 proteinopathy, hyperactivity, and reduced spike amplitude. Structurally, ALS networks exhibited neurite hypertrophy, suggesting attempts to form new connections. Mesoscale analyses revealed functional reconfigurations, including increased rich-club connectivity and network assortativity, indicating compensatory centralization. Our findings provide novel evidence that ALS network features can be recapitulated in in vitro models, and that these networks progressively become more centralized to preserve computational capacity, imposing growing demands on hub nodes and predisposing them to further damage. These results support models proposing common network reconfiguration mechanisms across neurodegenerative diseases.},
}

@article {pmid42529685,
year = {2026},
author = {Cheung, N},
title = {Cellular Logistics and Synaptic Vesicle Vulnerability in Major Depressive Disorder and Amyotrophic Lateral Sclerosis Comorbidity: Insights From Nicotinamide Mononucleotide Rescue and Transcriptome-Wide Association Study Integration.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e113549},
pmid = {42529685},
issn = {2168-8184},
abstract = {BACKGROUND: Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are usually treated as unrelated, yet depressive symptoms occur in a substantial minority of people with ALS and may appear early. These symptoms are heterogeneous and may reflect syndromal MDD, psychological and functional burden, fatigue, apathy, pseudobulbar affect, frontotemporal involvement, sleep or respiratory disturbance, medication effects, or shared affective vulnerability. A proposed pruning-continuum model suggests both disorders may share vulnerability in microglia-mediated synaptic pruning, with ALS amplified by autophagy and protein-quality-control failure and MDD by RNA-processing, stress, and immune dysregulation. We performed an exploratory secondary transcriptome-wide association study (TWAS)/pathway-integration analysis to test whether predefined nicotinamide mononucleotide (NMN)-nominated pathways map onto this vulnerability.

METHODS: We integrated precomputed S-PrediXcan outputs for MDD and ALS across available brain-relevant tissues. Ten Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were predefined from a prior re-analysis of NMN-associated transcriptional programs in aged mouse metabolic tissues. Mouse-derived candidates were represented by human ortholog symbols before the human TWAS screen. The analysis tested nominated pathways rather than the 35-gene NMN-robust list as a standalone set. Cross-tissue screening used Stouffer Z aggregation, tissue-level Wilcoxon testing, competitive permutation testing, percentile bootstrap intervals, pairwise disease statistics, Levene variance tests, concordance measures, and leave-one-out sensitivity analysis. No analysis was treated as confirmatory or evidence of causal mediation.

RESULTS: MDD showed the strongest Stouffer-based exploratory signal in the synaptic vesicle cycle pathway, with a meta-across-tissue Stouffer Z of 3.41 and a wide bootstrap 95% confidence interval of -0.46 to 7.40. This signal did not survive competitive permutation testing (p = 0.1222) or Wilcoxon testing (p = 0.1926). The strongest tissue-level result occurred in the amygdala (Z = 4.057; nominal Wilcoxon p = 0.0093), although tissue-level permutation testing was not performed in the multi-gene-set run. ALS showed no significant meta-across-tissue enrichment among the 10 nominated pathways but displayed candidate gene-level signals in autophagy, endosomal, and vesicle-related genes, including TBK1 and C9orf72. Exploratory Levene tests indicated variance heterogeneity in the regulation of the actin cytoskeleton, endocytosis, and neuroactive ligand-receptor interaction; the actin cytoskeleton and endocytosis remained significant in pooled global false discovery rate (FDR) analysis. Fourteen genes were influential in at least two focus pathways, including EGF, KNG1, FGF8, RAC1, PAK1, PAK2, RAF1, MAPK1, and FGFR1.

CONCLUSIONS: These findings are hypothesis-generating. MDD and ALS may stress overlapping cellular logistics processes while engaging largely different genes. MDD showed the strongest exploratory pathway-level signal in synaptic vesicle biology, whereas ALS showed candidate gene-level coherence in autophagy and endosomal processes without significant meta-pathway enrichment. NMN/NAD+ repletion is not established as a treatment for MDD, ALS, or their comorbidity. These findings generate hypotheses about NAD+-linked cellular stress pathways for future preclinical and clinical studies.},
}

@article {pmid42530312,
year = {2026},
author = {Ndungo, E and Islam, D and Gonwong, S and Ruamsap, N and Milletich, PL and Agnememel, A and Demons, ST and Pasetti, MF},
title = {Protective immunity against Shigella sonnei in vaccinated and challenged adult Thai volunteers.},
journal = {mSphere},
volume = {},
number = {},
pages = {e0026926},
doi = {10.1128/msphere.00269-26},
pmid = {42530312},
issn = {2379-5042},
abstract = {A safe, effective, and affordable vaccine that can prevent Shigella-induced diarrhea could have a significant impact on reducing morbidity and mortality in populations at risk. WRSS1, a live attenuated Shigella sonnei vaccine candidate, was well tolerated and immunogenic in adult Thai volunteers, achieving 40% efficacy against wild-type (WT) S. sonnei. We performed an in-depth analysis of mucosal and systemic antibodies in these individuals following WRSS1 vaccination and S. sonnei challenge, including a broader analysis of antibody specificity, functional features, and associations with clinical protection. IgG and IgA against Shigella proteins IpaB, IpaC, IpaD, IpaH, VirG, and LPS from multiple strains, as well as complement-mediated bactericidal and opsonophagocytic killing activity, were assessed in serum, fecal extracts, and antibodies in lymphocyte supernatants. Shigella-specific serum and ALS IgG and IgA increased after WRSS1 vaccination and S. sonnei challenge, particularly in naïve individuals, and most robustly post-challenge. Shedding the vaccine or infecting strain was associated with ALS responses. Fecal IgA was broadly reactive to most antigens, while fecal IgG was specific for S. sonnei LPS. Functional antibodies were detected prominently in fecal extracts; the highest responders were naïve individuals post-challenge. Notably, higher protein-specific serum IgA titers before challenge were associated with clinical protection against disease. Our results highlight the nuanced immunity to Shigella in endemic regions and the importance of understanding the elements that mediate protection in these settings to inform effective vaccine implementation.IMPORTANCEUnderstanding the immune response in Shigella-endemic regions is critical for the design and implementation of vaccines for the target population. We characterized the breadth of systemic and mucosal antibody responses to WRSS1 vaccination and WT S. sonnei challenge in Thai adult volunteers. Antigen-specific IgG and IgA in ALS were elevated only in individuals who shed the vaccine or challenge strain, indicating exposure. Serum IgA responses to Shigella proteins were associated with clinical protection. Our findings underscore the value of serosurveillance in guiding public health interventions and support the concept of protein-based vaccines to prevent disease in high-burden settings.},
}

@article {pmid42530583,
year = {2026},
author = {Graco, M and Russo, K and Grivell, N and Carey, K and Zaga, C and Saravanan, K and Sheers, NL and Berlowitz, DJ and , },
title = {A qualitative investigation of the factors influencing the uptake of noninvasive ventilation among Australians with motor neurone disease.},
journal = {Disability and rehabilitation},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/09638288.2026.2704454},
pmid = {42530583},
issn = {1464-5165},
abstract = {PURPOSE: Non-invasive ventilation (NIV) improves quality of life and extends survival for people with motor neurone disease (pwMND); however, uptake in Australia remains modest. This study explored the factors that influence the uptake of NIV from the perspectives of pwMND, caregivers, and healthcare professionals.

METHODS: Thirty-nine semi-structured interviews were conducted with pwMND (n = 8), family caregivers of pwMND (n = 4), and healthcare professionals (n = 27). A two-stage deductive-inductive analysis was performed to identify common themes that influence the uptake of NIV in MND.

RESULTS: Twenty-six key influencing factors were identified, relating to three major themes: influences on the pwMND's decision to trial NIV; healthcare professional knowledge, beliefs and behaviors; and inequity and lack of responsiveness in the healthcare system. Inductive analysis also identified a fourth theme, disparities in NIV uptake. Within this theme, women, older people, and First Nations Australians were acknowledged as demographic groups experiencing challenges to NIV uptake that warrant further investigation.

CONCLUSION: This research identified multiple modifiable factors influencing the uptake of NIV that can inform the design of targeted interventions to reduce inequitable access to NIV, increase uptake, and optimize quality of life for pwMND.},
}

@article {pmid42531420,
year = {2026},
author = {Burke, KM and Brown, R and Calcagno, N and Gupta, AS and Gajos, KZ and Scheier, Z and Clark, A and Iyer, A and Higgins, MP and Keegan, M and Royse, TB and Remington, E and Connaghan, KP and Johnson, SA and Chew, S and Erb, MK and Berry, JD},
title = {Digital Remote Assessment of Motor and Speech Changes in Amyotrophic Lateral Sclerosis: Longitudinal Observational Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e85142},
pmid = {42531420},
issn = {2561-326X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Female ; Longitudinal Studies ; Male ; Middle Aged ; Aged ; Disease Progression ; Remote Patient Monitoring ; Digital Health ; *Speech/physiology ; Adult ; Reproducibility of Results ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an active trial landscape that relies on the sensitivity of selected clinical trial endpoints. Traditional clinical outcome assessments perform well in trials but lack strong psychometric properties and may not detect small but clinically meaningful disease progression. Digital health technologies offer a promising alternative for tracking ALS disease progression.

OBJECTIVE: This study assessed the feasibility of remote digital monitoring in ALS using a comprehensive battery of prescribed home-based assessments via a smartphone, a wearable device, and a computer-based mouse-clicking task.

METHODS: Participants completed weekly remote assessments, including motor and speech tasks via a smartphone app and a computer mouse-clicking task for 24 weeks. They also participated in 3 remote telephone visits in weeks 1, 13, and 25. Reliability, minimal detectable change, and correlations with self-reported ALS Functional Rating Scale-Revised subdomain scores were calculated for 8 features across the speech, fine motor, and gross motor smartphone app tasks and for all 32 features from the computer mouse-clicking task. Sensitivity to longitudinal change was assessed for the 8 smartphone-derived features and for a representative subset of 8 computer mouse-clicking features.

RESULTS: Forty-two participants (19 with ALS and 23 controls) completed 10,237 smartphone assessments and 459 computer mouse-clicking sessions. Baseline discriminative models differentiated ALS from controls with AUC values of 0.75-0.92. Digital measures correlated strongly with self-reported ALS Functional Rating Scale-Revised subdomain scores. Both participants with ALS and controls demonstrated improvement in fine motor and speech measures, with the exception of nondominant-hand pegboard performance, which declined in the ALS group. Improvements were smaller in participants with ALS, leading to increasing group differences over time, although only one feature showed a statistically significant separation over the 24 weeks. Gait and balance performance declined in both groups, with greater but nonsignificant separation observed for balance measures.

CONCLUSIONS: These findings support the feasibility of digital remote assessments in ALS, demonstrate the ability to discriminate between ALS and controls based on certain features collected from speech, fine, and gross motor tasks, and in some cases, quantify functional decline over time. Further research is necessary to explore the natural history of these features longitudinally in larger cohorts of participants with ALS over extended periods to enable their potential integration into clinical trials.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications
Female
Longitudinal Studies
Male
Middle Aged
Aged
Disease Progression
Remote Patient Monitoring
Digital Health
*Speech/physiology
Adult
Reproducibility of Results

@article {pmid42532824,
year = {2026},
author = {Lin, YT and Yang, HL},
title = {[Applying Developmental Care Theory to the Improvement of Self-Regulation and Feeding Difficulties in a Late Preterm Infant Receiving Cardiac Surgery: A Nursing Experience].},
journal = {Hu li za zhi The journal of nursing},
volume = {73},
number = {4},
pages = {},
doi = {10.6224/JN.26413},
pmid = {42532824},
issn = {0047-262X},
mesh = {Humans ; Female ; Infant, Newborn ; *Infant, Premature ; *Self-Control ; *Cardiac Surgical Procedures ; *Feeding Behavior ; },
abstract = {When preterm infants present with organ anomalies that require immediate surgical intervention after birth, their immature nervous systems often limit their ability to cope with the stress of surgery and subsequent treatments. This often results in difficulties with self-regulation and related health issues. The case described in this study involves a late preterm female infant born at 36+4 weeks of gestation who underwent cardiac surgery on the fifth day after birth. Postoperatively, she exhibited neonatal neurodevelopmental disorganization, ineffective suck-swallow reflexes, and inadequate nutritional intake. The first author provided nursing care between April 22 to May 10, 2025, with a telephone follow-up on May 14. The provided interventions were guided by Als' Synactive Theory of Development and integrated the Seven Neuroprotective Core Measures of the Neonatal Integrative Developmental Care Model, encompassing environmental regulation, sleep and positioning support, stress and pain management, and family-centered care. Objective evaluation was conducted using the Preterm Infant Oral Feeding Readiness Assessment Scale (POFRAS). The results demonstrated improvements in both self-regulation and feeding difficulties. Notably, the incidence of crying episodes decreased, the infant was able to sustain a calm state for longer periods, coordination of suck-swallow-breathing improved, and oral intake increased. Consequently, the amount of supplemental gavage feeding was reduced, caregivers were able to provide effective care, and the POFRAS score rose from 21 to 32. The comprehensive care approach described in this study integrates theoretical frameworks with behavioral cue-based observations to effectively improve feeding difficulties and self-regulation in preterm infants undergoing invasive surgery while simultaneously enhancing caregiver competence and confidence.},
}

Humans
Female
Infant, Newborn
*Infant, Premature
*Self-Control
*Cardiac Surgical Procedures
*Feeding Behavior

@article {pmid42533344,
year = {2026},
author = {Bublitz, SK and Becker, B and Demleitner, AF and Dietz-Laukemann, P and Lingor, P and Littger, B and Lorenzl, S and Feddersen, B},
title = {Ethical challenges in treatment-goal transitions in invasively ventilated ALS: a case-based topical review.},
journal = {Neurological research and practice},
volume = {8},
number = {1},
pages = {},
pmid = {42533344},
issn = {2524-3489},
abstract = {INTRODUCTION: In advanced amyotrophic lateral sclerosis (ALS), eye movements often represent the last channel for intentional communication. While oculomotor function has traditionally been considered relatively preserved, emerging evidence indicates progressive impairment in long-term survivors on tracheostomy-invasive ventilation (TIV). As a result, eye-based communication may become increasingly unreliable before complete loss, challenging clinical decision-making and advance care planning (ACP).

METHODS: We conducted a case-based topical review integrating clinical observation and literature to examine the trajectory of oculomotor decline, its impact on communication, and implications for treatment decisions. Three patients with ALS receiving TIV in a home-care setting illustrate key clinical and ethical challenges.

RESULTS: Across cases and literature, oculomotor decline followed a gradual trajectory from effective eye-tracking communication to a complete locked-in syndrome. We identify a transitional phase of communicative ambiguity, in which residual ocular signals persist but can no longer be reliably attributed to intentional, patient-controlled communication. This phase is characterized by increasing inconsistency of signals and a divergence between observable responses and their interpretive certainty, creating uncertainty in assessing patient preferences.

IMPLICATIONS: Communicative ambiguity represents a clinically underrecognized but critical threshold in advanced ALS, marking the transition from direct patient autonomy to interpretative and surrogate-based decision-making. Failure to recognize this phase risks misinterpretation of patient intent and may undermine goal-concordant care. Timely and iterative ACP, initiated before communication becomes unreliable, is essential. We further propose four clinical pathways for treatment goal conversations, highlighting their differing implications for timing, symptom burden, and ethical decision-making.},
}

@article {pmid42533374,
year = {2026},
author = {Rotteau, L and Wong, BM and Mukerji, G and Moser, A and Feldman, S and Shojania, KG and Goldman, J},
title = {Qualitative study of the implementation of long-term care plus: An intervention-in-systems approach.},
journal = {Journal of health services research & policy},
volume = {},
number = {},
pages = {13558196261470275},
doi = {10.1177/13558196261470275},
pmid = {42533374},
issn = {1758-1060},
abstract = {ObjectivesReducing resident transfers from long-term care (LTC) to emergency departments (ED) is a well-established quality target. LTC plus (LTC+) provides medical consultations, healthcare navigation, rapid diagnostics, and education to LTC home providers, based on the logic that providing enhanced medical care in LTC homes will decrease ED transfers. LTC+ was implemented across six hospital-hubs and 54 homes in Toronto, Canada. An evaluation demonstrated positive program satisfaction and impacts on care, however limited program uptake and impact on ED transfers. We examine LTC+ intervention components and their implementation and adaptations to understand these discrepancies and identify improvement opportunities.MethodsWe conducted 32 qualitative interviews with LTC home providers and administrators and consultant physicians, and three focus groups with residents and family members, at six LTC homes and three hospital-hubs. Analysis drew on Lennox et al.'s conceptualization of "intervention-in-systems" which outlines four spheres to categorize intervention components (accessibility of evidence base, process of enactment, dependent processes and sociocultural issues) and their interconnectedness and adaptations when implemented and spread in complex systems.ResultsLTC+ design and implementation was centered within the accessibility of evidence base (e.g., educating about LTC+) and process of enactment (e.g., identify residents being considered for ED transfer) spheres to support program goals. LTC+ use was aligned with original program logic, however, providers also accessed LTC+ in cases where an ED transfer was not being considered highlighting limitations of a logic focused solely on ED transfers. LTC+ design and implementation was less attentive to intervention components in the dependant processes and sociocultural issues spheres (e.g., staffing models, interprofessional interactions) impacting adoption.ConclusionThe "intervention-in-systems" analytic lens was useful in examining intervention components across the four spheres, including their gaps, adaptations and interconnections. Study findings informed revisions to program goals, intervention components, and evaluative approach, reinforcing program and financial sustainability.},
}

@article {pmid42533837,
year = {2025},
author = {Edwards, CM},
title = {Response to Young et al.'s 'Letter to the Editor'.},
journal = {Journal of military, veteran and family health},
volume = {11},
number = {3},
pages = {198-201},
pmid = {42533837},
issn = {2368-7924},
}

@article {pmid42524305,
year = {2026},
author = {Longo, UG and Merone, M and Schena, E and Bandini, B and Nicodemi, G and Zsidai, B and Hilkert, AS and Senorski, EH and Grassi, A and Ley, C and Herbst, E and Hirschmann, MT and Kopf, S and Seil, R and Tischer, T and Feldt, R and Samuelsson, K and Oettl, FC},
title = {A practical guide to the implementation of AI in orthopaedic research-Part 4: Prerequisites for a successful orthopedics AI-driven project in terms of interdisciplinary collaboration, data management, ethical approval and technology.},
journal = {Journal of experimental orthopaedics},
volume = {13},
number = {3},
pages = {e70863},
pmid = {42524305},
issn = {2197-1153},
abstract = {UNLABELLED: Translating artificial intelligence (AI) research in orthopedics from proof-of-concept studies into production-grade clinical systems requires the systematic satisfaction of four prerequisite domains: interdisciplinary team architecture, technical data management, ethical and regulatory governance and production-grade technology and deployment infrastructure. Despite a tenfold increase in orthopedic AI publications, fewer than 6% of studies reach routine clinical deployment, reflecting persistent gaps in each of these domains. This article provides a technically rigorous, evidence-based framework organized around these four pillars. The interdisciplinary team may be structured using a product-centric topology that decouples stream-aligned clinical teams from platform infrastructure teams, following Huffman et al.'s six-step AI project lifecycle: obtain/curate/label data; establish a reference standard; develop the model; evaluate performance; externally validate and iteratively reinforce until clinical implementation is viable. Data management requires data extraction protocols, integration for bulk exports and a multi-component de-identification pipeline. A multi-stage Institutional Review Board framework governs ethical oversight, scaling from Exempt review for retrospective de-identified studies to Full Board Review with prospective validation and mandatory human-override mechanisms for interventional deployment. Responsible clinical deployment requires a multi-layer Clinical Machine Learning Operations framework, implementing privacy-preserving deployment, clinical observability, compliance audit trails and human-in-the-loop governance. Model drift has to be monitored with a degradation threshold triggering mandatory human review.

LEVEL OF EVIDENCE: Level V.},
}

@article {pmid42524894,
year = {2026},
author = {Guo, W and Cai, S and Li, Y and McGarry, BE and Caprio, TV and Temkin-Greener, H},
title = {User-Generated Google Maps Ratings, State Staffing and Training Regulations, and the Quality of Hospice Care in Assisted Living Communities.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70609},
pmid = {42524894},
issn = {1532-5415},
support = {Another Look 2020//Patrick and Catherine Weldon Donaghue Medical Research Foundation/ ; R01HS026893/HS/AHRQ HHS/United States ; },
abstract = {BACKGROUND: Hospice services are growing among Medicare beneficiaries, yet concerns remain about the hospice quality for residents in assisted living (AL) communities. Little is known about how AL characteristics and state regulations are associated with hospice care in these settings.

OBJECTIVES: To examine (1) whether AL user-generated google maps ratings (AL google maps ratings) and (2) state-level regulations on AL staffing are associated with hospice ratings: METHODS: We conducted a cross-sectional analysis of 15,947 AL communities. We included data on AL-specific direct care worker (DCW) state staffing and staff training regulations. Logistic regression models were used to assess associations, adjusting for AL, hospice, and market-level characteristics.

RESULTS: A one-star increase in an AL google maps rating was associated with 6% higher odds of being served by hospices with higher HIS scores (OR = 1.06, p = 0.032), but not with CAHPS scores. AL communities in states with higher regulatory specificity for DCW staffing had higher odds of being served by hospices with higher CAHPS (OR = 1.46, p < 0.001) and HIS scores (OR = 1.35, p < 0.001). ALs in states mandating more than 21 h of DCW training, AL communities were more likely to be served by hospices with higher CAHPS scores (OR = 1.33, p < 0.001).

CONCLUSION: Higher AL google maps ratings were associated with higher hospice HIS performance. DCW staffing regulations were associated with both CAHPS and HIS, and DCW training regulations were associated with CAHPS only. These findings underscore the role of organizational quality and state regulatory policies in guiding end-of-life care in AL communities.},
}

@article {pmid42525902,
year = {2026},
author = {Roberts, AL and Vilela Braga, AD and Tang, IW and Rotem, RS and Moo, LR and Miller, DR and Shirk, SD and Weisskopf, MG},
title = {Association of Military Branch and Rank With Amyotrophic Lateral Sclerosis Incidence Among United States Veterans.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218303},
doi = {10.1212/WNL.0000000000218303},
pmid = {42525902},
issn = {1526-632X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Male ; United States/epidemiology ; *Veterans/statistics & numerical data ; Female ; *Military Personnel/statistics & numerical data ; Incidence ; Middle Aged ; Longitudinal Studies ; Adult ; Risk Factors ; Aged ; Cohort Studies ; Proportional Hazards Models ; },
abstract = {BACKGROUND AND OBJECTIVES: Military service is one of the most consistent risk factors for the development of amyotrophic lateral sclerosis (ALS), but little is known about what aspects of military service matter. Understanding the distribution of ALS risk in military personnel may help identify key risk factors. We aimed to ascertain the association of United States (US) military branch and rank with incident ALS.

METHODS: We conducted a longitudinal cohort study including all veterans with a Veterans Health Administration encounter from January 1, 2000, through October 1, 2024, and more than 2 years of follow-up. Incident ALS was identified through medical records. Exposures included military branch (Army, Navy, Air Force, Marine Corps, Coast Guard, or multiple branches), military rank (officer, enlisted, or both), and length of service. Risk was estimated with Cox proportional hazards models, controlled for age, adjusted for race/ethnicity, and stratified by sex.

RESULTS: The analytic sample comprised 9,157,938 men (13,935 incident ALS cases, mean age = 56.9 years) and 784,941 women (484 cases, mean age = 42.4 at start of follow up). Among men, compared with service in the Army, service in the Air Force (hazard ratio [HR] = 1.29, 95% CI 1.23-1.35), Navy (HR = 1.15, 95% CI 1.10-1.20), and Coast Guard (HR = 1.26, 95% CI 1.06-1.50) was associated with higher rates of ALS and service in the Marines a lower rate (HR = 0.78, 95% CI 0.68-0.88). Officers had higher rates than enlisted personnel (men, HR = 1.64, 95% CI 1.53-1.74; women, HR = 1.72, 95% CI 1.31-2.27). Longer service was associated with lower rates of ALS. In age-stratified models, differences in hazard rates between Army veterans and Air Force, Navy, and Coast Guard veterans were greatest for the youngest men (17-61 years, HR range = 1.26 to 1.51) and smallest for the oldest (>75-104 years, HR range = 0.99 to 1.12).

DISCUSSION: ALS rates varied considerably by branch and rank in the US military, with larger differences among younger veterans. Officers and those serving in the Air Force, Navy, or Coast Guard may incur exposure to military environments that increase risk of ALS. It is imperative to identify relevant exposures to reduce harm to service members and, potentially, civilians with similar exposures.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology
Male
United States/epidemiology
*Veterans/statistics & numerical data
Female
*Military Personnel/statistics & numerical data
Incidence
Middle Aged
Longitudinal Studies
Adult
Risk Factors
Aged
Cohort Studies
Proportional Hazards Models

@article {pmid42525906,
year = {2026},
author = {Hardiman, O},
title = {Amyotrophic Lateral Sclerosis in the Military: A Uniform Risk?.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218481},
doi = {10.1212/WNL.0000000000218481},
pmid = {42525906},
issn = {1526-632X},
}

@article {pmid42526364,
year = {2026},
author = {Stevenson, C and McNamara, N and John, R and Gallagher, S},
title = {Local community identification improves wellbeing by reducing loneliness: Longitudinal evidence from two studies.},
journal = {Social science & medicine (1982)},
volume = {406},
number = {},
pages = {119543},
doi = {10.1016/j.socscimed.2026.119543},
pmid = {42526364},
issn = {1873-5347},
abstract = {Loneliness is a significant determinant of mental and physical health which has many root causes at local community level. Building on the Social Identity Approach to Health we test a longitudinal version of McNamara et al.'s (2021) neighbourhood identity model of wellbeing, which links local community identification to wellbeing via reduced loneliness. Study 1 was a two-wave survey of residents in mid-Nottinghamshire, UK (T1 N = 879; T2 N = 216). Mediation analyses showed that, over a one-year period, changes in community identification predicted increases in wellbeing via increases in perceived support and reductions in loneliness while controlling for a range of demographic factors. In Study 2, a secondary analysis of a large population-based UK study, i.e. Understanding Society (UKHLS; Waves 9 and 12; n = 38,056) showed that over a three-year period, increases in identification predicted improvements in GHQ-12 mental health and self-rated general health, again via increases in perceived support and reductions in loneliness. Across studies, the effect of neighbourhood identification on wellbeing occurred primarily through loneliness reduction. We discuss implications for reducing health inequalities through local community identity-building and social infrastructure, and outline priorities for policy and future research.},
}

@article {pmid42526365,
year = {2026},
author = {Ahsan, A and Ou, JC and Majumder, P and Chiang, YH and Huang, JK and Huang, CS},
title = {A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.},
journal = {Journal of neuroimmunology},
volume = {420},
number = {},
pages = {579028},
doi = {10.1016/j.jneuroim.2026.579028},
pmid = {42526365},
issn = {1872-8421},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS.

METHODS: A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I[2] statistic.

RESULTS: A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant.

CONCLUSION: This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder.

PROSPERO identifier CRD420251076035.},
}

@article {pmid42526625,
year = {2026},
author = {Guth, MAS},
title = {Targeting TDP-43 in ALS: Regulatory hurdles, trial design deficiencies, and the causal evidence gap for CTx1000.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104752},
doi = {10.1016/j.drudis.2026.104752},
pmid = {42526625},
issn = {1878-5832},
abstract = {The therapeutic landscape for amyotrophic lateral sclerosis (ALS) has been characterized by decades of clinical trial failures, often attributed to biological heterogeneity, end-point insensitivity, and a profound evidence gap regarding target engagement. With TAR DNA-binding protein 43 (TDP-43) aggregation emerging as a hallmark feature in the vast majority of ALS cases, new precision-medicine modalities - most notably the proteolysis-targeting chimera (PROTAC) CTx1000 - aim to address the underlying causal pathology through selective degradation of mislocalized TDP-43. This review critically evaluates the regulatory hurdles and trial design deficiencies that have historically undermined ALS clinical development, and incorporates the dual sequestration hypothesis as a framework to interpret the convergence of TDP-43 pathology across neurodegenerative diseases. It concludes that it is imperative that the field adopts more rigorous biomarker-led methodologies, and that although target-specific degraders offer a sophisticated technological leap, their success depends on addressing fundamental knowledge gaps in target engagement, age-dependent vector tropism, and trial design architecture.},
}

@article {pmid42520340,
year = {2026},
author = {Morgan-Jack, BR and Katz, ML and Kick, GR and Johnson, GC and Delgado, K and Makinen, M and Coates, JR},
title = {Pathology of general proprioception in a canine disease model of amyotrophic lateral sclerosis.},
journal = {Journal of the neurological sciences},
volume = {489},
number = {},
pages = {126108},
doi = {10.1016/j.jns.2026.126108},
pmid = {42520340},
issn = {1878-5883},
abstract = {Some forms of amyotrophic lateral sclerosis (ALS) are associated with sequence variants in the superoxide dismutase 1 gene (SOD1). The mechanisms by which these variants contribute to ALS disease pathogenesis are poorly understood. Degenerative myelopathy (DM), a naturally occurring canine disease, shares similarities with some forms of SOD1-associated ALS, especially cases with sensory impairment. While motor pathway involvement in ALS has been extensively studied, sensory pathology has received comparatively less attention. To investigate whether pathology in the general proprioceptive pathway is associated with pelvic limb general proprioceptive ataxia, an early DM sign, we examined sensory system components of this pathway from Pembroke Welsh Corgis with early- and late-stage DM and age-matched controls. The disease was characterized by axonal pathology in the spinocerebellar tracts and the fasciculus gracilis, pronounced accumulation of SOD1-positive inclusions in nucleus thoracicus and dorsal root ganglia (DRG) neurons, and altered SOD1 immunolabeling in dorsal and ventral root axons and ensheathing myelin. Axonal pathology was also observed in a pelvic limb sensory nerve. These findings suggest that pathology in the proprioceptive sensory pathways may play a significant role in general proprioceptive ataxia in DM. Some dogs that were homozygous for the SOD1 risk allele did not develop clinical disease or the associated neuropathology, indicating that other factors in addition to the SOD1 mutation influence disease onset and progression.},
}

@article {pmid42521602,
year = {2026},
author = {Pathapati, N and Nguyen, M and Ju, J and Maddukuri, M and Kiehl, J and Kvale, E and Thrift, AP and Berth, S and Grouls, A},
title = {Capturing Financial Burden Concerns in an ALS Multidisciplinary Clinic.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70364},
pmid = {42521602},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is associated with substantial financial burden. How financial concerns are documented or addressed in ALS multidisciplinary clinics (MDC) is unclear. We aimed to characterize financial concerns among people living with ALS (pALS) and how they are identified and documented by multidisciplinary clinic staff.

METHODS: We performed a retrospective electronic medical record (EMR) review for people living with ALS (pALS) attending at least two visits at the MDC, identifying documentation of financial concerns across all MDC notes throughout 2024. Semi-structured interviews with MDC staff explored experiences with financial concern discussions and documentation. Rapid qualitative analysis was used to analyze interview content.

RESULTS: Among 67 pALS with at least 2 MDC visits, 45 (67.2%) had ≥ 1 documented financial concerns. Financial concerns were most documented in neurology physician notes and portal messages (both 77.8%) and included insurance denials, medication costs, disability/Medicare navigation, caregiving expenses, and home modifications. Social work and patient portal notes provided greater detail than other staff notes. Staff interviews highlighted insurance and equipment costs as frequent financial concerns. Four qualitative themes emerged: insurance challenges and reliance on non-insurance resources, financial barriers limiting care and quality of life, limited proactive conversations/documentation, and the central role of social work.

DISCUSSION: Financial concerns are common among pALS but are inconsistently discussed and documented in the EMR, often arising through asynchronous communication or social work. Integrating financial screening and promoting proactive multidisciplinary documentation may improve identification of financial concerns and support more equitable, person-centered ALS care.},
}

@article {pmid42521811,
year = {2026},
author = {Willemse, SW and Demaegd, KC and Koole, W and van Eijk, RPA and van Rheenen, W and Veldink, JH and van den Berg, LH and van Es, MA},
title = {Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.},
journal = {European journal of human genetics : EJHG},
volume = {},
number = {},
pages = {},
pmid = {42521811},
issn = {1476-5438},
support = {09150161810018//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; V0000319//ZonMw (Netherlands Organisation for Health Research and Development)/ ; },
abstract = {The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.},
}