@article {pmid41931746,
year = {2026},
author = {Chalitsios, CV and Rudolf, O and Gao, J and Turner, MR and Thompson, AG},
title = {Long-Term Exposure to Ambient Air Pollution and Incident Amyotrophic Lateral Sclerosis: A Prospective Cohort Analysis of the UK Biobank.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214858},
doi = {10.1212/WNL.0000000000214858},
pmid = {41931746},
issn = {1526-632X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/etiology ; Middle Aged ; Female ; Male ; United Kingdom/epidemiology ; *Air Pollution/adverse effects ; Aged ; Prospective Studies ; Adult ; Biological Specimen Banks ; *Environmental Exposure/adverse effects ; Incidence ; Particulate Matter/adverse effects ; Gene-Environment Interaction ; *Air Pollutants/adverse effects ; Cohort Studies ; Nitrogen Oxides ; C9orf72 Protein/genetics ; UK Biobank ; },
abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex etiology. Although a range of genetic and lifestyle factors have been implicated, the potential role of environmental airborne pollution exposure is uncertain. This study examined the association between long-term ambient exposure to air pollutants and the incidence of ALS in UK Biobank participants.

METHODS: This prospective cohort study was based on the UK Biobank participants aged 40-69 years. The analytical sample comprised participants free of ALS at baseline and had complete data on air pollution exposure. Long-term exposure (2006-2021) to nitrogen dioxide (NO2), nitrogen oxides (NOX), fine particulate matter (PM2.5; <2.5 µm), and coarse particulate matter (PM10; <10 µm) was assessed using data from the UK Department for Environment, Food and Rural Affairs at a spatial resolution of 1 × 1 km. To evaluate the association between these pollutants and ALS risk, we used multivariable time-varying Cox proportional hazards models. Several sensitivity analyses were conducted to assess the robustness of the results. We also examined for gene-environment interaction stratified by C9orf72 status and UNC13A genotype.

RESULTS: Among the 501,308 participants with a mean age of 56.5 (SD 8.1) years at baseline, 272,764 (54.4%) were female. Over a median follow-up of 8.4 years, 687 individuals developed ALS. We did not observe any associations for any of the examined pollutants and ALS risk. Specifically, the hazard ratios per SD increment for PM10, PM2.5, NOX, and NO2 were 1.03 (95% CI 0.92-1.15), 1.00 (95% CI 0.88-1.14), 1.01 (95% CI 0.90-1.13), and 1.00 (95% CI 0.89-1.12), respectively. Individuals living in areas with the highest tertile of air pollutant exposure, compared with those in the lowest tertile, did not show a higher risk of ALS across any of the pollutants examined (p for trend >0.05). Restricted cubic spline analyses revealed no nonlinear associations between air pollution and ALS risk (all p for nonlinearity >0.05). These results remained robust in various subgroup and sensitivity analyses. No evidence of gene-environment interaction was found.

DISCUSSION: In this large population-based study with high statistical power, ambient air pollution was not a risk factor for the development of ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/genetics/etiology
Middle Aged
Female
Male
United Kingdom/epidemiology
*Air Pollution/adverse effects
Aged
Prospective Studies
Adult
Biological Specimen Banks
*Environmental Exposure/adverse effects
Incidence
Particulate Matter/adverse effects
Gene-Environment Interaction
*Air Pollutants/adverse effects
Cohort Studies
Nitrogen Oxides
C9orf72 Protein/genetics
UK Biobank

@article {pmid41932459,
year = {2026},
author = {Biscardi, T and Pepe, R and Cortini, E and Luongo, D and Notariale, R and Sharbafshaaer, M and Trojsi, F and Bergamo, P},
title = {Supplementation with Conjugated Linoleic Acid ameliorates the level of some Nrf2-activated systemic markers in patients with amyotrophic lateral sclerosis: a proof-of-principle study.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.03.067},
pmid = {41932459},
issn = {1873-4596},
}

@article {pmid41925964,
year = {2026},
author = {Oriquat, G and H, M and Maharana, L and Dhyani, A and Al-Hasnaawei, S and Singh-Chauhan, A and Arora, V and Sharma, J and Sadeghi-Samarjan, R},
title = {The Gut Microbiome in Amyotrophic Lateral Sclerosis: Emerging Mechanisms and Therapeutic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41925964},
issn = {1559-1182},
mesh = {*Amyotrophic Lateral Sclerosis/microbiology/therapy ; Humans ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons and a median survival of 2 to 3 years after symptom onset. Despite advances in genetics, particularly the identification of mutations in C9ORF72, SOD1, and TDP 43, substantial variability in disease onset and progression remains unexplained. Mounting evidence points to the gut microbiome as a potential modifier of ALS biology. Microbial communities within the intestine influence systemic and central immune responses, energy metabolism, and the bioavailability of nutrients and therapeutic agents. Animal studies reveal that dysbiosis contributes to intestinal barrier dysfunction, immune activation, and altered metabolite production, while supplementation with beneficial metabolites such as butyrate or nicotinamide can delay disease progression and extend survival. Human studies, though inconsistent in their findings, consistently identify microbial imbalances and loss of diversity in subsets of patients. The gut-brain axis provides a plausible framework for these effects, as microbial products can signal through endocrine, neural, and immune pathways to influence central nervous system function. Beyond motor decline, microbiota alterations may also contribute to non-motor symptoms such as depression, anxiety, and gastrointestinal dysfunction, further shaping quality of life. While methodological variability complicates interpretation, integration of microbiome research with host genomics and metabolomics offers a path toward precision medicine. Targeting microbial composition and function may ultimately represent a novel therapeutic approach capable of modifying both disease biology and patient outcomes in ALS.},
}

*Amyotrophic Lateral Sclerosis/microbiology/therapy
Humans
*Gastrointestinal Microbiome/physiology
Animals
Dysbiosis

@article {pmid41926450,
year = {2026},
author = {Christoforidou, E and Rowe, JS and Simoes, FA and Cassel, R and Dupuis, L and Leigh, PN and Hafezparast, M},
title = {Impaired dynein function preserves spinal interneuron survival and positioning in an ALS-like mouse model.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346246},
pmid = {41926450},
issn = {1932-6203},
mesh = {Animals ; *Interneurons/metabolism/pathology ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Spinal Cord/metabolism/pathology ; Disease Models, Animal ; Male ; Cell Survival ; *Dyneins/metabolism/genetics ; *Cytoplasmic Dyneins/metabolism/genetics ; },
abstract = {Impaired cytoplasmic dynein function has been implicated in amyotrophic lateral sclerosis (ALS) pathogenesis, yet the contributions of spinal interneurons to disease phenotypes remain unclear. We tested the hypothesis that hypomorphic dynein function in cholinergic neurons disrupts the development, survival, or positioning of inhibitory interneuron populations in the lumbar spinal cord. Using ChAT-Cre recombination, we generated four mouse genotypes with graded reductions in dynein activity in ChAT+ cells: Dync1h1+/+ (wildtype), Dync1h1-/+ (hemizygous wildtype), Dync1h1+/Loa (heterozygous Loa mutation), and Dync1h1-/Loa (hemizygous Loa). At 52 weeks of age, lumbar spinal cords (L3-L6) were harvested, cryosectioned, and immunostained for ChAT, GAD-67, Parvalbumin, and Calbindin. Cell counts were performed on confocal images from eight sections per mouse (N = 3 male mice/genotype), and radial distances from the central canal were normalised to gray matter width. Angular distributions were analysed via circular statistics. There were no significant genotype-dependent differences in the numbers of ChAT+, GAD-67+, Parvalbumin+, or Calbindin+ cells, nor in ChAT+ subpopulations (motor neurons versus interneurons) or double-positive interneuron subsets (e.g., ChAT+-GAD-67+, Parvalbumin+-GAD-67+, Parvalbumin+-Calbindin+). Radial positioning relative to the central canal was similarly preserved across all markers and genotypes. Circular-median tests revealed statistically significant shifts in mean angle for ChAT+, GAD-67+, and certain double-positive cells, but these amounted to only 5-10° displacements, translating to lateral shifts of ~10-20 µm, well within single laminar bands, and are unlikely to impact circuit connectivity. Despite substantial motor deficits and hallmark TDP-43 pathology previously seen in these models, impaired dynein function does not precipitate interneuron loss or gross migratory defects in the lumbar spinal cord. Instead, our findings suggest that the primary contributions of dynein to ALS-like phenotypes likely arise from functional disruptions in axonal transport, synaptic maintenance, and neuronal physiology rather than from structural alterations or loss of interneuron populations.},
}

Animals
*Interneurons/metabolism/pathology
Mice
*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics
*Spinal Cord/metabolism/pathology
Disease Models, Animal
Male
Cell Survival
*Dyneins/metabolism/genetics
*Cytoplasmic Dyneins/metabolism/genetics

@article {pmid41926608,
year = {2026},
author = {Mori, F and Kon, T and Itazawa, R and Akatsu, A and Miki, Y and Arai, A and Kurotaki, H and Tomiyama, M and Wakabayashi, K},
title = {Relationship between promyelocytic leukemia protein nuclear bodies and TAR DNA-binding protein-43 aggregation in spinal anterior horn cells in sporadic amyotrophic lateral sclerosis.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag029},
pmid = {41926608},
issn = {1554-6578},
support = {23K06802 (F.M.), 25K10784 (T.K.), 24K10654 (Y.M.), and 23K24209 (K.W.)//JSPS KAKENHI Grant/ ; },
abstract = {Promyelocytic leukemia protein nuclear bodies (PML-NBs) and stress granules serve as deposition sites for stress-induced, aggregation-prone proteins. We previously reported that TAR DNA-binding protein 43 (TDP-43) colocalizes with stress granules during early aggregation in sporadic amyotrophic lateral sclerosis (ALS), and recent studies have noted PML-NB loss in familial ALS. To explore the role of PML-NBs in TDP-43 inclusion maturation, we analyzed spinal cord specimens from 12 patients with sporadic ALS and 5 controls using immunostaining for PML and TDP-43. PML-NB counts in anterior horn cells (AHCs) were significantly lower in patients with ALS than in controls (P < 0.05), especially in AHCs with TDP-43 inclusions (P < 0.01). Average numbers of PML-NB decreased progressively with inclusion type (3.1 in diffuse punctate cytoplasmic staining, 2.3 in round inclusions, and 0.8 in skein-like inclusions); all of these were significantly lower than those in inclusion-free AHCs (controls: 4.6; ALS: 5.5; P < 0.01). AHCs in ALS without inclusions showed higher PML-NB counts than in controls (P < 0.05), suggesting an early protective response. In contrast, reduced PML-NBs in mature inclusions may reflect diminished cellular defense. These findings implicate PML-NBs in the pathogenesis of sporadic ALS.},
}

@article {pmid41928488,
year = {2026},
author = {Andersen, B and Krarup, C},
title = {Reappraisal of the Diagnostic Significance of Transcranial Magnetic Stimulation and Triple Stimulation in Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70560},
doi = {10.1111/ene.70560},
pmid = {41928488},
issn = {1468-1331},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Transcranial Magnetic Stimulation/methods ; Male ; Middle Aged ; Female ; Evoked Potentials, Motor/physiology ; Aged ; Electromyography ; Adult ; Prospective Studies ; Neural Conduction/physiology ; Motor Neurons/physiology ; },
abstract = {OBJECTIVE: To reassess the importance of transcranial magnetic stimulation (TMS), including the triple stimulation technique (TST), to detect upper motor neuron (UMN) involvement in amyotrophic lateral sclerosis (ALS).

METHODS: In this single-center prospective study, 144 consecutive patients suspected of having motor neuron disease were included over 5 years at the time of diagnosis. All patients were examined clinically and with EMG to assess UMN and lower motor neuron (LMN) involvement, and survival was ascertained 2 years after inclusion of the last patient. Our TMS protocol consisted of TST in both arms and conventional motor evoked potentials (MEP) in arms and legs to assess central motor conduction time (CMCT).

RESULTS: The TST could be performed in 142 patients who showed central conduction failure in 63%, which was often markedly asymmetrical, and 50% had prolonged CMCT in the legs. Combining TST in the arms and conventional MEP in the legs showed central abnormalities in 77%. In 62 patients with only signs of LMN involvement at clinical and EMG assessment, the TST amplitude ratio was reduced in 45%, and combined TST to the arms and conventional MEP to the legs disclosed a central abnormality in 61%.

CONCLUSION: The main clinical significance was the subclinical corticospinal involvement at TMS with TST in a large proportion of patients without clinical UMN involvement. TMS with TST is a sensitive, non-invasive electrophysiological method to detect corticospinal dysfunction in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology
*Transcranial Magnetic Stimulation/methods
Male
Middle Aged
Female
Evoked Potentials, Motor/physiology
Aged
Electromyography
Adult
Prospective Studies
Neural Conduction/physiology
Motor Neurons/physiology

@article {pmid41928634,
year = {2026},
author = {Dahshan, A and Khalil, MIM and Deraz, HADA},
title = {From theory to practice: physicians' knowledge, attitudes, and practices regarding amyotrophic lateral sclerosis in Egypt - a cross-sectional study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2026.2652326},
pmid = {41928634},
issn = {2167-9223},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with heterogeneous presentations that often mimic other conditions, leading to frequent misdiagnosis and delayed recognition. Physician awareness and diagnostic confidence are critical for early detection, yet little is known about these factors in the Middle East and North Africa (MENA) region, where ALS services and specialized centers remain limited.

METHODS: We conducted a nationwide cross-sectional survey of 1,320 physicians in Egypt. A validated online questionnaire assessed demographics, knowledge, attitudes, and practice patterns regarding ALS. Data were analyzed using appropriate statistics, with multivariate regression to identify predictors of knowledge, attitudes, and practices.

RESULTS: Overall, 41.0% of physicians demonstrated poor knowledge of ALS, while only 8.8% achieved good knowledge. Nearly half (46.5%) reported little or no diagnostic confidence, and 93.7% expressed a strong need for additional educational programs. Most respondents identified MRI (78.3%) as the main diagnostic test, whereas only 2.0% selected electrophysiological studies. Nevertheless, practice scores were higher: 65.7% reported good practice levels and 48.4% indicated they would directly refer suspected cases to specialists. Knowledge strongly correlated with attitudes (r = 0.610, p < 0.001) and both were moderately correlated with practice. Multivariate analysis identified neurology specialty, postgraduate ALS training, and urban practice as independent predictors of better knowledge and attitudes, while greater experience predicted improved practice.

CONCLUSION: Egyptian physicians show limited ALS knowledge and low diagnostic confidence despite reasonable practice behaviors. Training and structured referral pathways are urgently needed to improve ALS preparedness in Egypt and the wider MENA region.},
}

@article {pmid41928799,
year = {2026},
author = {Ouyang, Z and Walmsley, K and Luo, S and Tippett, D and Wyse-Sookoo, K and Fifer, M and Vansteensel, MJ and Angrick, M and Ramsey, N and Crone, NE},
title = {Stable speech BCI performance during slow progression of ALS: A longitudinal ECoG study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9156039/v1},
pmid = {41928799},
issn = {2693-5015},
abstract = {Background Electrocorticographic (ECoG) speech brain-computer interfaces (BCIs) show promise for restoring communication in amyotrophic lateral sclerosis (ALS), but the long-term stability of speech-related neural signals and decoding performance during disease progression remains unclear. We tracked signal characteristics and decoding over 25 months in a participant with ALS to determine how high-gamma (HG, 70-170 Hz) activity changes over time and whether these changes affect offline speech decoding. Methods We implanted two 8×8 subdural ECoG grids over left sensorimotor cortex (SMC) in a participant with slowly progressive bulbar variant ALS. Across 25 months, the participant performed an overt syllable-repetition task (12 consonant-vowel tokens) during simultaneous ECoG and audio recording. We quantified HG activation ratio (ActR), spectral signal-to-noise ratio (SNR; HG/HF, where HF = 300-499 Hz), and peak z-scored HG responses. Speech acoustics were evaluated using first/second formants (F1/F2) and the triangular vowel space area (tVSA). Offline EEGNet-based decoders were assessed in two stages: models trained on post-implant months 1-6 were tested on months 7-25, while models trained on stabilized data (months 7-11) were tested on the remaining period (months 12-25). Electrode-level saliency assessed spatial contributions to decoding. Results Acoustic analyses showed a significant reduction in tVSA over two years (-44.6 Hz[2]/day; P < 10 [-] [7]), consistent with mild intelligibility decline. Neural metrics (ActR and SNR) followed a biphasic trajectory: increasing during the first 6 months, after which ActR stabilized (0.041%/day; P = 0.13), and SNR declined gradually (-0.46%/day, P < 10 [- 4]). The model trained on months 1-6 achieved 55.7% accuracy (chance: 8.33%), but performance declined over time (-0.019%/day; P = 2.1×10 [-] [4]). Conversely, the model trained on months 7-11 achieved higher accuracy (65.9%) on subsequent data with no significant temporal decline (P = 0.23). Conclusions Speech-related HG features exhibited an initial unstable period followed by a long-term gradual SNR reduction, potentially reflecting disease progression. Models trained after signal stabilization generalized robustly to data recorded over a year later. These findings confirm that despite reduced absolute HG power and mild acoustic degradation of speech, cortical features remain stable enough to support durable ECoG speech BCIs without frequent recalibration. These findings will motivate future adaptive calibration algorithms that account for slow signal changes while leveraging stable spatial representations in ventral SMC. ClinicalTrials.gov Identifier NCT03567213.},
}

@article {pmid41928938,
year = {2026},
author = {Michels, S and Chen, C and Ruf, WP and Garcia Garcia, MM and Arnold, FJ and Wu, Z and Bennett, CL and Shams, D and Thompson, LM and Walker, AC and Dickson, DW and Petrucelli, L and Dorst, J and Prudencio, M and Li, W and La Spada, AR},
title = {Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.20.711195},
pmid = {41928938},
issn = {2692-8205},
abstract = {The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid-biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 non-disease controls. Following targeted enzymatic methyl-sequencing (EM-seq) of ∼4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of ∼70% of ALS patients with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.},
}

@article {pmid41929081,
year = {2026},
author = {Fodder, K and Murthy, M and de Silva, R and Raj, T and Farrell, K and Humphrey, J and Bettencourt, C},
title = {Cross-disease genetic and epigenetic architecture of the MOBP locus shows convergence in ALS-PSP.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.25.714147},
pmid = {41929081},
issn = {2692-8205},
abstract = {Myelin oligodendrocyte basic protein (MOBP) is an abundant oligodendrocyte gene implicated in multiple neurodegenerative diseases. Genetic variation at the MOBP locus has been associated with risk for progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), corticobasal degeneration (CBD), Alzheimer's disease (AD), Lewy body dementia (LBD), and Creutzfeldt-Jakob disease (CJD). Epigenetically, MOBP promoter hypermethylation and reduced expression have been reported in multiple system atrophy (MSA). Although MOBP is thought to play a role in oligodendrocyte morphology and myelin structure, how genetic and epigenetic variation at this locus influences gene regulation and contributes to disease risk remains poorly understood across neurodegenerative disorders. Here, we investigated whether shared or disease-specific genetic mechanisms at MOBP converge on altered DNA methylation and expression across neurodegenerative disorders. We analysed MOBP variants using summary statistics from recent GWAS for ALS, PSP, FTD, LBD, PD, MSA, AD, and CJD. Colocalisation (COLOC and SuSiE-coloc) was used to test whether disease-associated variants overlapped between diseases, and with oligodendrocyte expression quantitative trait loci (eQTLs) and bulk brain methylation quantitative trait loci (mQTLs). To further investigate mQTL effects at this locus, rs1768208, a variant previously associated with PSP, was genotyped in an overlapping brain methylation cohort, allowing direct testing of genotype-methylation associations in frontal white matter tissue. ALS and PSP GWAS demonstrated strong association at MOBP , with most strongly associated SNPs (e.g. rs631312, rs616147, rs1768208) shared between both disorders. Colocalisation analyses indicated high posterior probability that ALS and PSP share the same causal variant, with weaker overlap with FTD. mQTL colocalisation highlighted cg15069948, located near an exon junction within MOBP , as strongly colocalising with the ALS/PSP risk variants. In complementary tissue analyses, rs1768208-T carriers showed hypomethylation at cg15069948 in PSP brains. No genotype-methylation effects were detected in MSA or Parkinson's disease. Together with prior evidence of promoter hypermethylation and reduced expression in MSA, our findings identify cg15069948 as a regulatory methylation site linking ALS/PSP risk variants to altered MOBP methylation, and support MOBP dysregulation as a shared feature of neurodegeneration. However, the underlying mechanisms appear disease-specific, highlighting the complexity of involvement of this gene across neurodegenerative disorders.},
}

@article {pmid41929167,
year = {2026},
author = {Mahrous, AA and Heit, BS and Heckman, CJ},
title = {Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.23.713695},
pmid = {41929167},
issn = {2692-8205},
abstract = {Riluzole is the most commonly prescribed among the limited approved therapies for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motoneuron loss and paralysis. It is thought to act by suppressing motoneuron excitability and glutamate release, but its clinical benefits are modest and often diminish over time. We previously showed that homeostatic mechanisms in the SOD1 [G93A] (mSOD1) mouse model of ALS are hyperactive and prone to overcompensation. Here, we tested whether such dysregulated homeostasis antagonizes the effects of riluzole. Wild-type (WT) and presymptomatic mSOD1 mice received therapeutic doses of riluzole in drinking water for 10 days, with untreated littermates of both genotypes serving as controls. Motoneuron excitability and synaptic inputs were then examined using intracellular recordings from the isolated sacral spinal cord. The data showed that chronic riluzole treatment increased motoneuron excitability and polysynaptic inputs in mSOD1 mice but produced no detectable changes in WT motoneurons. These results suggest that hyperactive homeostatic mechanisms in ALS counteract the suppressive effects of riluzole. Notably, mSOD1 motoneurons exhibited larger membrane capacitance than WT, consistent with their increased cell size at this disease stage. Riluzole treatment reduced motoneuron membrane capacitance in mSOD1 mice to the range observed in WT animals, indicating normalization of cell size and potentially reduction in metabolic demand. Together, these findings help explain the limited clinical efficacy of riluzole while revealing a previously unrecognized neuroprotective mechanism of the drug in ALS.},
}

@article {pmid41929296,
year = {2026},
author = {Sebogo, MA and Frans, MC and Paulose, H and Rodriguez, CL and Hsiung, GY and Cashman, NR and Ly, CV and Leavens, MJ},
title = {Longitudinal Analysis of Superoxide Dismutase 1 Seeding Activity in Amyotrophic Lateral Sclerosis Cerebrospinal Fluid.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.20.26348753},
pmid = {41929296},
abstract = {Twenty percent of familial amyotrophic lateral sclerosis (fALS) cases are linked to mutations in the Superoxide Dismutase 1 (SOD1) gene and accumulation of misfolded SOD1 aggregates. SOD1 misfolding from the broader ALS population without SOD1 mutations is less clear. Here, we report SOD1 seeding activity in antemortem cerebrospinal fluid (CSF) from ALS participants with and without SOD1 mutations during ALS progression. Antemortem CSF from controls, SOD1- ALS, and sporadic ALS (sALS) patients was subjected to SOD1 seed amplification real-time quaking induced conversion (RT-QuIC) assays. SOD1 -ALS CSF exhibited shorter lag phase and increased ThioflavinT (ThT) fluorescence amplitude compared to healthy controls and those with spinal muscular atrophy. CSF from sALS participants, who had no mutations in SOD1 or nine other ALS risk genes, also displayed SOD1 seeding activity, indicating wild-type SOD1 is aggregate-prone in the broader ALS population. Longitudinal CSF data indicated that SOD1 seeding activity correlates with ALS progression via the ALS Functional Rating Scale Revised (ALSFRS-R) slope decline and CSF neurofilament light. Our sALS CSF cohort primarily comprised of participants less than 2 years from symptom onset, suggesting that SOD1 seeding activity is an early biomarker that may enable inclusion in clinical trials. With the FDA-approval of tofersen (Qalsody), a SOD1-lowering antisense oligonucleotide, new SOD1 diagnostic, prognostic and pharmacodynamic biomarkers may enable SOD1-targeting strategies that could benefit the broader ALS population.},
}

@article {pmid41929582,
year = {2026},
author = {Poyan Mehr, A and Sundang, A and Drasin, T and Bhalla, N and Zheng, S and Pravoverov, L},
title = {Comparison of peritoneal dialysis catheter placement outcomes: image-guided percutaneous technique versus advanced laparoscopic surgical technique.},
journal = {Clinical kidney journal},
volume = {19},
number = {4},
pages = {sfag048},
pmid = {41929582},
issn = {2048-8505},
abstract = {BACKGROUND: Peritoneal dialysis (PD) is an increasingly emphasized modality in nephrology care, due to patient autonomy, reduced healthcare cost and alignment with value-based care initiatives. A critical factor influencing successful PD uptake is the timely placement of peritoneal dialysis catheters (PDCs). Traditional advanced laparoscopic surgical (ALS) methods are effective but constrained by the need for general anesthesia and operating room access. The image-guided percutaneous (IGP) approach has emerged as a potentially safer and more accessible alternative.

METHODS: We conducted a retrospective study of adult patients who underwent PDC placement within Kaiser Permanente Northern California (KPNC) from 1 January 2018 to 31 December 2022. Patient characteristics, procedural variables, post-procedure length of stay, 90- and 180-day catheter intervention rates, 30-day readmission and mortality rates were compared between IGP and ALS techniques.

RESULTS: Among 3062 patients, 835 (27%) received PDCs via IGP and 2227 (73%) via ALS. While there were differences in patient characteristics due to selection biases, with the IGP group having higher prevalence of heart failure, and lower body mass index (BMI), estimated glomerular filtration rate, hemoglobin and albumin levels, IGP was associated with significantly shorter post-procedure length of stay among admitted outpatients (1.8 vs 3.1 days, P = .01) and lower catheter intervention rates at 90 days (1% vs 2.5%, P = .006) and 180 days (1.3% vs 4%, P < .0001). After adjustment for patient gender, race, BMI and polycystic kidney disease status, the ALS technique remained significantly associated with higher odds of catheter re-intervention compared with IGP at both 90 days [adjusted odds ratio (OR) 2.76, 95% confidence interval (CI) 1.30-5.85, P = .008] and 180 days (adjusted OR 3.16, 95% CI 1.67-5.96, P < .0004). Overweight BMI was independently associated with increased intervention risk.

CONCLUSIONS: Despite being applied to a potentially sicker patient cohort, IGP was associated with favorable short- and intermediate-term outcomes compared with ALS, including reduced catheter interventions, without compromising safety outcomes.},
}

@article {pmid41929709,
year = {2026},
author = {Gazwi, K and Zaza, T and Mitwally, H and Davda, N and Ganaw, A},
title = {Botulinum toxin injection induced autoimmune thyroiditis and myxedema coma: A case report.},
journal = {SAGE open medical case reports},
volume = {14},
number = {},
pages = {2050313X261430649},
pmid = {41929709},
issn = {2050-313X},
abstract = {This case describes a 28-year-old female with amyotrophic lateral sclerosis and recurrent urinary tract infections who developed myxedema coma following a botulinum toxin type-A (Btx) injection for muscle spasticity. On intensive care unit admission, she presented with hypothermia, bradycardia, and reduced consciousness. Laboratory evaluation revealed markedly elevated thyroid-stimulating hormone levels, confirming myxedema coma. Prompt treatment with intravenous levothyroxine and hydrocortisone resulted in rapid improvement in temperature and mental status. Further investigation showed elevated antithyroid peroxidase antibodies, suggesting drug-induced autoimmune thyroiditis triggered by Btx. This case highlights the potential link between Btx injection and thyroid autoimmunity, emphasizing the importance of early recognition and monitoring of thyroid function to prevent life-threatening complications in at-risk patients.},
}

@article {pmid41930586,
year = {2026},
author = {Pavithra, N and Begum, RF and Ashwini, ST and Nirenjen, S and Singh, A and Manisha, M and Sridevi, S and Singh, SA},
title = {AI-Driven Biomarker Discovery in Motor-Related Neurodegenerative Diseases.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273436955260126215111},
pmid = {41930586},
issn = {1996-3181},
abstract = {Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias (SCAs) are examples of neurodegenerative disorders (NDDs) that share overlapping neuropathological processes and largely affect motor coordination. For early diagnosis, illness monitoring, and treatment targeting, it is essential to find trustworthy biomarkers that represent motor circuit dysfunction. The purpose of this study is to summarize the state of the art regarding molecular, neurochemical, and imaging biomarkers that are pertinent to motor impairment and to investigate the function of artificial intelligence (AI) in their identification and verification Methods: With an emphasis on biomarker discovery, validation, and AI/ML applications in PD, HD, ALS, and SCAs, a thorough literature search was carried out in the PubMed, Scopus, and Google Scholar databases for research published between 2015 and 2025. The motor-specific correlations of key molecular (α-synuclein, tau, neurofilament light chain, TDP-43, mutant huntingtin), neuroimaging, and digital biomarkers were carefully examined Results: AI-driven methods, such as deep learning and machine learning, have shown great promise in combining multimodal data from digital, fluid, and imaging sources. These techniques enhanced the detection of disease-specific biomarker signatures, especially those associated with deficiencies in motor coordination Discussion: Data heterogeneity, biomarker standardization, model interpretability, and limited cross-disease validation are still issues despite encouraging developments. Improving the clinical reliability of AI-based biomarker models requires filling in these gaps Conclusion: An effective foundation for deciphering intricate motor neurological pathways is provided by AI-assisted biomarker discovery. Transparent algorithms, multicenter data integration, and ethical frameworks should be given top priority in future research to guarantee clinical translation and better patient stratification.},
}

@article {pmid41930760,
year = {2026},
author = {Patel, S and Sood, R and Shrivastava, S and Jeengar, MK},
title = {Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X385491251208144807},
pmid = {41930760},
issn = {1875-6190},
abstract = {Neurodegenerative Disorders (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and other less prevalent conditions, represent a growing challenge in medical science due to their progressive nature and the absence of curative treatments. Cruciferous vegetables, such as those from the Brassicaceae family and other species in the Brassicales order, have been reported to offer potential benefits for treating and preventing NDDs. Their neuroprotective effects have been attributed to secondary metabolites, glucosinolates (GLs), and their hydrolytic products, isothiocyanates (ITCs). One of these ITCs is Erucin (ERU), chemically known as 4-isothiocyanatobutane, which is a specific type of ITC. ERU is the isothiocyanate derivative of erucic acid and is structurally related to sulforaphane (SFN), another well-known ITC. This review aims to synthesize current scientific knowledge on ERU's mechanisms of action in neurodegeneration, highlighting preclinical evidence supporting its neuroprotective effects in diseases such as AD and PD, and suggesting its potential as a treatment strategy for NDDs. Preliminary studies suggest that ERU may confer neuroprotection through antioxidative stress pathways, modulation of neuroinflammatory responses, and upregulation of neurotrophic factors. This article discusses ERU's chemical properties, pharmacokinetics, and observed impacts on neurodegenerative models, suggesting potential therapeutic pathways it may influence, thereby highlighting its promise as a future component of neuroprotective strategies against NDDs.},
}

@article {pmid41741537,
year = {2026},
author = {Aouabed, Z and Therrien, V and Bouaoune, MA and Bakhtyari, M and Hijri, M and Makarenkov, V},
title = {Soil microbiome prediction using traditional machine learning and deep learning models.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41741537},
issn = {2045-2322},
abstract = {The accuracy of macrobiological community predictions largely depends on the taxonomic scale considered. Nowadays, the applicability of such predictions remains an important challenge when extended to microbial soil communities. This is not only due to the lack of reliable benchmark data, but also to a greater diversity of the soil microorganisms compared to other environments. In this study, we use six traditional machine learning regression models and one deep learning regressor to predict relative frequencies of bacterial and fungal communities within the soil microbiome based on environmental factors. We analyze the data from two publicly available soil microbiome datasets: (1) Data collected by Averill and co-authors and analyzed in a recent Nature Ecology and Evolution article, and (2) Data extracted from the NEON database, to estimate the composition of bacterial and fungal communities at the functional (i.e. functional group level) and taxonomic scales (i.e. phylum, class, order, family, and genus levels). Our findings suggest the presence of a general pattern across the observed taxonomic scales according to which the predictability of the soil microbiome increases with taxonomic scale. However, a notable exception occurs when machine learning models are applied to predict bacterial communities at the functional group level for Averill et al.’s data when all of them fail to provide accurate predictions results. The best overall results obtained include the value of the coefficient of determination [Formula: see text]=0.57 at the phylum taxonomic level, provided by the Gradient boosting model for the bacterial dataset collected by Averill et al., and the value of [Formula: see text]=0.45 at the functional group level, provided by both the Random forest and Gradient boosting models for the fungal dataset extracted from NEON. The best overall predictions were obtained using the Random forest and k-NN models. Random forest yielded the best average results on the phylim, class, and order taxonomic levels, while k-NN was particularly effective on lower taxonomic levels, including family and genus. Moreover, both of these traditional machine learning models usually outperformed the deep learning-based Multilayer perceptron regressor. This is probably due to a relatively limited number of samples available for model training in the two public datasets analyzed in our study. The data and code allowing one to reproduce the presented results can be accessed using our GitHub repository at: https://github.com/Vincent-Therrien/micropyome.},
}

@article {pmid41920737,
year = {2026},
author = {Jude, JJ and Haro, S and Levi-Aharoni, H and Hashimoto, H and Acosta, AJ and Card, NS and Wairagkar, M and Brandman, DM and Stavisky, SD and Williams, ZM and Cash, SS and Simeral, JD and Hochberg, LR and Rubin, DB},
title = {Decoding intended speech with an intracortical brain-computer interface in a person with long-standing anarthria and locked-in syndrome.},
journal = {Cell reports},
volume = {45},
number = {4},
pages = {117162},
doi = {10.1016/j.celrep.2026.117162},
pmid = {41920737},
issn = {2211-1247},
abstract = {Intracortical brain-computer interfaces (iBCIs) for decoding intended speech have provided individuals with ALS and severe dysarthria an intuitive method for high-throughput communication. These advances have been demonstrated in individuals who are still able to vocalize and move speech articulators. Here, we decoded intended speech from an individual with long-standing anarthria, locked-in syndrome, and ventilator dependence due to advanced symptoms of ALS. We found that phonemes, words, and higher order language units could be decoded well above chance. While sentence decoding accuracy was below that of demonstrations in participants with dysarthria, we attained an extensive characterization of neural signals underlying speech in a person with locked-in syndrome and identify directions for future improvement. These include closed-loop speech imagery training and decoding linguistic (rather than phonemic) units from neural signals in middle precentral gyrus to augment decoding at the sentence level. These results demonstrate that usable speech decoding from motor cortex may be feasible in people with anarthria and ventilator dependence.},
}

@article {pmid41921453,
year = {2026},
author = {Preuilh, A and Lackmy-Vallée, A and Béranger, B and Galléa, C and Bede, P and Querin, G and Pradat, PF and Pélégrini-Issac, M and Marchand-Pauvert, V},
title = {Impaired kinesthesia and cerebral integration during tendon vibration in amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {187},
number = {},
pages = {2111864},
doi = {10.1016/j.clinph.2026.2111864},
pmid = {41921453},
issn = {1872-8952},
abstract = {OBJECTIVE: This study investigates the cortical processing of spindle input in patients with amyotrophic lateral sclerosis (ALS), hypothesizing that functional MRI (fMRI) activation elicited by muscle-tendon vibration would reveal specific disruptions in the integration of this sensory pathway.

METHODS: A block-designed fMRI protocol was used, consisting of 20-second periods of focal muscle-tendon vibrations (∼70-Hz frequency) applied to the first dorsal interosseous tendon, alternating with rest periods. Parametric brain activation maps were examined in 22 patients with ALS without clinically overt sensory deficits and in an age- and sex-matched group of 23 healthy controls. The relationship between task-related brain activations and clinical scores was assessed in patients reporting vibration-induced kinesthetic sensations.

RESULTS: Muscle-tendon vibration elicited activation of the precentral gyrus contralateral to the vibration site, in both ALS patients and healthy controls. Compared to controls, ALS patients exhibited reduced activation in prefrontal and cerebellar lobule VI regions. Notably, a greater proportion of ALS patients (41%) failed to perceive kinesthetic stimuli compared to controls (13%). Furthermore, activations in contralateral prefrontal and cerebellar areas were associated with hand motor disability and cognitive impairment.

CONCLUSION: It suggests that motor impairment in ALS is accompanied by disrupted perception of movement, and concomitant altered brain integration of proprioceptive inputs.

SIGNIFICANCE: ALS-related motor impairment extends beyond motor output, underscoring the need for assessing movement (body) awareness in clinical practice.},
}

@article {pmid41921847,
year = {2026},
author = {Dong, YR and Wang, JR and Yang, Y and Chen, QZ and Jiang, YQ and Yang, X and Zhou, MC and Cao, SP and Zeng, SX and Zang, CX and Li, FF and Bao, XQ and Zhang, D},
title = {Unveiling the UFMylation Pathway: Implications in neurodegenerative diseases.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169772},
doi = {10.1016/j.jmb.2026.169772},
pmid = {41921847},
issn = {1089-8638},
abstract = {UFMylation is a recently characterized post-translational modification (PTM) system that conjugates Ubiquitin-Fold Modifier 1 (UFM1) to target proteins via a dedicated enzymatic cascade. This modification system regulates critical cellular processes by controlling protein subcellular localization, modulating protein-protein interactions, and coordinating with ubiquitination to regulate protein stability. Emerging evidence highlights UFMylation as a critical modifier of pathological proteins, including tau and α-synuclein, while impaired UFMylation pathways are observed in the brains of individuals with neurodegenerative disorders. In this review, we summarize the current role and mechanism of UFMylation in the pathogenesis of neurodegenerative diseases, offering the first comprehensive framework for targeting UFMylation in the treatment of neurodegenerative diseases.},
}

@article {pmid41924615,
year = {2026},
author = {Almalki, S and Salama, M and Taylor, MJ and Ahmed, Z and Tuxworth, RI},
title = {TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1671909},
pmid = {41924615},
issn = {1662-5099},
abstract = {Mislocalization and aggregation of the DNA/RNA binding protein, TDP-43, is seen in most cases of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Accumulating DNA damage in neurons is also a common feature of ALS-FTD. TDP-43 has several characterized roles in the regulation of the DNA damage response (DDR). This review systematically explored the relationship between TDP-43, DNA damage and the DNA damage response in various models of ALS-FTD, facilitating comparison of findings between studies using similar models. Twelve peer-reviewed papers, covering eight TDP-43 mutations out of nearly 40, were reviewed and five experimental models included: cell lines, patient-derived iPS cells, organoids, and rodent models, plus post-mortem cortex and spinal cord tissue from ALS-FTD patients. Across the studies and models, depletion of TDP-43 or ALS-linked mutations consistently increased genomic instability. Q331K-expressing cells showed a 2-3-fold reduction in DNA repair activity and a 4-6-fold increase in DDR activation, while TDP-43-depleted cells showed a 20-fold rise in double strand breaks. TDP-43 normally binds to damaged chromatin, participates in early DDR signaling and scaffolds core DNA damage repair factors, including Ku70, XRCC4 and DNA ligase 4. This systematic review and narrative synthesis sheds light on mechanisms that explain how TDP-43 dysfunction impairs genome maintenance. When TDP-43 is mislocalized, mutated or aggregated, these interactions are disrupted, resulting in impaired DNA repair. DNA damage is also caused by increasing R-loops, dysregulation of mismatch repair gene transcription, and sequestering of repair proteins into cytoplasmic inclusions. Upstream DNA damage can further drive TDP-43 mislocalisation, creating a feed-forward loop. Given the ubiquity of TDP-43 pathology across neurodegenerative diseases, targeting the DDR mechanisms affected by TDP-43 may offer new therapeutic opportunities.},
}

@article {pmid41924700,
year = {2026},
author = {McMackin, R and Tadjine, Y and Suleyman, N and Woods, E and Plaitano, S and Fasano, A and Awiszus, F and Hardiman, O and Carson, RG},
title = {Long-interval intracortical inhibition is similar in people with and without amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag091},
pmid = {41924700},
issn = {2632-1297},
abstract = {Long-interval intracortical inhibition, measured using transcranial magnetic stimulation, provides a non-invasive measure of spinal inhibition at interstimulus intervals below 100 ms and of GABA-B-mediated motor cortical inhibition at interstimulus intervals of 100-200 ms. To date, only a few small studies have investigated if long-interval intracortical inhibition is affected in amyotrophic lateral sclerosis. None have employed threshold tracking protocols or investigated multiple induced current directions. In this study, we aimed to determine if long-interval intracortical inhibition (i) differs between people with amyotrophic lateral sclerosis and healthy controls; (ii) relates to motor symptom severity, disease duration or survival time in those with amyotrophic lateral sclerosis; or (iii) relates to intracortical facilitation or short-interval intracortical inhibition. Employing automated threshold tracking during paired-pulse transcranial magnetic stimulation of the precentral gyrus, long-interval intracortical inhibition was recorded in 30 people with amyotrophic lateral sclerosis [9 female, 21 male, median (range) age: 63.5 (41-79) years] and 45 healthy controls [16 female, 29 male, median (range) age: 57 (34-76) years]. Long-interval intracortical inhibition was recorded with interstimulus intervals of 50, 100, 150 and 200 ms using posterior-to-anterior induced current (LICIPA), and with interstimulus intervals of 150 and 200 ms using anterior-to-posterior induced current (LICIAP). In subcohorts of both healthy controls and people with amyotrophic lateral sclerosis, short-interval intracortical inhibition was recorded with interstimulus intervals of 1 and 3 ms using posterior-to-anterior induced current and 3 ms using anterior-to-posterior current. Intracortical facilitation was recorded with an interstimulus interval of 10 ms using posterior-to-anterior induced current. No differences were found between those with and without amyotrophic lateral sclerosis in long-interval intracortical inhibition magnitude (P ≥ 0.44, Hedge's g ≤ 0.14) or in the interstimulus interval at which maximal long-interval intracortical inhibition occurs (P = 0.68, χ2 = 1.5). In those with amyotrophic lateral sclerosis, no statistically significant correlations were identified between long-interval intracortical inhibition measures and disease duration or functional rating scale scores. Statistically significant positive correlations were observed between LICIPA recorded with 100 and 150 ms interstimulus intervals, and between LICIPA recorded with 150 and 200 ms interstimulus intervals, but not between LICIPA and LICIAP measures or between long-interval intracortical inhibition and short-interval intracortical inhibition or intracortical facilitation. Our findings indicate that disinhibition manifested in this disease is primarily not mediated via changes in the cortical GABA-Bergic or spinal circuitry which underpins long-interval intracortical inhibition measures. As LICIPA and LICIAP measures show minimal covariation, it is possible that these measures are underpinned by distinct aspects of motor cortical inhibition.},
}

@article {pmid41925063,
year = {2026},
author = {Shtilbans, A and Lang, AE},
title = {Combination Disease-Modifying Therapy for Neurodegenerative Diseases Using Repurposed Drugs.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78190},
pmid = {41925063},
issn = {1531-8249},
abstract = {We review the positive effects of several existing drugs from different classes, such as chemical chaperones, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), iron chelators, and cluster-Abelson tyrosine kinase inhibitors (c-Abl TKIs), in preclinical disease models and in available published human data following use of these drugs in individuals with common neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). A concept of combinatory neuroprotective therapy using a drug-repurposing approach is then discussed. Finally, we propose a strategy to design an ideal combination of drugs able to address multiple pathogenic processes involved in neurodegeneration to achieve clinically meaningful results. ANN NEUROL 2026 ANN NEUROL 2026.},
}

@article {pmid41925076,
year = {2026},
author = {Krajewski, T and Koch, G},
title = {Randomization-Based Covariance Analysis for Confidence Intervals of Treatment Comparisons Based on Restricted Mean Survival Time With Categorized Time-to-Event Data.},
journal = {Statistics in medicine},
volume = {45},
number = {8-9},
pages = {e70422},
doi = {10.1002/sim.70422},
pmid = {41925076},
issn = {1097-0258},
support = {T32 ES007018/ES/NIEHS NIH HHS/United States ; },
mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Confidence Intervals ; Survival Analysis ; Analysis of Variance ; Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Models, Statistical ; Double-Blind Method ; Computer Simulation ; Data Interpretation, Statistical ; Random Allocation ; },
abstract = {This paper introduces a randomization-based method for covariate-adjusted comparisons of restricted mean survival time (RMST) between treatment arms in randomized controlled trials. Existing approaches for covariate-adjusted RMST analysis have model-based assumptions that may not be compatible with the complexity of survival data. We estimate the treatment difference in RMST using randomization-based analysis of covariance (RB-ANCOVA) for categorized time-to-event data by constraining the covariate mean differences between treatment groups to zero. Accordingly, we provide corresponding confidence intervals that offer greater precision than those based on unadjusted RMST differences. The methodology is detailed for comparing two treatment groups for a single or multiple time intervals, as well as for multiple treatment groups over a single interval. We demonstrate the application of these methods using data from a randomized, double-blind, placebo-controlled clinical trial evaluating three doses of a test treatment for ALS.},
}

Humans
*Randomized Controlled Trials as Topic/methods/statistics & numerical data
Confidence Intervals
Survival Analysis
Analysis of Variance
Amyotrophic Lateral Sclerosis/drug therapy/mortality
Models, Statistical
Double-Blind Method
Computer Simulation
Data Interpretation, Statistical
Random Allocation

@article {pmid41925483,
year = {2026},
author = {Kleinerova, J and Tahedl, M and Finegan, E and Siah, WF and Hengeveld, JC and Doherty, MA and Hardiman, O and McLaughlin, RL and Hutchinson, S and Tan, EL and Bede, P},
title = {Neuroimaging confirms selective cerebral involvement in primary lateral sclerosis and predilection to brain regions with high metabolic activity.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2026.03.003},
pmid = {41925483},
issn = {0035-3787},
abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a low incidence motor neuron disease manifesting in progressive limb spasticity, gait impairment, bulbar dysfunction and often in pseudobulbar affect. Varying degree of frontotemporal involvement has also been recently confirmed. Postmortem data is scarce in PLS and disease burden patterns are best characterised in vivo by purpose-designed neuroimaging protocols.

METHODS: A large prospective neuroimaging study has been undertaken to explore cerebral involvement patterns in PLS using a both structural T1-weighted data and diffusion MRI data. Neuroimaging data were complemented by genetic screening and comprehensive clinical profiling. Brain involvement patterns have been first characterised by standard morphometric and diffusivity analyses. Resulting disease burden maps were then correlated to physiological mitochondrial density (MitoD) maps. In an additional, region-of-interest analysis, brain regions with significant topological associations between neurodegeneration and MitoD were ranked based on their r-values.

RESULTS: Grey matter degeneration in PLS is not limited to the motor cortex, but also encompasses frontotemporal, caudate, thalamic, cerebellar and cingulate regions. Voxelwise statistics confirm topological associations between atrophy and physiological mitochondrial density. The most significant associations between neurodegeneration and MitoD were detected in the cerebellum, superior temporal lobe, precentral gyrus, inferior operculum, and orbitofrontal gyrus. Similarly, white matter degeneration is not limited to the corticospinal tracts, but includes the corpus callosum, frontotemporal association fibres, the cingulum, cerebellar peduncles, and the fornix. Anatomical associations were also detected between diffusivity alterations and focal MitoD.

DISCUSSION: PLS is associated with a selective disease burden pattern, and our data suggest that brain regions with high baseline metabolic activity are more likely to succumb to neurodegeneration. Cerebral areas showing the most significant anatomical associations between atrophy and mitochondrial density (precentral gyrus, cerebellum, frontotemporal regions) are pathognomonic brain regions of PLS driving its core clinical manifestations.},
}

@article {pmid41731540,
year = {2026},
author = {Sarigiovannis, P and Foster, NE and Jowett, S and Saunders, B},
title = {Development of an evidence-based framework to guide delegation of clinical tasks to physiotherapy support workers in musculoskeletal outpatient physiotherapy services.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41731540},
issn = {1472-6963},
support = {Clinical Doctoral Research Fellowship NIHR301550//National Institute for Health and Care Research/ ; Investigator grant (ID: 2018182)//Australian National Health and Medical Research Council/ ; },
abstract = {BACKGROUND: Delegation of clinical tasks to physiotherapy support workers (PSWs) is a key strategy in musculoskeletal (MSK) outpatient physiotherapy services to meet rising demand and optimise workforce use. However, delegation practices remain inconsistent, due to variability in training, role definition, supervision and patient communication. This paper presents the final phase of a mixed-methods research program. In this phase, findings from earlier phases were triangulated to inform the development of a practical, evidence-based framework to support safe and consistent delegation in MSK outpatient physiotherapy services.

METHODS: This final phase of the research program used a triangulation approach to integrate findings from three earlier phases: (1) a focused ethnography of real-world delegation practices; (2) a consensus study using nominal group technique to identify best practice components of a delegation framework; and (3) a discrete choice experiment capturing patient preferences. Triangulation followed Farmer et al.’s convergence coding matrix to assess agreement, partial agreement, silence, or dissonance across data sources. A component was included if supported by at least two phases.

RESULTS: Triangulation revealed strong convergence across professional and patient perspectives. Seven core components were identified for inclusion in the final framework: (1) training and development, (2) a clear delegation process, (3) defined roles, (4) a supportive team culture, (5) embedded safety mechanisms, (6) patient awareness and communication, and (7) implementation and evaluation strategies. The framework was developed with input from a clinical advisory group and public contributors to ensure relevance and applicability to real-world practice.

CONCLUSIONS: This final phase of the research program synthesised diverse findings to produce a framework for improving delegation to PSWs in MSK physiotherapy services. The framework offers structured, practical guidance to support consistent delegation in clinical teams. The principles may be transferable to other healthcare settings. Further research should explore implementation and evaluate impact in routine practice.},
}

@article {pmid41917198,
year = {2026},
author = {Yin, H and Ren, Z and Zhang, Y and Wang, Y and Sun, Y and Fu, X and Yan, W and Zhang, F and Zeng, L},
title = {Lisinopril activates BI1 to reprogram lipid metabolism and restore autophagy in ALS.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-09930-2},
pmid = {41917198},
issn = {2399-3642},
support = {20250206017ZP//Department of Science and Technology of Jilin Province (Jilin Province Science and Technology Department)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) involves disrupted lipid metabolism. Bax inhibitor 1 (BI1), an endoplasmic reticulum protein downregulated in ALS neuroprotective, represents a therapeutic target, but its metabolic regulatory mechanisms are incompletely understood. Using transcriptomics in skeletal muscle of ALS mice pre- and post-BI1 treatment, we identified BI1-regulated pathways. Structure-based virtual screening of FDA-approved compounds nominated lisinopril as a BI1 activator. Lisinopril upregulated BI1 protein expression, stabilizing mitochondrial membrane potential and protecting against SOD1[G93A]-induced apoptosis in NSC34 cells. Concurrently, it regulated TGF-β1/mTOR-dependent autophagy, maintained NMJ integrity, and reshaped triglyceride/sphingolipid/glycerophospholipid metabolism to attenuate spinal cord pathology in ALS mice, promoting energy metabolism shift toward glucose oxidation. Additionally, lisinopril inhibited the TGF-β1/Smad2/3 pathway to alleviate muscle fibrosis, downregulate Acp5/FN expression, and reduce type I collagen deposition. In conclusion, this study provides evidence that pharmacological activation of BI1 by lisinopril suppresses TGF-β1, modulates lipid metabolism, and ameliorates ALS pathology, demonstrating promising therapeutic repurposing potential.},
}

@article {pmid41917433,
year = {2026},
author = {Hop, PJ and Kooyman, M and Kenna, BJ and Zwamborn, RAJ and van Eijk, KR and Wang, Y and van Dijk, CH and Bekema, E and van Rheenen, W and Beele, P and van Vugt, JJFA and , and , and , and , and Khleifat, AA and Iacoangeli, A and Cooper-Knock, J and Smith, BN and Topp, S and van der Kooi, AJ and Fominykh, V and Drory, V and Lerner, Y and Shovman, Y and Rowe, DB and Williams, KL and McLaughlin, RL and Hurt, J and Huang, Y and Chen, CY and Tsai, E and Runz, H and Aronica, E and Groen, EJN and van Es, MA and Pasterkamp, RJ and Farhan, SMK and Garton, FC and McRae, AF and McCombe, PA and Henderson, RD and Fan, D and Šlachtová, L and Høyer, H and Nishimura, AL and Cauchi, RJ and Brylev, L and Rogelj, B and Koritnik, B and Zidar, J and Salas, T and Mora Pardina, JS and Gotkine, M and Povedano, M and Corcia, P and Vourc'h, P and Couratier, P and Weber, M and Kiernan, MC and Pamphlett, R and Blair, IP and de Carvalho, M and Başak, NA and Ingre, C and Andersen, PM and Zinman, L and Rogaeva, E and MacKenzie, IR and Dupre, N and Rouleau, GA and Traynor, BJ and Ticozzi, N and Chiò, A and Silani, V and Hardiman, O and Phatnani, H and Harms, MB and Dalgard, CL and Glass, JD and Landers, JE and Van Damme, P and Morrison, KE and Shaw, PJ and Shaw, CE and Al-Chalabi, A and van den Berg, LH and Kenna, KP and Veldink, JH},
title = {Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {41917433},
issn = {1546-1718},
support = {19-SI-459//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; ZonMW-VIDI 91719350//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; ZonMW-VIDI 91719350//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C, GBGT1 and KNTC1. We also provide strong, independent validation for genes with limited previous evidence: ARPP21, DNAJC7 and CFAP410. Notably, in ARPP21, we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies.},
}

@article {pmid41917466,
year = {2026},
author = {Liu, Y and Song, M and Wan, L and Guo, P and Han, D},
title = {Condensate protein aggregation in ALS/FTD is regulated by GGGGCC-repeat RNA scaffolds.},
journal = {Nature structural & molecular biology},
volume = {},
number = {},
pages = {},
pmid = {41917466},
issn = {1545-9985},
abstract = {Biomolecular condensates regulate essential biological processes relevant to health and disease. However, the mechanisms driving pathogenic condensate formation and their therapeutic targeting have not been fully elucidated. In amyotrophic lateral sclerosis and frontotemporal dementia caused by C9orf72 GGGGCC repeat expansions (c9ALS/FTD), the expanded repeat RNA and repeat-associated non-AUG translation products are key pathogenic factors. Here, we show that the GGGGCC-repeat RNA and poly(GR) form cocondensates in vitro and in cellulo. The G-quadruplex and hairpin structures of GGGGCC-repeat RNA act as scaffolds to accelerate liquid-to-solid phase transition and aggregation of poly(GR), with the hairpin structure promoting amorphous solid-like condensates in vitro and reducing poly(GR) mobility. The cocondensation of GGGGCC-repeat RNA and poly(GR) exacerbates nucleolar stress and cellular toxicity. Targeting both G-quadruplex and hairpin structures of GGGGCC-repeat RNA with small molecules diminishes poly(GR) aggregation and ameliorates cellular dysfunction. These findings expand our understanding of poly(GR) aggregation in c9ALS/FTD, highlight the importance of RNA structure in regulating protein aggregation and suggest that targeting the RNA scaffold may expand the druggable space of pathogenic condensates.},
}

@article {pmid41917768,
year = {2026},
author = {Jiang, Z and Ren, YL and Gu, XJ and Su, WM and Duan, QQ and Yin, KF and Cao, B and Li, JY and Yan, B and Chen, YP},
title = {Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis.},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71366},
doi = {10.1002/brb3.71366},
pmid = {41917768},
issn = {2162-3279},
support = {2022YFC2703101//National Key Research and Development Program of China/ ; 82371422//National Natural Science Fund of China/ ; 81971188//National Natural Science Fund of China/ ; 2022NSFSC0749//National Natural Science Fund of Sichuan/ ; 2023YFS0269//Science and Technology Bureau Fund of Sichuan Province/ ; //the National Natural Science Fund of China/ ; //the Science and Technology Bureau Fund of Sichuan Province/ ; //the National Natural Science Fund of Sichuan/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Mendelian Randomization Analysis/methods ; *Autophagy/genetics ; DNA Methylation/genetics ; Quantitative Trait Loci/genetics ; Genetic Predisposition to Disease/genetics ; Multiomics ; },
abstract = {BACKGROUND: Autophagy dysregulation has been implicated in the toxic protein aggregates of amyotrophic lateral sclerosis (ALS). However, the causal relationship between impaired autophagy and ALS remains ambiguous, necessitating further elucidation.

METHODS: This Mendelian randomization (MR) study employs a two-sample design, utilizing genetic instruments to proxy autophagy dysregulation as the exposure and ALS as the outcome. It incorporates summary statistics of ALS (27,205 cases, 110,881 controls), along with data on DNA methylation, RNA splicing, gene expression, and protein abundance quantitative trait loci (QTLs) in both blood and brain tissues (mQTL, sQTL, eQTL, and pQTL, respectively) sourced from European cohorts. Cis-variants situated proximal to or within the 604 autophagy-related genes, exhibiting robust associations with molecular alterations in autophagy, are employed as instrumental variables. Their causal links with ALS are assessed via summary-data-based MR (SMR) analyses, followed by Bayesian colocalization, sensitivity analyses, brain cell-specific MR analyses, protein-protein interaction (PPI), and druggable analyses.

RESULTS: Consistent evidence supported the causal effects of two lysosome genes (FNBP1 and IDUA), one autophagy core gene (C9orf72), and one mitophagy gene (USP35) on ALS risk. Specifically, brain FNBP1 splicing level (OR = 1.18, p = 3.38E-5) and blood USP35 expression level (OR = 1.17, p = 5.94E-5) were positively associated with higher ALS risk. In contrast, we found strong causal evidence of brain IDUA methylation level (OR = 0.96, p = 8.36E-6) and blood C9orf72 methylation level (OR = 0.55, p = 7.59E-12) with lower ALS risk. Cell-type-specific MR analyses, PPI, and druggable analyses further nominated the key brain cell type (astrocytes), potential interaction with known causative genes (SQSTM1 and PFN1), and promising druggability for FNBP1 in ALS.

CONCLUSIONS: This multi-omics MR study identified causal associations between the regulation of four autophagy-related genes and ALS risk, shedding light on autophagy-mediated mechanisms and offering early evidence of novel therapeutic targets for ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism
Humans
Mendelian Randomization Analysis/methods
*Autophagy/genetics
DNA Methylation/genetics
Quantitative Trait Loci/genetics
Genetic Predisposition to Disease/genetics
Multiomics

@article {pmid41917957,
year = {2026},
author = {Desnuelle, C and Couratier, P and Corcia, P and Arcelin, T and Nevoret, C and Duburcq, A and Baffert, S and Turgeman, S},
title = {The economic burden of amyotrophic lateral sclerosis for patients and families: a survey on out-of-pocket expenses and income loss in France.},
journal = {Orphanet journal of rare diseases},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13023-026-04326-1},
pmid = {41917957},
issn = {1750-1172},
support = {Association for Research on Amyotrophic Lateral Sclerosis and other Motor Neurone Diseases//Association for Research on Amyotrophic Lateral Sclerosis and other Motor Neurone Diseases/ ; },
}

@article {pmid41919222,
year = {2026},
author = {Spatafora, MG and Dubin, J and Domi, T and Lombardi, R and Cabras, P and Dalla Bella, E and Consonni, M and Quattrini, A and Verri, M and Lauria, G and Van Damme, P and Poesen, K and Riva, N and Peviani, M},
title = {Increased CSF levels of soluble AXL at diagnosis correlate with poor prognosis in patients affected by amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag086},
pmid = {41919222},
issn = {2632-1297},
abstract = {AXL, a receptor tyrosine kinase expressed in neurons and glial cells, involved in neuronal survival, myelination, and regulation of immune responses, can undergo shedding due to the activation of metalloproteases in neuroinflammatory conditions. Indeed, CSF and serum levels of soluble AXL (sAXL) have been correlated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). Based on these observations, we explored whether sAXL is implicated in amyotrophic lateral sclerosis (ALS). sAXL levels were measured in biofluids (CSF and serum) from two biorepositories, totalling 107 ALS patients, 76 healthy controls, 25 AD patients, 22 patients with multiple sclerosis and 51 patients with ALS disease mimicking disorders (i.e. patients that displayed symptoms resembling ALS, in whom eventually ALS was excluded after a thorough clinical examination). Gender and age were considered as covariate in the statistical analyses. Our results provide the first evidence of sAXL alterations in the CSF and serum of ALS patients at diagnosis and demonstrate a significant association between CSF sAXL levels and disease progression, as well as its prognostic value in ALS. While these observations require validation through multicentre studies, they suggest the involvement of the AXL pathway in ALS pathology and pave the way for leveraging CSF sAXL levels as a biomarker to aid ALS disease stratification.},
}

@article {pmid41919473,
year = {2026},
author = {Cheng, Y and Qiu, M and Yu, Z and Tang, X and Zhang, J},
title = {Long non-coding RNAs in neurodegenerative diseases - Molecular mechanisms, liquid biopsy biomarkers, and therapeutic targets: A review.},
journal = {Biomolecules & biomedicine},
volume = {},
number = {},
pages = {},
doi = {10.17305/bb.2026.13978},
pmid = {41919473},
issn = {2831-090X},
abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are age-related disorders characterized by progressive neuronal loss, cognitive decline, and limited options for disease-modifying treatments. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in neurodevelopment, neuronal homeostasis, and disease progression; however, their involvement in shared pathogenic pathways and clinical applications remains inadequately defined. This review consolidates recent experimental, transcriptomic, bioinformatic, and emerging clinical findings regarding the role of lncRNAs in NDDs. We examine how lncRNAs modulate common disease mechanisms, including protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, ferroptosis, synaptic failure, and aging-related neurodegenerative processes. These regulatory functions occur through various mechanisms, including epigenetic modifications, transcriptional regulation, post-transcriptional processes, and RNA-protein interactions, as well as novel mechanisms such as liquid-liquid phase separation (LLPS), peptide coding, and exosome-mediated intercellular communication. Current evidence supports the potential of lncRNAs as minimally invasive liquid biopsy biomarkers, detectable in blood, cerebrospinal fluid (CSF), and extracellular vesicles. Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms. Overall, lncRNAs have emerged as central molecular regulators and promising candidates for translation in NDDs. Nonetheless, challenges related to specificity, validation, delivery across the blood-brain barrier, and clinical standardization must be addressed before their routine application in precision neurology.},
}

@article {pmid41919495,
year = {2026},
author = {De Tito, S and Tooze, SA},
title = {Lysosomal homeostasis at the crossroads of neurodegeneration.},
journal = {The Journal of clinical investigation},
volume = {136},
number = {7},
pages = {},
doi = {10.1172/JCI199845},
pmid = {41919495},
issn = {1558-8238},
mesh = {Humans ; *Lysosomes/metabolism/pathology/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; *Homeostasis ; Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; *Neurons/metabolism/pathology ; },
abstract = {Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.},
}

Humans
*Lysosomes/metabolism/pathology/genetics
*Neurodegenerative Diseases/metabolism/pathology/genetics
Animals
*Homeostasis
Endosomal Sorting Complexes Required for Transport/metabolism/genetics
*Neurons/metabolism/pathology

@article {pmid41919981,
year = {2026},
author = {Liampas, I and Kimiskidis, VK and Zouvelou, V and Veltsista, D and Moscholouri, A and Triantafyllou, E and Daponte, A and Xirou, S and Sterpi, AE and Salakou, S and Poulidou, V and Arnaoutoglou, M and Tsouris, Z and Ralli, S and Dardiotis, E and Papagiannopoulos, S and Zampetakis, A and Zaganas, Ι and Mitsias, P and Giannakis, A and Konitsiotis, S and Kefalas, F and Alexiou, E and Stoiloudis, P and Parissis, D and Kiamelidis, S and Terzoudi, A and Tsivgoulis, G and Rentzos, M and Chroni, E},
title = {Clinical parameters affecting the course of amyotrophic lateral sclerosis: a longitudinal analysis of the Greek registry for amyotrophic lateral sclerosis (ALS-GR).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2648293},
pmid = {41919981},
issn = {2167-9223},
abstract = {BACKGROUND: Reliable prognostic factors are essential for both clinical and research purposes in amyotrophic lateral sclerosis (ALS). The current study aimed to investigate the prognostic properties of clinical parameters regarding the course of ALS.

METHODS: A mixed retrospective-prospective cohort study was conducted in 11 specialized centers in Greece. Participants with ALS were assessed on the ALS functional rating scale-revised (ALSFRS-R) at baseline and follow-up (on 6-9-12-18-24 months). In case of dropouts, we elucidated whether death had occurred. Adjusted survival analyses were used to explore associations with mortality; adjusted generalized estimating equations were used to examine associations with the rate of functional decline.

RESULTS: A total of 165 individuals with an average follow-up of 12.6 ± 6.3 months were included in the current longitudinal analysis. Baseline ALSFRS-R was the strongest determinant of survival [Hazard-ratio; HR = 0.949 (0.921-0.977)], followed by age at diagnosis [HR = 1.043 (1.011-1.075)] and restrictive respiratory pattern [HR = 2.321(1.193-4.515)], while cramps [HR = 0.485 (0.249-0.946)] and pain [HR = 2.007 (1.041-3.868)] were the least influential. Regarding functional decline rates, the strongest predictor was dysphagia [β= -0.633 (-0.992, -0.274)], followed by pseudobulbar syndrome [β= -0.460 (-0.832, -0.088)], depression [β= -0.375 (-0.688, -0.062)], pain [β=-0.362 (-0.627, -0.096)]. fatigue [β= -0.338 (-0.644, -0.033)], spasticity [β= -0.362 (-0.644, -0.081)] and the interval between diagnosis and baseline visit to a specialized unit in months [β = 0.031 (0.013, 0.048)].

CONCLUSIONS: Lower baseline ALSFRS-R scores, older age at diagnosis, restrictive respiratory pattern, pain and absence of cramps were linked to shorter survival in ALS. Dysphagia, pseudobulbar syndrome, depression, pain, fatigue, spasticity and shorter intervals between diagnosis and baseline visit to specialized units were related to steeper functional decline.},
}

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

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

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

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

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

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

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

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

@article {pmid41912662,
year = {2026},
author = {Liu, Y and Huang, Z and Hsu, YW and Deme, P and Frankenfield, AM and Wu, S and Zhao, X and Liu, H and Zhang, T and Alexander, EJ and Liu, M and Zhang, Y and Wang, H and Zhou, Y and Monteiro, MJ and Hao, L and Haughey, NJ and Wang, J},
title = {UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41912662},
issn = {1546-1726},
support = {NS089616//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS110098//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS074324//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS128494//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS098243//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; FS-2023-SBF-S6//Target ALS (Target ALS Foundation)/ ; },
abstract = {Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2-ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.},
}

@article {pmid41912988,
year = {2026},
author = {Zheng, H and Yu, S and Zhou, T and Fu, S and Zhang, J and Zhang, N and Liu, Y and Huang, Y and He, Z and Zhang, J and Liu, P and Gong, M and Zhou, C},
title = {Distinct amino acid metabolic subtypes predict prognosis and stratify treatment response in acute-on-chronic liver failure: a multicenter prospective study.},
journal = {Hepatology international},
volume = {},
number = {},
pages = {},
pmid = {41912988},
issn = {1936-0541},
support = {82305067//National Natural Science Foundation of China/ ; 2018ZX10725506-002//National Science and Technology Major Project of China during the 13th Five-Year Plan Period/ ; },
abstract = {BACKGROUND: Acute-on-chronic liver failure (ACLF) exhibits high mortality and heterogeneity, demanding precise risk stratification. We aimed to identify metabolic subtypes and explore their association with prognosis and real-world artificial liver support (ALS) responsiveness.

METHODS: This prospective, multicenter, observational cohort study enrolled 142 ACLF patients. Serum was collected at baseline, prior to ALS initiation. Patients were subtyped via metabolomics clustering. ALS exposure was analyzed using inverse probability of treatment weighting (IPTW) and Cox models to test for heterogeneity of treatment effect.

RESULTS: Two subtypes were identified (Cluster 1/2). Cluster 2 showed significantly higher 90 day mortality (p = 0.032) and severe amino acid metabolic reprogramming, particularly in branched-chain amino acid and glutamine pathways. Exploratory analysis suggested a differential association between ALS and survival across subtypes (interaction p = 0.12). ALS showed a weaker survival association in Cluster 2 after IPTW adjustment.

CONCLUSION: ACLF patients possess distinct amino acid-based metabolic subtypes that are potent prognostic indicators. Baseline metabolic profiling can serve as a stratification tool to identify patients who may derive the greatest clinical benefit from ALS therapy, guiding personalized treatment strategies.},
}

@article {pmid41913878,
year = {2026},
author = {Elfadil, U and Al-Majmuei, A and Alatoom, M and Juma, S and Shukralla, A},
title = {The Impact of Preoperative Nutritional Status on the Incidence of Anastomotic Leaks in Colorectal Surgery.},
journal = {Cureus},
volume = {18},
number = {2},
pages = {e104329},
pmid = {41913878},
issn = {2168-8184},
abstract = {Anastomotic leaks (ALs) are among the most serious complications following colorectal surgery, contributing to significant morbidity, reoperation, and prolonged hospitalisation. Poor preoperative nutritional status has been proposed as a modifiable risk factor; however, evidence from studies remains inconsistent. This systematic review, conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251034523), synthesised findings from 32 eligible studies, including randomised controlled trials, cohort studies, and case-control designs, published between 2005 and 2025. Across 474 initially identified articles, nutritional status was assessed using serum albumin, body mass index (BMI), Subjective Global Assessment (SGA), Nutritional Risk Index (NRI), or Prognostic Nutritional Index (PNI). AL incidence ranged from 2.8% to 11.3%, with hypoalbuminaemia and low nutritional indices consistently associated with increased risk. Several studies have suggested that nutritional optimisation, particularly immunonutrition and enteral support initiated 7-14 days preoperatively, improves secondary outcomes, such as wound infection rates, hospital stay, and overall morbidity. However, reductions in leak incidence are less consistent. The certainty of evidence linking poor nutritional status to leak risk was rated as moderate, while the evidence for nutritional interventions was rated as low due to heterogeneity and small sample sizes. Perioperative factors, including operative time, intraoperative blood loss, transfusion, and steroid use, were also significant contributors to leak risk. Overall, nutritional status is a key, modifiable predictor of AL; however, integration with surgical and perioperative optimisation is essential. High-quality multicentre trials are needed to define optimal nutritional strategies and establish standardised risk assessment tools for clinical practice.},
}

@article {pmid41914380,
year = {2026},
author = {Chen, L and Chen, EW and Chen, BW and Wang, D},
title = {Retinol Taking a Detour Promotes Neural Stem Cell Self-Renewal In Vivo Accompanied by Down-Regulation of Some Retinoic Acid Receptors.},
journal = {Stem cells and development},
volume = {},
number = {},
pages = {15473287261436286},
doi = {10.1177/15473287261436286},
pmid = {41914380},
issn = {1557-8534},
abstract = {Since our previous studies have indicated retinol promotes self-renewal of embryonic stem cells in vitro culture, we speculate that retinol may be directly involved in regulating adult stem cell self-renewal or developmental function in vivo. Vitamin A or retinoic acid (RA) solution was first injected into the abdominal cavities of mice, and then self-renewal and development marker gene expressions were investigated. The in vivo effects of retinol and RA on RA receptor expressions were further examined. The results showed that retinol not only significantly promotes self-renewal of neural stem cells in vivo but also induces orientational development of neural stem cells in vivo and significantly downregulates the expression of some RA receptor gene expression in the brain. This study provides experimental and theoretical bases for elucidating the regulation mechanism of retinol-mediated cell development in vivo, especially in brain, and the development of therapeutic drugs for neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, and Huntington's disease.},
}

@article {pmid41915953,
year = {2026},
author = {Zhang, Y},
title = {Letter to the editor: "Evolution of triglyceride and total cholesterol levels after critical illness: Preliminary insights into post-ICU metabolic sequelae".},
journal = {Journal of critical care},
volume = {94},
number = {},
pages = {155557},
doi = {10.1016/j.jcrc.2026.155557},
pmid = {41915953},
issn = {1557-8615},
abstract = {This letter evaluates Rousseau et al.'s recent study on post-intensive care unit dyslipidemia. While commending their focus on metabolic sequelae, we propose three clinical refinements. First, defining "de novo" hypertriglyceridemia using acute-phase ICU lipid troughs risks overestimating its true incidence, as these values represent pathological stress rather than physiological baselines. Second, profound post-discharge lifestyle transitions, particularly severe physical inactivity and ad libitum diets, must be considered alongside systemic inflammation as primary drivers. Finally, stratifying the cohort's diverse admission etiologies is essential to avoid diluting distinct metabolic phenotypes and improve targeted post-ICU care.},
}

@article {pmid41916013,
year = {2026},
author = {Phan, PQ and Nagata, JM and Le, TP},
title = {Queer Asian American men's self-objectification: A test of racially relevant factors.},
journal = {Body image},
volume = {57},
number = {},
pages = {102079},
doi = {10.1016/j.bodyim.2026.102079},
pmid = {41916013},
issn = {1873-6807},
abstract = {Queer Asian American men face pervasive experiences of racial discrimination within the queer community and the broader society, which may critically impact their body image outcomes. While some studies have documented how racially relevant factors may shape body image attitudes among queer Asian American men, no studies have investigated the racialized experience of self-objectification among this under-researched subgroup. Hence, the present study adopts Cheng et al.'s (2017) racially expanded model of objectification theory among Asian American college women and applies a strengths-based approach to examine the associations between resistance and empowerment against racism (REAR), internalized racism, pride in Asian features, and self-objectification. Thus, among a sample of 265 queer Asian American men, analyses of indirect effects revealed that REAR was indirectly associated with lower self-objectification via greater pride in Asian features, whereas internalized racism was not indirectly associated with self-objectification via pride in Asian features. Furthermore, internalized racism was directly associated with greater self-objectification and lower pride in Asian features. Our findings contribute to the limited yet growing literature on the racialized experience of body image among queer Asian American men, underscoring the nuanced ways in which resistance against racism and internalization of racial oppression are associated with self-objectification. Social justice-informed implications are discussed, including efforts to deconstruct the internalization of White supremacist ideologies and empower queer Asian American men to engage in resistance through future research, clinical interventions, and prevention programs.},
}

@article {pmid41916622,
year = {2026},
author = {Addington, C and Davies, N and Howell, P and Cruickshank, S and Hainsworth, E},
title = {Lived experiences of cancer care for people living with HIV who are treated for anal cancer: a scoping review.},
journal = {BMJ open},
volume = {16},
number = {3},
pages = {e114180},
doi = {10.1136/bmjopen-2025-114180},
pmid = {41916622},
issn = {2044-6055},
mesh = {Humans ; *Anus Neoplasms/therapy/psychology/complications ; *HIV Infections/complications/psychology ; *Quality of Life ; },
abstract = {OBJECTIVE: This scoping review aims to identify existing evidence on the lived experiences of people living with HIV and treated for anal cancer, and to identify what aspects of health and well-being are addressed in clinical guidance.

DESIGN: A preregistered protocol (Open Science Framework, 2025) guided the review. We followed the Arksey and O'Malley framework, incorporating Levac et al's refinements around stakeholder consultation. Joanna Briggs Institute (JBI) guidance informed eligibility and data for charting, and reporting adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines.

DATA SOURCES: Systematic searches were performed across multiple databases, including CINAHL, MEDLINE, PsycINFO and Embase, using EBSCOhost and Ovid, supplemented handsearching reference lists. Two search strategies were used: one for research studies and one for clinical guidelines.

ELIGIBILITY CRITERIA: Sources included people living with HIV treated for anal cancer, capturing lived experiences directly through qualitative studies or indirectly via quantitative patient-reported outcomes and/or health-related quality of life. Guidelines addressing HIV or anal cancer were also included.

DATA CHARTING AND SUMMARIES: Data were charted to capture patient experiences and outcomes on living with and beyond cancer, and how these are addressed in clinical management and guidance, including biomedical, psychosocial, sexual and functional aspects, and patient-reported outcomes.

RESULTS: Of 945 records, three studies and four guidelines met criteria. No study focused exclusively on people living with HIV; findings reflect broader anal cancer populations with HIV-positive subsets. Studies addressed aspects of health-related quality of life which we mapped into physical, psychosocial and sexual domains. Clinical guidance prioritised treatment dosage and survival, with limited attention to broader effects. Stakeholders highlighted that existing research and guidance miss important nuances of lived experience and care needs.

CONCLUSIONS: No identified research solely explored the lived experiences of people living with HIV treated for anal cancer, leaving guidance non-specific and biomedical. The identified domains offer a starting point for future research; however, to inform patient-centred care, stakeholders emphasised the need to understand how living with HIV and anal cancer shapes health needs.},
}

Humans
*Anus Neoplasms/therapy/psychology/complications
*HIV Infections/complications/psychology
*Quality of Life

@article {pmid41916881,
year = {2026},
author = {Calma, AD and Pavey, N and Silva, CS and Tsuji, Y and Ghapar, AA and Morris, K and Kiernan, MC and Farrar, MA and Menon, P and Vucic, S},
title = {Utility of Far-Field Potentials as a Biomarker of Neurodegeneration in Spinal Muscular Atrophy.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70231},
pmid = {41916881},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: Far field potentials (FFP) have been proposed as a reliable neurophysiological prognostic biomarker in amyotrophic lateral sclerosis (ALS). This study evaluated the utility of ulnar nerve FFP as a robust research biomarker of lower motor neuron degeneration in spinal muscular atrophy (SMA).

METHODS: Peripheral neurophysiological assessments were performed in 13 participants with SMA, 19 with amyotrophic lateral sclerosis (ALS), and 19 healthy controls. The ulnar nerve was stimulated at the wrist, and motor responses were recorded over the abductor digiti minimi (ADM) muscle. Recorded measures included compound muscle action potential (CMAP), FFP and near-field potential (NFP) amplitudes, and motor unit number index (MUNIX).

RESULTS: The FFP amplitude was significantly lower in SMA participants compared to healthy volunteers (p < 0.001), but comparable to ALS (p = 0.11). The FFP amplitude showed strong correlations with the Revised Upper Limb Module (RULM) (ρ = 0.92), ALS Functional Rating Score-Revised (ρ = 0.85), upper limb MRC score (ρ = 0.89), CMAP amplitude (ρ = 0.97), NFP amplitude (ρ = 0.88), and MUNIX values (ρ = 0.84), all of which were highly statistically significant. Multiple linear regression indicated that FFP amplitude was an independent predictor of RULM (p < 0.001).

DISCUSSION: FFP amplitude appears to be a promising neurophysiological biomarker for SMA, with potential utility for monitoring disease progression, particularly in a clinical trial setting.},
}

@article {pmid41917183,
year = {2026},
author = {Eom, E and Kim, J and Kim, J and Kang, SJ},
title = {STING is the scaffold protein for stress granule pre-condensation at the ER.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
pmid = {41917183},
issn = {1476-5403},
support = {RS-2024-00339685//National Research Foundation of Korea (NRF)/ ; RS-2024-00339685//National Research Foundation of Korea (NRF)/ ; },
abstract = {Stress granules (SGs) are dynamic, membraneless ribonucleoprotein condensates that assemble in response to cellular stress and coordinate diverse cellular stress responses and diseases. Although SG have been reported to associate with the endoplasmic reticulum (ER), how ER-localized stress granule assembly is organized and regulated remains unclear. STING (stimulator of interferon genes) is a central innate immune adaptor that has recently been implicated in diverse non-canonical cellular functions, yet its potential link to SG regulation has not been established. Independent of its canonical functions in innate immune signaling, we identified a novel role of STING as a regulator of SG formation. We found that prior to stress stimulation, STING interacts with key SG core components G3BP1 and UBAP2L via its C-terminal domain (CTD) at the ER, forming a pre-condensation complex that facilitates SG maturation in response to stress. Loss of STING reduces SG formation and increases stress-induced cell death, whereas ER-anchored STING CTD is sufficient to reverse them. Mechanistically, STING enhances basal interactions between G3BP1 and UBAP2L, lowering the threshold for SG maturation upon stress. In addition, STING promotes the pathologic effects of TDP-43 mutations associated with amyotrophic lateral sclerosis. Our findings implicate STING as an ER-resident regulator of SG dynamics that contributes to neurodegenerative pathology, highlighting it as a potential therapeutic target in diseases associated with aberrant SG assembly.},
}

@article {pmid41906032,
year = {2026},
author = {Abdelaal, Z and Boya, BR and Lee, JH and Lee, J},
title = {Targeting Als3 adhesin of clinically relevant Candida species using natural carotenoids: an in-silico study.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41906032},
issn = {1573-501X},
support = {RS-2025-00513239//the National Research Foundation of Korea (NRF)/ ; },
abstract = {Candidemia, caused by the opportunistic Candida spp., poses a severe global health threat, characterized by mortality rates reaching 75% and the increasing prevalence of multidrug-resistant biofilms. In this study, we targeted the Agglutinin-Like Sequence 3 (Als3) adhesin protein, the primary mediator of Candida species attachment, as a non-lethal strategy to inhibit biofilm formation. Using molecular docking, we screened a library of 1570 natural carotenoids against the conserved N-terminal domain of Als3 of Candida albicans and compared to five positive controls. Our virtual screening identified five compounds (mangicrocin, MODU, α-zeacarotene-3,17'-diol, BTTB, and (15Z)-zeaxanthin-3'-rhamnoside), with the best binding pose and the least binding energy. Among them, mangicrocin showed best binding affinity (docking score - 7.18 kcal/mol, ΔGbind - 35.23 kcal/mol) against C. albicans Als3, compared to the in vitro and in silico positive control, rutin (docking score - 5.772 kcal/mol, ΔGbind - 30.59). It consistently achieved the best docking scores across C. albicans Als family proteins (Als1 and Als5) and Als3 proteins of other species in the Candida genus like C. auris, C. tropicalis, C. parapsilosis, and C. dubliniensis. Molecular electrostatic potential (MESP) mapping analysis further clarified that the hydrophobic polyene backbone and the negative electrostatic potential of the OH groups on the aromatic rings aid in anchorage to the key cadherin-binding residues-Lys59 and Ser170 in the Als3 binding pocket. Density Functional Theory (DFT) analysis shows high electrophilicity and a narrow energy gap contributes to mangicrocin's interactions and chemical reactivity. Molecular dynamics simulations suggested stable retention of mangicrocin within the Als3 binding pocket, supported by stable structural parameters and favorable interaction energy profiles. In silico ADMET profiling concludes these top five hits had limited toxicity and are druggable. As this study is entirely computational, these findings are predictive and require future in vitro validation to confirm biological efficacy.},
}

@article {pmid41906147,
year = {2026},
author = {Zhou, X and Yu, P and Shen, X},
title = {m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01297-z},
pmid = {41906147},
issn = {1756-6606},
support = {82471208 and 82171184//National Natural Science Foundation of China/ ; },
abstract = {m6A is a pervasive post-transcriptional RNA modification that regulates RNA splicing, stability, localization, and translation in the brain. In this review, we outline the core m6A regulatory machinery and summarize its spatial organization across neurons and glial cells, highlighting established roles in brain development, synapse formation, and axon growth. We then focus on experience-dependent plasticity, synthesizing evidence that neuronal activity and environmental inputs dynamically reshape m6A to regulate immediate-early transcription and local translation at synapses across sensory, cognitive, emotional, and motor domains. With aging, m6A programs are reconfigured in a cell-type-specific manner, a shift associated with reduced plasticity and increased vulnerability. We further survey disease-associated alterations in m6A across Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke-related cognitive impairment, ALS and FTD, as well as metal or toxin exposure, emphasizing convergent effects on dopaminergic and glutamatergic signaling, synaptic integrity, inflammation, and cellular stress responses. Finally, we discuss emerging opportunities and conceptual challenges in targeting m6A enzymes or reader proteins, and outline priorities for future work, including cell-type- and subcellular-resolved mapping, causal perturbation in defined circuits and life stages, and the development of biomarkers and selective modulators. Together, these observations position m6A as a molecular interface linking experience-dependent plasticity, brain aging, and neurodegenerative vulnerability.},
}

@article {pmid41906403,
year = {2026},
author = {Correale, J},
title = {Glial Plasticity and Dysfunction: Mechanistic Insights and Therapeutic Opportunities in Neurodegeneration.},
journal = {Journal of neurochemistry},
volume = {170},
number = {4},
pages = {e70414},
doi = {10.1111/jnc.70414},
pmid = {41906403},
issn = {1471-4159},
mesh = {Humans ; *Neuroglia/metabolism/pathology/physiology ; Animals ; *Neurodegenerative Diseases/therapy/metabolism/pathology/physiopathology ; *Neuronal Plasticity/physiology ; *Cell Plasticity/physiology ; },
abstract = {Recent advances, including single-cell transcriptomics, lineage tracing, and in vivo imaging, have unveiled the heterogeneity, plasticity, and functional versatility of astrocytes, microglia, oligodendrocytes, and Schwann cells. These cells respond to metabolic and immune cues, participate in synaptic regulation, and provide metabolic and trophic support to neurons. Their dual roles in neuroprotection and neurodegeneration underscore the complexity of their contributions across CNS disorders. This review examines the diverse physiological and pathological roles of glia, emphasizing their involvement in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Mechanisms including metabolic dysfunction, inflammatory polarization, glial-immune crosstalk, and extracellular vesicle-mediated signaling are critically discussed. Emerging therapeutic strategies, ranging from glial reprogramming and senolytic therapies to the use of engineered extracellular vesicles and metabolic modulators, are evaluated for their potential to harness glial plasticity and mitigate disease progression. The review also outlines current challenges in translating glial biology into clinical interventions, including cellular heterogeneity, delivery barriers, and the need for specific biomarkers. A glia-centered therapeutic paradigm offers promising avenues to restore CNS homeostasis and promote regeneration in neurodegenerative diseases.},
}

Humans
*Neuroglia/metabolism/pathology/physiology
Animals
*Neurodegenerative Diseases/therapy/metabolism/pathology/physiopathology
*Neuronal Plasticity/physiology
*Cell Plasticity/physiology

@article {pmid41906714,
year = {2026},
author = {Schellenberg, KL and Nataraj, R},
title = {Reviewer Comment on Li et al. "Nocturnal Hypoxia and Sleep-Disordered Breathing as Potential Early Biomarkers of Respiratory Progression in Mild ALS".},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1},
doi = {10.1017/cjn.2026.10558},
pmid = {41906714},
issn = {0317-1671},
}

@article {pmid41907197,
year = {2026},
author = {Elshony, H and Almuhanna, R and Albazli, KO and Muddassir, R},
title = {Hereditary transthyretin amyloidosis mimicking ALS: First genetically proven case report from Saudi Arabia.},
journal = {eNeurologicalSci},
volume = {43},
number = {},
pages = {100607},
pmid = {41907197},
issn = {2405-6502},
abstract = {BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder that may mimic motor neuron disease (MND), leading to misdiagnosis and delayed access to disease-modifying therapies.

CASE REPORT: We report the first genetically confirmed case of ATTRv mimicking amyotrophic lateral sclerosis (ALS) in Saudi Arabia. A 47-year-old male presented with progressive right-sided limb weakness (proximal > distal) and dysarthria over 18 months. Neurological examination revealed fasciculations, distal atrophy, and brisk reflexes with normal muscle tone and no spasticity. Electrophysiological studies demonstrated a length-dependent sensorimotor axonal neuropathy with widespread denervation changes involving bulbar, cervical, and lumbosacral regions. Brain and spine MRI, along with whole-body CT, excluded structural or paraneoplastic causes. Genetic testing identified a pathogenic heterozygous variant in the TTR gene: NM_000371.4:c.424G > A (p.Val142Ile). Transthoracic echocardiography revealed mild concentric left ventricular hypertrophy. There was no clinical evidence of autonomic, renal, or ocular involvement.

DISCUSSION: This case underscores the importance of considering ATTRv in patients presenting with atypical MND, particularly when clinically significant sensory symptoms, absent upper motor neuron signs, or unexplained cardiac abnormalities are present. Early diagnosis enables access to targeted therapies such as TTR stabilizers and gene-silencing agents, which can alter disease trajectory.},
}

@article {pmid41907482,
year = {2026},
author = {Pham, N and Nguyen, CTH and Van, TT},
title = {Response to Brenaut et al., "Response to Pham et al's 'Sensory symptoms of scalp psoriasis are not sensitive scalp syndrome'".},
journal = {JAAD international},
volume = {25},
number = {},
pages = {139},
pmid = {41907482},
issn = {2666-3287},
}

@article {pmid41907560,
year = {2026},
author = {Ozgor, B and Goktas, OF and Baygin, M and Dogan, S and Tuncer, T},
title = {Differential quadruple pattern: A new EEG signal classification framework.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {492-505},
pmid = {41907560},
issn = {2667-2421},
abstract = {EEG signals are the letters of the brain and reflect neural activity. Abnormal EEG patterns indicate brain disorders such as epilepsy. Recently, machine learning has enabled automated EEG interpretation with high accuracy. This study introduces an explainable EEG classification model based on feature engineering. A novel feature extractor, Differential Quadruple Pattern (DiffQuadPat), is proposed. DiffQuadPat computes relations between four channel values using difference-based transformations and combinational transition tables. Feature selection is performed by Cumulative Weight Neighborhood Component Analysis (CWNCA), and classification is achieved with t-algorithm-based k-Nearest Neighbors (tkNN). For interpretability, Directed Lobish (DLOB) is used to produce symbolic explanations. The proposed DiffQuadPat-centric XFE framework was validated on two EEG datasets: Amyotrophic Lateral Sclerosis (ALS) and neonatal epilepsy detection. The model achieved over 98% accuracy under 10-fold cross-validation. Furthermore, cortical and hemispheric connectome diagrams were generated, enabling transparent visualization of brain-level interactions.},
}

@article {pmid41908423,
year = {2026},
author = {Girdthep, S and Yodsin, N and Phonprasert, J and Suwanchawalit, C and Swanglap, P},
title = {Sustainable Natural Lake Pigments from Caesalpinia sappan: Improving Stability through Inorganic Support Morphologies for Colored PLA Packaging Films.},
journal = {ACS omega},
volume = {11},
number = {11},
pages = {17948-17966},
pmid = {41908423},
issn = {2470-1343},
abstract = {Red-pink natural lake pigments were prepared from Caesalpinia sappan L. extract colorant powder (S-Alum, without inorganic supports) and as colorant-adsorbed inorganic supports: silica (S-Si) and kaolinite (S-Kaol). Among these, S-Kaol demonstrated the highest stability and color strength (K/S), supported by its superior initial thermal degradation at 450 °C, high pH and UV stability, and consistent hue (H° = 19-22). X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) analyses confirmed the formation of a stable structure in S-Kaol, involving strong electrostatic interactions between brazilein and the kaolinite surface through Al[3+] chelation. The DFT results further revealed an Al adsorption energy of -0.97 eV and a strong orbital hybridization between the Al (s) and the O (p) orbitals. The resulting pigments were incorporated into PLA to produce pinkish-red composite films. PLA/S-Kaol demonstrated superior pigment dispersity, thermal stability, and photostability, showing only a minor hue shift (H° shifting from 33.12° to 32.21°) after 168 h of UV exposure, attributed to the UV-shielding effect of kaolinite layers. In contrast, spherical S-Si particles introduced film defects, while amorphous S-Alum yielded moderate improvements. Overall, the inorganic supports acted as nucleating agents, enhancing PLA crystallization and thermal performance. These findings highlight S-Kaol as a renewable, nontoxic with heavy metal-free alternative to synthetic dyes for biodegradable polymer applications.},
}

@article {pmid41908699,
year = {2025},
author = {Barai, P and Leroy, G and Ahmed, A},
title = {Comparative Evaluation of Text and Audio Simplification: A Methodological Replication Study.},
journal = {Communications of the Association for Information Systems},
volume = {57},
number = {},
pages = {1059-1084},
pmid = {41908699},
issn = {1529-3181},
abstract = {This study serves as a methodological replication of Leroy et al.'s (2022) research, which investigated the impact of text simplification on healthcare information comprehension in the evolving multimedia landscape. Building upon the original study's insights, our replication study evaluates audio content, recognizing its increasing importance in disseminating healthcare information in the digital age. Specifically, we explored the influence of text simplification on perceived and actual difficulty when users engage with audio content automatically generated from that text. Our replication involved 44 participants for whom we assessed their comprehension of healthcare information presented as audio created using Leroy et al.'s (2022) original and simplified texts. The findings from our study highlight the effectiveness of text simplification in enhancing perceived understandability and actual comprehension, aligning with the original study's results. Additionally, we examined the role of education level and language proficiency, shedding light on their potential impact on healthcare information access and understanding. This research underscores the practical value of text simplification tools in promoting health literacy. It suggests the need for tailored communication strategies to reach diverse audiences effectively in the healthcare domain.},
}

@article {pmid41909467,
year = {2026},
author = {Nagamatsu, Y and Umezu, T and Hong, T and Niijima, T and Ohno, SI and Harada, Y and Kanekura, K and Ochiya, T and Kuroda, M},
title = {Exosome-like nanovesicles from acerola for CRISPR-Cas9 ribonucleoprotein delivery to the central nervous system.},
journal = {Molecular therapy. Nucleic acids},
volume = {37},
number = {2},
pages = {102896},
pmid = {41909467},
issn = {2162-2531},
abstract = {An aberrant six-base repeat in intron 1 of C9orf72 is the most frequent cause of solitary and familial amyotrophic lateral sclerosis and frontotemporal dementia. This mutation is a potential target for CRISPR/Cas9-based genome editing. However, the blood-brain barrier and limitations of current viral or nanoparticle-based delivery systems to neurons significantly restrict the clinical application of CRISPR-Cas9 in the brain. To address these challenges, we developed a drug delivery system using acerola-derived exosome-like nanoparticles (AELNs), which may overcome several limitations associated with human exosomes. AELNs stably form complexes with ribonucleoproteins (RNPs) comprised of Cas9 proteins and guide RNAs (gRNAs). We improved the delivery efficiency and selectivity of AELN/RNP complexes in GLP2-receptor-expressing neurons by incorporating GLP2 peptides into the AELN/RNP complexes. Intranasal administration of peptide-tagged AELN/RNP complexes in vivo confirmed the successful genome editing of C9orf72, demonstrating the potential of this system for treating neurodegenerative diseases. This study presents a potentially innovative approach for in vivo genome editing using a noninvasive delivery system.},
}

@article {pmid41909487,
year = {2026},
author = {Gowdy, J and Ahn, J and Miller, RH and Islam, Y},
title = {Neurovascular dysfunction in the development and progression of neuroinflammatory diseases.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1741928},
pmid = {41909487},
issn = {1662-5102},
abstract = {The neurovascular unit (NVU) is critical for brain homeostasis through its roles in maintenance of an effective blood brain barrier (BBB) and regulation of cerebral blood flow. Perturbation of the NVU is a hallmark of the pathology of multiple neurodegenerative diseases resulting in loss of BBB integrity, neuroinflammation and neuronal dysfunction. The NVU is a complex structure composed of endothelial cells, pericytes, as well as central nervous system (CNS) glial and neuronal components. While the importance of the CNS vasculature in health and disease is well established, the mechanisms underlying vascular pathology and its contributions to neurodegenerative diseases are less well defined. Neuroinflammation and reactive gliosis occurs in the majority of neurodegenerative diseases and recent studies suggest that immune mediated disruption of the BBB contributes to the induction of reactive gliosis and neuronal dysfunction. Potential consequences of NVU disruption include immune-driven vascular inflammation and leukocyte infiltration in Multiple Sclerosis (MS), protease-mediated tight junction degradation in ischemic stroke (IS), α-synuclein-associated endothelial dysfunction in Parkinson's Disease (PD), amyloid-β- and tau-induced pericyte injury in Alzheimer's Disease (AD), and complement-mediated vascular damage in Amyotrophic Lateral Sclerosis (ALS). Here we review the nature of NVU perturbations in these common neurodegenerative diseases, with an emphasis on the contribution of immune modulation of BBB disruption in neuropathology and disease progression.},
}

@article {pmid41909553,
year = {2026},
author = {J, MA and C, A},
title = {Gender euphoria reimagined: toward an Extended Theory of Trans-Identity.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1738195},
pmid = {41909553},
issn = {1664-1078},
abstract = {INTRODUCTION: The paper focuses on developing an Extended Theory of Trans-Identity integrating Nagoshi et al.'s trans-identity theory with the creative expression of the self to explore gender-euphoric experiences.

METHOD: Having explored Austin et al.'s research on the artistic expression of trans people, the article attempts to explore the creative manifestation of identity as an important aspect of trans-identity formation, alongside Nagoshi et al.'s trans-identity theory. The synthesis of four aspects, including physical embodiment, self-construction, social construction, and the creative manifestation of the identified gender leading to the attainment of gender-euphoric factors identified by Austin et al. and Leitch et al., culminates in an Extended Theory of Trans-Identity. The theoretical framework is applied to I Am Vidya: A Transgender's Journey (2013), the autobiography of Living Smile Vidya, who is an eminent trans theatre artist and activist from Tamil Nadu, India. Furthermore, the use of a literary text to validate the Extended Theory draws on Schilling's concept of theory extrapolation from literature. The exemplifying textual analysis of the dynamic role of the four aspects of trans-identity in asserting transness and achieving gender euphoria attempts to substantiate the proposed theoretical extension.

RESULTS: The results indicate that identity construction through the creative aspect, in combination with the biopsychosocial aspects, contributes to the utmost attainment of gender euphoria.

DISCUSSION: Therefore, the article formulates an extended version of the trans-identity framework, emphasising the inclusion of creativity in the gender-affirmative journeys of trans people.},
}

@article {pmid41910574,
year = {2026},
author = {Zhang, W},
title = {The evolving portrait of psychologists: A commentary on Xu et al. (2026).},
journal = {The American psychologist},
volume = {81},
number = {3},
pages = {423-425},
doi = {10.1037/amp0001694},
pmid = {41910574},
issn = {1935-990X},
mesh = {Humans ; *Psychology/trends ; Psychologists ; },
abstract = {Xu et al.'s (2026) portrayal of the evolving portrait of psychologists is valuable, yet several points merit further discussion or refinement. When interpreting the "decline of conscientiousness and rise of openness," additional factors should be considered-such as psychology's growing applied attribute, the public impact of psychoanalysis, transformations in book publishing, and the increasing number of female psychologists. The analysis could also benefit from: A stronger account of psychology's own disciplinary self-positioning, cross-cultural extensions and comparative findings, and comparisons with personality assessments of actual psychologists. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

Humans
*Psychology/trends
Psychologists

@article {pmid41910654,
year = {2026},
author = {Yu, Z and Li, H and Wang, Y and Li, Y and Shen, F and Wang, Y},
title = {The Microglial Lactate-Lactylation Axis as a Metabolic-Epigenetic Driver of Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1487},
pmid = {41910654},
issn = {2152-5250},
abstract = {The idea of amyloid-β (Aβ) plaques and tau neurofibrillary tangles has long been central to framing an understanding of Alzheimer disease (AD), but emerging and growing evidence now points to bioenergetic failure and metabolic-epigenetic crosstalk as central to AD progression. Hai et al. summarize animal and human biofluid and neuroimaging data to carve out the pathophysiology of AD in relation to the role of disrupted glucose metabolism, lactate build-up and protein lactylation in glucose metabolism, in their comprehensive review "Lactate, Lactylation and Alzheimer Disease". Building on Hai et al.'s key contributions, we offer a complementary perspective. The microglial lactate-lactylation axis may be remodeled across disease stages during chronic neuroinflammation, potentially serving compensatory functions early but shifting toward maladaptive, pro-inflammatory amplification at later stages. In light of emerging evidence for tau lactylation in human AD brain tissue, we propose a testable hypothesis of intercellular metabolic crosstalk: lactate exported from highly glycolytic microglia may alter local lactate availability and provide an additional substrate for neuronal tau lactylation. Although the causal contribution of lactate from distinct cellular sources remains to be established, this framework provides a useful lens for interpreting coupled metabolic and epigenetic mechanisms in AD. Our future efforts should focus particularly on glycolytic flux, lactate, epigenetic writers/erasers, therapeutic approaches, and non-pharmacological approaches to stage- and cell-specific lactylation profiling, biomarker development, and the incorporation of metabolic and epigenetic endpoints into interventional studies.},
}

@article {pmid41910849,
year = {2026},
author = {Akram, SW and K, C},
title = {Enhancing Parkinson's Disease Staging: An Integrative Deep Learning Framework for Multimodal Feature Selection.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {41910849},
issn = {1559-1166},
mesh = {Humans ; *Parkinson Disease/diagnostic imaging/genetics/pathology/diagnosis ; *Deep Learning ; Neuroimaging/methods ; Magnetic Resonance Imaging ; Male ; Female ; },
abstract = {Parkinson's disease (PD) affects 10 million globally, with accurate staging essential for personalized treatment planning. Current UPDRS assessments achieve < 93% accuracy due to subjective clinical judgment and unimodal data limitations, failing to capture complex genetic-neuroimaging-clinical interactions driving disease heterogeneity. This study introduces MAFNet, a novel deep learning framework pioneering Iterative Adaptive Vold-Kalman Filter (IAVKF) temporal denoising, Accelerated Binary Particle Swarm Optimization (ABPSO) swarm feature selection, Multilayer Perceptron-Lagrangian Support Vector Machine (MLP-LSVM) classification, and Graph-Attention Based Multimodal Fusion Network (GAMF). Applied to PPMI cohort (200 patients) with genetic SNPs (50), neuroimaging voxels (1,024), and UPDRS-III scores, the end-to-end pipeline delivers 97.6% accuracy, 98.2% precision, 96.8% recall, and 97.3% F1-score-outperforming CNN (92.4%), Autoencoder (90.8%), InceptoFormer (96.6%), and HCT (97.0%). IAVKF boosts SNR + 15.2dB (+ 2.9% accuracy vs. PCA/t-SNE); ABPSO reduces 1,276→340 features (73% reduction); regularization cuts overfitting gap to 0.9% (vs. 4.2% baseline). SHAP interpretability validates clinical plausibility (top predictors: LRRK2 SNPs, UPDRS-III tremor, hippocampal volume). Five-fold CV confirms stability with the Indian cohort external validation. Real-time inference (0.2s/patient, RTX 3090) enables clinical deployment. Future scope includes longitudinal temporal modelling, modality-agnostic fusion, edge deployment, federated learning, and extension to Alzheimer's/ALS. MAFNet transforms PD staging from subjective assessments to objective precision medicine, enabling biomarker discovery, progression forecasting, and personalized therapies across diverse global populations.},
}

Humans
*Parkinson Disease/diagnostic imaging/genetics/pathology/diagnosis
*Deep Learning
Neuroimaging/methods
Magnetic Resonance Imaging
Male
Female

@article {pmid41910875,
year = {2026},
author = {Rajagopalan, V and Pioro, EP},
title = {Diffusion network model analysis of multimodal neuroimaging reveals differential patterns of brain disease propagation in four subgroups of ALS patients.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41910875},
issn = {1931-7565},
}

@article {pmid41911331,
year = {2026},
author = {Kwan, JY and Lantz, CI and Korobeynikov, VA and Snyder, A and Huang, X and Haselhuhn, T and Dore, KN and Madruga, A and Danielian, LE and Schindler, AB and Chia, R and Rasheed, M and Crook, J and Szabo, M and Portley, M and Sherer, CM and King, MC and Huang, TH and Kosa, P and Bielekova, B and Ward, ME and Grunseich, C and Shneider, NA and Traynor, BJ and Narendra, DP},
title = {Clinical and biochemical characterization of amyotrophic lateral sclerosis in a CHCHD10 R15L family.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag115},
pmid = {41911331},
issn = {1460-2156},
abstract = {Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluated five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 4-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.},
}

@article {pmid41911483,
year = {2026},
author = {Nusir, A and Anthony, SM and Zhou, W and Kabbani, N},
title = {Microglial Adaptations to Chronic Nicotine in the Cerebellum: Proteomic Evidence for Neuroimmune Vulnerability.},
journal = {Journal of proteome research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jproteome.5c01027},
pmid = {41911483},
issn = {1535-3907},
abstract = {Smoking is a major public health concern with widespread effects on multiple organ systems, including the immune system. Chronic nicotine exposure can alter immune cell function through nicotinic receptors expressed on peripheral macrophages and microglia in the brain. Recent evidence indicates that the cerebellum is impacted by nicotine, contributing to motor and nonmotor outcomes, during drug use. In this study, we investigated the effect of chronic nicotine on microglia proteomes in the adult mouse cerebellum. Microglia were isolated by fluorescence-activated cell sorting (FACS) based on CD11b[high] CD45[low/intermediate] expression from male and female mice (n = 9 per group) exposed to 200 μg/mL nicotine (dissolved in 2% saccharin drinking water) for 30 days. Proteomic analysis was performed using liquid chromatography electrospray ionization (LC-ESI) mass spectrometry (MS) comparing the effect of nicotine relative to vehicle control. Our results reveal a sex-dependent effect of nicotine on microglial proteomes. While both males and females exhibited histone-related genomic responsiveness to nicotine, males demonstrated enrichment in cytoskeletal and metabolic proteins, and females showed complement-protein adaptations. The microglial proteome in male mice displayed nicotine-related adaptations in proteins that can contribute to neurodisorders including Huntington's disease and amyotrophic lateral sclerosis (ALS), of which smoking is a known risk factor. Together, these results highlight an effect of nicotine on the proteome of microglia providing insight into immune pathways that can contribute to smoking-related behavior and disease.},
}

@article {pmid41911992,
year = {2026},
author = {Di Napoli, G and Alfurno, L and Fissore, A and Raccuia, E and Olivieri, P and Marengo, M and Oliaro-Bosso, S and Piaz, FD and Catucci, G and Gilardi, G and Velazquez-Campoy, A and Prischi, F and De Simone, A and Spyrakis, F and Di Palma, F and Adinolfi, S},
title = {Calcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151719},
doi = {10.1016/j.ijbiomac.2026.151719},
pmid = {41911992},
issn = {1879-0003},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, leading to muscle paralysis and respiratory failure. Genetic mutations, notably in the ANXA11 gene, have been implicated in both familial and sporadic ALS forms. ANXA11 functions as a cellular "tether," orchestrating the transport of RNA-protein complexes and lysosomes through its N-terminal (Nt) and C-terminal (Ct) domains, respectively. This study uncovers a novel calcium-dependent regulatory mechanism governing the intramolecular interaction between these domains. Using biochemical, biophysical, and computational approaches, we suggest that in the absence of calcium, ANXA11 adopts a closed conformation with stable Nt-Ct interactions. Elevated calcium levels induce a conformational shift, disrupting this interaction and exposing binding sites for RNA and membranes. Crucially, we show that the ALS-associated D40G mutation in the Nt domain impairs this calcium-regulated interaction, favoring a persistent open conformation that predisposes to toxic protein aggregation. These findings reveal that calcium acts as a molecular switch modulating ANXA11 conformation and function, providing new insights into its role in ALS pathogenesis and potential therapeutic targets.},
}

@article {pmid41912102,
year = {2026},
author = {Li, A and Xiao, X and Liu, G and Li, K and Ling, Y and Deng, S and Xu, C and Cao, SQ and Wen, J and Lu, G and Yang, G and Fang, EF and Qin, D and Su, H},
title = {Isoginkgetin protects against degeneration of ALS motor neurons via regulating the GSK-3β-TFEB signaling axis.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108172},
doi = {10.1016/j.phrs.2026.108172},
pmid = {41912102},
issn = {1096-1186},
abstract = {Lysosomal dysfunction is a core pathological driver of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Transcription factor EB (TFEB) serves as a master regulator of lysosomal biogenesis, and its pharmacological activation represents a strategy to restore lysosomal function in disease and aging. Here, using a series of artificial intelligence-powered computational virtual screening workflows, we have identified isoginkgetin (ISO), a small-molecule compound, as a potent TFEB activator that promotes mechanistic target of rapamycin complex 1 (mTORC1)-independent TFEB nuclear translocation to enhance lysosomal biogenesis and function. Mechanistically, ISO functions as an ATP-competitive inhibitor that binds to the key Lys85 residue within the ATP-binding pocket of glycogen synthase kinase 3β (GSK-3β), thereby regulating the GSK-3β-TFEB signaling axis to activate TFEB nuclear translocation. Functionally, ISO improves lysosomal function and protects motor neurons differentiated from induced pluripotent stem cells derived from patients with ALS from degeneration. Collectively, these results support the hypothesis that lysosomal dysfunction is a druggable target for ALS.},
}

@article {pmid41912266,
year = {2026},
author = {Pennington, CR and Shaw, DJ and Skubera, M and Rose, AK and Jones, A},
title = {Declining trends in adolescent alcohol consumption and related harms: No room for complacency (an empirical reply to Vieira et al. 2025).},
journal = {Addiction (Abingdon, England)},
volume = {},
number = {},
pages = {},
doi = {10.1111/add.70413},
pmid = {41912266},
issn = {1360-0443},
support = {ES/Y001877/1//Economic & Social Research Council (ESRC)/ ; SBF0010\1109/AMS_/Academy of Medical Sciences/United Kingdom ; },
abstract = {Vieira et al. report that alcohol-related harms among adolescents have generally declined in high-income countries where youth drinking has decreased, but several methodological choices complicate this conclusion. By performing reproducibility analyses on Vieira et al.'s raw data, we show that their findings are more nuanced and complex. Secondary data analyses reveal that 19-24-year-olds have elevated vulnerability to alcohol-related harms. Any discussion of declining trends in adolescent alcohol consumption and related harms should acknowledge that current prevalence rates and harms remain unacceptably high and require continued public health attention.},
}

@article {pmid41912367,
year = {2026},
author = {Garbey, M and Lesport, Q and Öztosun, G and Ghodasara, V and Kaminski, HJ and Bayat, E},
title = {Authors' Response to "Comment on 'Improving Care for Amyotrophic Lateral Sclerosis with Artificial Intelligence and Affective Computing'".},
journal = {Journal of the neurological sciences},
volume = {},
number = {},
pages = {125885},
doi = {10.1016/j.jns.2026.125885},
pmid = {41912367},
issn = {1878-5883},
}

@article {pmid41856244,
year = {2026},
author = {Behling, E and Bloch, MH},
title = {Editorial: Should Weight Gain Be a Factor in Choosing an Antidepressant?.},
journal = {Journal of the American Academy of Child and Adolescent Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaac.2026.03.008},
pmid = {41856244},
issn = {1527-5418},
abstract = {There is limited evidence to guide clinicians regarding the side effect profiles of antidepressants in youth. Weight gain is a frequent concern raised by patients and their families when starting psychiatric medications. In the current issue of JAACAP, Rifas-Shiman et al.[1] present a retrospective cohort study using electronic health record (EHR) data from 67,039 patients 5 to 19 years of age to investigate the impact of antidepressants on body mass index (BMI) in children and adolescents over the longer term (up to 1 year). The authors found a small, albeit statistically significant, increase in BMI with the most commonly used selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, fluoxetine, sertraline), but not with bupropion.[1] Rifas-Shiman et al.'s findings of slight weight gain associated with SSRIs in youth align with observational studies in adults.[2] Previous smaller prospective cohort studies in youth have suggested possible differences in effect of SSRIs on weight gain, with (es)citalopram being associated with more weight gain than sertraline (fluoxetine was intermediate).[3] The weight changes seen with escitalopram and citalopram are highly variable across patients and potentially associated with slow CYP2C19 metabolizer status.[4] Rifas-Shiman et al. did not replicate these differences in weight change between SSRI agents at 1-year follow-up despite the much larger sample size.},
}

@article {pmid41901170,
year = {2026},
author = {Kwaśniewska, K and Fic, W and Polak-Szczybyło, E},
title = {Vitamins as Modulators of Neurodegenerative Disease Pathways: Mechanisms and Therapeutic Perspectives.},
journal = {Nutrients},
volume = {18},
number = {6},
pages = {},
pmid = {41901170},
issn = {2072-6643},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Vitamins/therapeutic use/pharmacology/administration & dosage ; *Neuroprotective Agents/pharmacology ; *Dietary Supplements ; Antioxidants ; Oxidative Stress/drug effects ; Ubiquinone/analogs & derivatives ; Animals ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, currently represent one of the major challenges in contemporary medicine and geriatrics. Progressive degeneration of the nervous system affects not only patients' physical functioning but also their psychosocial well-being, often leading to social isolation and disruption of interpersonal relationships. These processes are most strongly associated with individuals over 65 years of age, in whom metabolic syndrome is frequently diagnosed and constitutes a significant factor predisposing them to the exacerbation of neuropathological changes. This review analyzes the role of selected vitamins in modulating the course of neurodegenerative disorders, with particular emphasis on their neuroprotective potential. Specific attention is given to their involvement in antioxidant defense mechanisms, regulation of inflammatory pathways, prevention of abnormal protein aggregation, participation in neurotransmitter synthesis, and support of mitochondrial function and cellular energy metabolism. The review also considers key interactions between vitamins and coenzyme Q10, which synergistically enhance neuroprotective mechanisms. Deficiencies in certain vitamins may exacerbate oxidative stress, impair synaptic transmission, and intensify neuroinflammatory responses, thereby contributing to disease progression. The study analyzes the available data on therapeutic doses of vitamins and compares them with the recommended dietary intake and the upper tolerable intake levels (UL). The available evidence suggests that personalized vitamin supplementation, when integrated with a well-balanced and nutrient-dense diet, may constitute a valuable adjunctive therapeutic strategy. Such an approach may help attenuate disease progression, support neuronal integrity, and improve functional outcomes. Ultimately, targeted nutritional interventions may enhance overall well-being and quality of life in patients affected by neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Vitamins/therapeutic use/pharmacology/administration & dosage
*Neuroprotective Agents/pharmacology
*Dietary Supplements
Antioxidants
Oxidative Stress/drug effects
Ubiquinone/analogs & derivatives
Animals

@article {pmid41902308,
year = {2026},
author = {Datoo, M and Kadir, S},
title = {Voices from the minority: Understanding the acculturative experiences of British Shia Muslims.},
journal = {Psychology and psychotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1111/papt.70058},
pmid = {41902308},
issn = {2044-8341},
support = {//University of Leicester/ ; },
abstract = {OBJECTIVES: The aim of this research was to understand the acculturative experiences of British Shia Muslims, with hopes for practitioners to better understand how to support this population.

DESIGN: Qualitative methodology was used, utilising semi-structured interviews. Braun and Clarke's (Thematic analysis: A practical guide, Sage Publications Limited, 2022) reflexive thematic analysis was chosen to analyse the data and identify themes within 15 interview transcripts.

METHODS: Recruitment took place through mosques, with inclusion criteria involving British Shia Muslim participants over 18 years, who had lived in England for a minimum of 5 years. First-, second- and third-generation participants were recruited.

RESULTS: Five themes were identified, sitting under the main overarching theme, 'navigating through multiple worlds', which depicted acculturation as a fluid, complex journey, consistent with Schwartz et al.'s (American Psychologist, 2010, 65, 37) multidimensionality model of acculturation. These themes included: do I belong here, with subthemes of conflicting cultural values and who am I, the emotional toll of acculturation, with subthemes of negotiating authenticity and Muslim therapeutic support, negotiating faith in a secular society, living with layered discrimination, with a subtheme of Shia-specific discrimination and, finally, holding each other up: sources of strength.

CONCLUSIONS: This research demonstrates the multidimensional and complex journey of acculturation for British Shia Muslims. Through this, there is an emphasis on understanding more about the experiences of minoritised communities to improve their mental health support. The clinical implications to support this are diversifying the workforce, enhancing cultural competence and humility, adopting an intersectional approach and addressing discrimination.},
}

@article {pmid41903716,
year = {2026},
author = {Alam, Z and Nguyen, KT and Lauck, KC and Malick, H and Tolkachjov, SN},
title = {Response to Newell et al.'s commentary on DPP4 inhibitor use and skin cancer risk in type 2 diabetes.},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.03.073},
pmid = {41903716},
issn = {1097-6787},
}

@article {pmid41903799,
year = {2026},
author = {Chamorro-Muñoz, MI and Afkir-Ortega, MN and Aguilar-Monge, A},
title = {Impact of care by a multidisciplinary team on the assessment of cognitive aspects and decision-making at the end of life in a Spanish population with amyotrophic lateral sclerosis.},
journal = {Neurologia},
volume = {},
number = {},
pages = {501950},
doi = {10.1016/j.nrleng.2026.501950},
pmid = {41903799},
issn = {2173-5808},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a disease with a fatal course, often associated with unassessed cognitive-behavioural disturbances, and very relevant end-of-life care decisions. The aim of this study is to verify whether multidisciplinary team care for ALS patients in our setting has modified the cognitive assessment and the end-of-life decision making, compared to a model of uncoordinated specialist care.

METHODS: An observational, longitudinal, retrospective study was conducted on a cohort of patients with probable or definite ALS, in a referral hospital, between 01-01-2000 and 31-12-2022, differentiating whether they were treated before or after the implementation of a multidisciplinary model. We analysed the performance of cognitive assessment, the use of riluzole, gastrostomy, non-invasive ventilation and invasive ventilation, and the recording of patients' decisions regarding the care they wished to receive. Comparisons between variables were performed using the chi-square test or Fisher's exact test.

RESULTS: We evaluated 47 patients seen by uncoordinated specialists and 146 with a multidisciplinary model. Patients cared for using the multidisciplinary model were more frequently cognitively assessed (55.48% vs 12.8%, p < 0.001), diagnosed with dementia (11.6% vs 2.3%, p < 0.048) and their advance directives were recorded (56.8% vs 23.4%, p < 0.001). We found no differences in the use of advanced interventions, except for invasive ventilation, which was only performed in the context of multidisciplinary care.

CONCLUSIONS: The multidisciplinary model of care for ALS patients in our setting has improved cognitive assessment, promoted the registration of their advance directives, and thus helped to improve respect for their autonomous decisions and dignity.},
}

@article {pmid41903869,
year = {2026},
author = {Yang, Y and Yang, Y and Zhang, X and Ma, H and Ji, S and Zou, F and Yu, X and Du, G and Zhu, X and Tian, J},
title = {Targeting ME1 rescues redox-metabolic coordination in ALS: A core effector of NRF2-directed therapy.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110940},
doi = {10.1016/j.neuropharm.2026.110940},
pmid = {41903869},
issn = {1873-7064},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, muscle weakness, and respiratory failure, with dysregulated energy metabolism and oxidative stress representing core pathological features. Epidemiological studies indicate geographical variations in incidence, and recent multi-omics evidence identifies a hypermetabolic state and mitochondrial dysfunction as key drivers of disease progression. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which regulates antioxidant response and metabolism, represents a promising therapeutic target; however, the exploration of specific activators remains insufficient. This study evaluated the efficacy and mechanism of a novel KEAP1-NRF2 activator, MKL01351, in SOD1 G93A transgenic mice and NSC-34 motor neuron-like ALS models. Behavioral analyses demonstrated that MKL01351 significantly delayed disease onset, improved motor coordination in the rotarod and hanging tests, and extended survival. The compound alleviated oxidative stress by reducing malondialdehyde (MDA) levels and restoring the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, while also ameliorating the energy deficit by modulating glycolytic and mitochondrial functions, as confirmed by Seahorse analysis. Mechanistic investigations revealed that MKL01351 activated the NRF2 pathway, upregulating downstream targets such as NQO1 and HO-1, and specifically enhanced the expression of malic enzyme 1 (ME1). Loss-of-function experiments confirmed that ME1 knockdown abolished the protective effects, indicating that the NRF2-ME1 axis is a central hub for the synergistic regulation of metabolic and oxidative homeostasis. In conclusion, MKL01351 concurrently ameliorates oxidative stress and metabolic dysregulation via the NRF2-ME1 signaling pathway, offering a novel neuroprotective strategy for ALS treatment.},
}

@article {pmid41904003,
year = {2026},
author = {Kinger, S and Choudhary, A and Kumar, P and Jagtap, YA and Sharma, V and Dhiman, R and Prasad, A and Verma, R and Chinnathambi, S and Mishra, A},
title = {Molecular chaperones mediated proteostasis depletion: A cause of neurodegeneration?.},
journal = {Advances in protein chemistry and structural biology},
volume = {150},
number = {},
pages = {181-219},
doi = {10.1016/bs.apcsb.2025.10.033},
pmid = {41904003},
issn = {1876-1631},
mesh = {Humans ; *Proteostasis ; *Neurodegenerative Diseases/metabolism/pathology ; *Molecular Chaperones/metabolism ; Animals ; },
abstract = {Protein homeostasis is a critical aspect of cellular homeostasis as proteins are one of the most diverse biomolecules, responsible for multiple molecular and cellular functions. Protein quality control machinery is essential for maintaining integrity of cellular proteome via regulating its synthesis, structure, function, and degradation. Molecular chaperones are central to the protein quality control apparatus of cells and assist in folding nascent polypeptides, maturation, sequestration, solubilisation, and degradation of proteins. The coordination and cooperation between multiple cellular chaperones and other quality control elements, such as ubiquitin-proteasome system and autophagy, form a network, critical for proteostasis. Disturbed proteostasis and protein aggregation are hallmark features of neurodegenerative diseases. Re-establishing cellular proteostasis and enhancing chaperones' levels and functions can alleviate protein aggregation and associated cytotoxicity. Here, we have explored the potential of abundant cellular chaperone Hsp90, large chaperone Hsp110, small chaperone Hsp27, and anti-oxidant and mitoprotective chaperone DJ-1 in the regulation of proteostasis, with implications for neurodegenerative diseases, Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. We have focused on roles and mechanisms of function of these chaperones in countering disturbed proteostasis in neurodegenerative disorders.},
}

Humans
*Proteostasis
*Neurodegenerative Diseases/metabolism/pathology
*Molecular Chaperones/metabolism
Animals

@article {pmid41904009,
year = {2026},
author = {Chinnathambi, S and Malik, S},
title = {Cytoskeltal intermediate filaments in Tau pathology and neurodegeneration.},
journal = {Advances in protein chemistry and structural biology},
volume = {150},
number = {},
pages = {351-376},
doi = {10.1016/bs.apcsb.2025.10.028},
pmid = {41904009},
issn = {1876-1631},
mesh = {Humans ; *Intermediate Filaments/metabolism/pathology ; *tau Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Cytoskeleton/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Intermediate Filament Proteins/metabolism ; },
abstract = {Intermediate filaments are cytoskeletal proteins that are vital for proper cell structure formation and functioning. There are six types of these proteins. Type I includes acidic keratins, Type II includes basic and neutral keratins, both of which are present in epithelial cells. Type III includes vimentin, desmin, glial fibrillary acidic protein and peripherin, among which the last two are highly involved in neurodegenerative diseases. Type IV includes three types of neurofilament proteins, NF-L, NF-M and NF-H, where L signifies light, M signifies medium and H signifies heavy. The fourth protein in this category is α-internexin. All of these proteins are highly involved in neurodegenerative diseases, especially the neurofilament proteins. The type V intermediate filament proteins are lamins. The type VI intermediate filaments are nestins. Their involvement in a variety of neurodegenerative diseases has been observed, including Alzheimer's disease, Cerebral Ischemia, Multiple Sclerosis, Alexander Disease, Neuronal IF inclusion disease (NIFID) and Amyotrophic Lateral Sclerosis (ALS). Alzheimer's disease is a neurodegenerative disease in which two proteins are mainly involved, the Tau protein and the Amyloid-β protein. This review discusses the crosstalk of the intermediate filament proteins with the pathological proteins involved in the neurodegenerative diseases. For the case of the Alzheimer's disease, many of the intermediate filament proteins are involved in the disease pathology and are vital markers for the disease. One of the category of proteins involved is neurofilaments, among which NF-L is a marker for the disease. Keratin 9 and the glial fibrillary acidic protein (GFAP) are other intermediate filament proteins that are being explored as markers for the Alzheimer's disease.},
}

Humans
*Intermediate Filaments/metabolism/pathology
*tau Proteins/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Animals
*Cytoskeleton/metabolism/pathology
Alzheimer Disease/metabolism/pathology
Intermediate Filament Proteins/metabolism

@article {pmid41904011,
year = {2026},
author = {Selvaraj, C and Desai, D and Sumitha, E},
title = {The quest to restore neuronal structure: Targeting cytoskeletal proteins in neurodegenerative diseases.},
journal = {Advances in protein chemistry and structural biology},
volume = {150},
number = {},
pages = {397-422},
doi = {10.1016/bs.apcsb.2025.10.026},
pmid = {41904011},
issn = {1876-1631},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *Cytoskeletal Proteins/metabolism/genetics/antagonists & inhibitors ; Animals ; *Neurons/metabolism/pathology ; Cytoskeleton/metabolism ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease are characterized by progressive neuronal dysfunction and loss. A growing body of evidence implicates cytoskeletal disruption as a central pathological mechanism in these conditions. Cytoskeletal proteins, including microtubules, actin filaments, tau, neurofilaments, and alpha-synuclein, not only provide structural integrity but also regulate axonal transport, synaptic connectivity, and neuroplasticity. Its dysfunction will lead to impaired intracellular trafficking, protein aggregation, and neuronal degeneration. This chapter explores clearly about the specific cytoskeletal abnormalities that are evident in major neurodegenerative disorders, highlighting the biological mechanisms such as tauopathy-induced microtubule instability in Alzheimer's, actin cytoskeleton dysregulation in Parkinson's, and neurofilament aggregation in ALS. Current therapeutic strategies aimed at the stabilizing cytoskeletal components, enhancing protein clearance, and restoring transport dynamics are examined, alongside the cutting-edge approaches including the gene therapy, CRISPR/Cas9 editing, and nanotechnology-based delivery systems. Challenges such as limited blood-brain barrier penetration, off-target toxicity, and patient heterogeneity are also discussed with the focus on need for precision medicine. Additionally, we have also explored the future directions that specifically focused on the biomarker development, combination therapies, and strategies to promote neuroregeneration and structural plasticity. Targeting cytoskeletal pathways holds significant promise not only for suppressing the disease progression but also for rebuilding the structural foundation of the nervous system, potentially reversing the neurodegenerative decline.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology/therapy
*Cytoskeletal Proteins/metabolism/genetics/antagonists & inhibitors
Animals
*Neurons/metabolism/pathology
Cytoskeleton/metabolism

@article {pmid41904090,
year = {2026},
author = {Haidar, M and Viden, A and Daniel, C and Cuic, B and Wang, T and Rosier, M and Tomas, D and Mills, SA and Govier-Cole, A and Djouma, E and Perera, ND and Luikinga, S and Rytova, V and Barton, SK and Gonsalvez, DG and Palmer, LM and McLean, C and Kiernan, MC and Vucic, S and Turner, BJ},
title = {Corrigendum to "Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice"[Prog. Neurobiol. 252 (2025) 102809].},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102910},
doi = {10.1016/j.pneurobio.2026.102910},
pmid = {41904090},
issn = {1873-5118},
}

@article {pmid41904598,
year = {2026},
author = {Amholt, TT and Kurtzhals, M and Melby, P and Bølling, M and Møller, OM and Lise, MK and Stage, A and O'Brien, W and Belton, S and Elsborg, P and Nielsen, G and Bentsen, P},
title = {Feasibility of the Promoting Pupils' Physical Literacy (3PL) intervention: Does it work? Will it work?.},
journal = {Pilot and feasibility studies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40814-026-01806-w},
pmid = {41904598},
issn = {2055-5784},
support = {153181//TrygFonden/ ; },
abstract = {BACKGROUND: The rise in physical inactivity among children poses serious health risks impacting physical, mental, and social well-being. Physical literacy (PL) has been identified as an effective approach to encourage long-term physical engagement. Schools and communities, particularly through physical education (PE) programs, play a critical role in promoting PL. However, while there are several PL-focused PE interventions worldwide, no such programs have been specifically tailored to Nordic contexts, making feasibility testing essential for effective implementation. This study investigated the feasibility of a Danish adaptation of an Irish PL program, Y-PATH.

METHODS: The adapted program, the Promoting Pupils' Physical Literacy (3PL) intervention, provided PE teachers with resources, courses, and a website to enhance motivational climates in PE and promote PL among 4th and 5th grade pupils. The study was conducted in accordance with Medical Research Council guidelines and Bowen et al.'s (2009) framework. Feasibility indicators including acceptability, demand, implementation, practicality, adaptation, and integration were investigated using a weekly questionnaire for PE teachers, interviews (n = four teachers and 20 pupils), observations, and field notes. The quantitative data were analyzed descriptively, while the qualitative data were analyzed using thematic analyses.

RESULTS: 3PL was found to be feasible and acceptable among pupils and teachers (e.g., materials were used in 71% of lessons). While the materials supported implementation for teachers, workload adjustments are needed. Teachers adapted lessons effectively, balancing an inclusive and motivating learning environment. Despite minor challenges, 3PL fostered engagement among pupils and teachers with potential for expansion.

CONCLUSION: 3PL represents a feasible and promising approach to promote PL in a Danish school setting. Feasibility testing demonstrated the potential for scaling 3PL, while recognizing that large-scale trials are needed to validate its broader impact.

TRIAL REGISTRATION: A protocol for adaptation of 3PL was published in Open Science Framework, registered in December 2022 (1). The 3PL study was preregistered at ClinicalTrials.gov (ID NCT05822024), April 2023, version 1 (https://classic.

CLINICALTRIALS: gov/ct2/show/NCT05822024), before enrolment. A study protocol was written before intervention start (August 2023) and hereafter officially published in January 2024 (2).},
}

@article {pmid41905172,
year = {2026},
author = {Balaji, R and Joshi, H and Patel, BK},
title = {Elucidating the conformational dynamics of the mitochondrial localization signal, M3, of TDP-43 and accessing potential binders using molecular docking and simulation.},
journal = {Computational biology and chemistry},
volume = {123},
number = {},
pages = {109029},
doi = {10.1016/j.compbiolchem.2026.109029},
pmid = {41905172},
issn = {1476-928X},
abstract = {Aberrant mitochondrial localization of RNA/DNA-binding protein TDP-43 is implicated in amyotrophic lateral sclerosis (ALS), which may affect mitochondrial dynamics and contribute to neuronal toxicity. Inhibitors of the cytoplasmic aggregation of TDP-43 were reported previously, but their effect on the mitochondrial mislocalization of TDP-43 remains to be investigated. Three internal peptide sequences from TDP-43, M1, M3, and M5, were found to enable TDP-43's mitochondrial localization. The peptides carrying these sequences thwarted mitochondrial import of TDP-43 and rescued TDP-43-induced cytotoxicity to neurons. In the current study, we aimed to assess the repurposing potential of 2115 FDA-approved small molecules for binding to the M3 region of TDP-43 (aa: 146-150) through virtual screening. The M3 region is present in the RNA-recognition motif-1 (RRM-1); hence, multiple all-atom molecular dynamics (MD) simulations, with two different starting conformations, of the tandem RRM1-2 domains of TDP-43 in explicit solvent water were performed to understand the dynamics of the target M3 region. The analysis of the simulation trajectories suggests that the M3 region is relatively non-flexible and buried relative to the other regions of the tandem RRM1-2 domains. Cholecalciferol (Vitamin D3), as identified through virtual screening, consistently docked with the M3 region across various docking strategies, despite the region's poor accessibility in most conformations. Vitamin D3 also remained stably bound to the M3 region in most frames of four replica MD simulations, each of one microsecond. Taken together, our study proposes vitamin D3 as a potential binder to the M3 region, which may inhibit the pathogenic mitochondrial mislocalization of TDP-43.},
}

@article {pmid41905471,
year = {2026},
author = {Kuiper, MM and Cuppers, L and Sewell-Green, A and Kruithof, WJ and Visser-Meily, JMA and Beelen, A},
title = {Criterion validity of equations as alternatives to reference standards for assessing body composition and energy expenditure in amyotrophic lateral sclerosis - a systematic literature review.},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {103262},
doi = {10.1016/j.clnesp.2026.103262},
pmid = {41905471},
issn = {2405-4577},
abstract = {BACKGROUND & AIM: People living with amyotrophic lateral sclerosis (ALS) are at high risk of malnutrition, making it essential to monitor their nutritional status through measurements of body composition and energy expenditure. However, validity of equations, as alternatives to reference standards for assessing these parameters in ALS, is unclear. This systematic review evaluates criterion validity of equations to estimate body composition and energy expenditure in ALS.

METHODS: Four electronic databases (EMBASE, MEDLINE, CINAHL and Cochrane) were systematically searched from inception until July 7[th], 2025. Studies were included if criterion validity of an instrument or method for estimating body composition or energy expenditure was examined in people diagnosed with ALS. Methodological quality was assessed using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) risk of bias checklist. Criterion validity was rated as sufficient (+), indeterminate (?) or insufficient (-) based on COSMIN criteria for good measurement properties. Results were qualitatively summarised.

RESULTS: Twelve studies were included: five evaluated the criterion validity of equations to estimate body composition using Bioelectrical Impedance Analysis (BIA) or anthropometry, and seven to estimate resting or total daily energy expenditure. No equation was rated as sufficient for criterion validity across studies.

CONCLUSION: Equations to estimate body composition and energy expenditure should be applied with caution, as no equation exhibited high criterion validity in ALS. ALS-specific equations require further validation, and ideally, new equations tailored to the unique physiological characteristics of ALS should be developed.

PROSPERO REGISTRATION NUMBER: CRD42024573509.},
}

@article {pmid41905645,
year = {2026},
author = {Martín-Sánchez, FJ and Marcos Sastre, MC and Muñoz de Maya, E and Sánchez-Pinto Pinto, B and Trueba Vicente, Á and Artero Ortiz, J and Arribas Guerrero, J and Soto Vargas, N and García Sánchez, IM and Marco Martínez, J and , },
title = {Six months of experience at a specialized daytime care center for people with amyotrophic lateral sclerosis (ALS) in the Community of Madrid.},
journal = {Neurologia},
volume = {},
number = {},
pages = {502006},
doi = {10.1016/j.nrleng.2026.502006},
pmid = {41905645},
issn = {2173-5808},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to motor deterioration and a reduced quality of life. In the Community of Madrid, the ALS Network was established to improve patient care. In April 2024, the Specialized Day Care Centre for ALS (CEADELA) was inaugurated, complementing the care provided by the ALS Network. The aim of this study was to describe the experience of CEADELA during its first six months.

MATERIALS AND METHODS: A retrospective descriptive study was conducted on a cohort of CEADELA patients between April and October 2024. Clinical, functional, and therapeutic data were analyzed, along with overall satisfaction levels.

RESULTS: A total of 91 patients were included, with a mean age of 65.2 years (SD 11); of these, 59 (64.8%) were men. Most had spinal-onset ALS and were receiving treatment with riluzole. A significant increase was observed in the use of physiotherapy, speech therapy, and occupational therapy after referral to the centre. Functionality significantly declined over six months. The mortality rate was 12.1% (18.2% opted for assisted dying). Overall, 76 patients (83.5%) responded to the survey, with 100% reporting satisfaction or high satisfaction with the centre (80.2% very satisfied and 18.4% satisfied).

CONCLUSIONS: CEADELA has improved access to specialized therapies with a high level of satisfaction, although disease progression remains a challenge. The need to continue developing integrated, evidence-based care models to optimize ALS management is highlighted.},
}

@article {pmid41895273,
year = {2026},
author = {Kim, D and Kondo, T and Inoue, H},
title = {Dissecting microglial contributions to neurodegenerative disease pathophysiology using human pluripotent stem cells.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102866},
doi = {10.1016/j.stemcr.2026.102866},
pmid = {41895273},
issn = {2213-6711},
abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss. Microglia, the brain's resident macrophages, are key contributors to disease pathogenesis, with many genetic risk variants enriched in microglia-specific genes. While rodent models have provided valuable insights, human induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) technologies now enable the generation of human microglia-like cells, offering a physiologically relevant platform to study human microglial biology. This review discusses the developmental origins and functions of microglia, current differentiation approaches, and how these models help elucidate disease-relevant phenotypes and molecular mechanisms in neurodegeneration.},
}

@article {pmid41895675,
year = {2026},
author = {Barthes, R and Niérat, MC and Rivals, I and Gatignol, P and Raux, M and Faure, M and Bruneteau, G and Serresse, L and Morélot-Panzini, C and Similowski, T},
title = {Association between dyspnea and cognitive task performance in amyotrophic lateral sclerosis: an exploratory study.},
journal = {Respiratory physiology & neurobiology},
volume = {},
number = {},
pages = {104566},
doi = {10.1016/j.resp.2026.104566},
pmid = {41895675},
issn = {1878-1519},
abstract = {Dyspnea is a major sensory and emotional burden in patients with chronic respiratory insufficiency. While experimentally induced acute dyspnea has been shown to interfere with cognition in healthy participants, interferences between cognition and chronic clinical dyspnea have not been studied. We conducted an exploratory study to examine the association between dyspnea severity and cognitive performance in patients with amyotrophic lateral sclerosis (ALS) and chronic respiratory failure. Twenty patients were studied during unassisted breathing and during non-invasive ventilation (NIV). Dyspnea was assessed using the Multidimensional Dyspnea Profile, and cognitive performance was evaluated using the Paced Auditory Serial Addition Test (PASAT) and the Corsi block-tapping test. Respiratory-related cortical activity was assessed using electroencephalography. Linear mixed-effects models were used to examine associations between dyspnea descriptors and cognitive outcomes, adjusting for age, educational level, and disease severity. NIV markedly relieved dyspnea, anxiety, and respiratory-related cortical activity but was not associated with changes in cognitive performance. Dyspnea unpleasantness was independently associated with longer PASAT response time, whereas no associations were observed with PASAT accuracy measures or Corsi test outcomes. Neither ventilation condition nor respiratory-related cortical activity was associated with cognitive performance. These findings suggest that, in patients with ALS, dyspnea unpleasantness may be associated with slower PASAT response time without detectable relationships with other cognitive measures assessed in this study. Given the exploratory and focal nature of the study, further investigations are warranted to better characterize dyspnea-cognition interactions in this population.},
}

@article {pmid41896845,
year = {2026},
author = {Chang, J and Lipscombe, H and Lv, J and McCombe, PA and Henderson, RD and Ngo, ST and Steyn, FJ and Shaw, TB},
title = {White matter changes in reward circuits of amyotrophic lateral sclerosis: a fixel-based study of appetite loss.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04763-6},
pmid = {41896845},
issn = {1741-7015},
support = {UQ Graduate School Scholarship (RTP)//University of Queensland/ ; Scott Sullivan MND Research Fellowship//University of Queensland/ ; Faculty of Medicine//University of Queensland/ ; TU2201//Motor Neurone Disease Research Australia/ ; PDF2112//Motor Neurone Disease Research Australia/ ; Scott Sullivan MND Research Fellowship//Royal Brisbane and Women's Hospital Foundation/ ; Scott Sullivan MND Research Fellowship//MND and Me Foundation/ ; Scott Sullivan MND Research Fellowship//FightMND/ ; Collaborative Initiative Grant//FightMND/ ; 2017-07//Wesley Medical Research/ ; APP2029871//National Health and Medical Research Council/ ; },
abstract = {BACKGROUND: Non-motor symptoms such as appetite loss contribute to weight and fat mass reduction in people living with Amyotrophic Lateral Sclerosis (plwALS), both of which are strong prognostic factors in the disease. Consequently, understanding the neural mechanisms underlying appetite and other non-motor disturbances in ALS is of significant clinical concern. Previous studies highlight widespread grey and white matter involvement beyond the motor system, including hypothalamic volume loss and functional changes in reward-related regions. However, it remains unclear whether structural alterations in white matter tracts implicated in reward processing and behaviour contribute to the multisystem pathology of ALS.

METHODS: In this case-control study, we employ fixel-based analysis to examine changes in fibre characteristics of non-motor and motor tracts and their associations with clinical, anthropometric, and appetite-related measures within plwALS. Thirty-two plwALS and 24 non-neurodegenerative disease (NND) controls underwent multiband diffusion and structural imaging. Fixel-based analysis was conducted using MRtrix3 to model fibre pathways. For group-level statistical contrasts, fixels were generated in a common template space. We considered case-control differences, appetite, metabolism, body composition, and clinical measures.

RESULTS: Results reveal reductions in fibre density and cross-section in the corticospinal/corticobulbar and cerebellothalamic tracts. Exploratory analyses identified fibre density cross-section reductions throughout the temporo-ponto-cerebellar tract, the medial forebrain bundle, and the uncinate fasciculus. Though no direct associations were observed between fibre characteristics and measures of appetite or metabolism, we found significant correlation between fibre cross-section of the corticospinal/corticobulbar tracts and fat-free mass in NND controls, but not in plwALS. Furthermore, disease severity was associated with reduced fibre cross-section in the corticospinal/corticobulbar tract, medial forebrain bundle, uncinate fasciculus, and the temporopontine tract.

CONCLUSIONS: These findings highlight white matter fibre alterations in both motor and non-motor circuits in ALS. Although direct associations with appetite and metabolism were not observed, the results provide evidence of structural degeneration within reward- and behaviour-related pathways. Taken together, these findings reinforce that ALS is not confined to motor pathways but represents a multisystem neurodegenerative disease with both motor and extra-motor network involvement, offering important insights for future research into disease mechanisms and therapeutic targets.},
}

@article {pmid41897327,
year = {2026},
author = {Romano, R and Ruotolo, G and Perrone, F and Tomaselli, S and Mazzoni, M and Spataro, R and Conforti, FL and Rosati, J and Bucci, C},
title = {Selective Silencing of TDP-43 P. G376D Mutation Reverses Key Amyotrophic Lateral Sclerosis-Related Cellular Deficits.},
journal = {Biomolecules},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/biom16030393},
pmid = {41897327},
issn = {2218-273X},
support = {PRIN2022 N. 2022XTM2S3//Ministero dell'università e della ricerca/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; RNA, Small Interfering/genetics ; Induced Pluripotent Stem Cells/metabolism ; *Mutation ; Oxidative Stress ; Cell Survival ; Lysosomes/metabolism ; Gene Silencing ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which there is currently no cure. Dominant mutations in the TARDBP gene are causative of ALS. In particular, the p. G376D substitution in TDP-43 causes familial ALS and it is associated with TDP-43 mislocalization in the cytosol, increased presence of cytoplasmic aggregates, and lysosomal and mitochondrial dysfunction. We previously designed a small interfering RNA (siRNA) that specifically targets and silences the mutant allele and we demonstrated that, in patient-derived fibroblasts, it can reduce TDP-43 aggregation, decrease oxidative stress, and improve cell viability. Here, we investigated the ability of this siRNA to revert some ALS-associated pathological phenotypes in motor neurons derived from induced pluripotent stem cells (iPSCs), as motor neurons are the primary cells affected in ALS. siRNA treatment reduced TDP-43 mislocalization, enhanced lysosomal function and cell viability, and decreased oxidative stress. These findings indicate that this allele-specific siRNA effectively reverses key ALS-related cellular deficits in motor neurons, representing a promising candidate for targeted therapy in patients carrying the TDP-43 G376D mutation.},
}

*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
Humans
*DNA-Binding Proteins/genetics/metabolism
Motor Neurons/metabolism/pathology
RNA, Small Interfering/genetics
Induced Pluripotent Stem Cells/metabolism
*Mutation
Oxidative Stress
Cell Survival
Lysosomes/metabolism
Gene Silencing

@article {pmid41898328,
year = {2026},
author = {Nesci, S},
title = {Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030682},
pmid = {41898328},
issn = {2227-9059},
abstract = {Neurodegenerative diseases share a mitochondrial-immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and Huntington's models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.},
}

@article {pmid41898412,
year = {2026},
author = {Rakovskaya, A and Volkova, E and Pchitskaya, E},
title = {Neuronal Calcium Signaling and Cytoskeletal Dynamics in Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062550},
pmid = {41898412},
issn = {1422-0067},
support = {25-74-10019//Russian Science Foundation/ ; },
mesh = {Humans ; *Calcium Signaling ; *Cytoskeleton/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Neurons/metabolism/pathology ; Calcium/metabolism ; },
abstract = {Neuronal function relies on the precise coordination between intracellular calcium (Ca[2+]) signaling and the cytoskeletal architecture that underpins synaptic transmission, plasticity, and structural stability. Disruption of this calcium-cytoskeleton interplay has been noted in numerous neurodegenerative diseases. We discuss how Ca[2+]-dependent cytoskeletal remodeling governs long-term potentiation and depression, dendritic spine morphology, and presynaptic function, highlighting the functions of end-binding proteins, STIM (Stromal Interaction Molecule)/Orai-mediated store-operated calcium entry, and the spine apparatus. Disease-specific manifestations of cytoskeletal-calcium dysregulation are reviewed across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies, and prion disorders. Finally, we evaluate emerging therapeutic strategies targeting calcium homeostasis, cytoskeletal dynamics, and their downstream effectors, including multi-target approaches.},
}

Humans
*Calcium Signaling
*Cytoskeleton/metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Neurons/metabolism/pathology
Calcium/metabolism

@article {pmid41898662,
year = {2026},
author = {Katz, M and Robertson, T and Ngo, ST and Yarlagadda, S and Henderson, RD and McCombe, PA and Noakes, PG},
title = {Review of the Pathology of Muscle in Amyotrophic Lateral Sclerosis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062802},
pmid = {41898662},
issn = {1422-0067},
support = {DIS-202403-01216//Fight MND/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism ; Humans ; Animals ; *Muscle, Skeletal/pathology/metabolism ; Neuromuscular Junction/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Disease Models, Animal ; Biomarkers/metabolism ; },
abstract = {In amyotrophic lateral sclerosis (ALS), a central event is the withdrawal of the motor nerve terminal from its target muscle. Whether this defect is driven by faults in the motor neuron or faults that originate within the muscle remains an area of investigation. In this review, we focus on the pathological abnormalities that are found in skeletal muscle, focusing, when possible, on human ALS, with support from ALS animal models. We begin with an overview of skeletal muscle, including a review of muscle fiber type, motor units and the neuromuscular synapse. Next, we provide a description of the clinical and biomarker changes that occur in the muscles of patients with ALS. We provide an extensive account of the histopathological changes that are evident in ALS muscle, such as fiber type grouping, muscle inflammation, protein misfolding, mitochondrial dysfunction, and alterations in neuromuscular junctions and muscle satellite cells. Our review then concludes with an update of metabolic and molecular-genetic changes that are found in ALS muscle. The evidence shows that muscle can be an additional target for therapy in ALS, in combination with therapies targeting neurons and glia within the central nervous system (CNS).},
}

*Amyotrophic Lateral Sclerosis/pathology/metabolism
Humans
Animals
*Muscle, Skeletal/pathology/metabolism
Neuromuscular Junction/pathology/metabolism
Motor Neurons/pathology/metabolism
Disease Models, Animal
Biomarkers/metabolism

@article {pmid41899342,
year = {2026},
author = {Hermann, M and Stoiber, A and Schmid, A and Hamp, T and Santos, AA and Grassmann, D and Krammel, M and Lintschinger, JM and Ulbing, S and Stria, A and Hafner, C},
title = {Relevance of Reversible Causes of Out-of-Hospital Cardiac Arrest: The "REBECCA" Interactive Checklist.},
journal = {Journal of clinical medicine},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/jcm15062422},
pmid = {41899342},
issn = {2077-0383},
abstract = {Background/Objectives: Adequate cardiopulmonary resuscitation (CPR), defibrillation, and treatment of reversible causes are essential for improving the survival of patients suffering from out-of-hospital cardiac arrests (OHCAs). The Advanced Life Support (ALS) algorithm includes reversible causes for cardiac arrest. This study aimed to develop an interactive mobile checklist to identify reversible causes of OHCA (REBECCA) and evaluate their usability and usefulness among emergency physicians. Methods: This mixed-methods study was conducted at the Emergency Medical Service Vienna, Austria. All participants were emergency physicians from the Medical University of Vienna. An interactive mobile checklist was developed using a participatory design approach involving a focus group of 10 emergency physicians. Usability and applicability were assessed using structured questionnaires. Descriptive statistics were used to summarize participant characteristics and evaluation outcomes. Results: Among the included participants, 70% were specialists with a median prehospital experience of 2.0 (1.0-4.3) years. Although most participants were confident about their level of professional experience with OHCA, 85% still found the checklist to be helpful. The majority of the participants preferred the digital checklist over the paper-based checklist and appreciated its integration with the point-of-care ultrasound (POCUS) application. Although the participants did not communicate a significant need for further details on most causes, a small majority favored more information on intoxication and electrolyte disorders. Conclusions: The majority of the included emergency physicians found the REBECCA checklist helpful regardless of training level, whereas almost no physician needed further detailed information on the reversible causes. Our findings underscore the potential importance of future investigations aiming to reduce the cognitive load of emergency physicians during OHCA scenarios.},
}

@article {pmid41900026,
year = {2026},
author = {Jamerlan, A and Hulme, J},
title = {Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {6},
pages = {},
doi = {10.3390/molecules31060924},
pmid = {41900026},
issn = {1420-3049},
support = {RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; RS-2021-NR060117//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Autophagy/drug effects ; *TDP-43 Proteinopathies/metabolism/drug therapy/pathology ; Lysosomes/metabolism ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; Oligonucleotides, Antisense/pharmacology ; Proteolysis ; },
abstract = {The cytoplasmic accumulation of TDP-43 aggregates remains a persistent pathological hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The cell's natural clearance mechanisms, the Ubiquitin-Proteasome System (UPS) and the autophagy-lysosome pathway (ALP), are hypothesized to fail, at least in part, due to the sequestration of key components of these pathways by pathological TDP-43 species, thereby impairing autophagosome-lysosome fusion and lysosomal competence. Classical autophagic activators (e.g., rapamycin) can initiate upstream steps in the pathway but cannot address downstream flux bottlenecks, limiting their ability to restore effective TDP-43 clearance. This review revisits classical strategies and discusses newer approaches to modulate TDP-43 clearance, including transcription factor EB (TFEB) activators, proteolysis-targeting chimeras (PROTACs), and antisense oligonucleotides (ASOs). We propose that adopting multi-targeting strategies and developing better biomarkers are vital for clinical success.},
}

Humans
*Autophagy/drug effects
*TDP-43 Proteinopathies/metabolism/drug therapy/pathology
Lysosomes/metabolism
Animals
*DNA-Binding Proteins/metabolism/genetics
Oligonucleotides, Antisense/pharmacology
Proteolysis

@article {pmid41900140,
year = {2026},
author = {Krzymiński, K and Zadykowicz, B and Czechowska, J and Rudnicki-Velasquez, P and Serdiuk, I and Sieradzan, AK and Holec-Gąsior, L},
title = {Acridinium Chemiluminogenic Labels-Synthesis, Analytical Performance, and Mechanism of Light Generation-A Comparison in View of Biomedical Diagnostics.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {6},
pages = {},
doi = {10.3390/molecules31061041},
pmid = {41900140},
issn = {1420-3049},
support = {2011/03/D/ST4/02419//National Science Centre/ ; },
mesh = {*Acridines/chemistry/chemical synthesis ; Humans ; *Luminescent Measurements/methods ; Immunoassay/methods ; Luminescence ; Immunoglobulin G/chemistry ; },
abstract = {This paper presents the synthesis, physicochemical characterisation, and analytical applications of chemiluminescent (CL) labels based on acridinium salts (ALs) for biomedical diagnostics. These compounds emit light as a result of oxidative reactions and represent an established class of reagents widely employed in chemiluminescence immunochemical assays (CLIAs) today. A series of structurally differentiated acridinium labels (AL1-AL5) was synthesised applying mostly original synthetic routes and purified to chromatographic purity (>90%, RP-HPLC). The compounds, including a commercial product treated as a reference, were successfully conjugated to anti-human IgG, yielding stable immunochemical reagents suitable for immunoassays with CL detection. The chemiluminescence properties of the obtained labels and their protein conjugates were investigated in aqueous buffers and in the presence of surfactants. The emission profiles exhibited characteristic flash-type kinetics with emission maxima occurring within 0.15-0.25 s after reaction initiation. The presence of surfactants more or less significantly enhanced the emission intensity, with signal increases of up to approx. 2-fold compared to surfactant-free systems. Analytical calibration demonstrated a linear response of signal derived from native labels over at least one order of magnitude of concentration, with detection limits falling in the range of 10[-9]-10[-10] M, confirming the high sensitivity of the developed compounds. The experimental results were supported by theoretical studies using density functional theory (DFT), which confirmed the energetic feasibility of the CL reaction pathway and identified structural factors influencing activation barriers. Additional semiempirical calculations (PM7) indicated that the dielectric environment and proximity of ionic species can influence the reaction energetics, providing mechanistic support for the experimentally observed effects of surfactants. The results demonstrate that both molecular structure and microenvironment influence CL efficiency and kinetics of the investigated systems. The developed acridinium labels exhibit analytical performance better or comparable to commercial reagents and are fully compatible with standard immunodiagnostic conjugation protocols, confirming their suitability for use in modern chemiluminescent immunoassays.},
}

*Acridines/chemistry/chemical synthesis
Humans
*Luminescent Measurements/methods
Immunoassay/methods
Luminescence
Immunoglobulin G/chemistry

@article {pmid41900340,
year = {2026},
author = {Iungin, O and Potters, G and Kalinichenko, O and Prekrasna-Kviatkovska, Y and Moshynets, O and Kazakov-Kravchenko, O and Sidorenko, M and Okhmat, O and Mickevičius, S},
title = {Temperature-Dependent Biofilm Development in Antarctic Endophytic Microbial Communities.},
journal = {Microorganisms},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/microorganisms14030580},
pmid = {41900340},
issn = {2076-2607},
support = {0124U003829//National Antarctic Scientific Center of Ukraine/ ; 0125U003135//National Antarctic Scientific Center of Ukraine/ ; 984834//NATO SPS/ ; },
abstract = {Climate change is reshaping Antarctic ecosystems, where the resilience of Deschampsia antarctica and Colobanthus quitensis is mediated by endophytic microbial communities assembled under strong abiotic drivers. This study explores the temperature-dependent biofilm development in two Antarctic endophytic microbial communities (ALS and LS). Multivariate analysis revealed a fundamental trade-off between planktonic expansion and biofilm matrix investment as a function of thermal cues. While moderate warming (15-25 °C) optimized cell viability and turbidity, extreme thermal stress at 37-42 °C in nutrient-rich conditions triggered a significant shift toward a matrix-rich signature, characterized by a synergistic increase in total DNA and cellulose. Crucially, at the thermal extreme of 42 °C, we observed a decoupling of optical density from culturable biomass, where high turbidity did not translate into viable cells, signaling a state of severe environmental stress. These results identify 25 °C as the quantitative threshold for optimal growth, while temperatures of 37-42 °C act as a specific trigger for protective matrix production. Such thermal plasticity suggests that Antarctic endophytes are evolutionarily primed for persistence not only in cold native niches but also during bird-mediated dispersal at endothermic host temperatures.},
}

@article {pmid41900568,
year = {2026},
author = {Kostadinova-Slaveva, A and Savov, V and Antov, P and Malcheva, B and Todorova, E and Yusein, J and Dudeva, V and Ivanov, G},
title = {Aesthetic Profiling and Exploratory Composting Screening of Wood-Fiber Biocomposites Bonded with Spent Coffee Grounds and Ammonium Lignosulfonate.},
journal = {Materials (Basel, Switzerland)},
volume = {19},
number = {6},
pages = {},
doi = {10.3390/ma19061077},
pmid = {41900568},
issn = {1996-1944},
support = {BG16RFPR002-1.014-0015//European Regional Development Fund through Bulgarian Programme "Research, Innovation and Digitalisation for Smart Transformation"/ ; },
abstract = {Spent coffee grounds (SCGs) and lignin-derived binders, such as ammonium lignosulfonate (ALS), are increasingly being explored as renewable resources to reduce reliance on conventional formaldehyde-based resins in wood-fiber biocomposites. Although prior work has shown that SCG-ALS adhesive systems can achieve promising mechanical performance, two practical aspects essential for industrial applications and circular design remain insufficiently explored: a predictable and reproducible visual appearance and credible end-of-life options. In this study, sustainable wood-fiber biocomposites bonded with SCG and ALS were assessed from an aesthetic performance and end-of-life perspective. Color was quantified in the CIE L*a*b* (CIELAB) space and expressed as total color difference (ΔE*) relative to a reference panel. Increasing total SCG + ALS content from 40 to 75 wt.% based on oven-dry fibers produced pronounced darkening, with lightness decreasing from L* = 47.1 to 34.3 and ΔE* increasing from 18.38 to 32.51. Short-term composting behavior was explored by embedding fragments from formulations with 40-60 wt.% total SCG + ALS (based on oven-dry fibers; equal SCG/ALS shares) into a mixed organic substrate adjusted to an initial C/N ≈ 30 and monitored for 30 days in pots and trays. The process remained predominantly mesophilic (≈14-22 °C); nevertheless, visible microbial colonization and progressive surface degradation were observed, indicating susceptibility to biological activity under moist, nutrient-rich conditions. Overall, the results show that SCG-ALS content strongly governs the visual identity of the biocomposites and suggest composting-oriented routes as a potential end-of-life direction at an exploratory level, while highlighting the need for standardized compostability assessment and longer-term monitoring to substantiate circularity claims.},
}

@article {pmid41900684,
year = {2026},
author = {Pigato, M and Agresti, F and Benato, A and Bucci, C and Calliari, I and Cortis, D and D'Eramo, S and Fu, S and Giancarli, C and Pezzato, L and Zambon, A and D'Addabbo, A},
title = {Microstructural and Mechanical Characterization of Ultra-Pure Aluminum for Low-Amplitude-Vibration Cryogenic Applications.},
journal = {Materials (Basel, Switzerland)},
volume = {19},
number = {6},
pages = {},
doi = {10.3390/ma19061195},
pmid = {41900684},
issn = {1996-1944},
support = {2022KRKM2X//Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale/ ; },
abstract = {In fundamental physics, sensors operating below liquid helium temperatures are highly vulnerable to vibrations, which can affect the sensitivity, for example, of high-performance particle detectors. Pulse-tube refrigerators, while generating vibrations lower than those of conventional systems, may still introduce several disturbances. Hence, flexible thermal connections are a commonly used mechanical solution to mitigate these undesirable effects. Among the materials that can be used, ultra-high-purity aluminum (UHP-Al) has attracted the attention for low-amplitude-vibration cryogenic applications, including gravitational wave interferometry, quantum information systems, precision space instrumentation, and cryogenic resonators. Thus, the aim of the paper is the characterization of the mechanical and microstructure properties of three UHP-Als (i.e., 5N-99.999 wt%, 5N5-99.9995 wt% and 6N-99.9999 wt%) intended for the production of thermal flexible connections with low stiffness, specifically designed to reduce vibration transmission in cryogenic environments. Mechanical properties were evaluated through standard tensile tests from room (+25 °C) to low temperature (i.e., -150 °C), providing insights into yield strength, ultimate tensile strength, elongation and elastic modulus. In addition, the dynamic elastic modulus of material loads, at cryogenic conditions (i.e., about -180 °C), was determined by measuring the natural resonance frequency, thereby assessing the material's response to vibrational. Moreover, an extensive microstructural analysis was conducted using electron backscatter diffraction and x-ray diffraction. The correlation between the observed microstructure and the elastic properties was systematically examined. The results underscore the pivotal role of microstructural characteristics in dictating the elastic behavior of UHP Als. Eventually, the analysis provides valuable guidelines for the materials employment inside cryogenic systems, where severe vibration control is critical to maintain high operational performance.},
}

@article {pmid41885638,
year = {2026},
author = {Sadhukhan, A and Chauhan, A and Kumar, M and Singh, TG and Mujwar, S and Awasthi, A},
title = {Cryptoxanthin as a multitarget neuroprotective agent: mechanistic and in silico perspectives.},
journal = {The Journal of pharmacy and pharmacology},
volume = {78},
number = {3},
pages = {},
doi = {10.1093/jpp/rgag029},
pmid = {41885638},
issn = {2042-7158},
mesh = {*Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Molecular Docking Simulation ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Xanthophylls/pharmacology/therapeutic use ; Animals ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Computer Simulation ; },
abstract = {OBJECTIVES: Neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS) are complex disorders driven by multiple pathological processes, including oxidative stress, mitochondrial dysfunction, protein misfolding, and neuroinflammation. Due to this multifactorial nature, there is a growing interest in identifying natural compounds with multi-targeted neuroprotective properties. This review aims to evaluate the therapeutic potential of β-cryptoxanthin, a naturally occurring xanthophyll carotenoid, as a candidate molecule for mitigating neurodegenerative diseases.

METHODS: A comprehensive literature review was conducted to examine the neuroprotective mechanisms of β-cryptoxanthin, focusing on its antioxidant, anti-inflammatory, and immunomodulatory properties. In addition, in silico molecular docking studies were performed using AutoDock Vina to investigate the binding interactions of β-cryptoxanthin with key molecular targets associated with inflammation and neurodegenerative pathways.

KEY FINDINGS: β-Cryptoxanthin demonstrated strong neuroprotective potential due to its ability to scavenge reactive oxygen species (ROS) and modulate key molecular pathways involved in neuroinflammation and oxidative damage. Structurally characterized by a hydroxylated β-carotene backbone with 11 conjugated double bonds, β-cryptoxanthin showed favorable binding affinities with several inflammation- and neurodegeneration-related targets, including COX-2 (-11.6 kcal/mol), PI3K (-9.6 kcal/mol), mTOR1 (-9.2 kcal/mol), and GSK-3β (-8.7 kcal/mol). Additionally, interactions with JAK2, MAPK1, NF-κB, NRF2, and TLR4 suggest its involvement in regulating neuroimmune signalling pathways and inflammatory mediators.

CONCLUSIONS: The findings of this review highlight β-cryptoxanthin as a promising candidate for future neurotherapeutic investigation due to its multi-targeted mechanisms of action against key pathways implicated in neurodegeneration. Molecular docking results support its potential mechanistic role in modulating inflammation- and oxidative stress-related targets. However, these findings represent mechanistic plausibility rather than confirmed clinical efficacy, and further validation through preclinical and clinical studies is required.},
}

*Neuroprotective Agents/pharmacology/therapeutic use
Humans
Molecular Docking Simulation
*Neurodegenerative Diseases/drug therapy/metabolism
*Xanthophylls/pharmacology/therapeutic use
Animals
Oxidative Stress/drug effects
Anti-Inflammatory Agents/pharmacology
Antioxidants/pharmacology
Computer Simulation

@article {pmid41885937,
year = {2026},
author = {Akiyama, T and Zeng, Y and Guo, C and Gautier, O and Koepke, L and Lyons, H and Molotsky, E and Bombosch, JS and Sianto, O and Ross, JP and Hoang, P and Zhao, L and Spencer, C and Sumner, CJ and Monje, M and Day, JW and Gitler, AD},
title = {KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS.},
journal = {JCI insight},
volume = {},
number = {},
pages = {},
doi = {10.1172/jci.insight.197941},
pmid = {41885937},
issn = {2379-3708},
abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN regulated factor. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.},
}

@article {pmid41888300,
year = {2026},
author = {Sanchez-Mico, MV and Calvo-Rodriguez, M and Bacskai, BJ},
title = {Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.},
journal = {Nature reviews. Neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41888300},
issn = {1471-0048},
abstract = {Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca[2+] dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca[2+] signalling pathways are progressively remodelled during ageing and become profoundly dysregulated in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. Importantly, astrocyte Ca[2+] alterations are heterogeneous and context-dependent, ranging from aberrant spontaneous activity to loss of signalling in specific subcellular domains, reflecting the disease stage, brain region and molecular pathology. Disruption of astrocyte Ca[2+] homeostasis compromises core homeostatic functions and contributes to neuronal vulnerability, circuit dysfunction and impaired neurovascular regulation. By integrating current evidence across physiological, ageing and disease contexts, this Review highlights astrocytic Ca[2+] signalling as a central node in neurodegenerative pathophysiology and underscores its potential as a target for therapeutic intervention.},
}

@article {pmid41888437,
year = {2026},
author = {McLellan, C and Campos-Melo, D and Hammond, R and Strong, MJ},
title = {Preservation of miR-9-5p and miR-124-3p in ALS-resistant oculomotor neurons contrasts with their downregulation in vulnerable spinal motor neurons, irrespective of TDP-43 pathology.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {41888437},
issn = {1432-0533},
support = {201806SOP-411481/CAPMC/CIHR/Canada ; },
mesh = {*MicroRNAs/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; Humans ; Male ; Middle Aged ; Female ; Down-Regulation ; *DNA-Binding Proteins/metabolism ; Aged ; *Spinal Cord/pathology/metabolism ; Adult ; },
abstract = {Selective vulnerability of motor neurons is a defining feature of amyotrophic lateral sclerosis (ALS) and provides a valuable framework for uncovering mechanisms that distinguish resilient from vulnerable neuronal populations. We investigated whether dysregulation of neuroprotective microRNAs (miRNAs), miR-9-5p and miR-124-3p, contributes to the differential susceptibility of motor neuron subtypes. We focused on cervical spinal motor neurons (SMNs), which undergo drastic degeneration in ALS, and oculomotor neurons (OMNs), which remain functionally intact and rarely degenerate, allowing preservation of eye movement in ALS patients. Using a modified multiplexed fluorescent in situ hybridization protocol combined with immunofluorescence, we quantified the expression of miR-9-5p and miR-124-3p in cervical SMNs and OMNs from ALS and control cases. We observed significant downregulation of both miRNAs in ALS SMNs, while their expression was maintained in ALS OMNs. Stratification of ALS SMNs by TDP-43 pathological status revealed similarly reduced miRNA expression in neurons with and without cytoplasmic inclusions, suggesting that miRNA downregulation occurs independently of visible TDP-43 pathology. We assessed the localization of the Dicer cofactor TRBP and found that it colocalized with TDP-43 inclusions in ALS SMNs, suggesting that TRBP sequestration could prevent proper miRNA processing. However, TRBP remained normally localized in neurons without cytoplasmic inclusions, indicating that sequestration cannot fully account for miRNA reduction across all ALS motor neurons. These findings support a model in which early or subtle disruptions, preceding visible pathology, may also contribute to miRNA downregulation in ALS. By identifying preserved miRNA networks as correlates of oculomotor neuron resilience in ALS, this work also exposes new therapeutic targets potentially capable of reinstating miRNA expression and reprogramming vulnerable SMNs.},
}

*MicroRNAs/metabolism/genetics
*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics
*Motor Neurons/metabolism/pathology
Humans
Male
Middle Aged
Female
Down-Regulation
*DNA-Binding Proteins/metabolism
Aged
*Spinal Cord/pathology/metabolism
Adult

@article {pmid41888964,
year = {2026},
author = {Haddouali, K and Simma, K and Bellakhdar, S and El Otmani, H and El Moutawakil, B and Rafai, MA},
title = {Multifocal motor neuropathy secondary to gluten intolerance: a case report.},
journal = {Journal of medical case reports},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13256-026-05968-2},
pmid = {41888964},
issn = {1752-1947},
abstract = {BACKGROUND: Peripheral nervous system manifestations of gluten sensitivity usually present as distal symmetric axonal polyneuropathy, small fiber neuropathy, or sensory neuropathy, often accompanied by ataxia or painful symptoms. By contrast, motor neuropathies are extremely rare, with only a few cases of multifocal motor neuropathy reported. Notably, the most recent guidelines of the European Society for the Study of Coeliac Disease do not recognize multifocal motor neuropathy as a classical neurological manifestation of gluten-related disorders. The main differential diagnoses include amyotrophic lateral sclerosis and chronic inflammatory demyelinating polyneuropathy. Currently, strict adherence to a gluten-free diet remains the only therapeutic option. Although clinical improvement is not universal, when observed, it strongly supports the causal role of gluten-related neurotoxicity.

CASE PRESENTATION: We report the case of a 50-year-old North African man with a history of dermatitis herpetiformis and persistent chronic diarrhea. Over the past 5 years, he developed progressive asymmetric motor weakness. Clinical examination revealed an asymmetric, pure motor, peripheral neurogenic syndrome, confirmed by nerve conduction studies, without evidence of proximal conduction block. Cerebrospinal fluid analysis showed elevated protein levels (0.75 g/L), and serum anti-GD3 IgM antibodies were positive. Brachial plexus magnetic resonance imaging revealed bilateral hypertrophy on T1-weighted sequences, with hyperintensity on short tau inversion recovery sequences but no contrast enhancement. The motor deficit gradually improved after the introduction of a gluten-free diet. The patient also received intravenous immunoglobulin without significant clinical benefit. On the basis of clinical, paraclinical, and follow-up findings, a diagnosis of multifocal motor neuropathy secondary to gluten intolerance was established.

CONCLUSION: This case highlights the importance of considering gluten intolerance as a potential etiology, particularly given the reversible nature of this neuropathy, which can otherwise be misdiagnosed as a more severe condition such as amyotrophic lateral sclerosis. Further studies are needed to better elucidate the pathophysiology of this rare gluten-related neurological phenotype.},
}

@article {pmid41889878,
year = {2026},
author = {Hines, TJ and Funke, JR and Pratt, SL and Rice, AD and Twiss, JL and Burgess, RW},
title = {A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.710113},
pmid = {41889878},
issn = {2692-8205},
abstract = {Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36 [Y1003N]) and alpha-tubulin 4A (Tuba4a [Q176P]) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6J mice, which confirmed the Tuba4a [Q176P] variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.},
}