@article {pmid40504117,
year = {2025},
author = {Morgan, KJ and Carley, E and Coyne, AN and Rothstein, JD and Lusk, CP and King, MC},
title = {Visualizing nuclear pore complex plasticity with pan-expansion microscopy.},
journal = {The Journal of cell biology},
volume = {224},
number = {9},
pages = {},
doi = {10.1083/jcb.202409120},
pmid = {40504117},
issn = {1540-8140},
support = {R01 NS122236/NH/NIH HHS/United States ; F31 HL158119/NH/NIH HHS/United States ; R01 GM129308/NH/NIH HHS/United States ; R35 GM15374/NH/NIH HHS/United States ; 2420904//National Science Foundation/ ; },
mesh = {*Nuclear Pore/metabolism/ultrastructure ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Nuclear Envelope/metabolism ; *Microscopy/methods ; Membrane Glycoproteins ; },
abstract = {The exploration of cell-type and environmentally responsive nuclear pore complex (NPC) plasticity requires new, accessible tools. Using pan-expansion microscopy (pan-ExM), NPCs were identified by machine learning-facilitated segmentation. They exhibited a large range of diameters with a bias for dilated NPCs at the basal nuclear surface in clusters suggestive of local islands of nuclear envelope tension. Whereas hyperosmotic shock constricted NPCs analogously to those found in annulate lamellae, depletion of LINC complexes specifically eliminated the modest nuclear surface diameter biases. Therefore, LINC complexes may contribute locally to nuclear envelope tension to toggle NPC diameter between dilated, but not constricted, states. Lastly, POM121 shifts from the nuclear ring to the inner ring of the NPC specifically in induced pluripotent stem cell-derived neurons from a patient with C9orf72 amyotrophic lateral sclerosis. Thus, pan-ExM is a powerful tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.},
}

*Nuclear Pore/metabolism/ultrastructure
Humans
Induced Pluripotent Stem Cells/metabolism
Neurons/metabolism
Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
C9orf72 Protein/genetics/metabolism
Nuclear Envelope/metabolism
*Microscopy/methods
Membrane Glycoproteins

@article {pmid40503807,
year = {2025},
author = {Rudnicki, SA and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and Cudkowicz, ME and De Carvalho, M and Genge, A and Hardiman, O and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and Van Den Berg, LH and Zinman, L and Herder, KE and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Shefner, JM and , },
title = {Hospitalizations as an outcome measure in COURAGE-ALS.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2515907},
pmid = {40503807},
issn = {2167-9223},
abstract = {Objective: To describe the development of a methodology to characterize hospitalizations and their relationship to amyotrophic lateral sclerosis (ALS) and provide results using this process in a phase 3 trial of reldesemtiv in ALS. Methods: ALS clinical trialists assisted in developing a classification system to determine if a hospitalization was related to ALS (HR-ALS), unrelated (HU-ALS), or if the relationship was indeterminate (HI-ALS) and this was applied by the investigators to hospitalizations in COURAGE-ALS. Time to first hospitalization and number of hospitalizations were compared between those assigned reldesemtiv or placebo for up to 48 weeks. Demographic and clinical features were evaluated for prediction of hospitalization risk; this analysis was limited to those participants who completed the first 24-week double-blind placebo-controlled portion of the trial. Results: COURAGE-ALS terminated early due to futility. Time to first hospitalization was similar in the reldesemtiv compared to placebo arms as was the incidence, with 86 of the participants (17.6% of those originally assigned placebo and 18.0% originally on reldesemtiv) experiencing an event. The largest percentage of events was classified as HR-ALS for both placebo (64%, 18/28) and reldesemtiv (76%, 44/58). In a multivariate model, only bulbar or respiratory onset disease was a significant risk factor for hospitalization. Conclusion: While most hospitalizations in COURAGE-ALS were HR-ALS, HU-ALS and HI-ALS also occurred. When using hospitalization as an endpoint in an ALS clinical trial, recording its relationship to ALS provides additional details to characterize disease burden and clinical meaningfulness of the endpoint.},
}

@article {pmid40502782,
year = {2025},
author = {White, MA and Crowley, L and Massenzio, F and Li, X and Niblock, M and Coleman, MP and Barmada, SJ and Sreedha, J},
title = {Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependent manner.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6527592/v1},
pmid = {40502782},
issn = {2693-5015},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive and ultimately fatal diseases characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current disease modifying drugs have modest effects and novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila . Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. Expression of TDP-43 both activated GSK3 and promoted caspase mediated cleavage of TDP-43. Conversely, GSK3 inhibition reduced the abundance of full-length and cleaved TDP-43 in neurons expressing wild-type or disease-associated mutant TDP-43, ultimately ameliorating neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity has therapeutic value.},
}

@article {pmid40502754,
year = {2025},
author = {Cheng, F and Lorincz-Comi, N and Song, W and Chen, X and Paz, IR and Hou, Y and Zhou, Y and Xu, J and Martin, W and Barnard, J and Pieper, A and Haines, J and Chung, M},
title = {Combining xQTL and genome-wide association studies from ethnically diverse populations improves druggable gene discovery.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6700169/v1},
pmid = {40502754},
issn = {2693-5015},
abstract = {Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing new treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies (GWAS). Gene-based association tests provide a more powerful alternative to traditional single nucleotide polymorphism (SNP)-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate functional genomic data. To address these challenges, we developed GenT and its various extensions, comprising a framework of gene-based tests utilizing summary-level GWAS data. Using GenT, we identified 16, 15, 35, and 83 druggable genes linked to Alzheimer's disease (AD), amyotrophic lateral sclerosis, major depression, and schizophrenia, respectively. Additionally, our multi-ancestry gene-based test (MuGenT) uncovered 28 druggable genes associated with type 2 diabetes that previous trans-ancestry or ancestry-specific GWAS had missed. By integrating brain expression and protein quantitative trait loci (e/pQTLs) into our analysis, we identified 43 druggable genes (e.g., RIPK2, NTRK1, RIOK1) associated with AD that had supporting xQTL evidence. Notably, experimental assays demonstrated that the NTRK1 protein inhibitor GW441756 significantly reduced tau hyper-phosphorylation (including p-tau181 and p-tau217) in AD patient-derived iPSC neurons, thus providing mechanistic support for our predictions. Overall, our findings underscore the power of gene-based association testing as a strategic tool for informed drug target discovery and validation based on human genetic and genomic data for complex diseases.},
}

@article {pmid40502095,
year = {2025},
author = {Poch, D and Mukherjee, C and Mallik, S and Todorow, V and Kuiper, EFE and Dhingra, N and Surovtseva, YV and Schlieker, C},
title = {Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.07.658469},
pmid = {40502095},
issn = {2692-8205},
abstract = {UNLABELLED: Aberrant biomolecular condensates are implicated in multiple incurable neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and DYT1 dystonia. However, the role of condensates in driving disease etiology remains poorly understood. Here, we identify myeloid leukemia factor 2 (MLF2) as a disease-agnostic biomarker for phase transitions, including stress granules and nuclear condensates associated with dystonia. Exploiting fluorophore-derivatized MLF2 constructs, we developed a high-content platform and computational pipeline to screen modulators of NE condensates across chemical and genetic space. We identified RNF26 and ZNF335 as protective factors that prevent the buildup of nuclear condensates sequestering K48-linked polyubiquitinated proteins. Chemical screening identified four FDA-approved drugs that potently modulate condensates by resolving polyubiquitinated cargo and MLF2 accumulation. Our exploratory integrated chemical-genetics approach suggests that modulation of zinc, and potentially autophagy and oxidative stress, is critical for condensate modulation and nuclear proteostasis, offering potential therapeutic strategies for neurological disorders. Application of our platform to a genome-wide CRISPR KO screen identified strong enrichment of candidate genes linked to primary microcephaly and related neurodevelopmental disorders. Two hypomorphic microcephaly-associated alleles of ZNF335 failed to rescue nuclear condensate accumulation in ZNF335 KO cells, suggesting that aberrant condensates and impaired nuclear proteostasis may contribute to the pathogenesis of microcephaly.

HIGHLIGHTS: MLF2 emerges as a disease-agnostic condensate biomarker co-localizing with TDP-43 and G3BP1FDA-approved drugs target condensates linked to perturbed proteostasis.RNF26 and ZNF335 are identified as modulators of nuclear phase transitions.Microcephaly patient disease alleles fail to counteract aberrant condensates.},
}

@article {pmid40501612,
year = {2025},
author = {Bhuiyan, P and Yi, Y and Wei, B and Yan, A and Dong, L and Wei, H},
title = {Intranasal Dantrolene Nanoparticles for Treatment of Amyotrophic Lateral Sclerosis as a Disease-Modifying Drug.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.21.655232},
pmid = {40501612},
issn = {2692-8205},
abstract = {Calcium dysregulation, caused by pathological activation of ryanodine receptors, contributes to motor neuron degeneration, motor dysfunction, and muscle weakness in SOD1-G93A transgenic amyotrophic lateral sclerosis (ALS) mice. This study investigates the therapeutic efficacy of intranasally administered dantrolene nanoparticles, a ryanodine receptor antagonist, on motor neuron function, muscle strength, spinal cord degeneration, and survival outcomes. Male and female C57BL/6SJLF1 non-transgenic control and SOD1-G93A ALS transgenic mice were assigned to one of three experimental groups: 1) NO TX: No treatment control; 2) IN-DAN: Intranasal administration of dantrolene in the Ryanodex formulation vehicle (RFV), at a dosage of 5mg/kg, administered daily from ages 90-120 days; 3) IN-VEH: Intranasal administration of RFV alone (as a vehicle control), following the same dosing schedule as the IN-DAN condition. Body weight and general motor function were monitored weekly, with survival recorded daily throughout the treatment period. At the treatment conclusion, neurological function was comprehensively evaluated using a standardized neurological scoring system. Motor coordination and balance were assessed using the balance beam test (beam widths of 12 mm and 6 mm) and the rotarod test. Muscle strength was evaluated by measuring grip force using the Kondziela inverted screen test. After behavioral testing, spinal cord tissues were collected for analysis. The levels of neurofilament light chain (NFL), a skeletal neuron protein, and spinal cord weight were determined to measure spinal cord degeneration. Compared to non-transgenic control mice, SOD1-G93A mice exhibited significantly elevated neurological scores, indicating severely impaired neurological function. This deterioration was robustly and significantly ameliorated by IN-DAN treatment by 90% (P<0.0001). Similarly, ALS mice demonstrated impairments in motor coordination and balance on the beam balance test, with dramatic and significant increases in crossing time and the number of foot slips. These impairments were greatly and significantly mitigated by IN-DAN treatment, by 78% in crossing time (P<0.0001) and 84% in the number of slips (P<0.0001) on the 12 mm-wide beam, but not by the vehicle control. ALS mice demonstrated progressive body weight loss as well, which was similarly reversed by IN-DAN treatment, but not by the vehicle control. Muscle strength, as measured by grip force, was significantly reduced in ALS mice but robustly preserved IN-DAN treatment, which prevented the decrease by 213% (P<0.0001), while the vehicle control had no effect. Spinal cord weight was significantly reduced in ALS mice, a trend reversed by intranasal dantrolene nanoparticle treatment, but not by the vehicle control. Survival analysis revealed that 100% of control mice survived through the 30-day treatment period (up to 120 days of age), while survival in untreated or vehicle-treated ALS mice dropped to 67%. In contrast, ALS mice treated with intranasal dantrolene nanoparticles demonstrated a significantly improved survival rate of 89%. Thus, intranasal dantrolene nanoparticle treatment significantly and robustly improved neurological outcomes in SOD1-G93A ALS mice, inhibiting neurological impairment, motor dysfunction, balance deficits, and muscle weakness. These improvements were associated with a marked inhibition of spinal cord weight loss. Additionally, dantrolene treatment reversed body weight loss and significantly improved survival probability in ALS mice.},
}

@article {pmid40501554,
year = {2025},
author = {Trautwig, AN and Shantaraman, A and Chung, M and Dammer, EB and Ping, L and Duong, DM and Petrucelli, L and Ward, ME and Glass, JD and Nelson, PT and Levey, AI and McEachin, ZT and Seyfried, NT},
title = {Molecular Subtyping Based on Hippocampal Cryptic Exon Burden Reveals Proteome-wide Changes Associated with TDP-43 Pathology across the Spectrum of LATE and Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.30.656396},
pmid = {40501554},
issn = {2692-8205},
abstract = {TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimer's disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, β-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies (β-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts: STMN2, UNC13A, ELAVL3, KALRN, ARHGAP32, CAMK2B, PFKP, and SYT7 . While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of β-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, β-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43-depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease.},
}

@article {pmid40501419,
year = {2025},
author = {Bischoff, KE and Kojimoto, G and O'Riordan, DL and Leavell, YL and Maiser, S and Grouls, A and Smith, AK and Pantilat, SZ and Kluger, BM and Mehta, AK},
title = {Strengths and Opportunities: Clinicians' Perspectives on Palliative Care for Amyotrophic Lateral Sclerosis (ALS) in the United States.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28458},
pmid = {40501419},
issn = {1097-4598},
support = {/AG/NIA NIH HHS/United States ; //ALS Association/ ; },
abstract = {INTRODUCTION/AIMS: Little is known about the state of palliative care (PC) for people with ALS (pALS) in the U.S. We aimed to examine current practice regarding PC for pALS and how it can be improved.

METHODS: ALS and PC clinicians completed surveys about: (1) strengths and limitations of PC for pALS provided by ALS and PC teams, (2) reasons for and barriers to referring to specialty PC, and (3) how PC could be improved.

RESULTS: One hundred forty-one ALS clinicians from 72 institutions and 242 PC clinicians from 96 institutions in 30 states completed surveys. Half of ALS clinicians reported they are able to manage patients' pain (55%) and mood symptoms (52%) "very well." Fewer reported managing care partner needs (43%) and spiritual/existential distress (29%) "very well." Fifty-eight percent of pALS are referred to outpatient PC and 69% to hospice at some point in the illness. Barriers to referring include that PC programs are not sufficiently available to pALS. ALS clinicians generally felt satisfied with PC teams' care, but PC clinicians were less confident managing motor symptoms (51% confident) and helping care partners understand how to provide care (51%) and use equipment (25%). Most clinicians felt the quality of PC provided by ALS (77%) and PC (90%) teams is good/excellent. However, qualitative comments highlighted that both ALS and PC clinicians have knowledge gaps, and collaboration between ALS and PC clinicians should increase.

DISCUSSION: Clinician education, expansion of PC services, strengthened collaboration, and further research about PC for pALS are needed.},
}

@article {pmid40500504,
year = {2025},
author = {Niu, J and Verkhratsky, A and Butt, A and Yi, C},
title = {Oligodendroglia in Ageing and Age-Dependent Neurodegenerative Diseases.},
journal = {Advances in neurobiology},
volume = {43},
number = {},
pages = {363-405},
pmid = {40500504},
issn = {2190-5215},
mesh = {Humans ; *Oligodendroglia/pathology/physiology/metabolism ; *Neurodegenerative Diseases/pathology/physiopathology/metabolism ; *Aging/pathology/physiology ; Animals ; },
abstract = {The central nervous system is susceptible to gradual decline with age, affecting all types of glial cells in the process. Compared to other glial cells, the oligodendroglial lineage is highly vulnerable to ageing and undergoes significant characteristic changes that impact upon its structure and impair its physiological functions. Therefore, the ageing and degeneration of oligodendroglia become major risk factors for neurodegenerative diseases. During the age-related disease process, changes in oligodendroglia lead to a decline in their ability to regenerate myelin and respond to the aged microenvironment, which are closely linked to the pathogenesis of neurodegenerative diseases, facilitating the emergence of these diseases in older populations. In this chapter, we introduce the physiological changes of oligodendroglia during ageing and the related mechanisms and then summarise their pathophysiological contributions to age-related cognitive disorders. Finally, we discuss potential therapeutic strategies that target oligodendroglia for future research on neurodegenerative diseases.},
}

Humans
*Oligodendroglia/pathology/physiology/metabolism
*Neurodegenerative Diseases/pathology/physiopathology/metabolism
*Aging/pathology/physiology
Animals

@article {pmid40499018,
year = {2025},
author = {Yadav, V and Singh, R and Chaturvedi, M and Siddhanta, S and Chaturvedi, R},
title = {Multivariate and Machine Learning-Derived Virtual Staining and Biochemical Quantification of Cancer Cells through Raman Hyperspectral Imaging.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c01028},
pmid = {40499018},
issn = {1520-6882},
abstract = {Advances in virtual staining and spatial omics have revolutionized our ability to explore cellular architecture and molecular composition with unprecedented detail. Virtual staining techniques, which rely on computational algorithms to map molecular or structural features, have emerged as powerful tools to visualize cellular components without the need for physical dyes, thereby preserving sample integrity. Similarly, spatial omics enable the mapping of biomolecules across tissue or cell surfaces, providing spatially resolved insights into biological processes. However, traditional dye-based staining methods, while widely used, come with significant limitations. In this context, Raman spectroscopy offers a robust, label-free alternative for probing molecular composition at a high resolution. We present a novel algorithm that reconstructs super-resolved Raman images by extracting spectral patterns from surrounding pixels, enabling detailed, label-free visualization of cellular structures. By employing Raman spectroscopy in conjunction with chemometric tools such as principal component analysis (PCA), multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural network (ANN), we performed a quantitative analysis of key biomolecular components, including collagen, lipids, glycogen, and nucleic acids, and classify the different cancer cell lines with an accuracy of nearly 99%. This approach not only enabled the identification of distinct molecular fingerprints across the different cancer types but also provided a powerful tool for understanding the biochemical variations that underlie tumor heterogeneity. This innovative combination of virtual staining, spatial omics, and advanced chemometrics highlights the potential for more accurate diagnostics and personalized treatment strategies in oncology.},
}

@article {pmid40498717,
year = {2025},
author = {Komolafe, OO and Mustofa, J and Daley, MJ and Walton, D and Tawiah, A},
title = {Current applications and outcomes of AI-driven adaptive learning systems in physical rehabilitation science education: A scoping review protocol.},
journal = {PloS one},
volume = {20},
number = {6},
pages = {e0325649},
doi = {10.1371/journal.pone.0325649},
pmid = {40498717},
issn = {1932-6203},
mesh = {Scoping Review as Topic ; Humans ; *Artificial Intelligence ; *Rehabilitation/education ; *Learning ; },
abstract = {Rationale Integrating artificial intelligence (AI) into education has introduced transformative possibilities, particularly through adaptive learning systems. Rehabilitation science education stands to benefit significantly from the integration of AI-driven adaptive learning systems. However, the application of these technologies remains underexplored. Understanding the current applications and outcomes of AI-driven adaptive learning in broader healthcare education can provide valuable insights into how these approaches can be effectively adapted to enhance multimodal case-based learning in Rehabilitation Science education. Methods The scoping review is based on the Joanne Briggs Institute (JBI) framework. It is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRIMSA-ScR). A comprehensive search strategy will be used to find relevant papers in Scopus, PubMed, CINAHL, Education Resources Information Center (ERIC), Association for Computing Machinery (ACM), ProQuest Education Journal, Web of Science, ProQuest Dissertations & Theses Global, and IEEE Digital Library. This review will include all types of studies that describe or evaluate our outcomes of interest: AI models used, learning and teaching methods, effective implementation, outcomes, and challenges of ALS's in rehabilitation health science education. Data will be extracted using a pre-piloted data extraction sheet and synthesized narratively to identify themes and patterns. Discussion This scoping review will synthesize the applications of AI models in rehabilitation science education. It will provide evidence for educators, healthcare professionals, and policymakers to incorporate AI into educational curricula effectively. The protocol is registered on Open Science Framework registries at https://osf.io/e46s3.},
}

Scoping Review as Topic
Humans
*Artificial Intelligence
*Rehabilitation/education
*Learning

@article {pmid40498248,
year = {2025},
author = {Pahwa, R and Molho, E and Lew, M and Dashtipour, K and Gil, RA and Revilla, FJ and Clinch, T and Qin, P and Isaacson, SH and , },
title = {Long-Term Safety and Efficacy of Repeated Cycles of RimabotulinumtoxinB in the Treatment of Chronic Sialorrhea: Results of the OPTIMYST Trial.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {40498248},
issn = {2193-8253},
abstract = {INTRODUCTION: Botulinum toxin injections into the salivary glands inhibit saliva production by reducing the release of acetylcholine at the parasympathetic nerve terminals within the salivary gland. The phase 3 study reported here assessed the safety, tolerability, and effectiveness of repeated cycles of rimabotulinumtoxinB (RIMA) injections in adults with troublesome sialorrhea.

METHODS: In this phase 3, open-label multicenter study, 187 adult participants with troublesome sialorrhea due to Parkinson disease (65.8%), amyotrophic lateral sclerosis (13.9%), and other etiologies (20.3%) received up to 4 cycles of RIMA treatment (3500 U every 11-15 weeks).

RESULTS: Participants (69% male, 31% female; mean age 64.1 years) had sialorrhea for a mean of 3.2 years at baseline with a mean Unstimulated Salivary Flow Rate (USFR) of 0.63 ± 0.49 g/min. During the first treatment cycle, RIMA significantly reduced the mean±standard deviation (SD) USFR from baseline to week 4 by - 0.34 ± 0.37 g/min (p < 0.0001), and efficacy was maintained through week 13 (- 0.14 ± 0.29 g/min; p < 0.0001). Reductions were maintained at subsequent injection cycles 2-4, with mean absolute USFRs at weeks 4 and 13 of each cycle similar to those of cycle 1. Most adverse events (AEs) were mild, and the most commonly reported AEs in each cycle that were considered to be treatment-related were dry mouth (≤ 15.5% participants/cycle) and dental caries (≤ 6.0% participants/cycle).

CONCLUSION: This study demonstrates that RIMA 3500 U safely reduces saliva production over repeated treatment cycles through 1 year, thereby supporting its utility in the management of troublesome sialorrhea in adults.

GOV IDENTIFIER: NCT02610868.},
}

@article {pmid40412724,
year = {2025},
author = {Xu, Y and Hou, W and Gao, J and Wei, JC and Zhang, L},
title = {Letter to Alameddine et al's "Celiac disease associated with alopecia areata: A multicenter case-control study".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.05.1405},
pmid = {40412724},
issn = {1097-6787},
}

@article {pmid40498122,
year = {2025},
author = {Doronzio, PN and Lattante, S and Bernardo, D and Patanella, AK and Bisogni, G and Meleo, E and Del Giudice, E and Colavito, D and Porro, LM and Sabatelli, E and Conte, A and Zollino, M and Sabatelli, M and Marangi, G},
title = {Burden of pathogenetic and likely pathogenetic variants in SPG7, SPG11 and AP4 genes in Amyotrophic Lateral Sclerosis. A case-control study.},
journal = {Journal of neurology},
volume = {272},
number = {7},
pages = {455},
pmid = {40498122},
issn = {1432-1459},
support = {Linea D1//Catholic University of Sacred Hearth/ ; Linea D1//Catholic University of Sacred Hearth/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Case-Control Studies ; Aged ; Adult ; *Genetic Predisposition to Disease/genetics ; *Adaptor Protein Complex 4/genetics ; *Proteins/genetics ; Spastic Paraplegia, Hereditary/genetics ; Genetic Variation/genetics ; ATPases Associated with Diverse Cellular Activities ; Metalloendopeptidases ; },
abstract = {BACKGROUND: There is evidence that some Hereditary Spastic Paraplegia (HSP) genes are linked to Amyotrophic Lateral Sclerosis (ALS). In particular, KIF5A and SPG11 genes, which cause two different forms of HSP, are also associated with adult-onset and Juvenile ALS, respectively.

OBJECTIVES: To study the frequencies of pathogenetic and likely pathogenetic variants in HSP genes in ALS patients and to determine whether they act as predisposing factors.

METHODS: We analysed 72 HSP-associated genes in 1024 ALS and 44 Primary Lateral Sclerosis patients and applied customized ACMG criteria to identify pathogenic and likely pathogenic variants. Based on the frequency of identified variants, six genes, including SPG7, SPG11 and the four genes encoding the subunits of the AP4 adaptor protein, were selected for analysis in an additional cohort of 481 ALS patients. Overall results on 1549 patients were compared with 1138 controls.

RESULTS: The frequency of variants in SPG7 gene was 0.45% (7/1549) in patients vs 0.18% (2/1138) in controls (p = 0.19), in SPG11 was 0.77% (12/1549) in cases and 0.26% (3/1138) in controls (p = 0.06), in AP4 genes was 0.64% (10/1549) in patients and 0.26% (3/1138) in controls (p = 0.13). The total number of variants detected across SPG7, SPG11 and AP4 genes was statistically different between patients and controls (1.87% vs 0.7%; p = 0.006).

CONCLUSIONS: We found a significant enrichment of variants in a set of HSP genes, including SPG7, SPG11 and AP4 genes, in a large cohort of ALS patients, suggesting that they may act as predisposing factors for ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
Male
Female
Middle Aged
Case-Control Studies
Aged
Adult
*Genetic Predisposition to Disease/genetics
*Adaptor Protein Complex 4/genetics
*Proteins/genetics
Spastic Paraplegia, Hereditary/genetics
Genetic Variation/genetics
ATPases Associated with Diverse Cellular Activities
Metalloendopeptidases

@article {pmid40498024,
year = {2025},
author = {Pisoni, L and Donini, L and Gagni, P and Pennuto, M and Ratti, A and Verde, F and Ticozzi, N and Mandrioli, J and Calvo, A and Basso, M},
title = {Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis.},
journal = {Cells},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/cells14110848},
pmid = {40498024},
issn = {2073-4409},
support = {MUR PNRR project iNEST - Interconnected Nord-Est Innovation Ecosystem (ECS00000043)//NextGenerationEU/ ; PERMEALS - PNRR-MAD-2022-12375731//Ministero della Salute/ ; CUP E53D23019700001, project "MYSTICALS"//European Union - Next Generation EU, Mission 4, Component 1/ ; RF-2016-02361616//Ministero della Salute/ ; EVTestInALS//AriSLA/ ; Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics//Università degli Studi di Milano/ ; MUR-PRIN 2022 project EV-PRINT 2022CS9H53//Next Generation EU/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/diagnosis ; *Biomarkers/metabolism ; Extracellular Vesicles/metabolism ; Animals ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology/diagnosis
*Biomarkers/metabolism
Extracellular Vesicles/metabolism
Animals

@article {pmid40497426,
year = {2025},
author = {Bao, J and Zhou, J and Xie, Z and Zou, M and Napier, R and Li, J},
title = {CYP99A2 from Aegilops tauschii metabolizes pyroxsulam but not mesosulfuron-methyl, causing different natural sensitivity to two herbicides.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.8967},
pmid = {40497426},
issn = {1526-4998},
support = {2021YFD1700100//National Key Research and Development Program/ ; },
abstract = {BACKGROUND: Weed tolerance to herbicides poses a major threat to agricultural production. Aegilops tauschii has promising prospects for genetic development; however, the fact that this plant is invasive in China and other countries is often ignored owing to its pronounced adaptability. Among the current acetolactate synthase (ALS) inhibitors, only mesosulfuron-methyl (MM) can control A. tauschii, and pyroxsulam (P) is ineffective. However, a knowledge gap remains regarding differences in sensitivity of A. tauschii to these two ALS inhibitors.

RESULTS: We hypothesized that differences in sensitivity of A. tauschii to the ALS inhibitors MM and P are mediated by metabolic enzymes. Whole-plant experiments showed that the P450s inhibitor 1-Aminobenzotriazole (ABT) significantly increased the sensitivity of A. tauschii to P compared with MM. In A. tauschii, the P metabolism rate was higher than that of MMl, as detected by liquid chromatography with tandem mass spectrometry. Transcriptome sequencing and quantitative real-time polymerase chain reaction identified seven differentially expressed P450s after P and MM treatments, three of which were upregulated after P treatment and were unaffected by MM. AtCYP99A2 reduced plant sensitivity to P by metabolizing P without affecting MM by overexpressing it in Arabidopsis and inducing in vitro protein expression.

CONCLUSION: To the best of our knowledge, this is the first report on P450 involvement in A. tauschii sensitivity to two ALS-inhibitor herbicides. This study deepens current understandings of A. tauschii and facilitates subsequent screening of specific metabolic enzyme inhibitors to be used as synergists in combination with herbicides, which will provide new avenues for weed control. © 2025 Society of Chemical Industry.},
}

@article {pmid40496636,
year = {2025},
author = {Qiao, H and Cheng, X and Tian, H and Zhao, C and Sun, X and Zhao, J},
title = {Lower cervical C6/C7 andersson lesion with upper cervical C1/C2 fracture in ankylosing spondylitis: a case report and literature review.},
journal = {Frontiers in surgery},
volume = {12},
number = {},
pages = {1568553},
pmid = {40496636},
issn = {2296-875X},
abstract = {Cervical andersson lesions (ALs) are rare in patients with ankylosing spondylitis (AS), and even more rare in patients with simultaneous superior cervical atlantoaxial fracture and dislocation. Here, we present a case of C1 Jefferson fracture (C1 bilateral posterior arch fracture), C2 odontoid, lateral mass, vertebral fracture (nonclassic C2 hangman fracture), traumatic posterior atlantoaxial dislocation (AAD) and C6/C7 AL in a long-standing AS cervical spine. The patient with traumatic AS-related cervical fractures underwent a two-stage surgery. The stage I surgery involved a posterior atlantoaxial reduction and fixation surgery combined with C5/C6/T1/T2 posterior pedicle screw fixation plus C6/C7 decompression. One week later, C6/C7 anterior cervical corpectomy decompression and fusion (ACCF) with long anterior plate stabilization combined with iliac crest bone graft transplantation was performed for stage II surgery. The patient recovery observed during follow-up was satisfactory. Nine-month postoperative radiological images revealed fracture union of the upper and lower cervical spine with optimal reduction of the atlantoaxial segment. In conclusion, lower cervical ALs with simultaneous upper cervical C1/C2 fractures in the AS are very rare. Posterior C1-C2 fixation combined with C6-C7 AL corpectomy/fusion and posterior pedicle screw fixation may offer a desirable alternative approach for this complex case of cervical trauma. During treatment, complete decompression, effective reduction, and potent stabilization can comprehensively improve the clinical prognosis.},
}

@article {pmid40496269,
year = {2025},
author = {Liu, QZ and Zeng, L and Sun, NZ},
title = {Linguistic exclusion in orthopedic research: Cultural adaptation, multilingual innovations, and pathways to global health equity.},
journal = {World journal of orthopedics},
volume = {16},
number = {5},
pages = {106951},
pmid = {40496269},
issn = {2218-5836},
abstract = {This editorial critically evaluated the recent study by AlMousa et al, which examined the impact of the Arabic version of the American Academy of Orthopedic Surgeons Foot and Ankle Outcomes Questionnaire (AAOS-FAOQ) on postoperative quality of life and recovery in Arabic-speaking patients with traumatic foot and ankle injuries. In the context of systemic linguistic exclusion in orthopedic research-where English-language journals dominated most publications and non-English-speaking populations faced dual barriers of trial underrepresentation and semantic distortions (e.g., mistranslations of terms like "joint instability" in Arabic)-AlMousa et al's work highlighted the transformative potential of culturally adapted methodologies. Their rigorous four-stage adaptation framework validated the Arabic AAOS-FAOQ as a reliable tool, enhancing ecological validity and reducing bias in patient-reported outcomes. However, limitations such as regional specificity (Gulf-centric sampling) and short follow-up periods (4 months) underscored broader challenges in non-English research: Redundant studies, prolonged hospital stays for limited English proficiency patients, and underrepresentation of certain ethnic groups in trials. To dismantle linguistic hegemony, we proposed semantic reconstruction (e.g., integrating culturally specific indicators like "prayer posture"), dialect-aware neural translation, and World Health Organization led terminology standardization. In line with these proposed solutions, AlMousa et al's study exemplified how language-sensitive adaptations could bridge equity gaps, while future efforts would need to balance cultural specificity with cross-study comparability through AI-driven multilingual databases and policy mandates for cultural adaptation roadmaps.},
}

@article {pmid40496257,
year = {2025},
author = {Ding, LH and Wu, PF and Sun, NZ},
title = {Investigation of clinical outcomes in conservative management of hook fractures: Commentary on recent findings.},
journal = {World journal of orthopedics},
volume = {16},
number = {5},
pages = {106881},
pmid = {40496257},
issn = {2218-5836},
abstract = {This editorial critically evaluates the landmark study by Tanaka and Yoshii, which demonstrated a 100% union rate with conservative management of hamate hook fractures, challenging the historical preference for surgical intervention. In contrast to Scheufle et al's report of 90%-100% failure rates with early surgical approaches, Tanaka and Yoshii's protocol achieved universal healing despite delayed diagnoses in 25% of cases. Central to this success is the systematic integration of high-resolution computed tomography for early diagnosis and dynamic monitoring of trabecular bone regeneration, significantly reducing missed diagnoses and guiding personalized immobilization timelines. The patient-centered strategy-allowing temporary splint removal during low-risk activities-balanced fracture stability with joint mobility preservation, avoiding post-treatment stiffness. However, limitations such as small sample size (n = 16), selection bias, and insufficient long-term functional data (e.g., grip strength, return-to-sport metrics) underscore the need for comparative trials. Emerging trends, including adjunct therapies like low-intensity pulsed ultrasound and biologics (e.g., teriparatide), are proposed to accelerate healing while minimizing immobilization risks. This work redefines conservative fracture management paradigms, emphasizing innovation without compromising efficacy. Overall, this assessment deepens our understanding of the conservative management of hook fractures and provides evidence-based insights for improved clinical decision-making.},
}

@article {pmid40495844,
year = {2025},
author = {Byeon, H},
title = {Unveiling the invisible: How cutting-edge neuroimaging transforms adolescent depression diagnosis.},
journal = {World journal of psychiatry},
volume = {15},
number = {5},
pages = {102953},
pmid = {40495844},
issn = {2220-3206},
abstract = {Yu et al's study has advanced the understanding of the neural mechanisms underlying major depressive disorder (MDD) in adolescents, emphasizing the significant role of the amygdala. While traditional diagnostic methods have limitations in objectivity and accuracy, this research demonstrates a notable advancement through the integration of machine learning techniques with neuroimaging data. Utilizing resting-state functional magnetic resonance imaging (fMRI), the study investigated functional connectivity (FC) in adolescents with MDD, identifying notable reductions in regions such as the left inferior temporal gyrus and right lingual gyrus, alongside increased connectivity in Vermis-10. The application of support vector machines (SVM) to resting-state fMRI (rs-fMRI) data achieved an accuracy of 83.91%, sensitivity of 79.55%, and specificity of 88.37%, with an area under the curve of 0.6765. These results demonstrate how SVM analysis of rs-fMRI data represents a significant improvement in diagnostic precision, with reduced FC in the right lingual gyrus emerging as a particularly critical marker. These findings underscore the critical role of the amygdala in MDD pathophysiology and highlight the potential of rs-fMRI and SVM as tools for identifying reliable neuroimaging biomarkers.},
}

@article {pmid40495464,
year = {2025},
author = {Majtan, T and Mijatovic, E and Petrosino, M},
title = {Understanding the Impact of Mutations in the Cystathionine Beta-Synthase Gene: Towards Novel Therapeutics for Homocystinuria.},
journal = {Molecular and cellular biology},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/10985549.2025.2511338},
pmid = {40495464},
issn = {1098-5549},
abstract = {Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders, or toxic aggregation and gain-of-function, as in neurodegenerative diseases like Alzheimer's disease or amyotrophic lateral sclerosis. Classical homocystinuria (HCU), an inborn error of sulfur amino acid metabolism, results from cystathionine beta-synthase (CBS) deficiency. CBS regulates methionine conversion into metabolites critical for redox balance (cysteine, glutathione) and signaling (H2S). Pathogenic missense mutations in the CBS gene often impair folding, cofactor binding, stability or oligomerization rather than targeting the key catalytic residues of the CBS enzyme. Advances in understanding of CBS folding and assembly as well as CBS interactions with cellular proteostasis network offer potential for therapies using pharmacological chaperones (PCs), i.e., compounds facilitating proper folding, assembly or cellular trafficking. This review discusses progress in identifying PCs for HCU, including chemical chaperones, cofactors, and proteasome inhibitors. We outline future directions, focusing on high-throughput screening and structure-based drug design to develop CBS-specific PCs. These could stabilize mutant CBS, enhance its stability and restore activity, providing new treatments for HCU and possibly other conditions related to dysregulated CBS, such as cancer or Down's syndrome.},
}

@article {pmid40495157,
year = {2025},
author = {Gonsalves, GS},
title = {Still we rise: research on bias and discrimination will endure.},
journal = {International journal for equity in health},
volume = {24},
number = {1},
pages = {167},
pmid = {40495157},
issn = {1475-9276},
mesh = {Humans ; Racism ; Boston ; *Prejudice ; United States ; *Social Discrimination ; *Vaping/epidemiology ; Smoking/epidemiology ; Bias ; Sexism ; },
abstract = {This is a commentary on Reisner et al's Analyzing multiple types of discrimination using implicit and explicit measures, comparing target vs. Dominant groups, in a study of smoking/vaping among community health center members in Boston, Massachusetts (2020-2022). This manuscript is a study of the intersection of multiple forms of discrimination-racism, sexism, heterosexism, cissexism, ageism, and sizeism-and measures of implicit and explicit bias in the context of current smoking and vaping behavior among patients from targeted versus dominant groups at community health centers in Boston, Massachusetts (USA) from 2020 to 2022. The authors used logistic regression to assess smoking and vaping behavior with each type of discrimination, and then extended this analysis employing a meta-regression approach to better understand relationships across all types of discrimination under consideration in their study. Recently, the grant from the US National Institutes of Health, which supported this research was terminated in progress for ideological reasons by the current US administration under President Donald J. Trump for simply focusing on discrimination. While this study was among the first to be terminated by the Trump administration, hundreds of grants from the NIH and other US research funders have been cancelled in the first half of 2025. Reisner et al's paper is an important piece of research, but it represents the start of a sophisticated inquiry into discrimination and bias, and future work by this team and in this area of research is necessary and sadly, now impossible to do with federal scientific funding. Work on discrimination and bias has always faced obstacles, but the scope and scale of attacks on science in the US require all scientists to push back against this censorship and political interference in the funding and conduct of research.},
}

Humans
Racism
Boston
*Prejudice
United States
*Social Discrimination
*Vaping/epidemiology
Smoking/epidemiology
Bias
Sexism

@article {pmid40494757,
year = {2025},
author = {Luu, S and McGuiness, O and Menadue, C and Piper, AJ and Wong, K and Yee, BJ and Gray, EL},
title = {Inter-Night Variability of Nocturnal Pulse Oximetry in People Living With Motor Neuron Disease: A Retrospective Observational Study.},
journal = {Respirology (Carlton, Vic.)},
volume = {},
number = {},
pages = {},
doi = {10.1111/resp.70072},
pmid = {40494757},
issn = {1440-1843},
abstract = {BACKGROUND AND OBJECTIVE: Nocturnal pulse oximetry (NPO) is a simple and inexpensive assessment tool that has previously been shown to correlate with prognosis and timing of non-invasive ventilation (NIV) initiation in people living with motor neuron disease (plwMND). However, the optimal number of nights for measuring NPO has not been defined for this population, with other respiratory conditions exhibiting both low and high night-to-night variability in NPO parameters. This study aims to determine the inter-night variability in NPO data over three nights in plwMND.

METHODS: We conducted a retrospective analysis of 132 studies in which plwMND underwent three consecutive nights of NPO. Intraclass correlation coefficients (ICC) were used to assess the reliability of key NPO parameters, including mean percentage of total recording time with oxygen saturation (SpO2) < 90% (T90), oxygen desaturation index (ODI), basal SpO2 and nadir SpO2. The proportion of plwMND meeting NIV criteria based on single-night versus multi-night assessments was also compared.

RESULTS: Excellent reliability was observed for T90 (ICC(1) = 0.940) and ODI (ICC(1) = 0.901), while basal SpO2 (ICC(1) = 0.845) and nadir SpO2 (ICC(1) = 0.768) demonstrated good reliability. However, relying on a single-night NPO assessment failed to identify 12% of plwMND who met NIV criteria when evaluated over three nights.

CONCLUSION: Despite good to excellent inter-night variability of NPO data in plwMND, multi-night NPO monitoring improves the accuracy of identifying plwMND requiring NIV. These findings support the need for multi-night assessments to enhance clinical decision-making in MND management.},
}

@article {pmid40493571,
year = {2025},
author = {Nathan Kochen, N and Murray, M and Zafari, S and Vunnam, N and Liao, EE and Chen, L and Braun, AR and Sachs, JN},
title = {Fluorescence Lifetime-Based FRET Biosensors for Monitoring N Terminal Domain-Dependent Interactions of TDP-43 in Living Cells: A Novel Approach for ALS and FTD Drug Discovery.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00266},
pmid = {40493571},
issn = {1948-7193},
abstract = {Pathological aggregates of TDP-43 are implicated in Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. While therapeutic efforts have traditionally focused on mitigating end-stage TDP-43 aggregation, recent evidence highlights an upstream and potentially targetable event: the loss of functional nuclear TDP-43 multimers due to disrupted N-terminal domain (NTD) interactions. To address this, we developed fluorescence lifetime (FLT)-based FRET biosensors to monitor TDP-43 multimerization in living cells that couple a full-length TDP-43 FLT-FRET biosensor screen with an NTD-deletion counter screen, forming the foundation of a novel high-throughput screening (HTS) platform. Screening the 2682 compound FDA-approved Selleck library, we identified the small molecule ketoconazole, which stabilizes functional nuclear TDP-43 multimers in an NTD-dependent manner with low micromolar potency. Ketoconazole rescues TDP-43 mislocalization and aggregation, restores SREBP2 mRNA levels under TDP-43 overexpression, improves neuronal health, and partially restores motor function in a TDP-43 C. elegans model. These findings establish both the biosensors and the HTS platform as innovative tools for TDP-43 drug discovery and support an exciting translational approach for targeting TDP-43 proteinopathies.},
}

@article {pmid40493543,
year = {2025},
author = {Lucassen, HJ and Prinsen, EC and Asseln, M and van Vliet, RO and Tuijthof, GJM},
title = {Assistive devices for ALS patients: exploring wishes and values through focus groups.},
journal = {Disability and rehabilitation. Assistive technology},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17483107.2025.2516628},
pmid = {40493543},
issn = {1748-3115},
abstract = {PURPOSE: Amyotrophic Lateral Sclerosis (ALS) is a progressive disease leading to loss of muscle strength and control, and as such limiting patients' independence. Assistive devices can help individuals with ALS; however, their use by ALS patients is limited. To increase use rates, we expect that devices need to be tailored to ALS patients. The aim of this study was to identify wishes, requirements and values of ALS patients regarding assistive devices for the upper extremity through focus groups involving ALS patients, their relatives and medical professionals.

METHODS AND MATERIALS: Four focus groups were conducted, recorded and transcribed. Two focus groups with ALS patients and their relatives contained a "Day in a Life" and "Empathy map" method, while during two focus groups with medical professionals, "Day in the Life" method and "Provoking statements" were used. Activities mentioned were counted and categorized into "Daily activities" and "Elective activities".

RESULTS: Qualitative analysis of transcripts yielded three themes: (1) ALS patients' considerations on use and wishes for assistive devices, (2) external factors influencing the use of assistive devices and (3) change in ALS patients' needs over time. In addition to maintaining independence in activities of daily living, the results highlight that retaining the ability to perform elective activities such as hobbies, is important. Moreover, there is a clear need for assistive devices designed for ALS patients with limited upper extremity strength, but who are not confined to a wheelchair.

CONCLUSION: These findings can guide the development of assistive devices tailored to the needs of ALS patients.},
}

@article {pmid40493233,
year = {2025},
author = {Russo, T and Domi, T and Schito, P and Falzone, YM and Pozzi, L and Locatelli, M and Riva, N and Spinelli, EG and Agosta, F and Filippi, M and Quattrini, A},
title = {Osteopontin levels in the serum reflect anatomical disease progression in patients with amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {272},
number = {7},
pages = {452},
pmid = {40493233},
issn = {1432-1459},
support = {Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Università e della Ricerca/ ; RF-2021-12374238//Ministero della Salute/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/pathology/diagnosis ; *Osteopontin/blood ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; Retrospective Studies ; Biomarkers/blood ; Neurofilament Proteins/blood ; Adult ; Longitudinal Studies ; Severity of Illness Index ; Cohort Studies ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) lacks biomarkers for diagnosis, prognostic stratification, and evaluation of response to potential treatments. Previous research supported the role of serum osteopontin (OPN) levels as a potential biomarker in ALS. However, the associations of OPN serum levels with clinical features and their trend over the disease course have not been explored yet.

METHODS: We measured OPN serum levels in a retrospective cohort of 110 well-characterized patients with ALS, using a commercial ELISA kit, and analyzed their association with demographic and clinical features, as well as with other serum biomarkers. For a subset of patients, longitudinal measurements were available.

RESULTS: OPN serum levels differed significantly between patients with ALS and a cohort of 45 age and sex-matched healthy controls. However, when considering potential differential diagnoses, elevated OPN serum levels were not specific for ALS. Patients with an advanced disease stage (King's stage 3 or 4) exhibited significantly higher OPN serum levels compared to patients at earlier disease stages, whereas we did not observe any correlation with ALSFRS-R and progression rate. We observed an inverse correlation between OPN serum levels and BMI at diagnosis. Higher OPN serum levels predicted a shorter survival time and a shorter time to King's stage 4. No significant association between serum OPN and serum neurofilament light or glial fibrillary acid protein levels was observed. OPN serum levels were substantially stable over a 9-month observation time.

CONCLUSION: Our findings indicate that serum OPN is an informative biomarker in ALS, providing valuable prognostic insights, potentially reflecting the extent of disease, and demonstrating potential applications in clinical trials.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood/pathology/diagnosis
*Osteopontin/blood
Male
Female
*Disease Progression
Middle Aged
Aged
Retrospective Studies
Biomarkers/blood
Neurofilament Proteins/blood
Adult
Longitudinal Studies
Severity of Illness Index
Cohort Studies

@article {pmid40493155,
year = {2025},
author = {Kang, A and Qiao, Y and Pan, S and Yan, F and Chen, H and Bai, Y},
title = {From RIPK1 to Necroptosis: Pathogenic Mechanisms in Neurodegenerative Diseases.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {194},
pmid = {40493155},
issn = {1573-6903},
support = {24JRRA346//Natural Science Foundation of Gansu Province/ ; CY2023-QN-B03//"Cuiying Science and Technology Program" of the Second Hospital of Lanzhou University/ ; (23)0207//Foundation for International Medical Exchanges/ ; (23)1263//China Health Promotion Foundation/ ; },
mesh = {Humans ; *Necroptosis/physiology/drug effects ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; Signal Transduction/physiology ; },
abstract = {Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis, a newly identified mode of regulated cell death, represents a significant pathogenic mechanism in multiple neurodegenerative disorders. Substantial experimental evidence indicates that RIPK1 regulates necroptotic cell death pathways in both neuronal and glial cell populations through activation of the canonical RIPK3-MLKL signaling cascade, thereby exacerbating neuroinflammatory responses and accelerating neurodegenerative progression. The pathological relevance of this molecular pathway has been extensively validated across multiple major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Pharmacological interventions targeting RIPK1 or its downstream effectors-particularly RIPK3 and MLKL-have demonstrated significant efficacy in mitigating disease-associated pathological manifestations. This highlights the RIPK1 signaling axis as a promising therapeutic target for neuroprotective strategies. Consequently, thorough investigation of RIPK1-mediated necroptosis in neurodegenerative settings holds considerable translational potential. Such inquiry deepens mechanistic understanding of disease pathogenesis while accelerating the advancement of innovative therapeutic approaches with direct clinical relevance.},
}

Humans
*Necroptosis/physiology/drug effects
*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
*Neurodegenerative Diseases/metabolism/pathology/drug therapy
Animals
Signal Transduction/physiology

@article {pmid40492096,
year = {2025},
author = {Tzeplaeff, L and Galhoz, A and Meijs, C and Caldi Gomes, L and Kovac, A and Menzel, A and Değirmenci, H and Alaamel, A and Can Kaya, H and Günalp Çelik, A and Dinçer, S and Korucuk, M and Berker Karaüzüm, S and Bayraktar, E and Çiftçi, V and Bilge, U and Koç, F and Demleitner, AF and Buchberger, A and von Heynitz, R and Gmeiner, V and Knellwolf, C and Mouzouri, M and Wuu, J and Başak, AN and Munch Andersen, P and Kohlmayer, F and Ashton, NJ and Kuban, W and Lenz, C and Rogers, ML and Zilka, N and Corcia, P and Lerner, Y and Weber, M and Turcanova Koprusakova, M and Uysal, H and Benatar, M and Menden, MP and Lingor, P},
title = {Identification of a presymptomatic and early disease signature for Amyotrophic Lateral Sclerosis (ALS): protocol of the premodiALS study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.27.25328387},
pmid = {40492096},
abstract = {The median time to diagnosis of amyotrophic lateral sclerosis (ALS) is approximately 12 months after the onset of first symptoms. This diagnostic delay is primarily due to the nonspecific nature of early symptoms and the clinical challenges in differentiating ALS from its mimics. Therefore, the discovery of reliable biomarkers for the early and accurate diagnosis of ALS represents a critical medical need. A total of 330 participants will be recruited across six international study sites. The cohort will include (1) pre-symptomatic gene mutation carriers, (2) symptomatic individuals up to 12 months after symptom onset with either ALS, ALS mimics, or a pure motor syndrome with yet unclear assignment, and (3) healthy controls. Participants will engage in a one-year longitudinal study, consisting of an initial evaluation at baseline visit and a follow-up visit 12 months later. Assessments will include an environmental and medical history questionnaire, neurological examinations, olfactory testing, cognitive/behavioral evaluations, and the collection of biological samples (serum, plasma, urine, tear fluid, and cerebrospinal fluid). Proteomic, metabolomic, and lipidomic analyses will be performed using mass spectrometry and targeted immunoassays, with all samples processed under standardized protocols. The resulting multimodal dataset will be systematically integrated in an effort to uncover a clinico-molecular signature characteristic of presymptomatic and early ALS. These findings may have relevance to early ALS diagnosis and future clinical practice.},
}

@article {pmid40492044,
year = {2025},
author = {Roshni, J and Mahema, S and Janakiraman, V and Ahmad, SF and Al-Mazroua, HA and Ahmed, SSSJ},
title = {Effect of bovine milk-derived peptide on SNAP-25 of the neurotransmitter system in treating the sialorrhoea in chronic neurological diseases.},
journal = {Food science and biotechnology},
volume = {34},
number = {11},
pages = {2601-2610},
pmid = {40492044},
issn = {2092-6456},
abstract = {Sialorrhea is a prominent symptom of chronic neurological disorders like amyotrophic lateral sclerosis, Parkinson's disease, motor neuron disease, cerebral palsy, and stroke. Synaptosome-Associated Protein-25 (SNAP-25) plays a key role in triggering involuntary saliva secretion. This study aimed to identify SNAP-25-targeting bovine milk-derived peptides to mitigate sialorrhea, using computational and quantum atomistic simulation approach. Among 8559 bovine milk-derived peptides, 8499 were non-toxic, 7749 non-allergenic, 911 with blood-brain barrier crossing potential, and 175 with cell-penetrating capabilities. Using HAPPENN program, 20 non-hemolytic peptides were screened, while PeptideRanker predicted two physiologically active peptides. Protein-peptide docking followed by de novo structural modeling showed that CMPTFQFFK has a stronger inhibitory affinity (- 7.45 kcal/mol) for SNAP-25 than botulinum toxin. Additionally, dynamic simulations, free energy and quantum chemical studies confirmed the stability of CMPTFQFFK's with SNAP-25. Our study recommends CMPTFQFFK as a potential inhibitor of SNAP-25 for sialorrhea treatment, with further in vitro testing needed to confirm efficacy.},
}

@article {pmid40492022,
year = {2025},
author = {Ennis, R and Husted, C},
title = {Case Report: Treating Atrial Fibrillation with the Neubie Direct Current Electrical Stimulation.},
journal = {Medical devices (Auckland, N.Z.)},
volume = {18},
number = {},
pages = {291-295},
pmid = {40492022},
issn = {1179-1470},
abstract = {INTRODUCTION: A novel Neuro-Bio-Electric-Stimulation device (Neubie, Neufit, Austin, Texas, USA) using Direct Current (DC) has been used to treat various neurological conditions (ALS, MS, peripheral neuropathy, chronic pain) and functional limitations such as limited range of motion. One method, called the Master Reset Protocol, is thought to stimulate the vagus nerve system, impacting heart rate, digestion and other vital systems.

PURPOSE: We used the Master Reset Protocol on a subject experiencing paroxysmal Atrial Fibrillation (AFib) to assess whether this treatment might be effective in reversing a cardiac arrhythmia.

SUBJECT AND METHODS: A single subject is reported in this Case Report. The subject is a 62-year-old healthy, athletic male, 6'2″ tall, 165 lbs. with a good diet and is not obese nor has other exacerbating underlying conditions related to heart disease. The subject experiences arrhythmia approximately 1-2 times per month lasting generally 3 or more days per the subject. The Master Reset Method was initiated within 12 hours of arrhythmia onset, and arrhythmia before and after treatment was confirmed through subject observation and confirmed with pulse readings. A total of ten treatments were conducted over 7 months.

RESULTS: Reversal of arrhythmia was confirmed during or within 24 hours of treatment with DC application for all 10 treatments (100%). Two of the more severe cases of AFib required two treatments on the same day with confirmed reversal of AFib.

CONCLUSION: Treatment with Direct Current suggests a good correlation with reversal of arrhythmia. Further studies are planned to determine if similar, regular, treatments can be effective in preventing arrhythmia.},
}

@article {pmid40491620,
year = {2025},
author = {Sue, S and Yamazaki, S and Sue, K and Kinoshita, T and Yoshida, K},
title = {Combined Effects of Lung Volume Recruitment Training and Mechanical Insufflation-Exsufflation in a Patient With Advanced Amyotrophic Lateral Sclerosis Receiving Long-Term Mechanical Ventilation: A Case Report.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e83823},
pmid = {40491620},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis (ALS) degenerates both upper and lower motor neurons. Most patients with ALS require respiratory support due to deterioration of their respiratory muscles. Mechanical insufflation-exsufflation (MI-E) is one option that can help patients with weak cough strength to clear the airway, and it may potentially increase survival time. Another option is lung volume recruitment training (LVRT), a technique commonly used to maintain lung and chest wall flexibility. However, it requires specific equipment, such as one-way valves, to be applied to patients with ALS who undergo invasive mechanical ventilation with tracheostomy. Only limited studies have indicated the effectiveness of LVRT for patients with ALS. Moreover, no study is currently available on the effect of combining LVRT with MI-E. As the disease progresses, treatment options become increasingly limited, making it crucial to explore new therapeutic approaches for patients at the advanced stage. Here, we examined the effects of a combination of LVRT and MI-E in a 74-year-old female patient with ALS who had survived under invasive mechanical ventilation for nine years. We measured tidal volume (TV) and dynamic lung compliance (Cdyn) as respiratory parameters three months before and after the initiation of the combined therapy. Following the intervention, TV improved from 750.15 L/min (standard deviation (SD) ± 34.60) to 859.14 L/min (SD ± 75.63), and Cdyn increased from 24.18 cmH2O (SD ± 2.84) to 26.54 cmH2O (SD ± 2.92). These results suggest that MI-E combined with LVRT may improve lung compliance even in patients with ALS receiving long-term invasive mechanical ventilation.},
}

@article {pmid40491248,
year = {2025},
author = {Bernsen, S and Fabian, R and Koc, Y and Schumann, P and Körtvélyessy, P and Castro-Gomez, S and Meyer, T and Weydt, P},
title = {Serum Cardiac Troponin T Levels as a Therapy Response Marker in Tofersen-Treated ALS.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28453},
pmid = {40491248},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: Cardiac troponin T (cTnT) levels are elevated in the majority of persons with amyotrophic lateral sclerosis (ALS) and increase over time. Neurofilament light chain (NfL) is an established therapy response biomarker in ALS as superoxide dismutase1 (SOD1)-ALS patients treated with the antisense oligonucleotide tofersen show a decrease in NfL. In this study, we assess cTnT levels in SOD1-ALS at baseline and during tofersen treatment.

METHODS: cTnT was analyzed at baseline and during tofersen treatment in 23 SOD1-ALS patients at two specialized ALS centers in Germany and compared to a control cohort of 74 ALS patients without SOD1 variants.

RESULTS: cTnT levels increased in the control ALS cohort over time (p < 0.0001) but not in the tofersen group (p = 0.36). Creatine kinase (CK) and CK-MB levels did not show significant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02-0.08) in the control ALS cohort and 0.01 points (IQR -0.01-0.03) in the tofersen group (p = 0.0013). A significantly lower fold change in cTnT levels was observed in the tofersen-treated cohort (median 1.2; IQR 0.77-1.59) relative to the control group (median 1.89; IQR 1.35-2.75) (p = 0.0003). Nine (39%) patients treated with tofersen experienced a reduction in cTnT levels.

DISCUSSION: In this study, we describe a response signal of cTnT to tofersen treatment, which supports the value of cTnT as an independent biomarker in ALS. These results contribute to the notion that cTnT may provide additional value as a progression and treatment response biomarker in ALS complementary to NfL and warrant further investigation.},
}

@article {pmid40490178,
year = {2025},
author = {Akkum, FI and Ozbas, CE and Damar, M and Uversky, VN and Fayetorbay, R and Kang, DE and Woo, JA and Coskuner-Weber, O},
title = {Impacts of pathogenic mutations on the structures of the CHCHD10 monomer: An AlphaFold3 study linked to the generation of conformational ensembles.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {144970},
doi = {10.1016/j.ijbiomac.2025.144970},
pmid = {40490178},
issn = {1879-0003},
abstract = {CHCHD10, a member of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family, plays a critical role in mitochondrial function. The link between pathological mutations and CHCHD10 is important and increasingly recognized, especially due to mitochondrial dysfunction and its association with neurodegenerative diseases. Several mutations in CHCHD10 have been directly linked to human diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), mitochondrial myopathies, and Spinal Muscular Atrophy-Jokela type (SMAJ). In this study, we investigate the structural properties of wild-type and mutant CHCHD10 proteins using AlphaFold3 linked to the generation of conformational ensembles. Structural changes may modulate interactions, flexibility, and aggregation tendencies, potentially influencing neurodegenerative disease pathogenesis linked to mitochondrial dysfunction. Notably, disease-associated mutations like R15S, P23L, and S59L alter secondary structure formations such as 310-helices and β-sheets. Despite, we find that the compactness of CHCHD10 is not significantly altered by genetic mutations since radius of gyration values range between 32.69 Å and 35.94 Å. All in all, we find that the compactness is not but the secondary and tertiary structure properties are affected by pathological mutations. We propose that evolution may have optimized CHCHD10 to maintain a suitable radius of gyration that provides sufficient flexibility through its intrinsically disordered region while ensuring efficient interaction with diverse molecules. Thus, alterations in secondary and tertiary structures through mutations might be a mechanism for fine-tuning the protein's functionality while preserving its optimal state. These characteristics might be related to the pathologies of neurodegenerative diseases linked to mitochondrial dysfunction.},
}

@article {pmid40489983,
year = {2025},
author = {The Lancet Neurology, },
title = {Honouring the amyotrophic lateral sclerosis research pledge.},
journal = {The Lancet. Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1474-4422(25)00166-8},
pmid = {40489983},
issn = {1474-4465},
}

@article {pmid40489798,
year = {2025},
author = {Huang, J and Zhao, L and Xiang, P and Zhang, F and Yang, Y and Chao, L and Liu, W and Li, H and Zhang, X},
title = {Aminated Lignin/Cellulose-Based Hydrogel with High Adhesion for Wearable Sensors.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.5c01389},
pmid = {40489798},
issn = {1520-5827},
abstract = {Hydrogels play a significant role in the flexibility, stretchability, and conductivity of wearable sensors. However, it is still a challenge to achieve multifunctional hydrogel sensors with excellent mechanical strength, outstanding self-adhesion, and high stimulus responsiveness for meeting various demands of practical applications. Here, this work presents a one-pot method to prepare a conductive hydrogel with multifunction by introducing aminated lignosulfonate (A-LS) and aminated cellulose nanocrystals (A-CNC) into the hydrogel matrix. Benefiting from the synergistic effect of dynamic reversible noncovalent bond network with the introduction of nanoparticles in the system, the resultant hydrogel showed excellent mechanical properties. In addition, the prepared hydrogels exhibited remarkable adhesion strength (pig skin: 24 kPa) with sustainable adhesion, which still maintained an adhesion strength above 18 kPa after 20 cycles of adhesion/separation. The resultant hydrogel sensor showed a wide operating range (0-200%), high sensitivity (GF = 0.71 at 0-100% strain; GF = 3.15 at 100-200% strain), and fast response time (320 ms). The high-value utilization of renewable forest biomass resources is conducive to the sustainable development of green chemistry.},
}

@article {pmid40489721,
year = {2025},
author = {Levison, L and Jepsen, P and Blicher, JU and Andersen, H},
title = {Hospital-Diagnosed Traumatic Head Injury and Associated Risk of Developing ALS: A Nationwide Population-Based Case-Control Study.},
journal = {Neurology},
volume = {105},
number = {1},
pages = {e213809},
doi = {10.1212/WNL.0000000000213809},
pmid = {40489721},
issn = {1526-632X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology/diagnosis ; Male ; Female ; Case-Control Studies ; Middle Aged ; Aged ; Risk Factors ; *Craniocerebral Trauma/epidemiology/complications/diagnosis ; Registries ; Adult ; Aged, 80 and over ; },
abstract = {BACKGROUND AND OBJECTIVES: Previous studies have suggested that traumatic head injury (THI) may be a risk factor of amyotrophic lateral sclerosis (ALS) development, yet the association remains unclear. We aimed to determine whether hospital-diagnosed THI is an important ALS risk factor, and we investigated the magnitude and duration of associated ALS risk.

METHODS: In this population-based case-control study, we used individual-level data linkage across nationwide health registers from 1980 to 2021 to identify patients with hospital-diagnosed ALS. Each patient was matched 1:10 with individuals from the general population by age, sex, and diagnostic index date. We used conditional logistic regression to examine the relative risk of ALS associated with having previous hospital-diagnosed THI. To avoid the effect of reverse causation, we investigated ALS risk within several time windows and repeated all analyses after restricting THI exposures to more than 3 years before the date of ALS diagnosis.

RESULTS: THI was observed in 4.7% of 5,943 ALS cases vs 3.7% of 59,426 controls, with a matched odds ratio (OR) of 1.3 (95% CI 1.1-1.4). However, the risk of ALS declined considerably with increasing time since head injury, with a high OR of 4.5 (95% CI 2.8-7.3) observed within the 6 months before ALS diagnosis. If head injury was suffered 6-12 months before ALS diagnosis, the OR was 2.4 (95% CI 1.4-4.0). Restricting the analysis to THI suffered more than 3 years before ALS diagnosis, we found no association with an OR of 1.1 (95% CI 1.0-1.3).

DISCUSSION: Although a strong association of ALS with THI experienced ≤1 year before ALS diagnosis was evident, our results suggest that this is due to reverse causation. When restricting the analysis to a period deemed relevant for causative events leading to ALS development, no association was observed. Consequently, we do not consider THI an important ALS risk factor. This study was limited by the inability to consider minor THIs not receiving hospital attendance. Future research should explore alternative models to unfold this possible ALS risk factor.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/etiology/diagnosis
Male
Female
Case-Control Studies
Middle Aged
Aged
Risk Factors
*Craniocerebral Trauma/epidemiology/complications/diagnosis
Registries
Adult
Aged, 80 and over

@article {pmid40489271,
year = {2025},
author = {Li, B and Han, Y and Zhang, S and Wang, H and Zhao, Z and Zhai, Y},
title = {High-precision Edge Detection Guided by Flow Fields.},
journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TIP.2025.3572763},
pmid = {40489271},
issn = {1941-0042},
abstract = {Edge detection is frequently employed to support downstream visual tasks. However, current edge detection methods still encounter two significant challenges: extracting complex textured targets and capturing valuable information from complex backgrounds. We propose FFED, a flow field-guided edge detection model. FFED integrates the three components of our design. FFED incorporates three designed components: the Feature Broadcast Module (FBM), the Antagonistic Bio-inspired Spatial Attention Module (ABSAM), a novel pixel difference convolution named ALS. The FBM serves as an implementation mode of the flow field, with its input pair selection strategy inspired by video processing.The FBM broadcasts high-level semantic features to high-resolution ones, preserving more meaningful texture details. Inspired by biological studies, we propose the ABSAM. ABSAM extracts valuable information from complex backgrounds by optimizing spatial modeling of data. The ALS exhibits enhanced capability in extracting gradient information and capturing subtle texture details that are easily overlooked. Experimental results demonstrate that FFED achieved competitive detection results on NYUD, BSDS500, and BIPED datasets, as well as good performance on industrial datasets. Additionally, the experiment verified the auxiliary effect of FFED on downstream visual tasks. The code is available at https://github.com/hanyuchen2022/Flow-field-guided-edge-detection-FFED-.},
}

@article {pmid40489211,
year = {2025},
author = {Gautam, P and Yadav, R and Vishwakarma, RK and Shekhar, S and Pathak, A and Singh, C},
title = {An Integrative Analysis of Metagenomic and Metabolomic Profiling Reveals Gut Microbiome Dysbiosis and Metabolic Alterations in ALS: Potential Biomarkers and Therapeutic Insights.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00254},
pmid = {40489211},
issn = {1948-7193},
abstract = {ALS is a severe neurodegenerative disorder characterized by motor neuron degeneration, gut dysbiosis, immune dysregulation, and metabolic disturbances. In this study, shotgun metagenomics and [1]H nuclear magnetic resonance (NMR)-based metabolomics were employed to investigate the altered gut microbiome and metabolite profiles in individuals with ALS, household controls (HCs), and nonhousehold controls (NHCs). The principal component analysis (PCA) explained 33% of the variance, and the partial least-squares discriminant analysis (PLS-DA) model demonstrate R[2] and Q[2] values of 0.97 and 0.84, respectively, indicating an adequate model fit. The relative bacterial abundance was 99.34% in the ALS group and 98.94% in the HC group. Among the ten identified genera, Bifidobacterium, Lactobacillus, and Enterococcus were more prevalent in ALS individuals, while Lactiplantibacillus and Klebsiella were more abundant in the HC group. We identified 70 metabolites, including short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), carbohydrates, and aromatic compounds, using NMR. Orthogonal partial least-squares discriminant analysis (O-PLS-DA) explained 15.8% of the variance, with a clear separation between the ALS and HC groups. Univariate receiver operating characteristic (ROC) analysis identified three fecal metabolites with AUC values above 0.70, including butyrate (0.798), propionate (0.727), and citrate (0.719). These metabolites may serve as potential biomarkers for ALS. The statistical model for metabolic pathway analysis revealed interconnected pathways, highlighting the complexity of metabolic dysregulation, as well as potential microbial and metabolic biomarkers in ALS. These results highlight the role of gut microbiome alterations in ALS and suggest potential avenues for therapeutic intervention.},
}

@article {pmid40488810,
year = {2025},
author = {Kulkarni, SR and Thokchom, B and Abbigeri, MB and Bhavi, SM and Singh, SR and Metri, N and Yarajarla, RB},
title = {The role of L-DOPA in neurological and neurodegenerative complications: a review.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {40488810},
issn = {1573-4919},
abstract = {L-DOPA remains a cornerstone treatment for Parkinson's disease and is increasingly recognized for its role in various neurological and neurodegenerative disorders. As a direct precursor to dopamine, L-DOPA is synthesized from L-tyrosine through the action of tyrosine hydroxylase and is subsequently converted into dopamine via aromatic L-amino acid decarboxylase. Its ability to cross the blood-brain barrier (BBB) makes it a crucial therapeutic agent for restoring dopaminergic neurotransmission, thereby influencing motor function, cognition, and neuroprotection. Beyond Parkinson's, L-DOPA's therapeutic potential extends to neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, multiple sclerosis, Lewy body dementia, and amyotrophic lateral sclerosis, where dopamine modulation plays a critical role. Furthermore, L-DOPA has demonstrated efficacy in neurological disorders including epilepsy, peripheral neuropathy, cerebrovascular diseases, and traumatic brain injury, suggesting broader neurobiological applications. However, long-term use is associated with challenges such as motor fluctuations, dyskinesias, and loss of therapeutic efficacy due to progressive neurodegeneration and alterations in dopaminergic pathways. Recent advancements in drug delivery systems, combination therapies, and nanotechnology, including plant-derived carbon dots, offer promising strategies to enhance L-DOPA's effectiveness while mitigating its limitations. This comprehensive review explores L-DOPA's synthesis, pharmacokinetics, mechanism of action, and its evolving role in neurological diseases, while highlighting ongoing challenges and future directions for optimizing its clinical application.},
}

@article {pmid40488711,
year = {2025},
author = {Tang, IW and Knekt, P and Rantakokko, P and Heliövaara, M and Rissanen, H and Ruokojärvi, P and Mukherjee, R and Weisskopf, MG},
title = {Pre-disease biomarkers of persistent organic pollutants (POPs) and amyotrophic lateral sclerosis (ALS) risk in Finland.},
journal = {Environmental health perspectives},
volume = {},
number = {},
pages = {},
doi = {10.1289/EHP16539},
pmid = {40488711},
issn = {1552-9924},
abstract = {BACKGROUND: Persistent organic pollutants (POPs) are toxic chemicals that bioaccumulate and were used in pesticides and industrial products/processes. POP-exposed occupations and environmental exposure to POPs have been associated with amyotrophic lateral sclerosis (ALS), but no study has evaluated the association with ALS when measuring POPs in samples collected before ALS onset.

OBJECTIVES: This study examined the relationship between pre-disease POP exposure and ALS risk.

METHODS: We conducted a nested case-control study pooling three Finnish cohorts (n=56,862). During a median follow-up of 27 years, 97 incident ALS cases were identified (mean age at ALS=68). Within each cohort, two controls per case were selected by individual matching for age, sex, municipality, and serum freeze-thaw cycles. Thirteen polychlorinated biphenyls (PCB) and nine organochlorine pesticides (OCP) were determined in serum samples collected at baseline and stored at -20C. We considered these POPs both in groups (similar congener, isomer, metabolite groups) and separately. Odds ratios and 95% confidence intervals were estimated using a conditional logistic model in a two-stage approach, further adjusting for smoking, occupation, marital status, BMI, and serum cholesterol level in primary models.

RESULTS: In the main model hexachlorobenzene (HCB) showed a positive association with ALS occurrence. In contrast, Σnon-dioxin-like (NDL) PCB and ΣDDT were significantly inversely associated with ALS incidence. Most other POP groups were non-significantly inversely associated with ALS risk. In co-pollutant models, the only notable changes were that Σdioxin-like PCB and ΣHCH showed large non-significant, elevated, ORs, suggesting some negative co-pollutant confounding. There were some suggestions of stronger findings when limiting to some subgroups.

DISCUSSION: We found little evidence that POPs were associated with ALS, but we identified a suggestive positive association with HCB and HCH. ΣNDL PCB and ΣDDT were inversely associated with ALS. This could suggest protective mechanisms or uncontrolled confounding by neuroprotective factors (e.g. fish oils). https://doi.org/10.1289/EHP16539.},
}

@article {pmid40488544,
year = {2025},
author = {Benzo-Iglesias, MJ and Rocamora-Pérez, P and Valverde-Martínez, MLÁ and García-Luengo, AV and Benzo-Iglesias, PM and López-Liria, R},
title = {Efficacy of respiratory muscle training in improving pulmonary function and survival in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Therapeutic advances in respiratory disease},
volume = {19},
number = {},
pages = {17534666251346095},
doi = {10.1177/17534666251346095},
pmid = {40488544},
issn = {1753-4666},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/therapy/diagnosis ; *Respiratory Muscles/physiopathology ; *Breathing Exercises/adverse effects/methods ; Randomized Controlled Trials as Topic ; Quality of Life ; Muscle Strength ; *Lung/physiopathology ; Treatment Outcome ; Recovery of Function ; Male ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, resulting in muscle weakness, loss of function, and ultimately death due to respiratory failure. Due to the lethal prognosis of ALS, respiratory muscle training has been proposed as a potentially beneficial intervention.

OBJECTIVES: To systematically review the efficacy of respiratory muscle training on lung function and respiratory muscle strength in ALS patients.

DESIGN: A systematic review and meta-analysis of randomized controlled trials.

DATA SOURCES AND METHODS: Articles published in PubMed, PEDro, Scopus, and Web of Science databases up to July 2024. The Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement guideline was followed. Included studies had (1) ALS patients, (2) respiratory muscle training, (3) physical exercise, usual care or no intervention were provided as a comparison group, (4) assessments of lung function, respiratory muscle strength, quality of life, survival, fatigue, and functional capacity outcome measures, and (5) a randomized controlled trial design. Methodological quality was analyzed using the PEDro scale, and risk of bias with the Cochrane Collaboration Risk of Bias Tool. Meta-analyses were performed with Review Manager software.

RESULTS: Five randomized controlled trials with 170 participants were included. The results showed that respiratory muscle training improved muscle strength, particularly maximum expiratory and inspiratory pressures. One study suggested inspiratory muscle training as a survival predictor in ALS patients. No significant effects were observed in forced vital capacity or quality of life. No adverse effects were reported.

CONCLUSION: Respiratory muscle training improves ventilatory function, particularly respiratory muscle strength, in people with ALS. While evidence is limited, it shows promise as an adjuvant therapy to enhance quality of life and survival. It has been registered in the PROSPERO (CRD42024568235).},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/mortality/therapy/diagnosis
*Respiratory Muscles/physiopathology
*Breathing Exercises/adverse effects/methods
Randomized Controlled Trials as Topic
Quality of Life
Muscle Strength
*Lung/physiopathology
Treatment Outcome
Recovery of Function
Male

@article {pmid40488385,
year = {2025},
author = {Hermann, A and Prudlo, J and Kasper, E and Synofzik, M and Peters, O and Priller, J and Dinter, E and Wiltfang, J and Zerr, I and Flöel, A and Bürger, K and Höglinger, GU and Levin, J and Düzel, E and Teipel, S and Beichert, L and Brosseron, F and Wagner, M and Frommann, I and Ramirez, A and Yakupov, R and Schmid, M and Lingor, P and Haass, C and , and Spottke, A and Günther, R and Weydt, P and Neumann, M and Schneider, A},
title = {"The DESCRIBE-ALS-FTD study: a prospective multicenter observational study of the ALS-FTD spectrum".},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2509617},
pmid = {40488385},
issn = {2167-9223},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit significant clinical, genetic and neuropathological abnormalities, and are regarded as belonging to a common disease spectrum, referred to as the ALS-FTD spectrum disorders. Our understanding of the underlying mechanisms of these diseases has advanced significantly, including molecular neuropathology, genetics and molecular pathophysiology. The heterogeneity of these diseases poses significant challenges to translational research and drug development, particularly in sporadic cases. Consequently, there is an urgent need to improve patient stratification for the successful execution of future clinical trials. Methods/Results: We here describe the study design of the DESCRIBE-ALS/FTD study which aims to address this research gap by undertaking a systematic sampling of patients from the ALS FTD spectrum, encompassing all possible disease variants. The main objective of the study is to systematically document detailed cross-sectional phenotyping and the temporal progression of motor and neuropsychological abnormalities that occur in both ALS and FTD. Additionally, it seeks to systematically correlate these abnormalities with genetics and potentially predictive biomarkers including longitudinal biomaterial sampling, brain imaging and brain banking. Furthermore, first-degree relatives of patients with disease-causing gene variants undergo the same assessments to also sample presymptomatic risk gene carriers. Conclusion: With this prospective registry study we aim to generate datasets which will help researchers identifying different disease traits in people with sporadic and genetic ALS and FTD and to develop biomarkers to identify preclinical and prodromal disease stages.},
}

@article {pmid40488178,
year = {2025},
author = {Benetton, C and Preuilh, A and Khamaysa, M and Chaumon, M and Lackmy-Vallée, A and Er, A and Pélégrini-Issac, M and Querin, G and Rouaux, C and Pradat, PF and Marchand-Pauvert, V},
title = {Encephalography cross-frequency coupling and brain alteration in amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {7},
number = {3},
pages = {fcaf192},
pmid = {40488178},
issn = {2632-1297},
abstract = {The diagnosis of amyotrophic lateral sclerosis requires identifying degeneration in both brain and bulbospinal motor neurons. However, detecting cortical dysfunction remains challenging, as peripheral symptoms often overshadow upper motor neuron signs. Although transcranial magnetic stimulation and MRI are valuable tools, transcranial magnetic stimulation is challenged as disease progresses but also at early stage in some patients, and brain MRI shows in most cohorts no significant change at the time of diagnosis. This emphasizes the need for neuromarkers facilitating detection of cortical dysfunction and longitudinal monitoring. EEG offers promising avenues. Accordingly, we recently identified altered theta-gamma phase-amplitude coupling in amyotrophic lateral sclerosis. The present study aimed to further explore phase-amplitude coupling in patients, focusing not only on theta and gamma bands but also on alpha and beta bands, and the link with handedness and brain structure. Resting-state EEG was recorded in 26 patients with amyotrophic lateral sclerosis and 26 age- and sex-matched controls, alongside anatomical and diffusion MRI. PAC was calculated between slow and gamma oscillations at five sensorimotor electrodes bilaterally. Grey and white matter integrity was evaluated through cortical thickness measurements and diffusion metrics along the corticospinal tract. Results revealed significantly decreased theta-gamma PAC in the dominant hemisphere of patients, without changes in band powers or other frequency couplings. MRI confirmed well-known handedness-related brain structural asymmetry in both groups, although it was less pronounced in patients. Specifically, diffusion metrics were altered in the most caudal segment (brainstem level) of the pyramidal tract within the dominant hemisphere in patients. These findings align with lateralized theta-gamma PAC alterations and the greater vulnerability of the dominant hemisphere to amyotrophic lateral sclerosis. No correlation was found between electrophysiological and diffusion metrics, likely because they are related to different mechanisms: PAC alteration being presumably linked to excitation/inhibition imbalance preceding upper motor neuron degeneration. Moreover, theta-gamma PAC was found to be particularly altered in patients with altered cognitive scores, consistent with previous findings in patients with mild cognitive impairment. Lastly, receiver operating characteristic analyses demonstrated that PAC outperformed diffusion MRI in diagnostic accuracy, underscoring its potential as a very sensitive marker of cortical dysfunction in amyotrophic lateral sclerosis. Although these results need validation in a larger cohort at different stages of the disease and across different forms (sporadic and familial), they confirm that PAC can detect cortical dysfunctions in amyotrophic lateral sclerosis.},
}

@article {pmid40487949,
year = {2025},
author = {Kumar, S},
title = {Nomogram-based strategy to predict relapse-free survival in patients with gastrointestinal stromal tumor using inflammatory indicators.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {5},
pages = {103127},
pmid = {40487949},
issn = {1948-5204},
abstract = {Zhao et al's investigation on the assessment of inflammatory markers prognostic value for relapse-free survival in patients with gastrointestinal stromal tumor (GIST) using a nomogram-based approach is a scientific approach. This study explored the potential of an inflammatory marker-based nomograph model, highlighting the relapse-free survival-associated risk factors prognostic potential in patients with GIST. The author assessed 124 samples from patients with GIST to find an association between inflammatory markers and tumor size in a retrospective study using multivariate regression analysis. Further, a nomogram model was developed to identify the independent risk factors for the prognosis. GIST clinical treatment can use preoperative monocyte/lymphocyte ratio and platelet/lymphocyte ratio for relapse-free survival prognosis as independent factors.},
}

@article {pmid40486953,
year = {2025},
author = {Lehrer, S and Rheinstein, PH},
title = {Insulin and Metformin are Associated With Reduced Risk of Amyotrophic Lateral Sclerosis.},
journal = {Chronic diseases and translational medicine},
volume = {11},
number = {2},
pages = {148-155},
pmid = {40486953},
issn = {2589-0514},
abstract = {BACKGROUND: Type 2 diabetes (T2D), but not type 1, protected against amyotrophic lateral sclerosis (ALS). In T2D serum insulin is normal or elevated in the early stages. Type 1 diabetes, characterized by a total lack of insulin, is associated with an increased risk of ALS. The antidiabetic metformin also protects against ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open channel via which toxic substances from astrocytes reach motor neurons to cause ALS.

METHODS: In the current study we analyzed FDA MedWatch data to determine whether insulin or metformin could reduce the risk of ALS. We performed in silico molecular docking studies and molecular dynamics simulation with Cx43 to determine if insulin or metformin dock within the Cx43 channel and can block it effectively, again reducing risk of ALS.

RESULTS: In MedWatch, Insulin use is associated with a significantly reduced risk of ALS (Proportional Reporting Ratio 0.401). Metformin use is associated with a significantly reduced risk of ALS (PRR 0.567). The Human insulin heterodimer docked within center of the Cx43 channel, effectively blocking it. Molecular dynamics simulation showed that the block is highly stable and may be responsible for the protective effect of T2D on ALS. Metformin docks within the Cx43 channel, but the relatively small size of the metformin molecule may not allow it to obstruct the passage of toxic substances from astrocytes to motor neurons.

CONCLUSION: MedWatch data indicate that both insulin and metformin reduce risk of ALS. The results of our in silico docking study and molecular dynamics simulation corroborate our previous findings with Cx31. Insulin docks within the open hemichannel of hexameric Cx43, potentially blocking it. Molecular dynamics simulation showed that the block is stable and may be responsible for the protective effect of T2D and insulin on ALS.},
}

@article {pmid40485888,
year = {2025},
author = {Liu, Y and Ren, Y and Song, P},
title = {Traditional Chinese medicine for intractable and rare diseases: Research progress and future strategies.},
journal = {Intractable & rare diseases research},
volume = {14},
number = {2},
pages = {109-121},
pmid = {40485888},
issn = {2186-3644},
abstract = {Rare diseases have become a global public health challenge due to their low prevalence, difficult diagnosis, and limited treatment options. Intractable diseases are more common but often involve complex mechanisms, treatment with limited efficacy, and high medical costs, placing a heavy burden on patients and healthcare systems. In recent years, traditional Chinese medicine (TCM) has demonstrated unique advantages in the treatment of intractable and rare diseases and has gradually become an important complementary treatment. The current work is a systematic review of the progress of clinical and experimental research on TCM in typical rare diseases such as amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), mitochondrial encephalomyopathy, aplastic anemia (AA), and Wilson's disease (WD). It focuses on the multi-target therapeutic mechanisms of key Chinese herbal compound formulas, including immune regulation, antioxidative stress, and neuroprotection. The core TCM theories of "syndrome differentiation", "different treatments for the same disease" and the "same treatment for different diseases" are also discussed in the context of personalized medicine. In recent years, China has continuously promoted the development of TCM through a series of national plans and supportive policies, such as the 14th Five-Year Plan for TCM development, funding for key special projects, expedited approval pathways, and expanded coverage by medical insurance. These efforts have provided strong support for the clinical translation of TCM and technological innovation in the field of intractable and rare diseases. Notwithstanding the encouraging advances, the field of Chinese medicine continues to grapple with numerous challenges. In the future, the enhancement of mechanistic studies and quality multicenter clinical trials needs to be promoted while further enhancing policy support and international collaboration to substantiate the scientific basis and clinical value of TCM in the prevention and treatment of intractable and rare diseases.},
}

@article {pmid40485533,
year = {2025},
author = {Alves, I and Gromicho, M and Pronto-Laborinho, AC and Lopes, D and Oliveira Santos, M and De Carvalho, M},
title = {Federated sport activity in amyotrophic lateral sclerosis: a case-control study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2025.2511124},
pmid = {40485533},
issn = {2167-9223},
abstract = {Amyotrophic lateral sclerosis (ALS) develops in a multistep process combining environmental variables and genes. Among the identified risk factors, the role of regular vigorous physical activity is still debatable. Objective: This case-control study investigated the relationship between ALS and different degrees of sports engagement, with federated status as a proxy for strenuous activity. Methods: 586 ALS patients and 558 controls were consecutively assessed by using a standard questionnaire. Due to low female participation in regular or intensive sports activity, the study focused on men (327 with ALS and 314 controls). Results: Overall, football (soccer) had the most practitioners (n = 137, 35.8%), accounting for 62.1% of ALS and 32.3% of control federated athletes. Male football players have a 3.07-fold increased ALS risk (95% CI: 1.82-5.19) compared to other men (p < 0.0001) and 3.43-fold increase (95% CI: 1.77-6.68) compared to those federated in other sports (p = 0.0003). After controlling for age and trauma, football players still had 2.91-fold (95% CI: 1.70-5.01) increased risk compared to non-federated and non-participants in contact sports intensively. No significant ALS risk difference existed for other sports practiced with identical intensity and contact levels. Clinical characteristics of ALS federated football players were similar to other ALS patients. Conclusion: Our results suggest ALS susceptibility is not linked to general physical activity, but specifically to competitive football, regardless of a history of head and neck trauma. Given football's popularity, even a small risk increase could impact many. Further research is required to understand the mechanisms linking football to ALS, and why this association is not observed in other sports.},
}

@article {pmid40485494,
year = {2025},
author = {Genge, A and Pattee, GL and Sobue, G and Aoki, M and Yoshino, H and Couratier, P and Lunetta, C and Petri, S and Selness, D and Todorovic, V and Sasson, N and Hirai, M and Takahashi, F and Salah, A and Apple, S and Wamil, A and Kalin, A and Jackson, CE},
title = {Safety Extension Study of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis for up to an Additional 96 Weeks of Treatment.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28451},
pmid = {40485494},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America Inc/ ; },
abstract = {INTRODUCTION/AIMS: Edaravone intravenous (IV) and oral suspension have been shown to have similar pharmacokinetics, safety, and slowing of functional decline in patients with amyotrophic lateral sclerosis (ALS). Study MT-1186-A01 indicated that edaravone oral suspension was well-tolerated over 48 weeks, with no new safety concerns identified relative to existing safety data of IV edaravone, including Study MCI186-19. The aim of this study was to assess the long-term safety and tolerability of edaravone oral suspension in patients with ALS.

METHODS: Study MT-1186-A03 (NCT04577404) was a phase 3, open-label, multi-center, extension study that evaluated the long-term safety of edaravone oral suspension over an additional 96 weeks in patients with ALS who have completed the initial 48 weeks of Study MT-1186-A01, for a total of up to 144 weeks of treatment. Patients received a 105-mg dose of edaravone administered in treatment cycles identical to the approved edaravone on/off dosing schedule. Patients had definite, probable, probable-laboratory-supported, or possible ALS.

RESULTS: In Study MT-1186-A03, edaravone oral suspension was well tolerated with no new safety concerns. The most common treatment-emergent adverse events (TEAEs) were fall, muscular weakness, dyspnea, constipation, and dysphagia. These TEAEs were consistent with the safety profile for edaravone from previous clinical trials.

DISCUSSION: These results help establish the long-term safety and tolerability profile of edaravone oral suspension.},
}

@article {pmid40484835,
year = {2025},
author = {Zhao, JR and Pang, XY and Bai, JM and Zhang, JH and Wang, HF and Li, M and Chen, ZH and Cheng, HM and Ling, L and Huang, XS},
title = {[Progression patterns of lower motor neuron involvement in the lower medulla oblongata and cervical spinal cord of amyotrophic lateral sclerosis patients].},
journal = {Zhonghua yi xue za zhi},
volume = {105},
number = {21},
pages = {1721-1727},
doi = {10.3760/cma.j.cn112137-20241229-02957},
pmid = {40484835},
issn = {0376-2491},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; *Medulla Oblongata/pathology ; Male ; Female ; *Cervical Cord/pathology ; Electromyography ; *Motor Neurons/pathology ; Middle Aged ; Disease Progression ; Adult ; Aged ; *Spinal Cord/pathology ; },
abstract = {Objective: To investigate the lower motor neuron (LMN) involvement patterns in the lower medulla oblongata and cervical spinal cord in amyotrophic lateral sclerosis (ALS) patients. Methods: The needle electromyography (EMG) data of 200 patients with non-thoracic onset sporadic ALS, hospitalized in the Neurology Department of the First Medical Center of the Chinese PLA General Hospital from September 2022 to December 2023, were retropectively analyzed. All participants met the EI Escorial-Revised diagnostic criteria. According to the onset site, the patients were divided into the lower medulla oblongata onset group(34 cases), the spinal cord onset group(166 cases) [including the lower cervical spinal cord onset group (92 cases) and the lumbosacral spinal cord onset group (74 cases)]. Electromyography (EMG) abnormalities in the muscles innervated by the lower medulla oblongata and cervical cord were counted, and the characteristics of LMN involvement were analyzed. The binomial distribution test was used to determine whether the progression of LMN involvement to the second central nervous system segment was random. Results: Among 200 ALS patients, there were 111 males (55.5%) and 89 females (44.5%), with an age onset of 28-86 (56±11) years. 20 (10.0%) cases with normal sternocleidomastoid (SCM)-EMG or trapezius (TRA)-EMG results, and 7 (3.5%) cases with normal SCM-EMG and TRA-EMG results were observed in patients with LMN involvement in both the lower medulla oblongata and lower cervical spinal cord. The abnormal rates of EMG at the onset of lower cervical spinal cord were tongue muscle (GEN)-EMG (88.2%, 30/34), TRA-EMG (70.6%, 24/34) and SCM-EMG (67.6%, 23/34), respectively. The abnormal rates of EMG at the onset of lower cervical spinal cord were TRA-EMG (72.8%, 67/92), SCM-EMG (38.0%, 35/92) and GEN-EMG (32.6%, 30/92), respectively. The binomial distribution test showed that the progression of LMN involvement to the second segment of the central nervous system was not random (all P<0.05). In low bulbar onset patients, the abnormal rate of LMN involvement was higher in the lower cervical spinal cord segment [100.0% (34/34)], and lower in the lumbosacral spinal cord segment[91.2% (31/34)]. In the lower cervical spinal cord onset group, the abnormal rate of LMN involvement was lower in the the low medulla obliterum[32.6% (30/92)] and high in the lumbosacral spinal cord [96.7% (89/92)].In the lumbosacral spinal cord onset group, the abnormal rate of LMN involvement was low in the low medulla oblata [27.0% (20/74)] and high in the lower cervical spinal cord [94.6% (70/74)]. Conclusions: The progression of LMN involvement in the lower medulla oblongata and cervical spinal cord is primarily continuous, while a discontinuous progression pattern was also observed. The lower medulla oblongata of ALS patients with spinal onset is relatively less involved in disease progression.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/pathology
*Medulla Oblongata/pathology
Male
Female
*Cervical Cord/pathology
Electromyography
*Motor Neurons/pathology
Middle Aged
Disease Progression
Adult
Aged
*Spinal Cord/pathology

@article {pmid40482989,
year = {2025},
author = {Qin, J and He, Y and Yu, W and Zhang, Z and Chen, X and Hu, Y and Jiang, H},
title = {Knockdown of OPTN modulates miRNA-125b-5p expression via NF-κB pathways in amyotrophic lateral sclerosis.},
journal = {Archives of biochemistry and biophysics},
volume = {},
number = {},
pages = {110499},
doi = {10.1016/j.abb.2025.110499},
pmid = {40482989},
issn = {1096-0384},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterized by severe dysfunction in upper and lower motor neurons. Previous studies have reported that the optineurin gene (OPTN) downregulation is one of the causative genetic factors for ALS, leading to the dysfunction of optineurin (OPTN), a multifunctional protein implicated in several cellular processes. Herein, we found that conditional knockout of the OPTN gene in mouse microglia leads to activation of microglia. In subsequent studies, we also found that OPTN knockdown in BV2 cells leads to the activation of BV2 cells and promotes the apoptosis of co-cultured NSC34 cells via exosomes derived from BV2 cells in vitro. In contrast, OPTN knockdown in NSC34 cells did not cause apoptosis of the NSC34 cells themselves. It was suggested that microglia activation is involved in ALS initiation and development, but the nature of microglial-neuronal interactions remained elusive, requiring further exploration. Exosomes have been proven to be essential mediators. Notably, increased miRNA-125b-5p expression was uncovered in BV2 cells with the OPTN gene silenced, their derived exosomes, as well as the cocultured NSC34 cells. Interestingly, we proved that increased miRNA-125b-5p enhanced the apoptosis of NSC34 cells. We further noted that the overexpression of miRNA-125b-5p in BV2 cells can be regulated by an NF-κB activator (LPS) or inhibitor (withaferin A). Altogether, this study showed that silencing the OPTN gene may overexpress miRNA-125b-5p levels via the classical NF-κB pathway in BV2 cells. Up-regulated miRNA-125b-5p might be transmitted from exosomes to NSC34 cells, resulting in NSC34 cells apoptosis. Microglial-neuronal interactions mediated by exosomes were the crucial mechanism of OPTN gene downregulation leading to ALS, and this conclusion had been verified in cell models.},
}

@article {pmid40482900,
year = {2025},
author = {La Cognata, V and Guarnaccia, M and Morello, G and Gentile, G and Cavallaro, S},
title = {Predicting amyotrophic lateral sclerosis in the pre-symptomatic phase: Insights from SOD1G93A mouse gene expression profiles.},
journal = {Experimental neurology},
volume = {392},
number = {},
pages = {115329},
doi = {10.1016/j.expneurol.2025.115329},
pmid = {40482900},
issn = {1090-2430},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fast-paced fatal disease that requires immediate intervention to slow down the course of pathology and improve patients' quality of life. However, in most cases, ALS is diagnosed too late. For this reason, an accurate diagnostic test is urgently needed to identify ALS patients early, enabling a timely introduction of novel therapeutics and effective monitoring of disease progression. To address this significant unmet medical need, we explored a transcriptome-based signature to predict ALS during the preclinical phase. Using publicly available gene expression profiles from central nervous system (lumbar isolated motor neurons and spinal cord homogenates) of transgenic SOD1G93A mice with different genetic background and their respective control littermates, covering pre-symptomatic to late stages of the disease, we identified 463 differentially expressed genes (DEGs), primarily involved in immune response and metabolic processes. Based on this ALS gene-associated signature, we tested three machine learning binary classifiers (Support Vector Machine, Neural Network and Linear Discriminant Analysis), which demonstrated highly significant predictive power in discriminating mutant SOD1G93A from controls mice, even at pre-symptomatic stages. This was evident in both the discovery cohort and in two additional peripheral cross-tissue validation datasets from preclinical SOD1G93A sciatic nerve and muscles. Our study provides the first proof of concept for early ALS detection using a machine learning-based transcriptomic classifier. This could lead to earlier diagnosis, potentially enabling effective monitoring of disease progression and earlier interventions.},
}

@article {pmid40482733,
year = {2025},
author = {Ting, CH and Tai, ST and Chang, HY and Huang, PY and Jeng, LF and Lai, HJ and Kuo, YC and Kao, CH and Wang, IF and Tsai, LK},
title = {Baicalein benefits amyotrophic lateral sclerosis via reduction of Intraneuronal misfolded protein.},
journal = {Biochimica et biophysica acta. General subjects},
volume = {},
number = {},
pages = {130831},
doi = {10.1016/j.bbagen.2025.130831},
pmid = {40482733},
issn = {1872-8006},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by muscle weakness and atrophy, with limited treatment options. The accumulation of misfolded proteins, such as misfolded superoxide dismutase 1 (mSOD1), contributes significantly to neuronal degeneration in ALS. Therapies targeting misfolded proteins represent a promising strategy. Baicalein, a flavonoid compound with neuroprotective properties, has shown efficacy in clearing misfolded proteins and improving behaviors in rodent models of Alzheimer's and Parkinson's diseases. However, its effects in ALS remain largely unexplored. This study demonstrated that baicalein treatment reduced total and misfolded SOD1 protein levels in both soluble and insoluble fractions of a motor neuron cell line overexpressing mutant SOD1. Baicalein also reduced intracellular SOD1 aggregates in cultured motor neurons transfected with SOD1/G93A, preserving neurite length. In an ALS mouse model expressing the SOD1/G93A transgene, baicalein treatment decreased mSOD1 aggregation, increased spinal motor neuron density, and reduced neuromuscular junction denervation. Furthermore, baicalein partially improved motor behaviors, as assessed by the rotarod test. These findings highlight baicalein's potential as a therapeutic agent for ALS, targeting intraneuronal misfolded proteins to ameliorate pathological changes and preserve motor function.},
}

@article {pmid40482730,
year = {2025},
author = {Mori, H and Sato, T and Tsuboguchi, S and Takahashi, M and Nakamura, Y and Hoshina, K and Kato, T and Fujii, M and Onodera, O and Ueno, M},
title = {TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106988},
doi = {10.1016/j.nbd.2025.106988},
pmid = {40482730},
issn = {1095-953X},
abstract = {TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43[C173/175S] and TDP-43[G298S] as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43[C173/175S] induced insoluble inclusions more robustly than TDP-43[G298S] did. In contrast, TDP-43[G298S] induced cell death more severely than TDP-43[C173/175S]. TDP-43[G298S] was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43[C173/175S]. Instead, TDP-43[C173/175S] was frequently trapped in the axon initial segments. Finally, TDP-43[G298S] was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43[C173/175S] to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD.},
}

@article {pmid40482593,
year = {2025},
author = {Tankisi, H and Jacobsen, AB and Fanella, G and Cengiz, B and Kılınç, H and Matamala, JM and Moreno-Roco, J and Abrahao, A and Zinman, L and Koltzenburg, M and Howells, J and Samusyte, G and Awiszus, F and Bostock, H},
title = {Short-interval intracortical inhibition and facilitation in amyotrophic lateral sclerosis related to disease phenotype.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {176},
number = {},
pages = {2110770},
doi = {10.1016/j.clinph.2025.2110770},
pmid = {40482593},
issn = {1872-8952},
abstract = {OBJECTIVE: To investigate the relationship between short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF) and amyotrophic lateral sclerosis (ALS) phenotype, using threshold-tracking transcranial magnetic stimulation (TMS).

METHODS: A new paired-pulse TMS protocol was applied to 49 patients with ALS and 49 age-matched healthy controls. Motor evoked potentials (MEPs) were recorded from first dorsal interosseus muscle, while paired pulses were delivered at interstimulus intervals (ISI) of 1.0, 2.5 or 3.0 ms, with stimuli related to the resting motor threshold for a 200 µV MEP. For each ISI, 6 SICI and 3 SICF pulse pairs with different conditioning stimuli were randomised and interleaved with test-alone stimuli.

RESULTS: ALS phenotypes were characterised as Pyramidal (n = 12, with prominent upper motor neuron signs), Classic (n = 20, with limb onset), or Bulbar (n = 17). Compared with healthy controls, Bulbar patients had significantly less inhibition at all ISIs, while SICI in Pyramidal patients was normal, and in Classic patients intermediate. The only SICF abnormalities independent of the changes in SICI were less facilitation in Pyramidal patients at ISIs 1 and 3 ms.

CONCLUSION: Changes in SICI and SICF depend on ALS phenotype.

SIGNIFICANCE: ALS phenotypes should be matched between treatment and placebo arms of clinical trials.},
}

@article {pmid40482451,
year = {2025},
author = {Attiq, A and Afzal, S and Raman, H and Ahmad, W},
title = {Neuroinflammation to neurodegeneration: Boulevard of broken nerves.},
journal = {International immunopharmacology},
volume = {161},
number = {},
pages = {115015},
doi = {10.1016/j.intimp.2025.115015},
pmid = {40482451},
issn = {1878-1705},
abstract = {Neuroinflammation is caused by various factors, such as the activation of glial cells, the excessive release of chemokines and cytokines, and the accumulation of blood cells in the brain parenchyma. The inflammatory processes occur in acute and chronic phases, with traumatic brain injuries triggering the release of neurotoxins from CNS-specific glial cells. Furthermore, activation of microglia, astrocytes, and mast cells worsens the situation by producing pro-inflammatory cytokines, chemokines and glia maturation factors. Chronic activation of astroglia and microglial cells promotes loss of neurons, memory, and impaired learning capacity, leading to neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. These implications have led to a rational search for inflammatory druggable targets. Based on various preclinical and clinical studies, NSAIDs (aspirin, ibuprofen, diclofenac, and mefenamic acid), SSRIs (fluoxetine and sertraline), antipsychotics (risperidone), corticosteroids (dexamethasone), antidiabetics (metformin and rosiglitazone), and statins (simvastatin and atorvastatin) have exhibited promising results. These drugs have anti-inflammatory and neuromodulation activities that enhance neuroplasticity and effectively manage neurodegenerative symptoms. In addition, non-pharmacological interventions such as art creation and physical exercise have been linked with improving neural development and stimulating the production of anti-inflammatory cytokines, which can attenuate disease progression and promote synaptic plasticity. Hence, it is imperative to understand the complex interplay between glial cells, inflammatory signalling and neural pathways. We reviewed the interconnected pathways between neuroinflammation and neurodegeneration. Moreover, recommendations for pharmacological and non-pharmacological interventions to address these issues are discussed herein.},
}

@article {pmid40482112,
year = {2024},
author = {LaForge, JR},
title = {A Poem About ALS.},
journal = {The American journal of nursing},
volume = {124},
number = {5},
pages = {10},
doi = {10.1097/01.NAJ.0001016304.08449.3a},
pmid = {40482112},
issn = {1538-7488},
}

@article {pmid40481583,
year = {2025},
author = {Johnson, B and Gibson, G and Baskerville, D and Castellano, G and de Courcy, J and Iqbal, H and Piercy, J and Williams, A and Pinedo-Villanueva, R and Rylands, A},
title = {Health-related quality of life and productivity burden for non-professional caregivers of adults with rare diseases: a real-world study.},
journal = {Orphanet journal of rare diseases},
volume = {20},
number = {1},
pages = {282},
pmid = {40481583},
issn = {1750-1172},
mesh = {Humans ; *Quality of Life ; *Caregivers/psychology ; Male ; Female ; Middle Aged ; *Rare Diseases ; Adult ; Efficiency ; Aged ; Surveys and Questionnaires ; Cost of Illness ; },
abstract = {BACKGROUND: Rare diseases present a substantial patient burden, but the impact on non-professional caregivers is poorly understood. We explored the health-related quality of life (HRQoL) and productivity burden on caregivers of adults with rare diseases.

METHODS: We analysed physician- and caregiver-reported real-world data from France, Germany, Italy, Spain, the United Kingdom, and the United States of America collected July 2017-March 2021 via Adelphi Disease Specific Programmes™ in amyotrophic lateral sclerosis (ALS), eosinophilic esophagitis (EoE), graft versus host disease (GvHD), Huntington's disease (HD), myasthenia gravis (MG), and progressive supranuclear palsy (PSP). Non-professional caregivers completed the EQ-5D-5L and Work Productivity and Activity Impairment questionnaire. Multivariate regression analysis modelled the relationship of care recipient/caregiver characteristics with caregiver HRQoL and productivity.

RESULTS: Data were provided by 365 caregivers; 114, 89, 75, 32, 29 and 26 in GvHD, PSP, ALS, MG, EoE and HD, respectively. Care recipients' mean (standard deviation [SD]) age was 58.7 (15.6) years, 59% were male and 23% had both professional and non-professional caregivers. Patients' mean (SD) EuroQol visual analogue scale (EQ VAS) score was 50.9 (23.3) and mean EQ-5D utility was 0.460 (0.350). Caregivers' mean age was 55.8 (13.8) years, 66% were female. Caregivers' EQ-5D-5L indicated their greatest problems in anxiety/depression. Overall, 45% of caregivers were employed, mostly part-time. In the past 7 days, mean (SD) caregiver absenteeism was 5.2% (13.1%), presenteeism was 28.0% (23.7%), and activity impairment was 43.1% (27.2%). Regressions identified multiple significant associations with caregivers' HRQoL and productivity. Caregivers' HRQoL (EQ-5D utility and EQ VAS) was associated with care recipients' EQ-5D utility and caregivers' age. Outcomes relating to caregivers' employment and productivity (hours spent caring, employment status, hours in employment, hours of employment missed, absenteeism, presenteeism, work impairment and activity impairment) were most frequently associated with care recipients' EQ-5D utility, caregivers' age and sex, caregiver living with the care recipient, the presence of a professional caregiver, and the care recipient having HD.

CONCLUSIONS: The substantial burden of providing non-professional caregiving to adults with rare diseases is associated with multiple factors. Interventions improving care recipient HRQoL could enhance caregiver HRQoL and productivity.},
}

Humans
*Quality of Life
*Caregivers/psychology
Male
Female
Middle Aged
*Rare Diseases
Adult
Efficiency
Aged
Surveys and Questionnaires
Cost of Illness

@article {pmid40480719,
year = {2025},
author = {Fuentes, CA and Montoya, D and Öztop, M and Rojas-Rioseco, M and Bravo, M and González, F and Castillo, RDP},
title = {Interval resonance analysis (InRA): A versatile tool for automated untargeted [1]H NMR fingerprinting - A case study in sugar beet field authentication.},
journal = {Analytica chimica acta},
volume = {1363},
number = {},
pages = {344175},
doi = {10.1016/j.aca.2025.344175},
pmid = {40480719},
issn = {1873-4324},
mesh = {*Beta vulgaris/chemistry ; *Proton Magnetic Resonance Spectroscopy/methods ; Least-Squares Analysis ; Software ; Automation ; Multivariate Analysis ; Algorithms ; },
abstract = {BACKGROUND: The extraction of relevant information from proton nuclear magnetic resonance ([1]H NMR) spectra through preprocessing and multivariate analysis requires integrating multiple software tools and extensive manual intervention, compromising efficiency and reproducibility when the technique is used. Consequently, the development of automated, versatile, and reliable methodologies has become imperative to streamline workflows, improve analytical performance, and broaden the applicability of multivariate methods for the analysis of diverse sample types and experimental conditions.

RESULTS: This work presents the development and application of Interval Resonance Analysis (InRA), an alternative software tool focused on [1]H NMR multivariate analysis. InRA includes a novel algorithm for resonance signal detection (intervals), specifically designed to operate with flexibility across diverse [1]H NMR spectra. All intervals are integrated using multivariate curve resolution with alternating least squares (MCR-ALS) and analyzed by exploratory analysis. The performance of InRA was tested by evaluating the [1]H NMR spectra of hydrophilic sugar beet root extracts cultivated in three different fields and their discrimination by partial least squares - discriminant analysis (PLS-DA). The workflow provided by InRA yielded consistent results regarding the distribution of samples according to their field, enabling the identification of subtle sources of variation and achieving classification accuracies ≥ 88.9 %.

SIGNIFICANCE: The proposed methodology represents an advancement in the multivariate analysis of [1]H NMR spectra for untargeted studies and enhances analytical efficiency by reducing manual intervention and reliance on analyst experience. InRA is versatile and can be applied to various sample types and analytical objectives, as it is not restricted by specific experimental conditions.},
}

*Beta vulgaris/chemistry
*Proton Magnetic Resonance Spectroscopy/methods
Least-Squares Analysis
Software
Automation
Multivariate Analysis
Algorithms

@article {pmid40480675,
year = {2025},
author = {Reitzle, L and Rohmann, JL and Kurth, T and Audebert, HJ and Piccininni, M},
title = {External validation of risk prediction models for post-stroke mortality in Berlin.},
journal = {BMJ open},
volume = {15},
number = {6},
pages = {e089320},
doi = {10.1136/bmjopen-2024-089320},
pmid = {40480675},
issn = {2044-6055},
mesh = {Humans ; Male ; Female ; Aged ; Berlin/epidemiology ; Registries ; Risk Assessment/methods ; *Stroke/mortality ; Hospital Mortality ; Aged, 80 and over ; Middle Aged ; Risk Factors ; },
abstract = {OBJECTIVES: Prediction models for post-stroke mortality can support medical decision-making. Although numerous models have been developed, external validation studies determining the models' transportability beyond the original settings are lacking. We aimed to assess the performance of two prediction models for post-stroke mortality in Berlin, Germany.

DESIGN: We used data from the Berlin-SPecific Acute Treatment in Ischaemic or hAemorrhagic stroke with Long-term follow-up (B-SPATIAL) registry.

SETTING: Multicentre stroke registry in Berlin, Germany.

PARTICIPANTS: Adult patients admitted within 6 hours after symptom onset and with a 10th revision of the International Classification of Diseases discharge diagnosis of ischaemic stroke, haemorrhagic stroke or transient ischaemic attack at one of 15 hospitals with stroke units between 1 January 2016 and 31 January 2021.

PRIMARY OUTCOME MEASURES: We evaluated calibration (calibration-in-the-large, intercept, slope and plot) and discrimination performance (c-statistic) of Bray et al's 30-day mortality and Smith et al's in-hospital mortality prediction models. Information on mortality was supplemented by Berlin city registration office records.

RESULTS: For the validation of Bray et al's model, we included 7879 patients (mean age 75; 55.0% men). We observed 763 (9.7%) deaths within 30 days of stroke compared with 680 (8.6%) predicted. The model's c-statistic was 0.865 (95% CI: 0.851 to 0.879). For Smith et al's model, we performed the validation among 1931 patients (mean age 75; 56.2% men), observing 105 (5.4%) in-hospital deaths compared with the 92 (4.8%) predicted. The c-statistic was 0.891 (95% CI: 0.864 to 0.918). The calibration plots of both models revealed an underestimation of the mortality risk for high-risk patients.

CONCLUSIONS: Among Berlin stroke patients, both models showed good calibration performance for low and medium-risk patients and high discrimination while underestimating risk among high-risk patients. The acceptable performance of Bray et al's model in Berlin illustrates how a small number of routinely collected variables can be sufficient for valid prediction of post-stroke mortality.},
}

Humans
Male
Female
Aged
Berlin/epidemiology
Registries
Risk Assessment/methods
*Stroke/mortality
Hospital Mortality
Aged, 80 and over
Middle Aged
Risk Factors

@article {pmid40480424,
year = {2025},
author = {Lin, CY and Wu, HC and Fu, RH and Weng, EF and Hsieh, WC and Su, TP and Wu, HE and Wang, SM},
title = {Sigma-1R-Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106992},
doi = {10.1016/j.nbd.2025.106992},
pmid = {40480424},
issn = {1095-953X},
abstract = {Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC34 cells and in an AAV-mediated poly-PR42 mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in C9orf72-linked ALS.},
}

@article {pmid40480222,
year = {2025},
author = {Oldani, EG and Reynolds Caicedo, KM and Spaeth Herda, ME and Sachs, AH and Chapman, EG and Kumar, S and Linseman, DA and Horowitz, S},
title = {The effect of G-quadruplexes on TDP43 condensation, distribution, and toxicity.},
journal = {Structure (London, England : 1993)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.str.2025.05.006},
pmid = {40480222},
issn = {1878-4186},
abstract = {Many proteins implicated in neurodegenerative diseases (e.g., trans-active response DNA binding protein 43 kDa [TDP43]) interact with nucleic acids, including RNA G-quadruplexes (G4s). We here investigate whether RNA G4s play a role in TDP43 condensation in biophysical and cellular models. We find that G4s modulate TDP43 aggregation in vitro and condensation in multiple cell types, including yeast, HEK293T, and motor-neuron-like NSC-34 cells. In yeast cells, treatment with G4s causes increased TDP43 accumulation in cells before cellular death. In HEK293T cells expressing TDP43, incubation with G4-binding small molecules causes an increase in G4 stability that also stabilizes TDP43 and reduces TDP43 condensation induced by proteasomal or oxidative stress. Finally, in NSC-34 cells overexpressing exogenous TDP43, we show that G4s co-localize with TDP43 condensates under stress conditions, and treatment with G4-binding small molecules decreases TDP43-mediated toxicity. Together, these findings suggest exploring treating protein misfolding diseases by targeting specific RNA structures such as G4s.},
}

@article {pmid40478288,
year = {2025},
author = {Wilbert, D and Voigt, M and Jaeger, M},
title = {A process analyzer assembly for real-time automated near-infrared, Raman, and proton nuclear magnetic resonance spectroscopic monitoring enhanced by heterocovariance spectroscopy and chemometry applied to a Schiff base formation.},
journal = {Analytical and bioanalytical chemistry},
volume = {},
number = {},
pages = {},
pmid = {40478288},
issn = {1618-2650},
abstract = {Process analytical technology (PAT) plays a key role in enhancing the efficiency and resulting quality of chemical processes. Hitherto, suitable methods enable real-time analysis and provide meaningful and robust data and models. Spectroscopic techniques, e.g., vibrational or absorption, offer in situ insight into reaction progress but may require advanced data analysis to interpret the complex spectra. In this study, inline and online monitoring by spectroscopic techniques was applied to a Schiff base formation as an illustrative example and enhanced by data analysis. Two-dimensional heterocorrelation spectroscopy was used to identify and select relevant spectral regions. The results allowed data reduction and data fusion for model building and process description. First, qualitative process representation was achieved through principal component analysis (PCA). Quantitative prediction models were then developed using multivariate curve resolution-alternating least squares (MCR-ALS) with evolving factor analysis (EFA), partial least squares (PLS), and supporting vector regression (SVR) analysis. The low- and mid-level data fusion based on the spectroscopic data and the multivariate models enabled the development of accurate predictive models, with the best prediction achieved by PLS models from low-level data fusion. The results demonstrate the strength of the combination of spectroscopy, multivariate data analysis, and-in the field of PAT rarely exploited-heterocovariance transformation and data fusion to obtain process understanding and reaction models. The methodology may provide further contributions to automatable process control in industrial applications.},
}

@article {pmid40476320,
year = {2025},
author = {Bombaci, A and De Marco, G and Casale, F and Salamone, P and Marchese, G and Fuda, G and Calvo, A and Chiò, A},
title = {Peripherin: A Novel Early Diagnostic and Prognostic Plasmatic Biomarker in Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {32},
number = {6},
pages = {e70241},
pmid = {40476320},
issn = {1468-1331},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Male ; Female ; Middle Aged ; *Peripherins/blood ; Biomarkers/blood ; Aged ; Prognosis ; Disease Progression ; Adult ; Early Diagnosis ; },
abstract = {BACKGROUND: Motor neuron diseases (MND) are heterogeneous and complex neurodegenerative disorders. Biomarkers could facilitate early diagnosis, prognosis determination, and patient stratification. Among the most studied biomarkers are neurofilaments, with peripherin (PRPH), a specific type predominantly expressed in the peripheral nervous system, gaining attention. To date, no studies have evaluated PRPH in human plasma.

METHODS: Sandwich-ELISA was used to quantify plasma peripherin from 120 MND (100 ALS, 4 PMA, 15 PLS), 73 MND-mimics, and 38 healthy-controls (HCs). Plasma was collected at diagnosis or some months earlier. 41 ALS were evaluated longitudinally. ALSFRSr, MRC, spirometry, genetic tests, disease progression rate (PR), blood examinations, and neuropsychological tests were performed. Statistical analyses included Kruskal-Wallis, Mann-Whitney, Cox regression, and Kaplan-Meier curves.

RESULTS: Plasma PRPH levels differed significantly among groups (p < 0.0001), showing higher values in MND participants than MND mimics and HCs. Moreover, PRPH levels were elevated in PLS compared with HSP patients (p = 0.0001). Differences persisted after adjusting for age and sex. ROC curve demonstrated that PRPH discriminated MND from MND mimics (AUC = 0.85). Elevated PRPH correlated positively with ALSFRSr and lower motor neuron index, whereas inversely with disease progression rate. Higher PRPH levels at the beginning of the disease were associated with longer survival.

DISCUSSION: Plasma PRPH is raised in MND, particularly ALS, from the earliest stages, distinguishing MND from mimics and correlating with clinical parameters and survival. This suggests PRPH may reflect an endogenous response of lower motor neuron to injury. Further multicenter studies are required to refine the diagnostic and prognostic utility of PRPH in MND.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood/diagnosis
Male
Female
Middle Aged
*Peripherins/blood
Biomarkers/blood
Aged
Prognosis
Disease Progression
Adult
Early Diagnosis

@article {pmid40476303,
year = {2025},
author = {Mustafa, MA and Bansal, P and Pallavi, MS and Panigrahi, R and Nathiya, D and Kumar, S and Al-Hasnaawei, S and Chauhan, AS and Singla, S},
title = {Exploring the Role of NLRP3 in Neurodegeneration: Cutting-Edge Therapeutic Strategies and Inhibitors.},
journal = {Developmental neurobiology},
volume = {85},
number = {3},
pages = {e22982},
doi = {10.1002/dneu.22982},
pmid = {40476303},
issn = {1932-846X},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Inflammasomes/metabolism ; *Neuroprotective Agents/pharmacology ; },
abstract = {Inflammasomes, particularly the NLRP3 inflammasome, play a pivotal role in mediating neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD). Recent findings indicate that the activation of the NLRP3 inflammasome in microglia and astrocytes triggers the release of pro-inflammatory cytokines, including IL-1β and IL-18, which contribute to chronic inflammation and neuronal damage. This process accelerates neurodegeneration and exacerbates disease progression. Misfolded protein aggregates, mitochondrial dysfunction, and oxidative stress are key factors in the pathological activation of the NLRP3 inflammasome in these diseases. Recent studies have highlighted that targeting the NLRP3 inflammasome, either through direct inhibitors like MCC950 or natural compounds such as oridonin and β-hydroxybutyrate, shows promise in mitigating neuroinflammation and protecting neuronal integrity. These inhibitors have demonstrated neuroprotective effects in animal models of AD, PD, and MS, presenting a new therapeutic approach for halting disease progression. However, the complexity of NLRP3 regulation requires further investigation to balance its inflammatory and protective roles. This review examines the recent advancements in NLRP3 inflammasome research and discusses potential strategies for modulating inflammasome activity to slow or prevent the progression of neurodegenerative diseases.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors
Humans
Animals
*Neurodegenerative Diseases/metabolism/drug therapy
*Inflammasomes/metabolism
*Neuroprotective Agents/pharmacology

@article {pmid40475252,
year = {2025},
author = {Seyedi Asl, FS and Malverdi, N and Ataei Kachouei, FS and Zarei, F and Ghiabi, S and Baziyar, P and Nabi-Afjadi, M},
title = {Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease.},
journal = {Frontiers in chemistry},
volume = {13},
number = {},
pages = {1569777},
pmid = {40475252},
issn = {2296-2646},
abstract = {Protein misfolding and aggregation in superoxide dismutase 1 (SOD1) are linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 mutations have a significant role in the pathophysiology and fast behavior of protopathic proteins in ALS illness. The E100K mutation may be useful in uncovering the pathogenic mechanism of SOD1 associated with ALS. According to several studies, giving small molecule inhibitors made from polyphenolic flavonoid compounds may be a viable treatment strategy for neurological conditions. Using molecular docking and MD simulations, we have identified a potential flavonoid drug that may successfully inhibit SOD1's amyloidogenic activity. Puerarin, Fisetin, and Peonidin provided intriguing pharmacological hints during the initial screening of flavonoids. The Fisetin-E100K complex had a larger residual energy contribution and substantial binding than other flavonoid compounds. The findings showed that, unlike other materials, Fisetin increased the structural stability, hydrophobicity, and flexibility of the mutant while reducing the amount of β-sheets. Furthermore, to distinguish aggregation in the mutant (unbound/bound) states, we displayed modifications in the free energy landscape (FEL). As a result, Fisetin was identified as having therapeutic potential against the E100K, which might make it a viable pharmacological option for the creation of inhibitors that lower the chance of ALS death.},
}

@article {pmid40474686,
year = {2025},
author = {Rothstein, J and Genge, A and De Silva, S and Zinman, L and Chum, M and Chio, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Sasson, N and Hirai, M and Takahashi, F and Salah, A and Wamil, A and Apple, S},
title = {Efficacy and Safety of Once Daily Dosing vs. Approved On/Off Dosing of Edaravone Oral Suspension Up to 48 Weeks in Patients With Amyotrophic Lateral Sclerosis (Study MT-1186-A02).},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28448},
pmid = {40474686},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America Inc./ ; },
abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is approved in the US for the treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed IV edaravone slows the rate of physical functional decline. This study evaluated whether investigational daily dosing displayed superior efficacy vs. approved on/off dosing of edaravone oral suspension, and assessed safety and tolerability, over 48 weeks in patients with ALS.

METHODS: Study MT-1186-A02 (NCT04569084) was a multicenter, phase 3b, double-blind, parallel group, superiority study that randomized patients to edaravone oral suspension (105-mg dose) administered Once Daily or the same edaravone oral suspension dose administered according to the approved On/Off regimen including placebo to mimic daily drug dosing. Patients had definite or probable ALS, baseline forced vital capacity ≥ 70%, and baseline disease duration ≤ 2 years. The primary endpoint was a combined assessment of function and survival (CAFS) at week 48, which included change in ALS Functional Rating Scale-Revised (ALSFRS-R) and time to death.

RESULTS: CAFS at week 48 indicated Once Daily dosing did not show a statistically significant difference vs. approved on/off dosing (p = 0.777). Both dosing regimens provided comparable change from baseline ALSFRS-R total score to week 48 (least squares mean difference: 0.27 [95% CI -1.43 to 1.97]). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.

DISCUSSION: Daily edaravone oral suspension did not show superiority and had equivalent safety and tolerability vs. the approved On/Off regimen, reinforcing the appropriateness of the approved dosing regimen.},
}

@article {pmid40473629,
year = {2025},
author = {Li, Y and Fang, J and Ding, Y and Zhang, X and Liu, Y and Qiu, W and Xu, H and Kang, Y and Chen, J and Gao, Y and Zhao, YG and Yang, P and Wang, B and Tian, W and Chen, Y and Bi, W and Zhang, P},
title = {β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5227},
pmid = {40473629},
issn = {2041-1723},
support = {20240484503//Beijing Nova Program/ ; 7244365//Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)/ ; 32471202//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32270856//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Humans ; *Stress Granules/metabolism ; RNA Recognition Motif Proteins/metabolism/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Carrier Proteins/metabolism/genetics ; Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism/genetics ; RNA Helicases/metabolism/genetics ; Animals ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mutation ; Mice ; HEK293 Cells ; Phase Separation ; DNA Helicases ; },
abstract = {β-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked neurodegenerative disorder caused by mutations in the WDR45 gene, yet its molecular mechanisms remain poorly understood. Here, we identify a role for WDR45 in stress granule (SG) disassembly, mediated through its phase separation with Caprin-1. We demonstrate that WDR45 forms gel-like condensates via its WD5 domain, which competitively displaces G3BP1 from Caprin-1 to promote SG disassembly. BPAN-associated WDR45 mutations impair condensate formation and Caprin-1 interaction, leading to delayed SG disassembly, which correlates with earlier disease onset. WDR45 depletion also exacerbates amyotrophic lateral sclerosis-associated pathological SGs, highlighting its broader relevance to neurodegenerative diseases. Using iPSC-derived midbrain neurons from a BPAN patient, we demonstrate delayed SG recovery, directly linking WDR45 dysfunction to neurodegeneration. These findings establish WDR45 as a critical regulator of SG dynamics, uncover a potential molecular basis of BPAN pathogenesis, and identify therapeutic targets for neurodegenerative diseases associated with SG dysregulation.},
}

Humans
*Stress Granules/metabolism
RNA Recognition Motif Proteins/metabolism/genetics
*Cell Cycle Proteins/metabolism/genetics
*Neurodegenerative Diseases/genetics/metabolism/pathology
*Carrier Proteins/metabolism/genetics
Neurons/metabolism
Induced Pluripotent Stem Cells/metabolism
Poly-ADP-Ribose Binding Proteins/metabolism/genetics
RNA Helicases/metabolism/genetics
Animals
Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
Mutation
Mice
HEK293 Cells
Phase Separation
DNA Helicases

@article {pmid40473505,
year = {2025},
author = {Song, W and Huang, Q and Jiang, Z},
title = {Clinical efficacy of athletic taping-assisted physiotherapy for plantar fasciitis: A systematic evaluation and meta-analysis.},
journal = {Foot and ankle surgery : official journal of the European Society of Foot and Ankle Surgeons},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.fas.2025.05.013},
pmid = {40473505},
issn = {1460-9584},
abstract = {BACKGROUND: Plantar fasciitis is a common sports injury with long-term chronic pain in the heel as the main symptom, and athletic taping has achieved certain therapeutic effects to improve it, but the clinical efficacy of the problem is still controversial, which was evaluated by Meta-analysis to evaluate the clinical efficacy of the athletic taping technique on patients with plantar fasciitis.

METHODS: The Cochrane Library, Embase, PubMed, Web of Science, CNKI, Wanfang, and Vip databases were searched by computer for randomized controlled trial on the clinical efficacy of exercise taping in patients with PF from the time of construction to 1 September 2024, and the PRISMA 2020 checklist was strictly followed. Quality was assessed using the cochrane 2.0 randomized controlled trials scale by two independent reviewers. Endings were meta-analysis using RevMan 5.4.1 analysis software to analyse the data.

RESULTS: Eleven randomized controlled trial with a total of 395 patients were included. On VAS scores, KT effectively reduced VAS pain scores (MD=-0.79,95 % CI -1.10,-0.48, P < 0.00001); on AOFAS scores, KT improved AOFAS function scores (MD=6.58, 95 % CI 5.03,8.13, P < 0.00001) and the results remained consistent across intervention durations; on plantar fascia thickness measurements, KT significantly reduced plantar fascia thickness (MD=-0.33, 95 % CI -0.56,-0.10, P = 0.005); on BBS scores, KT significantly improved BBS scores [MD= 4.75, 95 % CI (3.17, 6.32), P < 0.00001]; on FFI-FPS scores, KT effectively improved FFI-FPS scores [MD = -2.59, 95 % CI (-3.50, -1.69), P < 0.00001]; on FFI-FDS scores, there was a significant improvement on FFI-FDS scores; on FFI-ALS scores, KT had a significant improvement on the FFI-ALS score had a significant effect [MD= -11.03, 95 % CI (-14.79, -7.27), P < 0.00001]; and on VAS scores after follow-up, the pain relief effect was sustained (MD=-1.03, 95 % CI -1.21, -0.85, P < 0.00001).

CONCLUSION: Based on the available evidence, preliminary analyses suggest that KT combined with conventional rehabilitation may have some advantages in improving pain, ankle-hindfoot function, and plantar fascia thickness in patients with plantar fasciitis, and some of the efficacy is short-term sustained. However, due to the heterogeneity and sample size of the included studies, the above conclusions need to be further validated by more high-quality studies.},
}

@article {pmid40473122,
year = {2025},
author = {Mueller, KA and Suneby, EG and Ferola, MH and Moreno, AJ and Kidd, JD and Thompson, K and Vieira, FG and Valdez, G and Hatzipetros, T},
title = {Comprehensive characterization and validation of the Prp-hPFN1[G118V] mouse model: Guidelines for preclinical therapeutic testing for ALS.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106975},
doi = {10.1016/j.nbd.2025.106975},
pmid = {40473122},
issn = {1095-953X},
abstract = {The hPFN1[G118V] mouse model, overexpressing mutant human profilin1 linked to a rare form of ALS, was comprehensively characterized to assess its suitability for preclinical drug testing. Using a large cohort of nearly 250 transgenic and wild-type mice in a longitudinal study, we combined behavioral, electrophysiological, and neuropathological assessments to define the chronology of pathological events and assess inherent subject variability. The early stage of the disease in this model was characterized by elevated plasma neurofilament light chain levels, an effect that persisted and progressed throughout the course of the disease, followed by spinal cord neuroinflammation, suggesting that axonal pathology is the initiating event. The middle stage of the disease involved progressive neuromuscular decline, including reductions in compound muscle action potential (CMAP) and grip strength, accompanied by neuromuscular junction degeneration. The end-stage of the disease was characterized by the onset of visible changes such as weight loss, gait abnormalities and hindlimb paresis that quickly progressed to paralysis. At end-stage we also observed spinal motor neuron loss and TDP-43 pathology. The average humane endpoint was 213 days for females and 237 days for males. Our findings demonstrate that hPFN1[G118V] mice recapitulate key ALS features with moderate disease progression and a reproducible disease course, making them a valuable model for therapeutic testing. Recommendations are provided to optimize study design for preclinical testing, emphasizing survival duration as the primary endpoint, with CMAP and plasma NFL as key secondary readouts.},
}

@article {pmid40470490,
year = {2025},
author = {Ren, S and Che, X and Hu, S and Feng, X and Zhang, J and Shi, P},
title = {The effect of exercise intervention on amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1499407},
pmid = {40470490},
issn = {1664-2295},
abstract = {OBJECTIVE: Quantitative evaluation of the effect of exercise intervention in amyotrophic lateral sclerosis (ALS).

METHODS: The CNKI, WOS, PubMed, and Scopus databases were searched by computer, and randomized controlled trials (RCTs) of exercise intervention in ALS were screened out according to the inclusion and exclusion criteria of the PICOS principle. Stata 12.0 software was used for statistical analysis.

RESULTS: A total of 12 RCTs including 430 participants were included. Meta-analysis results show that exercise intervention can significantly improve the overall function, walking test (WT) distance and maximum expiratory pressure (MEP) of ALS patients (p < 0.05). However, exercise interventions did not show significant effects on fatigue, maximum inspiratory pressure (MIP), forced vital capacity (FVC), and peak expiratory flow (PEF) in ALS patients (p > 0.05). Subgroup analysis showed that resistance exercise is the most effective intervention for improving the function of ALS patients, while aerobic exercise is the most effective intervention for improving FVC in ALS patients.

CONCLUSION: Exercise intervention in ALS has a positive effect, but due to the small number of included studies and possible heterogeneity, risk of bias and sensitivity issues, further research is needed.},
}

@article {pmid40469844,
year = {2025},
author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L},
title = {Genetic analysis of ERBB4 gene in Chinese patients with amyotrophic lateral sclerosis: a single-center study and systematic review of published literature.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1584541},
pmid = {40469844},
issn = {1663-4365},
abstract = {BACKGROUND: Rare ERBB4 variants have been implicated in amyotrophic lateral sclerosis (ALS), but their prevalence and clinical significance remain poorly understood, particularly across different ethnic populations.

METHODS: We performed genetic screening of ERBB4 in 1627 Chinese ALS patients using whole-exome sequencing. A systematic review and meta-analysis of the published literature were conducted to evaluate the global frequency of ERBB4 variants and their clinical correlations.

RESULTS: We identified 14 missense variants and 6 splice region variants in 23 unrelated patients, with four variants classified as damaging (p.R782P, p.M799T, p.R847C, and p.S997R). The splice variant c.1490-3C > T, associated with a 50% reduction in ERBB4 mRNA expression, was maternally inherited by a male ALS patient, while its presence in his asymptomatic mother suggests the involvement of potential genetic modifiers. ERBB4 variant carriers demonstrated earlier disease onset compared to non-carriers (46.9 ± 10.3 vs. 52.6 ± 11.2 years; p = 0.015), though survival duration remained comparable. Meta-analysis revealed a pooled ERBB4 variant frequency of 0.83% (95% CI, 0.56-1.10%) in ALS patients globally, with notable ethnic differences (1.36% in Chinese, 0.66% in European, and 1.44% in American populations).

CONCLUSION: Our findings establish the prevalence of ERBB4 variants in ALS across different populations and suggest their potential role as disease modifiers, particularly affecting the age of onset. The ethnic variation in mutation frequency highlights the importance of population-specific genetic screening strategies in ALS.},
}

@article {pmid40468914,
year = {2025},
author = {Cao, Y and Yuan, B and Jiang, X and Xie, C and Wu, D and Zhang, Z},
title = {Quantification of Skeletal Muscle at the First Lumbar Level for Prognosis in Amyotrophic Lateral Sclerosis.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {16},
number = {3},
pages = {e13827},
doi = {10.1002/jcsm.13827},
pmid = {40468914},
issn = {2190-6009},
support = {81830040//National Natural Science Key Foundation of China/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/pathology/diagnostic imaging/diagnosis ; Female ; Male ; Middle Aged ; Prognosis ; *Muscle, Skeletal/diagnostic imaging/pathology ; Aged ; *Lumbar Vertebrae/diagnostic imaging ; Tomography, X-Ray Computed ; },
abstract = {BACKGROUND: Skeletal muscle parameters at the first lumbar vertebra (L1) level on computed tomography (CT) are common indicators for muscle mass. However, their relationship with the severity and prognosis of amyotrophic lateral sclerosis (ALS) patients remains unclear.

METHODS: This cohort study included ALS patients who underwent chest CT scans between January 2018 and January 2022 and healthy controls (HCs) matched for gender and age. Overall survival (OS) was determined from the date of chest CT to death, tracheal intubation or 1 January 2024. Using ImageJ software, skeletal muscle area and density (L1 SMA/SMD), skeletal muscle index (L1 SMI), paraspinal muscle area and density (L1 PMA/PMD) and subcutaneous fat area and density (L1 SFA/SFD) at L1 were quantified. The relationships between the quantified muscle parameters and both King's clinical stages and the Revised ALS Functional Rating Scale (ALSFRS-R) were analysed. The Cox proportional hazard model was used to evaluate the hazard ratio (HR) of skeletal muscle parameters as risk factors for outcome events, and to construct a nomogram.

RESULTS: Muscle parameters in ALS patients (n = 102; 36.27% female; mean age, 60.85 ± 10.58 years) were significantly lower compared with HCs (p < 0.001). L1 SMD (p = 0.047) and L1 PMD (p = 0.003) both differed significantly across the King's clinical stages. ALSFRS-R scores correlated with L1 SMA (r = 0.35, p < 0.001), L1 SMI (r = 0.34, p < 0.001), L1 PMA (r = 0.27, p = 0.007) and L1 PMD (r = 0.27, p = 0.007). Multivariate Cox regression analysis revealed that L1 SMA (HR = 0.96, 95% confidence interval [CI] = 0.94-0.98, p = 0.001), L1 SMD (HR = 0.92, 95% CI = 0.88-0.96, p < 0.001) and L1 PMA (HR = 1.06, 95% CI = 1.01-1.11, p = 0.022) significantly influenced ALS survival, with area under the curves (AUCs) of 0.687 and 0.851 for 1- and 3-year OS prediction. The consistency index (C-index) for the nomogram was 0.72 (95% CI = 0.641-0.793).

CONCLUSIONS: Skeletal muscle parameters at L1 level on CT are significantly associated with clinical severity and prognosis in ALS.

TRIAL REGISTRATION: Chinese Clinical Trial Registration Center: ChiCTR230078702.},
}

Humans
*Amyotrophic Lateral Sclerosis/mortality/pathology/diagnostic imaging/diagnosis
Female
Male
Middle Aged
Prognosis
*Muscle, Skeletal/diagnostic imaging/pathology
Aged
*Lumbar Vertebrae/diagnostic imaging
Tomography, X-Ray Computed

@article {pmid40468389,
year = {2025},
author = {Rummens, J and Da Cruz, S},
title = {RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {64},
pmid = {40468389},
issn = {1750-1326},
support = {G064721N//Fonds Wetenschappelijk Onderzoek/ ; 1S15218N//Fonds Wetenschappelijk Onderzoek/ ; 962700//Muscular Dystrophy Association/ ; SAO-FRA 20230035//Alzheimer's Research Foundation/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Frontotemporal Dementia/metabolism/pathology/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Animals ; DNA-Binding Proteins/metabolism ; RNA-Binding Protein FUS/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders with overlapping clinical, genetic and pathological features. A large body of evidence highlights the critical role of RNA-binding proteins (RBPs) - in particular TAR DNA-binding protein 43 (TDP-43) and Fused in sarcoma (FUS) - in the pathogenesis of these diseases. These RBPs normally regulate various key aspects of RNA metabolism in the nervous system (by assembling into transient biomolecular condensates), but undergo cytoplasmic mislocalization and pathological aggregation in ALS and FTD. Furthermore, emerging evidence suggests that RBP-containing aggregates may propagate through the nervous system in a prion-like manner, driving the progression of these neurodegenerative diseases. In this review, we summarize the genetic and neuropathological findings that establish RBP dysfunction as a central theme in ALS and FTD, and discuss the role of disease-associated RBPs in health and disease. Furthermore, we review emerging evidence regarding the prion-like properties of RBP pathology, and explore the downstream mechanisms that drive neurodegeneration. By unraveling the complex role of RBPs in ALS and FTD, we ultimately aim to provide insights into potential avenues for therapeutic intervention in these incurable disorders.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics
*Frontotemporal Dementia/metabolism/pathology/genetics
*RNA-Binding Proteins/metabolism/genetics
Animals
DNA-Binding Proteins/metabolism
RNA-Binding Protein FUS/metabolism

@article {pmid40466410,
year = {2025},
author = {Guillen-Sola, A and Bertran-Recasens, B and Martinez-Llorens, J and Balaña, A and Villatoro, M and Rubio, MA},
title = {[Use of tongue pressure to determine the indication for instrumental swallowing assessment in patients with spinal ALS].},
journal = {Rehabilitacion},
volume = {59},
number = {3},
pages = {100917},
doi = {10.1016/j.rh.2025.100917},
pmid = {40466410},
issn = {1578-3278},
abstract = {OBJECTIVE: Systematic swallowing assessment in amyotrophic lateral sclerosis (ALS) is essential, as approximately 85% of patients will develop dysphagia, and 8% of these cases may remain clinically silent. Although instrumental diagnostic tools exist, they are not always accessible. Recent studies suggest that lingual pressure measurements may be valuable for early detection of bulbar dysfunction. This study aims to establish lingual pressure cutoff points for early screening of such dysfunction.

DESIGN: Transversal study based on prospectively collected data from patients with spinal-onset ALS at the Motor Neuron Unit, Hospital del Mar (Barcelona).

MATERIALS AND METHODS: A total of 58 patients were included. Anterior (PA) and posterior (PP) lingual pressures were measured using the IOPI system and analyzed alongside the ALSFRS-R scale. Statistical analysis included descriptive statistics, Spearman correlation, and ROC curve analysis (SPSS v25).

RESULTS: A moderate correlation was found between lingual strength and ALSFRS-R scores (PA: r=.634, P<.001; PP: r=.539, P<.001). Identified cutoff values: PA: 39.5kPa (AUC=.766; 95%CI: .700-.831; P<.001), sensitivity 64.6%, specificity 76.4%. PP: 37.0kPa (AUC=.726; 95%CI: .653-.799; P<.001), sensitivity 55.1%, specificity 72.2%.

CONCLUSION: In spinal-onset ALS, a moderate correlation exists between global functionality and lingual pressures. Cutoff points of PA=39.5kPa and PP=37.0kPa are proposed for early screening of bulbar dysfunction.},
}

@article {pmid40465292,
year = {2025},
author = {Chourpiliadis, C and Lovik, A and Ingre, C and Press, R and Samuelsson, K and Valdimarsdottir, U and Fang, F},
title = {Use of Common Psychiatric Medications and Risk and Prognosis of Amyotrophic Lateral Sclerosis.},
journal = {JAMA network open},
volume = {8},
number = {6},
pages = {e2514437},
doi = {10.1001/jamanetworkopen.2025.14437},
pmid = {40465292},
issn = {2574-3805},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Female ; Case-Control Studies ; Middle Aged ; Sweden/epidemiology ; Aged ; Prognosis ; *Antidepressive Agents/adverse effects/therapeutic use ; *Hypnotics and Sedatives/adverse effects/therapeutic use ; *Mental Disorders/drug therapy ; *Anti-Anxiety Agents/adverse effects/therapeutic use ; Risk Factors ; Registries ; Disease Progression ; *Psychotropic Drugs/adverse effects/therapeutic use ; },
abstract = {IMPORTANCE: Although several studies have shown an increased risk of subsequent amyotrophic lateral sclerosis (ALS) diagnosis for individuals with a history of psychiatric disorders, the evidence of an association between use of common psychiatric medications and ALS is scarce and inconclusive.

OBJECTIVE: To examine whether there is an association of prescribed use of common psychiatric medications, namely anxiolytics, hypnotics and sedatives, and antidepressants, with the risk and disease progression of ALS.

This nationwide register-based case-control study was conducted in Sweden among all patients diagnosed with ALS from January 1, 2015, to July 1, 2023, according to the Swedish Motor Neuron Disease Quality Registry, who were age- and sex-matched with as many as 5 individuals with no ALS as well as their full siblings and spouses. Patients with ALS were followed up for a median (IQR) of 1.33 (0.64-2.37) years after diagnosis.

EXPOSURES: At least 2 prescriptions of the studied psychiatric medications before ALS diagnosis.

MAIN OUTCOMES AND MEASURES: The risk of ALS diagnosis associated with prediagnostic prescribed use of common psychiatric medications was estimated using conditional logistic regression models, comparing patients with ALS with population or relative control participants. Patients with ALS were followed up from diagnosis to assess the association of prediagnostic prescribed use of common psychiatric medications with disease progression. The association of mortality (or use of invasive ventilation) with the use of common psychiatric medications was estimated with a joint longitudinal-survival model accounting for the longitudinal changes of ALS Functional Rating Scale-Revised (ALSFRS-R) in the time-to-event analysis.

RESULTS: Among the 1057 case participants and 5281 population control participants, the mean (SD) age at diagnosis of the case participants (ie, date of selection of the control participants) was 67.5 (11.5) years, and 3363 (53.1%) were male. In the population comparison, prescribed use of common psychiatric medications across all studied time windows before ALS diagnosis was associated with a higher risk of ALS (eg, among individuals prescribed hypnotics and sedatives 0-1 year before diagnosis: odds ratio [OR], 6.10; 95% CI, 3.77-9.88; prescribed anxiolytics 1-5 years before diagnosis: OR, 1.60; 95% CI, 1.15-2.23; prescribed antidepressants >5 years before diagnosis: OR, 1.21; 95% CI, 1.02-1.44). Excluding the year before diagnosis from the analysis, prescribed use of anxiolytics (OR, 1.34; 95% CI, 1.12-1.60), hypnotics and sedatives (OR, 1.21; 95% CI, 1.02-1.43), or antidepressants (OR, 1.26; 95% CI, 1.06-1.49) was associated with an increased risk of ALS. Similar results were noted in the comparison with relative control participants, partially alleviating the concern on familial confounding, with the exception of hypnotics and sedatives. Shorter survival was demonstrated among patients with ALS who had prediagnostic use of anxiolytics (hazard ratio [HR], 1.52; 95% CI, 1.12-2.05) or antidepressants (HR, 1.72; 95% CI, 1.30-2.29), compared with patients with ALS without such experience.

CONCLUSIONS AND RELEVANCE: In this case-control study, prescribed use of anxiolytics, hypnotics and sedatives, or antidepressants was associated with a higher subsequent risk of ALS. Prediagnostic use of such medications was also associated with a poor prognosis after ALS diagnosis.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/diagnosis
Male
Female
Case-Control Studies
Middle Aged
Sweden/epidemiology
Aged
Prognosis
*Antidepressive Agents/adverse effects/therapeutic use
*Hypnotics and Sedatives/adverse effects/therapeutic use
*Mental Disorders/drug therapy
*Anti-Anxiety Agents/adverse effects/therapeutic use
Risk Factors
Registries
Disease Progression
*Psychotropic Drugs/adverse effects/therapeutic use

@article {pmid40464816,
year = {2025},
author = {Savran, Z and Baltaci, SB and Aladag, T and Mogulkoc, R and Baltaci, AK},
title = {Vitamin D and Neurodegenerative Diseases Such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and Amyotrophic Lateral Sclerosis (ALS): A Review of Current Literature.},
journal = {Current nutrition reports},
volume = {14},
number = {1},
pages = {77},
pmid = {40464816},
issn = {2161-3311},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Vitamin D/metabolism ; Multiple Sclerosis ; Alzheimer Disease ; Parkinson Disease ; Receptors, Calcitriol/metabolism ; Amyotrophic Lateral Sclerosis ; Oxidative Stress/drug effects ; Animals ; Cholecalciferol ; },
abstract = {PURPOSE OF REVIEW: This review explores the role of Vitamin D3 and its derivatives as inhibitors of pathological metabolic modifications in neurodegenerative diseases. The manuscript investigates how Vitamin D3 impacts neuronal calcium regulation, antioxidative pathways, immunomodulation, and neuroprotection during detoxification, beyond its known functions in intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization.

RECENT FINDINGS: Recent studies have highlighted the synthesis of the active metabolite 1,25(OH)2D3 (vitamin D) in glial cells via the hydroxylation process of CY-P24A1, an enzyme in the cytochrome P450 system in the brain. The effects of vitamin D occur through the vitamin D receptor (VDR), a nuclear steroid receptor, which has been identified in various brain regions, including the cerebellum, thalamus, hypothalamus, basal ganglia, hippocampus, olfactory system, temporal, and orbital regions. Neurodegeneration is primarily associated with oxidative stress, protein aggregation, neuroinflammation, mitochondrial dysfunction, apoptosis, and autophagy changes, all of which Vitamin D and VDR are believed to influence. Vitamin D and VDR are recognized as both environmental and genetic factors in the etiopathogenesis of neurodegenerative diseases such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and Amyotrophic Lateral Sclerosis (ALS). A deficiency in Vitamin D is postulated to have detrimental effects on the brain and other diseases throughout various stages of life. This review consolidates findings from clinical and experimental studies, as well as past publications, focusing on the implications of Vitamin D deficiency in these neurodegenerative conditions. Current articles published in PubMed were extensively considered for this review.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Vitamin D/metabolism
Multiple Sclerosis
Alzheimer Disease
Parkinson Disease
Receptors, Calcitriol/metabolism
Amyotrophic Lateral Sclerosis
Oxidative Stress/drug effects
Animals
Cholecalciferol

@article {pmid40464500,
year = {2025},
author = {Dedoni, S and Avdoshina, V and Olianas, MC and Onali, P},
title = {Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {5},
pages = {28245},
doi = {10.31083/FBL28245},
pmid = {40464500},
issn = {2768-6698},
mesh = {Humans ; *Lysophospholipids/metabolism ; *Nervous System Diseases/physiopathology/metabolism/drug therapy ; Animals ; Receptors, Lysophosphatidic Acid/metabolism ; Signal Transduction ; },
abstract = {Lysophosphatidic acid (LPA), a bioactive lipid molecule, has been identified as a critical regulator of several cellular processes in the central nervous system, with significant impacts on neuronal function, synaptic plasticity, and neuroinflammatory responses. While Alzheimer's disease, Multiple Sclerosis, and Parkinson's disease have garnered considerable attention due to their incidence and socioeconomic significance, many additional neurological illnesses remain unclear in terms of underlying pathophysiology and prospective treatment targets. This review synthesizes evidence linking LPA's function in neurological diseases such as traumatic brain injury, spinal cord injury, cerebellar ataxia, cerebral ischemia, seizures, Huntington's disease, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, autism, migraine, and human immunodeficiency virus (HIV)-associated complications Despite recent advances, the specific mechanisms underlying LPA's actions in various neurological disorders remain unknown, and further research is needed to understand the distinct roles of LPA across multiple disease conditions, as well as to investigate the therapeutic potential of targeting LPA receptors in these pathologies. The purpose of this review is to highlight the multiple functions of LPA in the aforementioned neurological diseases, which frequently share the same poor prognosis due to a scarcity of truly effective therapies, while also evaluating the role of LPA, its receptors, and signaling as promising actors for the development of alternative therapeutic strategies to those proposed today.},
}

Humans
*Lysophospholipids/metabolism
*Nervous System Diseases/physiopathology/metabolism/drug therapy
Animals
Receptors, Lysophosphatidic Acid/metabolism
Signal Transduction

@article {pmid40464332,
year = {2025},
author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Islam, A},
title = {The Role of Kinases in Neurodegenerative Diseases: From Pathogenesis to Treatment.},
journal = {The European journal of neuroscience},
volume = {61},
number = {11},
pages = {e70156},
doi = {10.1111/ejn.70156},
pmid = {40464332},
issn = {1460-9568},
mesh = {Humans ; *Neurodegenerative Diseases/enzymology/drug therapy/metabolism ; Animals ; *Protein Kinases/metabolism ; Protein Kinase Inhibitors/therapeutic use ; },
abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid-β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α-synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood-brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/enzymology/drug therapy/metabolism
Animals
*Protein Kinases/metabolism
Protein Kinase Inhibitors/therapeutic use

@article {pmid40463912,
year = {2025},
author = {Liu, T and Sun, W and Guo, S and Yuan, Z and Zhu, M and Lu, J and Chen, T and Qu, Y and Feng, C and Yang, T},
title = {Role of mitochondrial quality control in neurodegenerative disease progression.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1588645},
pmid = {40463912},
issn = {1662-5102},
abstract = {Neurodegenerative diseases are a diverse group of neurological disorders, in which abnormal mitochondrial function is closely associated with their development and progression. This has generated significant research interest in the field. The proper functioning of mitochondria relies on the dynamic regulation of the mitochondrial quality control system. Key processes such as mitochondrial biogenesis, mitophagy, and mitochondrial dynamics (division/fusion) are essential for maintaining this balance. These processes collectively govern mitochondrial function and homeostasis. Therefore, the mitochondrial quality control system plays a critical role in the onset and progression of neurodegenerative diseases. This article provides a concise overview of the molecular mechanisms involved in mitochondrial biogenesis, mitophagy, and mitochondrial dynamics, explores their interactions, and summarizes current research progress in understanding the mitochondrial quality control system in the context of neurodegenerative diseases.},
}

@article {pmid40463522,
year = {2025},
author = {Cohen, Y and Sinai, I and Magen, I and Danino, MY and Wuu, J and Malaspina, A and Benatar, M and Hornstein, E},
title = {IsomiR Utility in ALS Prognostication.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.12.25325848},
pmid = {40463522},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are microRNA isoforms that arise from alternative processing or editing events during miRNA biogenesis. While isomiRs may carry distinct biological and clinical relevance, their potential as cell-free biomarkers in neurodegeneration remains largely unexplored. Intriguingly, loss of TAR DNA-binding protein 43 (TDP-43) nuclear function is a hallmark of disease and is known to impair isomiR expression. Here, we investigated the prognostic utility of plasma isomiRs in ALS, using next-generation sequencing. We profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified higher levels of one isomiR, let-7g-5p.t, to be associated with longer survival. This finding was independently validated in an international ALS cohort of 200 patients and was in two orthogonal approaches. let-7g-5p.t prognostic utility was comparable to that of neurofilament light chain (NfL) or miR-181. These results establish isomiRs as a novel class of blood-based biomarkers in ALS with potential to refine prognostication in clinical trials for neurodegenerative diseases.},
}

@article {pmid40462869,
year = {2025},
author = {Acan, D and Cakar, BB and Karahan, E},
title = {Low anterior chamber volume as a risk factor in non-arteritic anterior ischemic optic neuropathy.},
journal = {Frontiers in ophthalmology},
volume = {5},
number = {},
pages = {1554279},
pmid = {40462869},
issn = {2674-0826},
abstract = {PURPOSE: This study aimed to compare the anterior chamber depth (ACD), anterior chamber volume (ACV), and iridocorneal angle (ICA) of the eyes of patients with non-arteritic anterior ischemic optic neuropathy (NAION) and normal eyes.

METHODS: In this cross-sectional study, 28 patients with NAION who were admitted to our institution were examined. Central corneal thickness (CCT), ACV, ACD, and ICA of all eyes were measured using corneal topography (Sirius, CSO, Italy). Axial lengths (ALs) were measured using an IOL-Master 500 (Carl Zeiss, Meditec). The eyes of these patients were compared with the eyes of 29 healthy individuals of similar age and gender.

RESULTS: The mean ALs of the eyes with NAION and those in the control group were not statistically different, measuring 22.95 ± 0.68 mm and 23.13 ± 0.80mm, respectively (p=0.651). While the average ACV was 137.93 ± 41.01 mm[3] in the control group, it was significantly lower at 117.86 ± 22.23 mm[3] in the patients with NAION (p=0.038). The mean ACD, ICA, and CCT values in the control and study groups were not statistically different, with 2.82 ± 0.57 mm and 2.64 ± 0.31 mm, 41.62 ± 6.99° and 40.14 ± 7.04°, and 542.48 ± 19.39µm and 544.68 ± 31.26 µm, respectively (p1 = 0.236, p2 = 0.693, and p3 = 0.959). No statistical differences were found between the eyes with NAION and their fellow eyes in terms of AL, CCT, ACD, ACV, and ICA (p>0.05).

CONCLUSION: Differences in anterior segment morphology were observed in eyes with NAION compared to healthy eyes. Decreased ACV may be a risk factor for NAION.},
}

@article {pmid40462740,
year = {2025},
author = {DeCastro, J and Mehta-Doshi, A and Liu, C and Ray, A and Aran, K},
title = {Red Blood Cell-Derived Exosomes as Mediators of Age-Related Neurodegeneration.},
journal = {Rejuvenation research},
volume = {},
number = {},
pages = {},
doi = {10.1089/rej.2025.0013},
pmid = {40462740},
issn = {1557-8577},
abstract = {Age-associated neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are marked by progressive degeneration of the nervous system. Current diagnostic approaches, such as neuroimaging and cerebrospinal fluid biomarkers, are invasive, costly, and lack early diagnostic reliability. Recent studies highlight the potential of extracellular vesicles, particularly exosomes, derived from erythrocytes or red blood cells (RBCs), as emerging indicators of aging and age-associated diseases. Exosomes carry noncoding RNA, lipid, and protein molecules, and modulate cellular pathways at distant sites, providing neuroprotective and anti-inflammatory effects. In this study, we isolated RBC-derived exosomes of young and old mice. MicroRNA sequencing analysis revealed differential expression of several miRNA species between young and old mice. We report an upregulation of miR-125a-5p and a downregulation of miR-302a-5p in old mice that are potentially linked to neurodegenerative pathways. This study underscores the potential of RBC-derived exosomes as noninvasive biomarkers for NDDs.},
}

@article {pmid40462656,
year = {2025},
author = {Gong, Z and Cao, R and Zhu, H},
title = {Exploring the Causal Association Between 91 Circulating Inflammatory Proteins and Neurodegenerative Diseases: A Bidirectional Two-Sample Mendelian Randomization and Bioinformatics Analysis.},
journal = {Brain and behavior},
volume = {15},
number = {6},
pages = {e70586},
doi = {10.1002/brb3.70586},
pmid = {40462656},
issn = {2162-3279},
support = {2025JJ70054//Natural Science Foundation of Hunan Province/ ; },
mesh = {Humans ; Mendelian Randomization Analysis/methods ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/blood ; Computational Biology ; CD40 Antigens/genetics ; Polymorphism, Single Nucleotide ; Amyotrophic Lateral Sclerosis/genetics ; Quantitative Trait Loci ; Parkinson Disease/genetics ; Multiple Sclerosis/genetics ; Alzheimer Disease/genetics ; Inflammation/genetics ; },
abstract = {BACKGROUND: Circulating inflammatory proteins play a significant role in the pathogenesis of neurodegenerative diseases (NDDs). However, the precise causal relationship and the underlying mechanisms of their interaction remain elusive.

METHODS: Genome-wide association study (GWAS) data for 91 circulating inflammatory proteins were obtained from the GWAS Catalog. Additionally, GWAS data for Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and ischemic stroke (IS) were acquired from the IEU Open GWAS Project. Four Mendelian randomization (MR) methods were employed to analyze causal effects, accompanied by sensitivity and pleiotropy analyses. Expression quantitative trait loci (eQTL) analyses for CD40 and MS-associated SNPs were performed. Transcriptomic data from the peripheral blood of MS patients were used to identify differentially expressed genes (DEGs) in relapsing-remitting MS (RRMS). RRMS patients were divided into two subgroups (C1 and C2) based on CD40 expression levels for comparative analysis. A single gene set enrichment analysis (GSEA) was conducted to investigate potential molecular mechanisms through which CD40 influences MS.

RESULTS: MR analyses indicated that CD40 ligand receptor (CD40) is associated with a reduced risk of MS (OR, 0.78; 95% CI, 0.72-0.84; PFDR = 8.75E-07). No statistically significant bidirectional causal relationships were found between other inflammatory proteins and PD, AD, ALS, or IS, and the findings were robust. Functional enrichment analysis revealed that these eQTLs primarily relate to transcriptional regulation, herpes simplex virus 1 (HSV-1) infection, and bile and fatty acid metabolism. In MS peripheral blood microarray data, CD40 is significantly downregulated in RRMS. Intergroup comparisons revealed elevated levels of resting memory CD4[+] T cells, activated NK cells, and neutrophils in C1, alongside increased autophagy, apoptosis, multiple immune responses, and upregulation of transforming growth factor-β (TGF-β) signaling pathways. Conversely, C2 exhibited higher levels of Tregs, resting NK cells, and activated dendritic cells, as well as upregulation in processes such as cholesterol homeostasis, glucose metabolism, and CD4/CD8 downregulation. Single-GSEA results suggest that CD40 promotes nucleotide metabolism, mitochondrial calcium ion transport, unfolded protein response (UPR), and adaptive immune regulation, while inhibiting androgen response and TGF-β signaling pathways, thereby influencing the progression of RRMS.

CONCLUSION: CD40 may exert neuroprotective effects in MS patients via diverse cellular and molecular pathways, potentially representing a novel target for MS intervention.},
}

Humans
Mendelian Randomization Analysis/methods
Genome-Wide Association Study
*Neurodegenerative Diseases/genetics/blood
Computational Biology
CD40 Antigens/genetics
Polymorphism, Single Nucleotide
Amyotrophic Lateral Sclerosis/genetics
Quantitative Trait Loci
Parkinson Disease/genetics
Multiple Sclerosis/genetics
Alzheimer Disease/genetics
Inflammation/genetics

@article {pmid40462477,
year = {2025},
author = {Shaka, Z and Mojtabavi, H and Taebi, M and Mahmoodi-Bakhtiari, B and Sarraf, P},
title = {Examining cognitive decline over time in Iranian ALS patients: Adapting successive versions B and C of the Edinburgh cognitive and behavioral screen to Persian.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2025.2509615},
pmid = {40462477},
issn = {2167-9223},
abstract = {OBJECTIVE: To adapt successive versions B and C of the Edinburgh Cognitive and Behavioral Screen (ECAS) into Persian and evaluate cognitive and behavioral changes over time in Iranian ALS patients.

METHODS: This study included 38 ALS patients in the ECAS-B group and 29 in the ECAS-C group, diagnosed between May 2021 and February 2023 at the Iranian Center of Neurological Research, Imam Khomeini Hospital, Tehran, Iran. Additionally, 59 age- and education-matched healthy controls were enrolled (30 for ECAS-B and 29 for ECAS-C). The Montreal Cognitive Assessment (MoCA) was used to validate the ECAS versions.

RESULTS: The Persian versions of ECAS-B and ECAS-C demonstrated strong internal consistency (Cronbach's alpha: 0.88 for ECAS-B and 0.89 for ECAS-C) and a positive correlation with MoCA and ALS-FRS-r scores. The area under the ROC curve was 0.851 for ECAS-B and 0.861 for ECAS-C. ECAS-C scores were significantly lower than ECAS-B scores, suggesting a faster cognitive decline over time. Optimal cutoff values of 72 for ECAS-B and 78 for ECAS-C were identified for detecting cognitive impairment. Cognitive impairment was observed in 10 patients (26.31%) in the ECAS-B group and 15 patients (51.72%) in the ECAS-C group.

CONCLUSIONS: The Persian versions of ECAS-B and ECAS-C demonstrate good validity and reliability for detecting cognitive impairment and tracking cognitive decline in ALS patients.},
}

@article {pmid40462117,
year = {2025},
author = {Akif, A and Nguyen, TTM and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J},
title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {55},
pmid = {40462117},
issn = {2045-8118},
support = {R21NS133895-01//National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS105787//National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism/drug effects ; Mice ; *Dementia, Vascular/drug therapy/metabolism ; *Signal Transduction/drug effects ; *Sulfonylurea Compounds/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Carotid Stenosis/complications ; Brain/drug effects/metabolism ; },
abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.

METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.

RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.

CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.

CLINICAL TRIAL NUMBER: Not applicable.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism/drug effects
Mice
*Dementia, Vascular/drug therapy/metabolism
*Signal Transduction/drug effects
*Sulfonylurea Compounds/pharmacology
*Cognitive Dysfunction/drug therapy/metabolism
Male
Disease Models, Animal
Mice, Inbred C57BL
Carotid Stenosis/complications
Brain/drug effects/metabolism

@article {pmid40461666,
year = {2025},
author = {Orologio, I and Russo, A and Trojsi, F and Todisco, V and Cirillo, M and Tessitore, A and Silvestro, M},
title = {A case of rapidly progressive juvenile amyotrophic lateral sclerosis associated with a pathogenetic heterozygous de novo variant in the FUS gene.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40461666},
issn = {1590-3478},
}

@article {pmid40460399,
year = {2025},
author = {Pommée, T and Bouvier, L and Barnett-Tapia, C and Maffei, MF and Gutz, SE and Tilton-Bolowsky, VE and Martino, R and Berry, JD and Abrahao, A and Zinman, L and Green, JR and Yunusova, Y},
title = {Construct Validity of the Amyotrophic Lateral Sclerosis Bulbar Dysfunction Index-Remote.},
journal = {American journal of speech-language pathology},
volume = {},
number = {},
pages = {1-23},
doi = {10.1044/2025_AJSLP-24-00489},
pmid = {40460399},
issn = {1558-9110},
abstract = {PURPOSE: The Amyotrophic Lateral Sclerosis Bulbar Dysfunction Index-Remote (ALSBDI-R) is a clinician-administered tool designed to assess bulbar dysfunction remotely in patients with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate the construct validity of the ALSBDI-R by examining its correlation with established clinical measures and its ability to discriminate among different bulbar disease severities.

METHOD: A total of 92 patients with ALS were recruited from two multidisciplinary clinics. Participants were assessed using the ALSBDI-R, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), the Center for Neurologic Study Bulbar Function Scale (CNS-BFS), the Sentence Intelligibility Test, and the Eating Assessment Tool (EAT-10). Construct validity was established through Spearman correlations and comparison of ALSBDI-R scores across bulbar severity groups (asymptomatic, mild, moderate, severe).

RESULTS: Strong correlations were found between ALSBDI-R total scores and bulbar-specific measures such as ALSFRS-R bulbar subscore (r = -.85), CNS-BFS (r = .85), and EAT-10 (r = .77). The ALSBDI-R effectively discriminated between severity groups, supporting its construct validity. Severity bins were created based on median ALSBDI-R total scores for each group.

CONCLUSIONS: The ALSBDI-R is a valid tool for remotely assessing bulbar dysfunction in patients with ALS. Despite several limitations, its ability to capture varying degrees of severity makes it valuable for clinical use and research, offering a standardized approach to monitor disease progression remotely.},
}

@article {pmid40460337,
year = {2025},
author = {van Unnik, JWJ and Ing, L and Oliveira Santos, M and McDermott, CJ and de Carvalho, M and van Eijk, RPA},
title = {Remote Monitoring of Amyotrophic Lateral Sclerosis Using Digital Health Technologies: Shifting Toward Digitalized Care and Research?.},
journal = {Neurology},
volume = {105},
number = {1},
pages = {e213738},
doi = {10.1212/WNL.0000000000213738},
pmid = {40460337},
issn = {1526-632X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; *Telemedicine ; Wearable Electronic Devices ; Videoconferencing ; Digital Technology ; *Biomedical Technology ; Monitoring, Physiologic/methods ; Digital Health ; },
abstract = {Current care and research pathways for amyotrophic lateral sclerosis (ALS) primarily rely on regularly scheduled visits to specialized centers. These visits provide intermittent clinical information to health care professionals and require patients to travel to the clinic. Digital health technologies enable continuous data collection directly from the patient's home, bringing new opportunities for personalized, timely care and a refined assessment of disease severity in clinical trials. In this review, we summarize the state of the art in digital health technologies for remote monitoring of patients with ALS, ranging from televisits through videoconferencing to sensor-based wearable devices. We explore how these technologies can benefit clinical care and advance treatment development. Despite significant progress, real-world adoption of these technologies remains limited. An overview is provided of the key barriers hindering their widespread implementation and the opportunities to advance the field. Significantly, there is an urgent need for harmonization across stakeholders through consensus guidelines and consortia. These efforts are essential to accelerate progress and harness the full potential of digital health technologies to better meet the needs of patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/diagnosis
*Telemedicine
Wearable Electronic Devices
Videoconferencing
Digital Technology
*Biomedical Technology
Monitoring, Physiologic/methods
Digital Health

@article {pmid40459673,
year = {2025},
author = {Dengri, C and Mayberry, W and Koriesh, A and Nouh, A},
title = {Neurology of Androgens and Androgenic Supplements.},
journal = {Current neurology and neuroscience reports},
volume = {25},
number = {1},
pages = {39},
pmid = {40459673},
issn = {1534-6293},
mesh = {Humans ; *Androgens/metabolism/therapeutic use ; *Nervous System Diseases/drug therapy/metabolism ; *Dietary Supplements ; Receptors, Androgen/metabolism ; Animals ; Testosterone/therapeutic use ; },
abstract = {PURPOSE OF REVIEW: This article explores the intricate relationship between androgens, androgen receptors, and the central nervous system. We examine the role of physiologically derived androgens and androgenic supplements in neurodevelopment and neuroplasticity and delve into the involvement of androgen pathways in the pathogenesis of various neurological disorders.

RECENT FINDINGS: This review highlights the increasing recognition of testosterone and androgen signaling in various neurological conditions, with evidence of both protective and harmful effects depending on dosage and context. Although limited to experimental use, testosterone replacement therapy (TRT) may serve potential benefits in the management of multiple sclerosis, epilepsy, headache, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and Parkinson disease. On the other hand, androgen-blocking treatments may help alter disease progression in spinal and bulbar muscular atrophy. Testosterone supplementation can have potential adverse events when used at a supratherapeutic level, and prenatal testosterone exposure is believed to contribute to the pathogenesis of neurodevelopmental disease. Additionally, androgen-blocking agents could increase the risk of neurodegenerative conditions, such as Parkinson disease and Alzheimer disease. Despite the above findings, there is no established indication of TRT or androgen-blocking medication in neurological disorders. The body of evidence highlighting the involvement of androgens and androgen receptors (ARs) in pathogenesis of neurological diseases is growing. This includes ongoing research exploring the potential therapeutic targets involving the androgen signaling pathway for management of neurological disorders. Future placebo-controlled clinical trials are essential to determine the efficacy and safety of TRT or androgen-blocking therapies in managing neurological disease.},
}

Humans
*Androgens/metabolism/therapeutic use
*Nervous System Diseases/drug therapy/metabolism
*Dietary Supplements
Receptors, Androgen/metabolism
Animals
Testosterone/therapeutic use

@article {pmid40459635,
year = {2025},
author = {Abraham, I and Martin, P and Vaghela, S and Klein, T and Chow, E and Rush, M and Morlock, R and Huang, H},
title = {Budget impact analysis of revumenib for the treatment of relapsed or refractory acute leukemias with a KMT2A translocation in the United States.},
journal = {Journal of managed care & specialty pharmacy},
volume = {},
number = {},
pages = {1-14},
doi = {10.18553/jmcp.2025.25027},
pmid = {40459635},
issn = {2376-1032},
abstract = {BACKGROUND: Acute leukemias (ALs), including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), are heterogeneous diseases characterized by different phenotypic, genetic, and molecular alterations that can guide treatment decisions. ALs harboring lysine methyltransferase 2A gene translocation (KMT2t), previously known as mixed-lineage leukemia, are associated with high rates of relapsed or refractory (R/R) disease. Revumenib, a first-in-class oral menin inhibitor, has shown improved clinical outcomes in patients with R/R KMT2At ALs.

OBJECTIVE: To estimate, using a budget impact model (BIM), the financial impact of introducing revumenib for the treatment of adult patients with R/R KMT2At ALs on the formulary of a hypothetical US 1-million-member commercial health plan.

METHODS: The BIM compared scenarios with or without revumenib and the resulting impact on commercial US third-party payers over a 3-year time horizon. Although no other therapies specifically targeted for R/R KMT2At ALs were approved during BIM development, 11 additional pharmacotherapies for R/R ALs (5 for AML and 6 for ALL, not including revumenib) were included as treatment options in the model. Clinical data included adverse event (AE) rates, duration of treatment, time to subsequent treatment, and survival outcomes. Cost inputs (USD 2024) included in the model comprised drug acquisition and administration, grade 3 or greater AEs, treatment-related supportive care and monitoring, subsequent treatment, and end-of-life costs. The differential cost per member per month (PMPM) was estimated. One-way sensitivity analyses varying the costs of drug acquisition and toxicity by ±20% and scenario analyses varying uptake of revumenib and epidemiology inputs, as well as excluding costs related to supportive care and posttreatment discontinuation, were performed.

RESULTS: An estimated 1.7 adult patients (AML, 1.1; ALL, 0.6) were treatment eligible annually. Estimated 3-year total plan costs without and with revumenib were $2,146,564 and $2,126,919, respectively, for savings of -$19,646. Including revumenib was estimated to yield a differential PMPM cost of -$0.0005 over 3 years. The total number of grade 3 or greater AEs was lower over 3 years (10.82 vs 10.99, respectively) in the plan with revumenib vs without. Sensitivity and scenario analyses validated the robustness of the model.

CONCLUSIONS: The BIM demonstrated that including revumenib in a formulary for adult patients with R/R KMT2At ALs was approximately cost neutral, offering patients access to a targeted treatment with potential for improved clinical outcomes.},
}

@article {pmid40458045,
year = {2025},
author = {Weng, R and Li, X and Yue, H and Xu, Y and Wei, Z and Xu, S and Li, B and Zhang, Z},
title = {A missense mutation in close proximity of ALS-linked PFN1 mutations causes only early-onset Paget's disease of bone.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1210/clinem/dgaf314},
pmid = {40458045},
issn = {1945-7197},
abstract = {CONTEXT: Paget's disease of bone (PDB) is a metabolic disorder characterized by abnormal osteoclast activation. Recently, mutations in the PFN1 gene, which encodes Profilin 1, an actin-binding protein controlling actin dynamics and cell movement, have been linked to early-onset PDB. Interestingly, mutations in PFN1 (C71G, T109M, M114T, E117G, G118V, etc.) are associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons.

OBJECTIVE: To provide insights into the underlying molecular mechanism of early-onset PDB.

METHODS: We observed the clinical responses to denosumab in early-onset PDB patients. Additionally, a mouse model carrying the c.335T>C mutation in the Pfn1 gene was generated.

RESULTS: We reported a second Chinese family affected by early-onset PDB with malignant giant cell tumor (GCTs), in which we indentified the same heterozygous missense mutation (c.335T>C/p. L112P) in PFN1 that we have reported previously in another family. Despite its proximity to ALS-linked PFN1 mutations, the PFN1 L112P mutation did not induce ALS in affected individuals. These early-onset PDB patients exhibited a significantly poorer response to denosumab compared to typical PDB patients. The heterozygous mice displayed PDB-like phenotypes, including skeletal deformities and focal osteoclastic lesions with giant osteoclasts, and did not show ALS-like phenotypes. We further show that mutation of Pfn1 leads to enhanced actin ring-like structures at the bone surfaces without affecting NF-κB activation in osteoclast cultures.

CONCLUSION: The observation of recurrent mutations highlights the causative role of PFN1 (L112P) in early-onset PDB/GCT within the Chinese population and provides insights into the physio-pathological functions of Profilin 1.},
}

@article {pmid40457777,
year = {2025},
author = {Martin, EM and Cichon, C and Choudhury, R and Day, SR and Fatemi, Y and Luther, VP and Stillwell, T and Sung, A},
title = {Society for Healthcare Epidemiology of America (SHEA) infectious diseases fellow infection prevention and control and healthcare epidemiology curriculum.},
journal = {Infection control and hospital epidemiology},
volume = {},
number = {},
pages = {1-10},
doi = {10.1017/ice.2025.85},
pmid = {40457777},
issn = {1559-6834},
abstract = {With the rapid expansion of the Infection Prevention Control/Healthcare Epidemiology (IPC/HE) fields over recent decades, the pivotal roles of IPC/HE in hospital regulation, quality improvement, patient safety, and healthcare finances have become increasingly apparent. Consequently, the demand for effective IPC/HE leaders has surged.[1,2] Training in IPC/HE is essential for all infectious diseases (ID) fellows (both adult and pediatric), including those planning a career in hospital epidemiology as well as those planning to focus on general ID, transplant, HIV, etc. ID fellows, however, have historically felt ill-prepared in IPC/HE. Joiner et al's survey highlighted this gap, revealing that only half of respondents felt adequately trained in infection control, despite half of them participating in infection control in their practice.[3] IPC/HE fellow education is not currently standardized, and most IPC/HE training is led by individual mentors and healthcare facilities.},
}

@article {pmid40457619,
year = {2025},
author = {Alaydin, HC and Kocak, OK and Arslan, I and Kılınc, H and Boran, HE and Tankisi, H and Cengiz, B},
title = {Assessing MScanFit MUNE in Amyotrophic Lateral Sclerosis: Influence of Nerve Conduction Distance and Temporal Dispersion.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28446},
pmid = {40457619},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: MScanFit is a promising method for motor unit number estimation (MUNE) based on compound muscle action potential (CMAP) scanning. Considering that CMAP morphology may be altered by temporal dispersion associated with nerve conduction distance, it is important to evaluate the potential impact of these changes on MScanFit measurements. Therefore, we aimed to investigate the effect of nerve conduction distance on MScanFit MUNE in patients with amyotrophic lateral sclerosis (ALS).

METHODS: MScanFit MUNE was recorded from the abductor digiti minimi (ADM) muscle by stimulating the ulnar nerve at the wrist and elbow in twenty-three ALS patients. Consistency of MScanFit MUNE and size parameters, CMAP amplitude, and CMAP duration were evaluated using intraclass correlation coefficients (ICC).

RESULTS: Significant differences were noted in CMAP amplitudes (6.35 ± 2.5 mV vs. 5.7 ± 2.4 mV; p = 0.003) and CMAP durations (5.8 ± 0.7 ms vs. 6.2 ± 0.8 ms; p < 0.001), reflecting temporal dispersion effects. MUNE values showed high consistency between wrist and elbow stimulations (61 ± 32.4 vs. 61.1 ± 30.7; p = 0.99), with an ICC of 0.86. Similar repeatability was also observed for MScanFit size parameters.

DISCUSSION: The reliability of MScanFit MUNE in determining motor unit values in ALS patients remains consistent regardless of the stimulation distance. Our findings highlight the effectiveness of MScanFit MUNE in evaluating motor unit loss of ALS patients and demonstrate its resilience to temporal dispersion effects. Proximal stimulation serves as a viable alternative, enhancing the utility of MScanFit in clinical settings.},
}

@article {pmid40457327,
year = {2025},
author = {Gilchrist, L and Mutz, J and Hysi, P and Legido-Quigley, C and Kõks, S and Lewis, CM and Proitsi, P},
title = {Evaluating metabolome-wide causal effects on risk for psychiatric and neurodegenerative disorders.},
journal = {BMC medicine},
volume = {23},
number = {1},
pages = {326},
pmid = {40457327},
issn = {1741-7015},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Mendelian Randomization Analysis ; *Metabolome ; *Mental Disorders/genetics/metabolism ; Bayes Theorem ; Risk Factors ; },
abstract = {BACKGROUND: Evidence indicates phenotypic and biological overlap between psychiatric and neurodegenerative disorders. Further identification of underlying mutual and unique biological mechanisms may yield novel multi-disorder and disorder-specific therapeutic targets. The metabolome represents an important domain for target identification as metabolites play critical roles in modulating a diverse range of biological processes.

METHODS: We used Mendelian randomisation (MR) to test the causal effects of ~ 1000 plasma metabolites and ~ 300 metabolite ratios on anxiety, bipolar disorder, depression, schizophrenia, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and multiple sclerosis. Follow-up analyses were conducted using statistical colocalisation, multivariable Bayesian model averaging MR (MR-BMA) and polygenic risk score analysis in the UK Biobank.

RESULTS: MR analyses identified 85 causal effects involving 77 unique metabolites passing FDR correction and robust sensitivity analyses (IVW-MR OR range 0.73-1.48; pFDR < 0.05). No evidence of reverse causality was identified. Multivariable MR-BMA analyses implicated sphingolipid metabolism in psychiatric disorder risk and carnitine derivatives in risk for amyotrophic lateral sclerosis and multiple sclerosis. Although polygenic risk scores for prioritised metabolites showed limited prediction in the UK Biobank, those nominally significant were directionally consistent with MR estimates. Downstream colocalisation in regions containing influential variants identified greater than suggestive evidence (PP.H4 ≥ 0.6) for a shared causal variant for 29 metabolite/psychiatric disorder trait-pairs on chromosome 11 at the FADS gene cluster. Most of these metabolites were lipids containing linoleic or arachidonic acid. Additional colocalisation was identified between the ratio of histidine-to-glutamine, glutamine, Alzheimer's disease and SPRYD4 gene expression on chromosome 12.

CONCLUSIONS: Although no single metabolite had a causal effect on both a psychiatric and a neurodegenerative disease, results suggest a broad effect of lipids across brain disorders, with a particular role for lipids containing linoleic or arachidonic acid in psychiatric disorders. The metabolites identified here may help inform future targeted interventions.},
}

Humans
*Neurodegenerative Diseases/genetics/metabolism
Mendelian Randomization Analysis
*Metabolome
*Mental Disorders/genetics/metabolism
Bayes Theorem
Risk Factors

@article {pmid40456951,
year = {2025},
author = {Douglas, AGL},
title = {Penetrance and pleiotropy in ATXN2-related amyotrophic lateral sclerosis.},
journal = {European journal of human genetics : EJHG},
volume = {},
number = {},
pages = {},
pmid = {40456951},
issn = {1476-5438},
support = {HMR04192 HM40.01//DH | National Institute for Health Research (NIHR)/ ; },
}

@article {pmid40456907,
year = {2025},
author = {Rhine, K and Li, R and Kopalle, HM and Rothamel, K and Ge, X and Epstein, E and Mizrahi, O and Madrigal, AA and Her, HL and Gomberg, TA and Hermann, A and Schwartz, JL and Daniels, AJ and Manor, U and Ravits, J and Signer, RAJ and Bennett, EJ and Yeo, GW},
title = {Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {40456907},
issn = {1546-1726},
support = {R01-HG004659//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35-GM148339//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35-GM148339//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01-NS103172//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 23-PDF-639//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; DGE-2038238//National Science Foundation (NSF)/ ; T32-CA067754//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; U01-CA267031//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30-CA014195//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; U01-CA267031//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; IL-2023-C2-L4//Target ALS (Target ALS Foundation)/ ; P30-AG068635//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins-like the dementia- and ALS-associated protein TDP-43-mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.},
}

@article {pmid40454831,
year = {2025},
author = {Santos Silva, C and Pavey, N and Calma, AD and Kiernan, MC and Menon, P and van den Bos, M and Vucic, S},
title = {Utility of Cortical Inhibitory and Facilitatory Neuronal Circuits in Amyotrophic Lateral Sclerosis Diagnosis.},
journal = {European journal of neurology},
volume = {32},
number = {6},
pages = {e70203},
doi = {10.1111/ene.70203},
pmid = {40454831},
issn = {1468-1331},
support = {//Motor Neurone Disease Research Institute of Australia/ ; 1024915//National Health and Medical Research Council of Australia/ ; 1055778//National Health and Medical Research Council of Australia/ ; 233//National Health and Medical Research Council of Australia/ ; 510//National Health and Medical Research Council of Australia/ ; GIA 1726//National Health and Medical Research Council of Australia/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Transcranial Magnetic Stimulation/methods ; Cross-Sectional Studies ; Aged ; *Neural Inhibition/physiology ; *Evoked Potentials, Motor/physiology ; Adult ; *Motor Cortex/physiopathology ; },
abstract = {BACKGROUND: Cortical hyperexcitability is an early feature of amyotrophic lateral sclerosis (ALS), linked to dysfunction in inhibitory and facilitatory cortical circuits, measurable using paired-pulse transcranial magnetic stimulation (TMS). Short-interval intracortical inhibition (SICI) is a robust biomarker of inhibitory function and an ALS diagnostic marker. Short interval intracortical facilitation (SICF) serves as a biomarker of facilitatory function, while the index of excitation assesses the contribution of these circuits to hyperexcitability. This study aimed to evaluate the diagnostic effectiveness of SICF and the index of excitation in distinguishing ALS from non-ALS mimic disorders.

METHODS: This cross-sectional study assessed cortical excitability in participants with suspected ALS from two Sydney centres, classified using the Gold Coast criteria. Threshold tracking TMS measured SICI, SICF, and the index of excitation. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis, with sensitivity, specificity, and optimal cut-off values determined.

RESULTS: Of 154 participants, 95 were diagnosed with ALS and 48 with non-ALS mimics. SICI demonstrated a marginally higher diagnostic accuracy (AUC 0.84, 95% CI:0.77-0.89) compared to SICF (AUC 0.77, 95% CI:0.68-0.84, p = 0.028). The index of excitation showed comparable accuracy to SICI (AUC 0.82, 95% CI: 0.75-0.88, p = 0.328). The optimal SICF cut-off (≤ -13.6%) provided 70.5% sensitivity and 70.8% specificity, while the index of excitation cut-off (≥ 64.5%) yielded 71.6% sensitivity and 70.8% specificity.

CONCLUSIONS: The present study established modest diagnostic potential of increased SICF and index of excitation in differential ALS from mimic disorders, thereby enhancing understanding of the role of inhibitory and facilitatory cortical circuits in ALS diagnosis.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology
Male
Female
Middle Aged
Transcranial Magnetic Stimulation/methods
Cross-Sectional Studies
Aged
*Neural Inhibition/physiology
*Evoked Potentials, Motor/physiology
Adult
*Motor Cortex/physiopathology

@article {pmid40454774,
year = {2025},
author = {Madrer, N and Perera, ND and Uccelli, NA and Abbondanza, A and Andersen, JV and Carsana, EV and Demmings, MD and Fernandez, RF and de Fragas, MG and Gbadamosi, I and Kulshrestha, D and Lima-Filho, RAS and Marian, OC and Markussen, KH and McGovern, AJ and Neal, ES and Sarkar, S and Šimončičová, E and Soto-Verdugo, J and Yandiev, S and Fernández-Moncada, I},
title = {Neural Metabolic Networks: Key Elements of Healthy Brain Function.},
journal = {Journal of neurochemistry},
volume = {169},
number = {6},
pages = {e70084},
doi = {10.1111/jnc.70084},
pmid = {40454774},
issn = {1471-4159},
mesh = {Humans ; *Brain/metabolism ; Animals ; *Nerve Net/metabolism ; *Energy Metabolism/physiology ; *Metabolic Networks and Pathways/physiology ; *Neurons/metabolism ; },
abstract = {Neural networks are responsible for processing sensory stimuli and driving the synaptic activity required for brain function and behavior. This computational capacity is expensive and requires a steady supply of energy and building blocks to operate. Importantly, the neural networks are composed of different cell populations, whose metabolic profiles differ between each other, thus endowing them with different metabolic capacities, such as, for example, the ability to synthesize specific metabolic precursors or variable proficiency to manage their metabolic waste. These marked differences likely prompted the emergence of diverse intercellular metabolic interactions, in which the shuttling and cycling of specific metabolites between brain cells allows the separation of workload and efficient control of energy demand and supply within the central nervous system. Nevertheless, our knowledge about brain bioenergetics and the specific metabolic adaptations of neural cells still warrants further studies. In this review, originated from the Fourth International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Schmerlenbach, Germany (2022), we describe and discuss the specific metabolic profiles of brain cells, the intercellular metabolic exchanges between these cells, and how these bioenergetic activities shape synaptic function and behavior. Furthermore, we discuss the potential role of faulty brain metabolic activity in the etiology and progression of Alzheimer's disease, Parkinson disease, and Amyotrophic lateral sclerosis. We foresee that a deeper understanding of neural networks metabolism will provide crucial insights into how higher-order brain functions emerge and reveal the roots of neuropathological conditions whose hallmarks include impaired brain metabolic function.},
}

Humans
*Brain/metabolism
Animals
*Nerve Net/metabolism
*Energy Metabolism/physiology
*Metabolic Networks and Pathways/physiology
*Neurons/metabolism

@article {pmid40454605,
year = {2025},
author = {Zheng, X and Zhang, K and Zhao, X and Zhou, J and Shen, H and Kong, J and Guo, Y},
title = {Achieving High-Yield Conversion of Janus Transition Metal Dichalcogenides on Diverse Substrates.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c02687},
pmid = {40454605},
issn = {1936-086X},
abstract = {Janus transition metal dichalcogenides (TMDCs) with intrinsic broken mirror symmetry and vertical dipole moment provide an additional degree of freedom to manipulate material symmetry down to atomic-layer thickness. However, despite advances in synthesis strategies, fundamental understanding of this atomic substitution process remains limited, which has impeded their implementation in advanced devices. Here, by using a room-temperature atomic-layer substitution (RT-ALS) strategy, we systematically investigate the critical factors facilitating the high-yield conversion of Janus TMDCs on diverse substrates. Combining Raman spectroscopy probes, X-ray photoelectron spectroscopy (XPS) measurements, and density functional theory (DFT) calculations, we demonstrate that substrates with enhanced electron doping or larger surface polarity substantially benefit the conversion of Janus TMDCs reaching a near-unity yield. Intriguingly, the strong affinity between Janus TMDCs and substrates (e.g., Au) brings about abnormal Raman spectroscopic phenomena. These findings highlight the significance of substrates in achieving the reliable synthesis of Janus two-dimensional materials with improved homogeneity on various substrates. In addition, this takes us one step closer to utilizing Janus TMDCs as a versatile platform in next-generation optoelectronic devices, sensors, and quantum technologies.},
}

@article {pmid40454469,
year = {2025},
author = {Arnold, FJ and Cui, Y and Michels, S and Colwin, MR and Stockford, CM and Ye, W and Maheswari Jawahar, V and Jansen-West, K and Philippe, J and Gulia, R and Gou, Y and Tam, OH and Menon, S and Situ, WG and Cazarez, SL and Zandi, A and Ehsani, KC and Howard, S and Dickson, DW and Gale Hammell, M and Prudencio, M and Petrucelli, L and Li, W and La Spada, AR},
title = {TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia.},
journal = {The Journal of clinical investigation},
volume = {135},
number = {11},
pages = {},
doi = {10.1172/JCI182088},
pmid = {40454469},
issn = {1558-8238},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Polyadenylation ; tau Proteins/metabolism/genetics ; },
abstract = {Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from an RNA-Seq (DaPars) tool to ALS/FTD transcriptome datasets and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional relevance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3' UTRs, corresponding with a change in the subcellular distribution of MARK3 and increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
Humans
*Frontotemporal Dementia/genetics/metabolism/pathology
*DNA-Binding Proteins/metabolism/genetics
*Polyadenylation
tau Proteins/metabolism/genetics