@article {pmid40778304,
year = {2025},
author = {Zhang, K and Wen, M and Nan, X and Zhao, S and Li, H and Ai, Y and Zhu, H},
title = {NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1604378},
pmid = {40778304},
issn = {1663-4365},
abstract = {NMDA receptors (NMDARs) are widely distributed throughout the central nervous system (CNS) and play pivotal roles in normal physiological processes such as synaptic plasticity, learning, and memory. Substantial evidence indicates that NMDAR dysfunction, particularly excessive calcium influx, critically contributes to the pathogenesis of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Dysregulated glutamatergic signaling synergizes with pathological protein aggregation (e.g., Aβ, α-synuclein, mutant huntingtin) to drive neuronal loss. We systematically delineate NMDAR-related mechanisms underlying neurodegeneration, highlighting spatial-specific roles (e.g., synaptic NMDAR-mediated neuroprotection versus extrasynaptic NMDAR-mediated excitotoxicity) and crosstalk with mitochondrial dysfunction and oxidative stress. We critically evaluate current therapeutic strategies targeting NMDARs, including subunit-selective modulators, downstream effector modulation, and glutamate transporter modulation designed to restore NMDAR homeostasis. Consequently, NMDARs and their modulators represent promising therapeutic targets for these refractory conditions. This review comprehensively summarizes current research on the involvement of NMDARs and the glutamatergic system in neurodegenerative diseases. Furthermore, we discuss the clinical application of NMDAR-targeting agents and explore emerging therapeutic strategies focused on modulating NMDAR-related pathways. This article aims to provide a reference for elucidating the molecular mechanisms underlying these neurodegenerative disorders and to highlight potential avenues for future drug development.},
}

@article {pmid40449630,
year = {2025},
author = {Vu Trung, K and Abou-Ali, E and Gulla, A and Soares, K and Caillol, F and Paik, WH and Napoleon, B and Halimi, A and Masaryk, V and Bruno, MJ and Pérez-Cuadrado-Robles, E and Bolm, L and Seyfried, S and Petrone, MC and Yilmaz, B and Vollmer, C and Berger, A and Maggino, L and Schemmer, P and Wichmann, D and Karam, E and Dugic, A and Kunovsky, L and Regner, S and Gaujoux, S and Hollenbach, M and , },
title = {Development and validation of the SDLD score: a simplified tool to predict successful endoscopic papillectomy in ampullary lesions.},
journal = {Gastrointestinal endoscopy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.gie.2025.03.1333},
pmid = {40449630},
issn = {1097-6779},
abstract = {BACKGROUND AND AIMS: Endoscopic papillectomy (EP) is the standard treatment for noninvasive ampullary lesions (ALs), whereas advanced cases require surgery. Managing ALs is challenging and may lead to over- or undertreatment. We developed a score to identify the best candidates for endoscopic or surgical treatment.

METHODS: We analyzed 447 patients who underwent EP. The cohort was randomly split into a training set (n = 325) and validation set (n = 122). Logistic regression identified predictors for incomplete resection (R1), which were incorporated into a 4-item score. Performance was assessed using the area under the receiver-operating characteristic curve (AUROC).

RESULTS: Independent predictors for R1 included size ≥30 mm (S), high-grade dysplasia and/or invasive cancer (D), laterally spreading-lesion (L), and bile or pancreatic duct dilation (D), which we named the SDLD score. ALs with 0 to 1 points had the highest complete resection rates (training, 86.0%; validation, 88.5%), whereas ≥2 points significantly increased R1 rates (training, 52.0%; validation, 57.7%; P < .001). The AUROC was 0.792 (training) and 0.708 (validation).

CONCLUSIONS: The SDLD score predicts R1 in EP and aids in treatment decisions.},
}

@article {pmid40777887,
year = {2025},
author = {Ek, JE and Wittig, J and Rogers, J and Soar, J and , },
title = {A survey of Advanced Life Support practices in countries implementing the European Resuscitation Council guidelines.},
journal = {Resuscitation plus},
volume = {25},
number = {},
pages = {101032},
pmid = {40777887},
issn = {2666-5204},
abstract = {OBJECTIVE: The 2025 European Resuscitation Council (ERC) Advanced Life Support (ALS) Guidelines writing group aims to produce inclusive guidelines enabling implementation by National Resuscitation Councils (NRC) based on local resources and practices. We aimed to describe ALS practices across NRCs to further inform the 2025 ERC ALS Guidelines.

METHODS: A cross-sectional survey was conducted to assess clinical practices for defibrillation, drugs and airway management during ALS in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) amongst countries represented by an NRC. NRCs were invited to suggest practices for consideration in the 2025 ERC ALS Guidelines.

RESULTS: Among 31 NRCs, 30 (96.8 %) provided data. Defibrillation pads were used for OHCA in 21 (70 %) and for IHCA in 15 (50 %) of countries, while paddles were reported by 3 (10 %) and 6 (20 %) for OHCA and IHCA, respectively. Most NRCs reported not using a pre-charging strategy (23 [76.7 %] OHCA; 26 [86.7 %] IHCA). Amiodarone was the primary antiarrhythmic (26 [89.7 %], OHCA; 28 [93.3 %], IHCA), and adrenaline was the primary vasopressor (27 [90 %], OHCA; 29 [96.7 %], IHCA). Airway management practices varied, 12 (41.4 %) reported supraglottic airway devices as the primary choice for OHCA and 1 (3.3 %) for IHCA, while 22 (73.3 %) reported tracheal tubes for IHCA and only 9 (31 %) for OHCA. Open-ended responses emphasised the importance of guidance in low-resource settings.

CONCLUSION: Current ALS practices vary across countries, and between OHCA and IHCA settings with a need to consider low-resource settings. Understanding these practices has implications for guideline development and research planning.},
}

@article {pmid40777853,
year = {2025},
author = {Zhao, Q and Zhang, B and Chen, X and Fu, P and Yang, Y and Wang, Q},
title = {Global, regional, and national burden of motor neuron disease in adults aged 65 years and older from 1990 to 2021 and forecast to 2040.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1641887},
pmid = {40777853},
issn = {1664-2295},
abstract = {AIM: Given the significant social burden of motor neuron disease (MND) among elderly patients (aged ≥ 65 years) and the lack of detailed research on its epidemiological characteristics, this study aims to elucidate the temporal trends and distributional characteristics of MND in the elderly from 1990 to 2021, as well as to forecast its future burden.

METHODS: The age-standardized rates (ASR) and absolute numbers of MND-related incident, prevalent, death, and disability-adjusted life years (DALYs) among older patients (aged ≥ 65 years) globally were derived from the Global Burden of Disease (GBD) study from 1990 to 2021. The data were derived by gender, age group and geographic region. An estimated annual percentage change (EAPC) was estimated to represent temporal trends, and a Bayesian Age-Period-Cohort model was used to forecast the future burden of elderly MND.

RESULTS: In 2021, the global ASRs of incidence, prevalence, mortality, and DALYs for elderly MND were 3.63 (95% uncertainty intervals [UI], 2.95-4.36), 11.45 (95% UI, 8.69-14.88), 3.28(95% UI, 2.90-3.61), and 59.92 (95% UI, 53.94-65.53), respectively. Elderly patients those were from high socio-demographic index (SDI) region, as well as males, exhibited the highest burden. From 1990 to 2021, the global ASRs of elderly MND increased, with EAPCs of 0.43 (95% confidence interval [CI], 0.38-0.49), 0.58 (95% CI, 0.48-0.68), 0.90 (95%CI, 0.75-1.06), and 0.84 (95% CI, 0.71-0.96), respectively. Positive correlations were found between sociodemographic index and the burden of elderly MND. Health inequalities were evident across 204 countries and regions, with the inequality slope index raised from 23.46 (95% CI: 18.52-28.40) in 1990 to 80.70 (95% CI: 65.07-96.32) in 2021. Compared to the figures observed in 2021, our forecasts indicate a continued rise in the burden of elderly MND up to 2040, with the projected ASIR expected to reach 3.15 (95% UI, 2.28-4.01) and the ASMR anticipated to be 3.32 (95% UI, 2.11-4.55).

CONCLUSION: The burden of MND among elderly patients is substantial, particularly in high SDI region and among males. From 1990 to 2021, the global burden of elderly MND has exhibited an increasing trend. The burden of elderly MND varies significantly across the world, necessitating more targeted screening strategies and preventive measures to address the issue of elderly MND.},
}

@article {pmid40777082,
year = {2025},
author = {Otomo, A and Nishijima, K and Murakami, Y and Ishikawa, M and Yudahira, H and Shimakura, K and Okano, H and Aoki, M and Kimura, H and Hadano, S},
title = {Investigation of early axonal phenotypes in an iPSC-derived ALS cellular model using a microfluidic device.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1590732},
pmid = {40777082},
issn = {1662-5102},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of upper and lower motor neurons. Mutations in the FUS/TLS gene have been reported as the second most common mutation in Japanese patients with familial ALS. In recent years, lower motor neurons (LMNs) differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients have been widely used to analyze the mechanisms of neuronal cell death and degeneration.

METHODS: In this study, we developed a microfluidic device designed to observe axonal growth, morphology, and trafficking at high resolution in neurons derived from induced pluripotent stem cells (iPSCs) and tested whether our microfluidic device effectively evaluates neurodegenerative phenotypes. We used iPSCs carrying homozygous FUS/TLS mutations (FUS_H517D) to induce LMNs by expressing NEUROG2, ISL1, and LHX3 under the control of the tetracycline regulation system.

RESULTS AND DISCUSSIONS: After seven days of in vitro differentiation (DIV7), we confirmed that over 95% of iPSCs differentiated into HB9-positive LMNs. Notably, the cell viability of FUS_H517D LMNs was comparable to that of LMNs differentiated from iPSCs without the FUS/TLS mutation at DIV7. However, by DIV14 and DIV21, the viability of FUS_H517D LMNs was notably lower than that of control LMNs, indicating degeneration of FUS_H517D LMNs after differentiation. Using our microfluidic device, we assessed axonal phenotypes in FUS_H517D LMNs. Under oxidative stress conditions, we observed that the axonal length of FUS_H517D LMNs was significantly shorter than that of control cells as early as DIV7, with this axonal growth restriction becoming more pronounced by DIV11. This suggests that axonal growth restriction is an early detectable phenotype in degenerating neurons. Additionally, we examined mitochondrial trafficking within axons in our device, which is often disrupted in degenerative neurons. Our results showed a significant increase in the number of motile mitochondria in FUS_H517D LMNs, with retrograde transport accounting for a large portion of trafficking. Our microfluidic device-based culture and evaluation system using FUS_H517D LMNs offers a valuable ALS cellular model focused on early axonal phenotypes. This approach contributes to the study of molecular mechanisms underlying axonal degeneration in ALS.},
}

@article {pmid40776984,
year = {2025},
author = {Wen, D and Li, Q and Li, Y and Yan, W and Wang, Y and Liu, Y},
title = {OPTN deficiency through CRISPR/Cas9 downregulates autophagy and mitophagy in a SOD1-G93A-expressing transgenic cell line.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {307-316},
pmid = {40776984},
issn = {2667-2421},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the loss of upper and lower motor neurons (MNs) and is the most common adult paralysis neurodegenerative disease. Dysregulated autophagy, which has been reported in the pathogenesis of familial ALS, has been found in superoxide dismutase 1 (SOD1) transgenic mice and cell lines. Optineurin (OPTN) is a signal regulator that coordinates many crucial cellular processes, including autophagy, mitophagy and aggrephagy. Recent studies have shown that OPTN gene mutations are correlated with ALS, glaucoma and Paget's disease of the bone. Indeed, defects in autophagosome-lysosome fusion have been reported in patients with ALS-associated OPTN mutations. However, the exact function of OPTN in the pathology of ALS remains unknown. To determine the function of OPTN, we generated OPTN-knockdown cell lines from SOD1-G93A-expressing NSC34 cells with the clustered regularly interspaced short palindromic repeats/associated system 9 (CRISPR/Cas9) approach. In our research, we observed that the loss of OPTN resulted in the impairment of autophagy and mitophagy pathways. Moreover, the mitochondrial transmembrane potential was depolarized by LV-sgRNA-OPTN. On the basis of observations of live cells, the production of reactive oxygen species (ROS) was increased, the autophagic flux decreased, and the autophagic flux merged with that of mitochondria according to confocal live-cell imaging. A decreased LC3-II and an increased p62 levels indicated that autophagy pathway activation was decreased. The protein levels of VDAC1 and TBK1 decreased after OPTN knockdown, suggesting that mitophagy was blocked. Our results suggest that OPTN plays a pivotal role in regulating autophagy and mitophagy.},
}

@article {pmid40776416,
year = {2025},
author = {Thiry, L and Pulimood, NS and Tang, YM and Stifani, S},
title = {Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in C9orf72-ALS/FTD Microglia.},
journal = {ASN neuro},
volume = {17},
number = {1},
pages = {2542998},
doi = {10.1080/17590914.2025.2542998},
pmid = {40776416},
issn = {1759-0914},
mesh = {*Microglia/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Inflammasomes/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Induced Pluripotent Stem Cells ; *Extracellular Matrix/genetics/metabolism ; DNA Repeat Expansion/genetics ; Cells, Cultured ; },
abstract = {Hexanucleotide repeat expansion (HRE) in the non-coding region of the gene C9orf72 is the most prevalent mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 HRE contributes to neuron degeneration in ALS/FTD through both cell-autonomous mechanisms and non-cell autonomous disease processes involving glial cells such as microglia. The molecular mechanisms underlying the contribution of C9orf72-HRE microglia to neuron death in ALS/FTD remain to be fully elucidated. In this study, we generated microglia from human C9orf72-HRE and isogenic iPSCs using three different microglia derivation methods. RNA sequencing analysis reveals a cell-autonomous dysregulation of extracellular matrix (ECM) genes and genes involved in pathways underlying inflammasome activation in C9orf72-HRE microglia. In agreement with elevated expression of inflammasome components, conditioned media from C9orf72-HRE microglia enhance the death of C9orf72-HRE motor neurons implicating microglia-secreted molecules in non-cell autonomous mechanisms of C9orf72 HRE pathology. These findings suggest that aberrant activation of inflammasome-mediated mechanisms in C9orf72-HRE microglia results in a pro-inflammatory phenotype that contributes to non-cell autonomous mechanisms of motor neuron degeneration in ALS/FTD.},
}

*Microglia/metabolism
*C9orf72 Protein/genetics/metabolism
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
Humans
*Inflammasomes/genetics/metabolism
*Frontotemporal Dementia/genetics/pathology/metabolism
Induced Pluripotent Stem Cells
*Extracellular Matrix/genetics/metabolism
DNA Repeat Expansion/genetics
Cells, Cultured

@article {pmid40775651,
year = {2025},
author = {Li, MJ and Li, Q and Zhao, MM and Kim, H and Feng, RQ and Guo, MN and Heng, JP and Yang, JK and Liu, C},
title = {Spectrum and epidemiology of rare diseases in a Chinese natural population of 14.31 million residents, 2012-2023.},
journal = {Orphanet journal of rare diseases},
volume = {20},
number = {1},
pages = {410},
pmid = {40775651},
issn = {1750-1172},
support = {82341076//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Rare Diseases/epidemiology ; Female ; Male ; China/epidemiology ; Child ; Adolescent ; Adult ; Middle Aged ; Child, Preschool ; Young Adult ; Aged ; Infant ; Incidence ; Registries ; Infant, Newborn ; East Asian People ; },
abstract = {BACKGROUND: Rare diseases, though individually uncommon, collectively affect a significant portion of the population. However, their epidemiology in China remains underexplored. A population-based rare disease registry comprising 14.31 million individuals was conducted between 2012 and 2023 by the Beijing Municipal Health Big Data and Policy Research Center. Rare disease cases were identified via ICD-10 codes mapped to China's national rare disease lists (2018 and 2023) and international databases. Age-standardized incidence rates (ASIR) were calculated per 100,000 person-years with 95% confidence intervals.

RESULTS: Our analysis identified 12,371 rare disease cases, with the overall ASIR increasing from 6.109 in 2012 to 7.394 in 2023. Rare neurologic diseases accounted for 52.12% of cases, followed by systemic and rheumatologic diseases (16.89%) and rare neoplastic diseases (9.99%). The most frequently diagnosed rare diseases included generalized myasthenia gravis, ANCA-associated vasculitis, and malignant melanoma. Significant sex-based differences were observed, with female patients more affected by systemic and rheumatologic conditions, while male patients showed a higher incidence of respiratory disorders. Pediatric patients predominantly presented with inborn errors of metabolism and rare immune diseases. Comparisons with global data revealed notable disparities, such as a higher prevalence of Wilson's disease and a lower incidence of amyotrophic lateral sclerosis (ALS) in China.

CONCLUSIONS: This study represents the first large-scale, population-based analysis of rare diseases in China, revealing distinct epidemiological patterns. These findings underscore the critical need for healthcare policies that address the unique challenges posed by rare diseases in China.},
}

Humans
*Rare Diseases/epidemiology
Female
Male
China/epidemiology
Child
Adolescent
Adult
Middle Aged
Child, Preschool
Young Adult
Aged
Infant
Incidence
Registries
Infant, Newborn
East Asian People

@article {pmid40775435,
year = {2025},
author = {Xu, W and Guo, Z and Guan, Y and Lv, S and Gao, X and Luo, W and Cheng, T and Shao, Z and Tao, B and Wang, T and Qiu, Z},
title = {Machine learning-based proteomics profiling of ALS identifies downregulation of RPS29 that maintains protein homeostasis and STMN2 level.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {1177},
pmid = {40775435},
issn = {2399-3642},
support = {82473207//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32271000//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *Proteomics/methods ; *Machine Learning ; Down-Regulation ; *Ribosomal Proteins/metabolism/genetics ; Motor Neurons/metabolism ; *Proteostasis ; Animals ; Biomarkers/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The molecular understanding of ALS is hampered by the lack of experimental models recapitulating disease heterogeneity and analytical framework integrating multi-omics datasets. Here, we developed a pipeline integrating machine learning and consensus clustering to analyze a large-scale dataset of patient-derived motor neuron models from Answer ALS. Compared to the transcriptome, proteomic profiling closely correlates with ALS pathology, which is interrogated to identify 110 proteomics-based biomarkers (Proteomics Markers for ALS 110, PMA110). Functional enrichment highlights dysregulation of ALS pathways, including protein translation and neuronal function. By integrating ALS subtype-specific proteins with patient postmortem proteomics, we found that RPS29 was consistently downregulated in ALS models and patient motor neurons. RPS29 is required for neuronal viability by maintaining ribosome profiling and accurate translation, and suppressing pathological translation. RPS29 downregulation suppresses translation of STMN2, an essential protein for motor neurons, in iPSC-derived motor neurons. Taken together, this study provides a robust framework for ALS proteomics, identifies RPS29 as a quality controller of protein translation, and presents a translational mechanism for STMN2 maintenance in ALS.},
}

*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
Humans
*Proteomics/methods
*Machine Learning
Down-Regulation
*Ribosomal Proteins/metabolism/genetics
Motor Neurons/metabolism
*Proteostasis
Animals
Biomarkers/metabolism

@article {pmid40775105,
year = {2025},
author = {Pasternack, N and Paulsen, O and Nath, A},
title = {Machine learning predicts distinct biotypes of amyotrophic lateral sclerosis.},
journal = {European journal of human genetics : EJHG},
volume = {},
number = {},
pages = {},
pmid = {40775105},
issn = {1476-5438},
support = {NS003130//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS003130//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is universally fatal and has no cure. Heterogeneity of clinical presentation, disease onset, and proposed pathological mechanisms are key reasons why developing impactful therapies for ALS has been challenging. Here we analyzed data from two postmortem cohorts: one with bulk transcriptomes from 297 ALS patients and a separate cohort of single cell transcriptomes from 23 ALS patients. Using unsupervised machine learning, we found three groups of ALS patients characterized by synaptic dysfunction (34%), neuronal regeneration (47%), and neuronal degeneration (19%). Each of these ALS subtypes had unique patterns of transcriptional dysregulation that could represent novel therapeutic targets. We then developed a supervised machine learning model that was about 80% accurate at predicting ALS subtype based on patient demographic and clinical data. Together, we established three biologically distinct subtypes of ALS that can be predicted by clinical and demographic data.},
}

@article {pmid40774708,
year = {2025},
author = {Brown, KR and Quinton, ML and Tidmarsh, G and Cumming, J},
title = {Athletes' access to, attitudes towards and experiences of help-seeking for mental health: a scoping review.},
journal = {BMJ open},
volume = {15},
number = {8},
pages = {e097492},
doi = {10.1136/bmjopen-2024-097492},
pmid = {40774708},
issn = {2044-6055},
mesh = {Humans ; *Athletes/psychology ; *Patient Acceptance of Health Care/psychology ; *Mental Health ; *Mental Disorders/therapy/psychology ; *Help-Seeking Behavior ; *Mental Health Services ; *Health Services Accessibility ; },
abstract = {OBJECTIVES: Athletes have been found to experience a similar prevalence of mental health issues to non-athletes. However, they are subjected to a greater array of barriers to help-seeking for mental health, including sport-specific factors. This scoping review synthesised the literature on athletes' access to, attitudes towards and experiences of help-seeking for mental health from formal (mental health professionals such as psychiatrists) and semiformal sources (those who are not mental health professionals but are a service provider such as a coach).

DESIGN: The Joanna Briggs Institute framework and recommendations were used alongside the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocols checklist for scoping reviews. This scoping review was predominantly informed by Arksey and O'Malley's framework for scoping reviews, supplemented by Levac et al's additional recommendations. Rickwood and colleagues' help-seeking frameworks informed the research question, inclusion/exclusion criteria and analysis.

DATA SOURCES: The search terms and synonyms of "athlete" AND "mental health" AND "help-seeking" were searched in PsychINFO, Embase, MEDLINE, APA PsychArticles Full Text, Web of Science Core Collection, Scopus, Sport Discus, CINAHL and Proquest (Education Database, Health & Medical Collection, Nursing & Allied Health database, Psychology Database, Public Health Database, Education Collection, and Medicine & Education). These searches were conducted at three time points between April 2022 and 2024.

ELIGIBILITY CRITERIA: The inclusion and exclusion criteria were initially predetermined and specified in the protocol paper published in BMJ Open. Primary research articles, interventions and systematic reviews that referred to semiformal and formal sources of support were included.

DATA EXTRACTION AND SYNTHESIS: The lead reviewer (KRB) screened all titles and abstracts, and full texts, and extracted data from all included studies. A second reviewer was involved in screening and extracting 20%-30% of studies at each stage. Findings were synthesised descriptively (eg, study population, data collection method and location of studies) and by content (eg, access, attitudes and experiences, sources of support, use of theory and the validity of quantitative measures used).

RESULTS: After screening 4954 titles and abstracts and 275 full texts in Covidence, 104 papers were included in the review. This comprised of 87 primary research articles, 13 interventions and 4 systematic reviews. Most of the primary articles and interventions were published in the USA (50%). 49.4% of the primary articles used quantitative methods, 34.5% used qualitative methods and 16.1% used mixed methods. Attitudes towards mental health help-seeking were investigated in 78.8% of the included studies, experiences of help-seeking in 53.8% and access to sources of support in 31.7% of studies. Of the primary articles and interventions, formal sources were investigated in 55% of studies, semiformal sources in 2% and both in 26% of studies.

CONCLUSIONS: This scoping review of 104 papers showed the benefit of using help-seeking frameworks to shape and analyse a review. Analysing the results using these frameworks provided a novel contribution to the literature, showing where the athlete help-seeking literature base is currently focused and identified gaps for further research. For example, there is a need for further research on athletes in less developed nations, more qualitative and mixed methods studies, and further research on athletes' access to mental health support and their interactions with semiformal sources. The results have applied implications in public health and sport by highlighting the different factors that impact athlete help-seeking, and therefore areas where they require support.},
}

Humans
*Athletes/psychology
*Patient Acceptance of Health Care/psychology
*Mental Health
*Mental Disorders/therapy/psychology
*Help-Seeking Behavior
*Mental Health Services
*Health Services Accessibility

@article {pmid40774338,
year = {2025},
author = {Honold, S and Loizides, A and Skalla, E and Gruber, L and Plaikner, M and Gruber, H},
title = {Minimally invasive ultrasound-guided carpal tunnel release: long-term clinical outcomes.},
journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2678-8214},
pmid = {40774338},
issn = {1438-8782},
abstract = {PURPOSE: In cases of severe or refractory carpal tunnel syndrome (CTS), carpal tunnel release (CTR) can be performed using open surgery, endoscopic techniques, or minimally invasive approaches under high-resolution ultrasound (HRUS) guidance. This study aimed to evaluate the long-term clinical outcomes following HRUS-guided CTR.

MATERIALS AND METHODS: A retrospective analysis was conducted on 302 HRUS-CTR cases performed. Patients available for a phone interview and had a minimum follow-up period of one year were assessed using the Boston Carpal Tunnel Questionnaire (BCTQ). Symptom severity and functional limitations were compared before and after the procedure.

RESULTS: Of the 302 cases screened, 111 cases had to be excluded due to unavailability for the phone call, missing data or death. Accordingly, 191 cases were included. The average patient age was 60.4 ± 15.5 years (range 19 to 87 years). 126 cases (66%) were female and 65 cases (34.0%) were male. Overall, there was a significant reduction of 91.9% in CTS-related symptom severity and frequency for all items recorded in the questionnaire. Similarly, a significant reduction of 84.8% in difficulties with all self-reported daily activities was found. In addition, the procedures were performed by four physicians showing no significant differences in technical success and symptoms reduction.

CONCLUSION: HRUS-CTR is a safe and effective method for the treatment of CTS, showing a statistically but mostly clinically significant reduction of symptom severity and hand discomfort, which persisted 1 year after release and should therefore be considered as an alternative approach to open or endoscopic CTR. Zusammenfassung: Ziel: Bei schwerem oder therapierefraktärem Karpaltunnelsyndrom (CTS) wird die Spaltung des Ligamentum transversum carpi (CTR) offen chirurgisch, endoskopisch oder minimal-invasiv unter hochauflösender Ultraschall-kontrolle (HRUS) durchgeführt. Diese Studie hatte zum Ziel, die langfristigen klinischen Ergebnisse nach HRUS-geführter CTR (HRUS-CTR) zu eruieren. Material und Methode: Eine retrospektive Analyse wurde an 302 HRUS-CTR-Fällen durchgeführt. Patienten, die für ein telefonisches Interview verfügbar waren und eine Nachbeobachtungszeit von mindestens einem Jahr hatten, wurden mit dem Boston Carpal Tunnel Questionnaire (BCTQ) untersucht. Die Schwere der Symptome und funktionelle Einschränkungen wurden vor und nach dem Verfahren verglichen. Ergebnisse: Von den 302 geprüften Fällen mussten 111 Fälle aufgrund der Nichtverfügbarkeit des Telefonanrufs, fehlender Daten oder des Todes ausgeschlossen werden. Dementsprechend wurden 191 Fälle aufgenommen. Das durchschnittliche Alter der Patienten betrug 60,4 ± 15,5 Jahre (19 - 87 Jahre). 126 Fälle (66%) waren weiblich und 65 Fälle (34,0%) männlich. Insgesamt gab es eine signifikante Reduktion von 91.9% der CTS-bedingten Symptomschwere und -häufigkeit für alle im Fragebogen erfassten Fragen. In ähnlicher Weise wurde eine signifikante Reduktion von 84.8% der Schwierigkeiten bei allen selbstberichteten täglichen Aktivitäten festgestellt. Zusätzlich wurden die Verfahren von vier Ärzten durchgeführt ohne Nachweis signifikanter Unterschiede im technischen Erfolg und in der Symptomreduktion. Schlussfolgerungen: HRUS-CTR ist eine sichere und effektive Methode zur Behandlung von CTS mit einer statistisch, aber vor allem über einem Jahr anhaltenden klinisch signifikanten Reduktion der Symptomschwere und des Handunbehagens und sollte daher als alternativer Ansatz zur offen-chirurgischen oder endoskopischen CTR in Betracht gezogen werden.},
}

@article {pmid40773352,
year = {2025},
author = {Setsu, S and Morimoto, S and Nakamura, S and Ozawa, F and Okano, H},
title = {Protocol for the induction of human spinal motor neurons from human induced pluripotent stem cells for studying amyotrophic lateral sclerosis.},
journal = {STAR protocols},
volume = {6},
number = {3},
pages = {104016},
doi = {10.1016/j.xpro.2025.104016},
pmid = {40773352},
issn = {2666-1667},
abstract = {Here, we present a protocol for inducing spinal lower motor neurons (LMNs) from human induced pluripotent stem cells (iPSCs). We describe steps for preparation of a chemically induced transitional state (CTraS), transduction with Sendai virus, and LMN differentiation and maintenance. We then detail procedures for live imaging for single-cell-based survival analysis and neurite length of LMNs using BioStation and immunocytochemistry for induction efficiency check. This protocol is optimized for amyotrophic lateral sclerosis (ALS) research and large-scale screening. For complete details on the use and execution of this protocol, please refer to Setsu et al.[1].},
}

@article {pmid40772974,
year = {2025},
author = {Anjum, F and Bakhuraysah, MM and Hulbah, MJ and Alsharif, A and Mohammad, T and Hassan, MI},
title = {Aggregation-Prone Pathogenic SOD1 Variants in Amyotrophic Lateral Sclerosis: Insights from Computational Genomics and Evolutionary Conservation.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {3},
pages = {99},
pmid = {40772974},
issn = {1559-1166},
support = {KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Humans ; *Mutation, Missense ; Evolution, Molecular ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and a median survival of 3-5 years post-diagnosis. While the etiology of ALS remains elusive, mutations in SOD1, encoding the Cu/Zn superoxide dismutase enzyme, are strongly associated with familial ALS (fALS). These mutations promote a toxic gain-of-function, primarily through SOD1 misfolding and aggregation. We systematically assessed 244 SOD1 missense mutations using a multi-tiered computational framework encompassing structural, functional, and pathogenic predictors. Sequence-based predictors (SIFT, PolyPhen-2, FATHMM) and structure-guided tools (mCSM, PremPS, DynaMut2) identified 79 destabilizing mutations, 64 of which were classified as pathogenic by phenotype predictors (PhD-SNP, SNPs&GO, MutPred2). Twelve mutations resided in evolutionarily conserved regions, with eight (D84N, G73C, H72Y, P67A, P67R, P67S, R144G, S60I) exhibiting pronounced aggregation propensity via SODA analysis. Notably, H72Y disrupts a zinc-binding residue critical for structural integrity and catalysis. Protein-protein interaction networks linked SOD1 to ALS-associated pathways, highlighting its involvement in oxidative stress and protein homeostasis. Our integrative approach highlights the power of computational genomics in unraveling mutation-driven SOD1 dysfunction, offering mechanistic insights into ALS pathogenesis and guiding therapeutic strategies focused on aggregation-prone variants.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism
*Superoxide Dismutase-1/genetics/chemistry/metabolism
Humans
*Mutation, Missense
Evolution, Molecular

@article {pmid40772881,
year = {2025},
author = {Zheng, Y and Li, M and Chen, X and Zheng, Z and Chen, Z and Tian, R and Zhao, YG},
title = {SOD1 is delivered to lysosomes via autophagy to maintain lysosomal function and integrity.},
journal = {The Journal of cell biology},
volume = {224},
number = {10},
pages = {},
doi = {10.1083/jcb.202501007},
pmid = {40772881},
issn = {1540-8140},
support = {32222021//National Natural Science Foundation of China/ ; 32170753//National Natural Science Foundation of China/ ; 2021YFA1300800//National Key Research and Development Program/ ; 2021 ZT09Y104//Guangdong Innovative and Entrepreneurial Research Team Program/ ; KQTD20210811090115021//Shenzhen Talent Program/ ; ZDSYS20220402111000001//Shenzhen Science and Technology Innovation Program/ ; GZNL2024A01008//R&D Program of Guangzhou Laboratory/ ; 2021QN02Y378//Guangdong Program/ ; //SUSTech Distinguished Young Scientist Team Program/ ; },
mesh = {*Lysosomes/metabolism/enzymology ; *Autophagy ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; Reactive Oxygen Species/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology/enzymology ; Animals ; HEK293 Cells ; Autophagy-Related Protein 8 Family/metabolism/genetics ; Mice ; },
abstract = {The gene encoding superoxide dismutase 1 (SOD1) is often mutated in familial amyotrophic lateral sclerosis (ALS), affecting motor neurons. Compared with ALS-associated mutant SOD1, the function of WT SOD1 is less explored. We demonstrate that during starvation, WT and mutant SOD1 are transported into lysosomes. Genome-wide CRISPR interference (CRISPRi) screening identified autophagy-related proteins and the autophagic receptor TP53INP1 as key mediators. TP53INP1 binds ATG8 family proteins, preferentially LC3C, and directly interacts with SOD1. Within lysosomes, SOD1 retains its enzymatic activity. Starvation induces elevated levels of lysosomal reactive oxygen species (ROS), which are further increased by knocking down SOD1 or TP53INP1. Lysosomal degradation activities and membrane integrity are also compromised in the absence of SOD1 or TP53INP1. We reveal a novel function of SOD1 in maintaining lysosomal activity and integrity, and a previously unrecognized role of autophagy in delivering cytosolic enzymes into lysosomes for catalytic purposes, rather than for degradation.},
}

*Lysosomes/metabolism/enzymology
*Autophagy
*Superoxide Dismutase-1/metabolism/genetics
Humans
Reactive Oxygen Species/metabolism
Amyotrophic Lateral Sclerosis/genetics/pathology/enzymology
Animals
HEK293 Cells
Autophagy-Related Protein 8 Family/metabolism/genetics
Mice

@article {pmid40772655,
year = {2025},
author = {He, J and Fan, D},
title = {Amyotrophic lateral sclerosis in Mainland China: clinical translational challenges and opportunities.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
pmid = {40772655},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) imposes a growing medical and socioeconomic burden in China. This review synthesizes recent advances in understanding ALS epidemiology, biomarker discovery, therapeutic innovations, and policy frameworks in China. It highlights the urgency of addressing challenges, including fragmented healthcare resources, translational medicine gaps, and regional inequities, while emphasizing China's unique contributions to global ALS research.

RECENT FINDINGS: Chinese ALS cohorts exhibit distinct epidemiological profiles, including a younger mean age of onset and prolonged median survival. Policy initiatives, such as ALS inclusion in rare disease registries and insurance reforms, aim to reduce financial burdens of patients. Multimodal biomarker exploration has advanced integrated diagnostic models combining neurofilament light chain (NfL) and clinical data platforms. Neuroimaging and electrophysiological studies reveal glymphatic dysfunction, white matter degeneration, and neuromuscular junction abnormalities, with novel links to hepatic metabolism. Genomic analyses identify population-specific variants. Therapeutic innovations in China include not only biopharmaceuticals, but also integrative traditional Chinese medicine (TCM) approaches.

SUMMARY: China's ALS landscape is transitioning towards precision medicine through biomarker-guided diagnostics and multidisciplinary care models. Key priorities include establishing a national ALS registry, standardizing biomarker validation, and expanding clinical trials to bridge translational medicine gaps.},
}

@article {pmid40772638,
year = {2025},
author = {Menge, S and Decker, L and Freischmidt, A},
title = {Genetics of ALS - genes and modifier.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
pmid = {40772638},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a complex genetic disorder, and the pace of discoveries is very rapid. This review aims at briefly summarizing our current knowledge, and at discussing the progress of the last two years.

RECENT FINDINGS: Common variation in numerous genes and variants in some nuclear-encoded mitochondrial genes were linked to an increased or modified risk of ALS, respectively. Mitochondrial function, i.e. specific mitochondrial haplotypes and loss-of-function variants in mitochondria-related genes, was identified as potent modifier of ALS survival, but not risk. Pioneering analyses of copy number variations in ALS-related genes revealed an increased load in ALS, but causality is unclear. A rare hyperactive variant of ER stress associated transcription factor CREB3 was linked to both substantially decreased ALS risk and slower disease progression. Furthermore, variants in IGFBP7 were linked to rare "ALS reversals", but existence of such phenotypes is controversial.

SUMMARY: Common variation increasing ALS risk contributes to our understanding of sporadic ALS, and novel structural variants have the potential to at least partly explain the missing heritability in ALS. Identification of mitochondrial function and ER stress signaling as potent disease modifiers provide valuable starting points for therapeutic approaches beyond targeting single causative genes.},
}

@article {pmid40772263,
year = {2025},
author = {Atwal, MS and Nimac, J and Čerček, U and Goesch, SR and Goesch, HR and Tziortzouda, P and Ercolani, T and Zatorska, A and Pasha, T and Carre, I and Mitchell, J and Troakes, C and Tummers, B and Župunski, V and Rogelj, B and Hortobágyi, T and Hirth, F},
title = {Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1558227},
pmid = {40772263},
issn = {1662-4548},
abstract = {Cytoplasmic mislocalisation and nuclear depletion of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS), including mutations in the C9ORF72 gene that characterise the most common genetic form of ALS (C9ALS). Studies in human cells and animal models have associated cytoplasmic mislocalisation of TDP-43 with abnormalities in nuclear transport receptors, referred to as karyopherins, that mediate the nucleocytoplasmic shuttling of TDP-43. Yet the relationship between karyopherin abnormalities and TDP-43 pathology are unclear. Here we report karyopherin-α4 (KPNA4) pathology in the spinal cord of TDP-43-positive sporadic ALS and C9ALS patients. Structural analyses revealed the selective interaction between KPNA subtypes, especially KPNA4, with the nuclear localisation signal (NLS) of TDP-43. Targeted cytoplasmic mislocalisation and nuclear depletion of TDP-43 caused KPNA4 pathology in human cells. Similar phenotypes were observed in Drosophila whereby cytoplasmic accumulation of the TDP-43 homolog, TBPH, caused the nuclear decrease and cytosolic mislocalisation of the KPNA4 homolog, Importin-α3 (Impα3). In contrast, induced accumulation of Impα3 was not sufficient to cause TBPH mislocalisation. Instead, targeted gain of Impα3 in the presence of accumulating cytosolic TBPH, restored Impα3 localisation and partially rescued nuclear TBPH. These results demonstrate that cytoplasmic accumulation of TDP-43 causes karyopherin pathology that characterises ALS spinal cord. Together with earlier reports, our findings establish KPNA4 abnormalities as a molecular signature of TDP-43 proteinopathies and identify it as a potential therapeutic target to sustain nuclear TDP-43 essential for cellular homeostasis affected in ALS and frontotemporal dementia.},
}

@article {pmid40771731,
year = {2025},
author = {Shi, DD and Tian, J and Ding, J},
title = {Adenosine deaminase in pleural effusion: Bridging diagnosis and the pathophysiology of inflammation.},
journal = {World journal of clinical cases},
volume = {13},
number = {22},
pages = {106925},
pmid = {40771731},
issn = {2307-8960},
abstract = {This editorial underscores the importance of Maranhão et al's study, which investigates pleural adenosine deaminase (P-ADA) as a biomarker for inflammatory pleural effusions. Despite advances in imaging, distinguishing between inflammatory and non-inflammatory causes of pleural effusion remains a diagnostic challenge. The authors conducted a rigorous retrospective cohort analysis of 157 patients (124 with inflammatory exudates and 33 with non-inflammatory transudates), establishing a robust cutoff value of P-ADA ≥ 9.00 U/L for diagnosing inflammatory diseases using receiver operating characteristic curve analysis and internal statistical calibration. This is the first study to define a standardized P-ADA threshold in a Brazilian cohort, addressing previous inconsistencies in cutoff values. Furthermore, the authors delved into the pathophysiological mechanisms underlying elevated P-ADA, linking it to purinergic signaling pathways and immune cell activation, particularly emphasizing the role of ADA2 isoforms in macrophages and lymphocytes. Their findings support P-ADA as a non-invasive, cost-effective biomarker for early diagnosis, treatment stratification, and minimizing the need for invasive procedures such as thoracentesis. This has particular relevance in resource-limited settings, where streamlined diagnostics can reduce healthcare costs and improve patient outcomes. Future studies must prioritize global validation, explore the integration of adenosine deaminase with additional biomarkers (e.g., interleukin 6, C-reactive protein), and support the development of point-of-care technologies.},
}

@article {pmid40771035,
year = {2025},
author = {Hattori, N and Mukai, Y and Nishikawa, N and Hasegawa, K and Tomiyama, M and Kimura, Y and Tsuboi, Y and Takahashi, R and Nakamura, R and Izumi, Y and Watanabe, H and Seki, M and Sekiguchi, K and Tateishi, S and Matsushita, Y and Nakamura, Y},
title = {Efficacy and Safety of IncobotulinumtoxinA for Treatment of Sialorrhea: A Multicenter, Phase 3 Study in Japan.},
journal = {Movement disorders clinical practice},
volume = {},
number = {},
pages = {},
doi = {10.1002/mdc3.70259},
pmid = {40771035},
issn = {2330-1619},
support = {//Teijin Pharma/ ; },
abstract = {BACKGROUND: Sialorrhea, caused by various neurological diseases, impairs patient health and quality of life. After the results of a randomized controlled trial, incobotulinumtoxinA was approved for the treatment of chronic sialorrhea in the United States and Europe; however, no pharmacotherapy has been approved in Japan.

OBJECTIVE: The aim was to evaluate the efficacy and safety of incobotulinumtoxinA treatment for chronic sialorrhea in a single-arm phase 3 study in Japan.

METHODS: Patients with chronic sialorrhea caused by neurological diseases (Parkinson's disease, atypical parkinsonism, and stroke, group A) and broader diseases (eg, muscular dystrophy and amyotrophic lateral sclerosis, group B) were enrolled. IncobotulinumtoxinA 100 U was injected into the salivary glands once every 16 weeks for 48 weeks. A primary endpoint was assessed in group A, whereas secondary endpoints and safety were assessed in both groups.

RESULTS: From November 2021 to August 2023, 92 patients (58 and 34 in groups A and B, respectively) received incobotulinumtoxinA at 28 institutions. The primary endpoint, the least square mean (standard error) of change in unstimulated salivary flow rate from baseline to 4 weeks, was -0.08 (0.009, 95% confidence interval [CI]: -0.10, -0.06) g/min, achieving the prespecified efficacy criteria (upper limit of the 95% CI <-0.04). The secondary endpoints were consistent across efficacy measures, indicating that reduced salivary secretion and improved drooling symptoms persisted for 48 weeks. The most common adverse events were dry mouth and dysphagia.

CONCLUSIONS: The first study in Japan confirmed the efficacy of incobotulinumtoxinA treatment for chronic sialorrhea with good patient tolerability and no new safety concerns.},
}

@article {pmid40767769,
year = {2025},
author = {Petre, AM and Thieschafer, JS and Palsuledesai, C and Cornille, K and Chang, A and Li, L and Distefano, MD},
title = {In Vivo Metabolic Labeling with an Isoprenoid Probe Reveals APOE Allele-Specific Differences in the Prenylome.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.5c00320},
pmid = {40767769},
issn = {1554-8937},
abstract = {Prenylation is a ubiquitous process in eukaryotes consisting of the irreversible post-translational modification of proteins through the attachment of a lipophilic isoprenoid moiety to a cysteine residue near their C-terminus. Due to the important functional roles of prenylated proteins, their participation and/or dysregulation has been linked to numerous diseases, including ALS, progeria, cancer, and Alzheimer's disease (AD). In humans, the APOE4 variant is the greatest known genetic risk factor for late-onset sporadic AD with carriers of two E4 alleles having up to 15 times the risk of developing AD. To begin to unravel the potential relationship between protein prenylation, AD, and APOE variants, it is necessary to study whether different APOE genotypes affect protein prenylation systemically. In the work described here, a methodology for metabolic labeling of prenylated proteins in living mice was first developed. It was then applied to humanized mouse strains that carry human APOE3 or APOE4 alleles. Prenylomic profiling revealed that a number of prenylated proteins were present at higher levels in animals harboring the APOE4 gene compared with those with the APOE3 allele, especially in the liver─a major APOE-producing organ. Importantly, some of these proteins have links to AD neuropathology.},
}

@article {pmid40767591,
year = {2025},
author = {Garrou, F and De Marchi, F and Corrado, L and Sacchetti, GM and D'alfonso, S and Morbelli, SD and Perani, D and Mazzini, L and Tondo, G},
title = {Challenging the boundaries: c9orf72 mutation presenting as Alzheimer's disease.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/21678421.2025.2541761},
pmid = {40767591},
issn = {2167-9223},
abstract = {C9orf72 hexanucleotide repeat expansion is a major cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), while its link with Alzheimer's disease (AD) is still unclear. We describe the case of a 53-year-old man with progressive memory and language deficits, mood disturbances, and a positive family history for ALS-FTD. Cerebrospinal fluid showed amyloid positivity, confirmed by amyloid-PET, with normal tau levels; [[18]F]FDG-PET revealed an AD-like temporoparietal hypometabolism. Genetic testing detected a pathogenic C9orf72 expansion, also present in his mother. This case suggests phenotypic heterogeneity of C9orf72-related disorders and a possible interplay with amyloid pathology.},
}

@article {pmid40767546,
year = {2025},
author = {Dupuis, L and Robertson, J},
title = {Is amyotrophic lateral sclerosis less severe in mice than in humans?.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
pmid = {40767546},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: We review here novel knock-in models of amyotrophic lateral sclerosis (ALS).

RECENT FINDINGS: Knock-in mouse models of various familial forms of ALS generally display a mild motor phenotype, with limited progression, that do not recapitulate the full-blown clinical picture of ALS.

SUMMARY: ALS is a devastating neurodegenerative disease in humans. Typically manifesting in the fifth or sixth decade of life, ALS leads to progressive motor dysfunction and death, usually within 2-5 years from symptom onset. A subset of ALS cases are dominantly inherited. Over the last 30 years, multiple mouse models of ALS have been generated, and recent advances in mouse genome editing techniques have enabled the generation of mouse strains carrying orthologous mutations in endogenous genes that mirror those causing familial forms of ALS. Intriguingly, many of these knock-in mouse models develop much milder phenotypes than patients with ALS carrying the same mutations. A full-blown ALS clinical phenotype seems to be only elicited upon overexpression of mutant genes beyond the endogenous levels. Here, we review these novel models and argue that these models could represent how ALS manifests in the mouse species. We also evaluate how these models could be used for characterizing mechanisms and preclinical drug evaluation.},
}

@article {pmid40766632,
year = {2025},
author = {Lacour, A and Vassallu, F and Rayes, D and Igaz, LM},
title = {Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.30.667669},
pmid = {40766632},
issn = {2692-8205},
abstract = {TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because i) serotonin deficits are a feature of ALS/FTD and ii) in C. elegans , they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors-including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter-with the cytoplasmic ΔNLS form causing more severe deficits. Serotonergic neurons remained i) morphologically intact, indicating that neuronal dysfunction precedes overt neurodegeneration; and ii) partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release is still partially functional. Altogether, our findings demonstrate that cytoplasmic TDP-43 disrupts neuronal signaling and behavior early in disease progression. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD.},
}

@article {pmid40766389,
year = {2025},
author = {Ferreon, JC and Choi, KJ and Quan, MD and Tsoi, PS and Ferreon, CC and Coskun, U and Liao, SJ and Ferreon, ACM},
title = {Modulation of biomolecular aggregate morphology and condensate infectivity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.30.667758},
pmid = {40766389},
issn = {2692-8205},
abstract = {Neurodegenerative diseases are characterized by pathological aggregates exhibiting distinct morphologies, such as neurofibrillary tangles and dense circular Lewy body-like structures in Alzheimer's disease, and round hyaline gel-like inclusions and skein-like filaments in amyotrophic lateral sclerosis. However, the mechanisms driving the formation of these diverse morphological structures remain poorly understood. Employing advanced microscopy, including fluorescence lifetime imaging, we investigated condensate aging and aggregation mechanisms of the prion-like domain of hnRNPA1 (A1PrD), a ribonucleoprotein implicated in both disorders. Using a simplified system across various salt and RNA conditions, we demonstrate that homotypic and heterotypic interactions between A1PrD and RNA significantly influence aggregate morphology and amyloid fibril formation, yielding diverse structures including thin fibrils, solid gels, and filamentous starburst aggregates. By tracking aggregate morphogenesis, we observed shifts in fluorescence lifetimes that reflect differences in condensate microenvironments, highlighting distinct homotypic and heterotypic interaction dynamics. Our findings indicate that amyloid fibril formation can initiate within fluid condensates or at the interfaces of solid gels. Moreover, early amyloid-rich fluid starbursts demonstrated the capability to fuse with or recruit younger amyloid-poor droplets, exemplifying prion-like infectivity and accelerating fibril formation. Collectively, our study provides evidence that the interplay between solution composition and the kinetic balance of liquid-liquid phase separation, gelation, and fibrillation contributes to the diverse pathological aggregate morphologies observed in neurodegenerative diseases.},
}

@article {pmid40766128,
year = {2025},
author = {Homann, J and Smith, AG and Morgan, S and Frick, EA and Liu, F and Viallon, V and Maurya, R and Korologou-Linden, R and Dobricic, V and Ohlei, O and Deecke, L and Hajizadah, F and Zhao, Y and Artaud, F and Smith-Byrne, K and Kolijn, PM and Huerta, JM and Winter, N and Guevara, M and Jimenez-Zabala, A and Sánchez, MJ and Trobajo-Sanmartín, C and Cabrera-Castro, N and Vinagre, A and Petrova, D and Sieri, S and Key, TJ and Wareham, N and Kaaks, R and Travis, RC and Hahn, T and Baker, S and Kelly, SM and Vermeulen, R and Peters, S and Masala, G and Sacerdote, C and Finkel, N and , and Elbaz, A and Hess, M and Katzke, V and Bertram, L and Gudnason, V and Robinson, O and Chen, H and Middleton, L and Winchester, LM and Tzoulaki, I and Gudmundsdottir, V and Walker, KA and Ferrari, P and Riboli, E and Gunter, MJ and Lill, CM},
title = {Large-scale plasma proteomics uncovers preclinical molecular signatures of Parkinson's disease and overlap with other neurodegenerative disorders.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.30.25332433},
pmid = {40766128},
abstract = {Parkinson's disease (PD) remains incurable, with a long preclinical phase currently undetectable by existing methods. In the largest proteomic study in neurodegenerative diseases to date, we analyzed blood samples from ∼74,000 individuals across discovery and validation cohorts. In the EPIC4PD discovery case-cohort, large-scale profiling of 7,285 proteins (SomaScan-7K) in 4,538 initially unaffected participants (574 incident cases) identified 17 proteins that predict PD up to 28 years before diagnosis. Additional proteins revealed sex-specific effects and time-dependent effect trajectories, capturing disease progression before symptom onset. Replication in three prospective cohorts (n=64,856; 1,034 incident cases) confirmed at least 12 key pre-diagnostic biomarkers with strong evidence, including TPPP2, HPGDS, ALPL, MFAP5, OGFR, ACAD8, TCL1A, GPC4, GSTA3, LCN2, KRAS, and GJA1. Preclinical biomarkers showed 86% concordant effect directions in independent prevalent PD cases (n=2,592; p=1.6×10 [-19]). Furthermore, in the longitudinal Tracking PD cohort (n=794), HPGDS and MFAP5 also predicted cognitive decline. Notably, several of the identified PD biomarkers overlapped with those for incident Alzheimer's disease and amyotrophic lateral sclerosis, indicating shared molecular signatures. A machine learning-derived protein score improved PD risk prediction in external validation. This extensive proteomics effort identified novel, actionable biomarkers opening new avenues for early PD risk stratification and precision medicine.},
}

@article {pmid40764817,
year = {2025},
author = {Hu, Y and Chourpiliadis, C and Ingre, C and Ahlqvist, VH and Sun, J and Song, H and Pawitan, Y and Piehl, F and Fang, F},
title = {Hospital-treated infections and the risk and prognosis of amyotrophic lateral sclerosis: A population-based study.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70008},
pmid = {40764817},
issn = {1365-2796},
support = {MegaALS 802091//European Research Council Starting Grant/ ; R01TS000348/ACL/ACL HHS/United States ; 2023-02428//Swedish Research Council/ ; 1R01NS131433-01//National Institute for Aging and the National Institute of Neurological Disorders and Stroke/ ; },
abstract = {BACKGROUND: Infection has been suspected as a risk factor for amyotrophic lateral sclerosis (ALS). However, previous research has focused on specific pathogens and rarely examined the influence of infection on disease progression.

OBJECTIVES: To assess whether hospital-treated infections correlate with the risk and prognosis of ALS.

METHODS: Using data from the Swedish Motor Neuron Disease Quality Registry, we conducted three nested case-control studies, including 1159 individuals diagnosed with ALS during 2015-2023 and 5795 age- and sex-matched population controls, 1558 full-sibling controls, and 680 spouse controls, respectively. We used conditional logistic regression to estimate the association of hospital-treated infections with subsequent risk of ALS and Cox model to assess the association of pre- or post-diagnostic infections with mortality after an ALS diagnosis.

RESULTS: Hospital-treated infections before diagnosis were associated with an increased risk of ALS in the population comparison (odds ratio [OR] 1.31; 95% confidence interval [CI] 1.15-1.49). A similar association was noted after excluding infections within 3-, 5-, or 10-years preceding ALS diagnosis and was confirmed in sibling and spouse comparisons, although results were not always statistically significant. Patients with a hospital-treated infection before diagnosis were more likely to present with bulbar symptoms, poorer functional status, and higher prevalence of anxiety and depressive symptoms at diagnosis than others. Pre-diagnostic infections were not associated with mortality, whereas post-diagnostic infections were associated with increased mortality (hazard ratio [HR] 1.89; 95%CI 1.59-2.24) among ALS patients.

CONCLUSION: Hospital-treated infections are associated with an increased risk of ALS and may modify its clinical presentation at diagnosis. Post-diagnostic infections are associated with poor survival in ALS.},
}

@article {pmid40764463,
year = {2025},
author = {Landry, C and Costanzo, JP and Mitne-Neto, M and Zatz, M and Schaffer, AE and Hatzoglou, M and Muotri, AR and Miranda, HC},
title = {Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s44321-025-00279-3},
pmid = {40764463},
issn = {1757-4684},
support = {K01NS116119//NIH NINDS/ ; R01NS123524/GF/NIH HHS/United States ; DK060596/GF/NIH HHS/United States ; },
abstract = {Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials.},
}

@article {pmid40764342,
year = {2025},
author = {Lépine, S and Maussion, G and Schneider, A and Nauleau-Javaudin, A and Castellanos-Montiel, MJ and Ambriz, GJ and Spiegelman, D and Abdian, N and Franco-Flores, AK and Haghi, G and Gursu, L and Fiorini, MR and Dilliott, AA and Farhan, SMK and Chaineau, M and Durcan, TM},
title = {Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {28555},
pmid = {40764342},
issn = {2045-2322},
mesh = {*Pyrimidines/pharmacology ; Humans ; *Motor Neurons/metabolism/drug effects ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; *Cyclopentanes/pharmacology ; *Transcriptome ; *NEDD8 Protein/metabolism/antagonists & inhibitors ; Gene Knock-In Techniques ; Gene Expression Profiling ; Mutation ; Induced Pluripotent Stem Cells/metabolism ; },
abstract = {A growing body of knowledge implicates perturbed RNA homeostasis in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that currently has no cure and few available treatments. Dysregulation of the multifunctional RNA-binding protein TDP-43 is increasingly regarded as a convergent feature of this disease, evidenced at the neuropathological level by the detection of TDP-43 pathology in most patient tissues, and at the genetic level by the identification of disease-associated mutations in its coding gene TARDBP. To characterize the transcriptional landscape induced by TARDBP mutations, we performed whole-transcriptome profiling of motor neurons (MNs) differentiated from two knock-in iPSC lines expressing the ALS-linked TDP-43 variants p.A382T or p.G348C. Our results show that the TARDBP mutations significantly altered the expression profiles of mRNAs and microRNAs of the 14q32 cluster in MNs. Using mutation-induced gene signatures and the Connectivity Map database, we identified compounds predicted to restore gene expression toward wild-type levels. Among top-scoring compounds selected for further investigation, the NEDD8-activating enzyme inhibitor MLN4924 effectively improved cell viability and neuronal activity, highlighting a possible role for protein post-translational modification via NEDDylation in the pathobiology of TDP-43 in ALS.},
}

*Pyrimidines/pharmacology
Humans
*Motor Neurons/metabolism/drug effects
Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*DNA-Binding Proteins/genetics/metabolism
*Cyclopentanes/pharmacology
*Transcriptome
*NEDD8 Protein/metabolism/antagonists & inhibitors
Gene Knock-In Techniques
Gene Expression Profiling
Mutation
Induced Pluripotent Stem Cells/metabolism

@article {pmid40764041,
year = {2025},
author = {Nguyen, M and Orengo, JP and Grouls, A},
title = {Letter: Advance Care Planning Documentation Changes Among Neurologists in an Amyotrophic Lateral Sclerosis Clinic with Addition of Specialist Palliative Care.},
journal = {Journal of palliative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1177/10966218251365262},
pmid = {40764041},
issn = {1557-7740},
}

@article {pmid40763713,
year = {2025},
author = {Linna, N and Tervonen, LA and Aaltonen, M and Portaankorva, AM and Krüger, J},
title = {Epidemiology of Amyotrophic Lateral Sclerosis in Western and Northern Finland.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-18},
doi = {10.1159/000547562},
pmid = {40763713},
issn = {1423-0208},
abstract = {INTRODUCTION: The aims of this study were to define the incidence and prevalence of amyotrophic lateral sclerosis (ALS) in two north-western regions in Finland and to assess clinical ALS phenotypes in these areas.

METHODS: We conducted a retrospective epidemiologic study by using hospital discharge registers in the regions of Central Ostrobothnia (population 68 158 in 2019) and Northern Ostrobothnia (population 412 830). All patients diagnosed with ALS during 2010-2019 and living in either region were included in the incidence study. The prevalence day was December 31, 2019. All ALS diagnoses were retrospectively re-evaluated and the clinical phenotype data reviewed and reassessed.

RESULTS: In total, 214 ALS patients were identified. The age-adjusted 10-year incidence of ALS was 5.4/100 000 person-years in Central Ostrobothnia and 4.6/100 000 person-years in Northern Ostrobothnia. The age-adjusted prevalence rates were 13.1 and 14.6/100 000, respectively. The mean survival after the diagnosis was 16.8 months. Frontotemporal dementia (FTD) was identified in 15% of all patients. ALS-FTD was relatively more common among patients with bulbar or respiratory onset ALS (25%) than among those with limb-onset ALS (8%). Approximately 13% of the ALS patients had a positive family history for ALS. Genetic testing had been performed in 53 % of all cases and the most tested mutations were C9orf72 hexanucleotide repeat expansion (32%) and D90A-SOD1 (40%). C9orf72 repeat expansion was detected in 8% and a D90A-SOD1 mutation in 6% of all cases, that is 26% and 14% of all tested cases, respectively.

CONCLUSION: The incidence and prevalence rates of ALS in Finland are among the highest in the world. ALS-FTD seems to be more common among patients with bulbar or respiratory onset ALS than among those with spinal-onset disease. Cognitive evaluation of ALS patients and offering a possibility to genetic testing should be systematic in clinical practise.},
}

@article {pmid40762423,
year = {2025},
author = {Mietzner, G and Lümkemann, L and Schreiber, F and Brüggemann, J and Benramadan, A and Al-Dubai, M and Sciarra, A and Knoll, C and Kuehn, E and Speck, O and Schreiber, S and Mattern, H},
title = {Assessing Arterial Patterns in the Motor Cortex With 7 Tesla Magnetic Resonance Imaging and Vessel Distance Mapping.},
journal = {Human brain mapping},
volume = {46},
number = {11},
pages = {e70311},
doi = {10.1002/hbm.70311},
pmid = {40762423},
issn = {1097-0193},
support = {362321501//Deutsche Forschungsgemeinschaft/ ; 425899996//Deutsche Forschungsgemeinschaft/ ; 446268581//Deutsche Forschungsgemeinschaft/ ; 501214112//Deutsche Forschungsgemeinschaft/ ; BB-DARS//Deutsche Alzheimer Gesellschaft/ ; MD-DARS//Deutsche Alzheimer Gesellschaft/ ; },
mesh = {Humans ; *Motor Cortex/blood supply/diagnostic imaging/anatomy & histology ; Male ; *Magnetic Resonance Imaging/methods ; Female ; Adult ; Young Adult ; *Cerebral Arteries/diagnostic imaging/anatomy & histology ; Image Processing, Computer-Assisted ; Middle Aged ; },
abstract = {Leveraging high-resolution 7 T magnetic resonance imaging (MRI) and vessel distance mapping (VDM), the arterial supply patterns and dominances of the motor cortex, which could previously only be studied postmortem, were assessed in vivo and fully noninvasively. Beyond vessel patterns and dominances, the potential relation between the vascularization and the motor cortex thickness was studied. Twenty-one healthy participants underwent 7 T MRI scans to map arterial supply and motor cortex at 0.45 mm isotropic resolution. The motor cortex vasculature was segmented manually with vessel-specific labels. VDM was utilized to estimate the vessel-specific supply regions and, subsequently, assess vessel patterns and dominances. Statistical tests were applied to test if the vasculature impacts mean motor cortical thickness estimates. Vessel patterns, that is the presence of supplying vessels, were classified as three-, four-, and five-vessel patterns with a prevalence of 26.3%, 50.0%, and 23.7%, respectively. Vessel dominance, that is the ratio of supply volumes, of the ACA branches showed dominance of the pericallosal artery, callosomarginal artery, and equal contribution, in 34.2%, 34.2%, and 31.6% of the cases, respectively. For the MCA groups, the prevalence of precentral group dominance, central group dominances, and equal contribution was 13.2%, 34.2%, and 52.6%, respectively. Although the central and precentral groups were found in all hemispheres, the postcentral group was found in 28.9% of hemispheres with highly variable supply contribution. Statistical tests returned no significance for the effect of vessel patterns and dominances on the mean motor cortex thickness. With 7 T MRI and VDM, the motor cortex vascularization can be assessed fully noninvasively and longitudinally while providing overall good concordance with previous post mortem studies. Our comprehensive analysis of arterial motor cortex vascularization showed considerable variability between hemispheres, rendering the usage of pattern-specific atlases and analysis more suitable than single normative representations. The successful translation from post mortem to in vivo enables the study of vascular reserve in disorders affecting the motor cortex, such as ALS, and can be translated to other brain regions and neurodegenerative diseases in the future.},
}

Humans
*Motor Cortex/blood supply/diagnostic imaging/anatomy & histology
Male
*Magnetic Resonance Imaging/methods
Female
Adult
Young Adult
*Cerebral Arteries/diagnostic imaging/anatomy & histology
Image Processing, Computer-Assisted
Middle Aged

@article {pmid40762148,
year = {2025},
author = {Mascias Cadavid, J and Mena Bravo, A and Barkhaus, P and Barnes, B and Benatar, M and Breevoort, S and Brown, A and Carter, GT and Crayle, J and Foucher, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Mcdermott, C and Pattee, G and Pierce, K and Pioro, E and Ratner, D and Rivner, M and Tito, E and Wicks, P and Bedlack, R},
title = {ALSUntangled #80: ISRIB (Integrated stress response InhiBitor).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/21678421.2025.2542919},
pmid = {40762148},
issn = {2167-9223},
abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we assess ISRIB, a molecule that attenuates the integrated stress response (ISR). The ISR is an intracellular signaling network through which cells normally respond to stress, but in ALS it appears to be overactive, leading to the formation of "stress granules" which some but not all investigators believe can triggerapoptotic cell death. ISRIB can attenuate the formation of these stress granules while still allowing parts of protein synthesis to continue. Pre-clinical data demonstrate that ISRIB is beneficial in cell models of ALS. A small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects, though we have not been able to independently verify these benefits. There are no clinical trials evaluating ISRIB in any condition and questions about its solubility and bioavailability have arisen. Currently, we do not have enough evidence to endorse the use of ISRIB for treating ALS. We support further research in disease models and clinical trials to study pharmacokinetics, safety and efficacy.},
}

@article {pmid40760897,
year = {2025},
author = {Kicherova, OA and Doyan, YI and Kicherova, KP and Reichert, LI and Root, VA},
title = {[Sporadic form of Guam disease (ALS-parkinsonism-dementia complex)].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {125},
number = {7},
pages = {135-141},
doi = {10.17116/jnevro2025125071135},
pmid = {40760897},
issn = {1997-7298},
mesh = {Humans ; Male ; Diagnosis, Differential ; *Frontotemporal Dementia/diagnosis ; Middle Aged ; Aged ; *Parkinsonian Disorders/diagnosis ; Female ; *Dementia/diagnosis ; },
abstract = {Guam disease (ALS-parkinsonism-dementia complex) is a rare endemic condition of progressive generalized degeneration of CNS neurons. Despite the apparent association of the disease with the Pacific region, sporadic cases of Guam disease have been described in other countries of the world, where the term "ALS with frontotemporal dementia" is used to refer to it. The authors cite their own clinical case of the disease, as well as discuss aspects of the clinical presentation, etiology, pathogenesis, diagnosis, and differential diagnosis of similar conditions.},
}

Humans
Male
Diagnosis, Differential
*Frontotemporal Dementia/diagnosis
Middle Aged
Aged
*Parkinsonian Disorders/diagnosis
Female
*Dementia/diagnosis

@article {pmid40760788,
year = {2025},
author = {Ke, S and Yan, J and Li, B and Feng, X},
title = {Causal Association Between Immune Cell Traits and Risk of Multiple Malignant and Nonmalignant CNS Diseases: A Mendelian Randomization and Single-Cell Transcriptomic Analysis.},
journal = {Brain and behavior},
volume = {15},
number = {8},
pages = {e70632},
doi = {10.1002/brb3.70632},
pmid = {40760788},
issn = {2162-3279},
mesh = {Humans ; Mendelian Randomization Analysis ; Single-Cell Analysis ; Quantitative Trait Loci/genetics ; Glioblastoma/genetics/immunology ; *Central Nervous System Diseases/genetics/immunology ; Transcriptome ; Gene Expression Profiling ; Brain Neoplasms/genetics/immunology ; },
abstract = {BACKGROUND: The influence of immune cell traits (ICTs) on the onset of multiple brain diseases has been previously investigated; however, it is limited by the sample size or colocalization evidence. Besides, the impact remains inconclusive.

METHODS: We performed a Mendelian randomization (MR) study to elucidate the causal correlation between significant ICTs and diverse brain disorders and explored the biomarkers linked to glioblastoma (GBM), a form of solid tumor, by integrating expression quantitative trait locus (eQTL) and single-cell RNA sequencing (scRNA-seq) analyses. The nonnegative matrix factorization (NMF) method was utilized to reclassify malignant cells into distinct cell states. Related functional analyses at the scRNA-seq level were also performed.

RESULTS: We examined 731 ICTs across 13 brain disorders; impacts from these ICTs varied a lot across different brain diseases. Such ICTs mainly involved T/natural killer (NK) cell activation, B cell differentiation, and myeloid cell suppression or activation. Pleiotropy or heterogeneity in current results has been checked and excluded via sensitivity analyses. Specifically, colocalization analyses demonstrated protective roles of distinct ICTs in T/B/NK cell panels for amyotrophic lateral sclerosis (ALS) and GBM, while myeloid and human leukocyte antigen (HLA)-associated traits were associated with increased risk of Alzheimer's disease (AD), and then two memory cell traits were linked to the increased risk of major depressive disease (MDD). By NMF, we identified six distinct cell states within GBM cells. Furthermore, we established an eight-marker glioblastoma risk signature (GBRS) using scRNA-seq and eQTL data, with higher GBRS scores observed in the NFkB cluster and EGFR cluster, indicating their highlighted aggression among malignant cells. Epigallocatechin gallate could be an effective treatment candidate targeting the EGFR cluster via markers of SQLE and VCP.

CONCLUSION: Our findings identified causal effects of distinct ICTs on both malignant and nonmalignant brain diseases and underscored the pivotal role of neuroinflammation in their etiology. With combined evidence from eQTL and scRNA-seq, GBM could be better characterized and managed.},
}

Humans
Mendelian Randomization Analysis
Single-Cell Analysis
Quantitative Trait Loci/genetics
Glioblastoma/genetics/immunology
*Central Nervous System Diseases/genetics/immunology
Transcriptome
Gene Expression Profiling
Brain Neoplasms/genetics/immunology

@article {pmid40760594,
year = {2025},
author = {Zhang, Q and Zhou, X and Yang, G and Zhang, L},
title = {Atopic dermatitis in amyotrophic lateral sclerosis successfully treated by dupilumab: A case report.},
journal = {Medicine},
volume = {104},
number = {31},
pages = {e43737},
doi = {10.1097/MD.0000000000043737},
pmid = {40760594},
issn = {1536-5964},
mesh = {Humans ; Male ; Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/complications ; *Dermatitis, Atopic/drug therapy/complications ; Pruritus/drug therapy/etiology ; },
abstract = {RATIONALE: Atopic dermatitis (AD) is a common skin disorder characterized by symmetric erythematous papules in flexural areas, with pruritus of varying intensity persisting throughout its course. Amyotrophic lateral sclerosis (ALS) is a neurological disease with progressive loss of muscle function, and its treatment remains a challenge worldwide. When patients suffer from both conditions, the skin issues are often overlooked by both physicians and family members. However, the pruritus becomes unbearable for the patients, particularly as they experience a progressive loss of the ability to scratch autonomously.

PATIENT CONCERNS: An elderly 75-year-old male patient with comorbid ALS and AD, suffering from prolonged pruritus, had lost faith in all topical and oral medications.

DIAGNOSIS: AD and ALS.

INTERVENTIONS: The patient received subcutaneous dupilumab with an initial 600 mg dose followed by 300 mg every 2 weeks, and was monitored for 12 weeks during follow-up.

OUTCOMES: The patient exhibited gradual reduction in pruritus severity and skin lesions throughout the treatment course. No adverse reactions other than mild conjunctivitis were reported.

LESSONS: This case demonstrates the successful application of dupilumab in an AD patient with comorbid ALS. It not only provides a clinically instructive case reference for dupilumab therapy in AD, but also underscores that pruritus in ALS patients warrants greater clinical attention.},
}

Humans
Male
Aged
*Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage
*Amyotrophic Lateral Sclerosis/complications
*Dermatitis, Atopic/drug therapy/complications
Pruritus/drug therapy/etiology

@article {pmid40760014,
year = {2025},
author = {Farahani, A and Hansen, JY and Bazinet, V and Shafiei, G and Collins, DL and Dadar, M and Kalra, S and Dagher, A and Misic, B},
title = {Network spreading and local biological vulnerability in amyotrophic lateral sclerosis.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {1153},
doi = {10.1038/s42003-025-08561-3},
pmid = {40760014},
issn = {2399-3642},
support = {RGPIN-2017-04265//Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)/ ; PJT-180439//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; CRC-2022-00169//Canada Research Chairs (Chaires de recherche du Canada)/ ; MJFF-021133//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/metabolism/physiopathology/genetics ; Humans ; Female ; Atrophy ; Male ; Middle Aged ; *Motor Cortex/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Neuroimaging ; Aged ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that predominantly targets the motor system. Spread of pathology is thought to be driven by both local vulnerability and network architecture. Namely, molecular and cellular features may confer vulnerability to specific neuronal populations, while synaptic contacts may also increase exposure to pathology in connected neuronal populations. However, these principles are typically studied in isolation and it remains unknown how local vulnerability and network spreading interact to shape cortical atrophy. Here, we investigate how network structure and local biological features shape the spatial patterning of atrophy in ALS. We analyze the Canadian ALS Neuroimaging Consortium (CALSNIC) dataset and estimate cortical atrophy using deformation based morphometry (DBM). The course of atrophy closely aligns with structural connectivity. Atrophy is also more likely to occur in regions that share similar metabolic profiles. Disease epicenters are located in motor cortex. Epicenter probability maps show transcriptomic enrichment for biological processes involved in mitochondrial function as well as support cells, including endothelial cells and pericytes. Finally, individual differences in epicenter location correspond to individual differences in clinical and cognitive symptoms and differentiate patient subtypes.},
}

*Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/metabolism/physiopathology/genetics
Humans
Female
Atrophy
Male
Middle Aged
*Motor Cortex/pathology/diagnostic imaging
Magnetic Resonance Imaging
Neuroimaging
Aged

@article {pmid40759286,
year = {2025},
author = {Gunner, G and Basu, H and Lu, Y and Bergstresser, M and Sun, L and Neel, D and Choi, SY and Chiu, IM},
title = {Gasdermin D is activated but does not drive neurodegeneration in SOD1[G93A] model of ALS: Implications for targeting pyroptosis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107048},
doi = {10.1016/j.nbd.2025.107048},
pmid = {40759286},
issn = {1095-953X},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1[G93A] mouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1[G93A] animals with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred C57Bl/6 J.SOD1[G93A] mice onto a C57Bl/6NJ.GSDMD-deficient background. In comparing SOD1[G93A]; Gsdmd+/+ and SOD1[G93A]; Gsdmd-/- mice, we found that Gsdmd loss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1[G93A] mice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.},
}

@article {pmid40758998,
year = {2025},
author = {Jin, Y and Ganguly, P and Shea, JE and Buratto, SK and Bowers, MT},
title = {Aggregation of TDP-43307-319: A Dual Pathway to Forming Cylindrins and Fibrils and a Contribution to the Etiology of Amyotrophic Lateral Sclerosis.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c02640},
pmid = {40758998},
issn = {1520-5207},
abstract = {The pathological aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a hallmark of amyotrophic lateral sclerosis, and mutations within its low-complexity domain are known to influence its aggregation propensity and toxicity. Previous studies from our group and others have shown that TDP-43307-319 located at the C-terminus of TDP-43 is toxic and can form higher-order oligomers and fibrils. Of particular interest are the hexamers, which adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we used a combination of ion mobility spectroscopy-mass spectrometry (IMS-MS), atomic force microscopy (AFM), and molecular dynamics simulations to probe the oligomer distribution resulting from the earliest times (the first 5 to 15 min) of incubation at varying concentrations for three different TDP-43307-319 mutations: wild-type (WT), A315T, and G314V. In this way, it was possible to trace the oligomer distributions at the initial stages of aggregation while avoiding the complication from aggregation-induced sedimentation over long periods. We found that both WT and A315T rapidly form stable hexamers and higher-order oligomers at low concentrations. As the concentration is increased, the IMS-MS oligomer distribution changes to favor small oligomers over the hexamers and higher-order oligomers for both WT and A315T. AFM shows that this shift in oligomer distribution is due to the formation of fibrils that are seeded by trimers and tetramers. This complex concentration dependence is attributed to two different kinetic paths: one at low concentration that favors the formation of hexamers/cylindrins and one at high concentration that favors fibril formation. Furthermore, the G314V mutation is nontoxic and does not show evidence of the two kinetic paths as hexamers are not formed at any concentration whereas fibril formation is observed at all concentrations.},
}

@article {pmid40758885,
year = {2025},
author = {Miller, SL and Green, KM and Crone, B and Switzenberg, JA and Tank, EMH and Krans, A and Jansen-West, K and Wieland, CM and Ji, EW and Petrucelli, L and Barmada, SJ and Boyle, AP and Todd, PK},
title = {Cryptic intronic transcriptional initiation generates efficient endogenous mRNA templates for C9orf72-associated RAN translation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {32},
pages = {e2507334122},
doi = {10.1073/pnas.2507334122},
pmid = {40758885},
issn = {1091-6490},
support = {F31127371//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; F31NS100302//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS097542 P01NS08497 and R35NS097273//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS113943 and 1R56NS128110//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21HG011493 and R01GM144484//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS099280//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; BLRD BX004842//U.S. Department of Veterans Affairs (VA)/ ; },
mesh = {*C9orf72 Protein/genetics/metabolism ; Animals ; *Introns/genetics ; Humans ; *RNA, Messenger/genetics/metabolism ; Mice ; *Protein Biosynthesis ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/metabolism ; DNA Repeat Expansion ; *ran GTP-Binding Protein/genetics/metabolism ; Transcription, Genetic ; },
abstract = {Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5' RNA ligase-mediated rapid amplification of cDNA ends (5' Repeat-RLM-RACE), we identified C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m[7]G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, intronic template transcripts-even those with short (32 nucleotide) leaders-exhibited robust expression compared to exon-intron and repeat-containing lariat reporters. To assess endogenous repeat-containing lariat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m[7]G-capped intron-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development.},
}

*C9orf72 Protein/genetics/metabolism
Animals
*Introns/genetics
Humans
*RNA, Messenger/genetics/metabolism
Mice
*Protein Biosynthesis
Amyotrophic Lateral Sclerosis/genetics/metabolism
Frontotemporal Dementia/genetics/metabolism
DNA Repeat Expansion
*ran GTP-Binding Protein/genetics/metabolism
Transcription, Genetic

@article {pmid40758370,
year = {2025},
author = {Lam, K and Cenzer, I and Ankuda, CK and Levy, CR and Smith, AK and Covinsky, KE and Kotwal, AA},
title = {Social Participation Among Older Adults Before and After Long-Term Care Facility Entry.},
journal = {JAMA internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamainternmed.2025.3684},
pmid = {40758370},
issn = {2168-6114},
abstract = {IMPORTANCE: Social participation is essential throughout life and is associated with decreased mortality and increased quality of life. It is unknown whether long-term care facility (LTCF) entry disrupts or facilitates it.

OBJECTIVES: To determine longitudinal trends in social participation before and after entry into nursing homes (NHs) and assisted living facilities (ALs) and to explore factors associated with participation.

This nationally representative longitudinal cohort study using prospectively collected annual data from the US National Health and Aging Trends Study from 2011 to 2019 included community-dwelling Medicare beneficiaries entering LTCFs. Interviews conducted 4 years before and 2 years after NH or AL entry (index date) were included. Data analysis was performed from September 16, 2022, to May 25, 2025.

MAIN OUTCOMES AND MEASURES: Two categories of social participation comprising 5 activities were assessed: socialization (visiting with friends or family and going out for enjoyment) and community participation (attending religious services, participating in clubs or other organized activities, and volunteering). Participation over time was modeled using linear splines before, upon, and after LTCF entry. Modified Poisson regressions were used to explore associations with maintaining and starting activities, adjusted for age, sex, race and ethnicity, and proxy response were used.

RESULTS: The total sample included 606 LTCF entrants (weighted mean [SD] age 85 [7.4] years, 404 female [66% weighted]), of whom 104 individuals were Black (7%), 23 Hispanic (4%), 464 White (86%); and 15 of any other race and ethnicity (3%). Before entry, social participation decreased in all activities (-4.7 to -2.0% annually). Of the total, 275 (44%) entered a NH and 331 (56%) entered an AL facility. Upon entry, going out for enjoyment decreased (-14.1%), but club participation and religious attendance increased (15.6% and 12.6%, respectively). Before LTCF entry, social participation decreased in all activities (-4.7 to -2.0% annually). After entry, going out for enjoyment decreased (-14.1%), but club participation and religious attendance (12.6%) increased (15.6% and 12.6%, respectively). In exploratory analyses, women were more likely to maintain visits (adjust risk ratio [aRR], 1.3; 95% CI, 1.1-1.5) and start attending religious services (aRR, 1.6; 95% CI, 1.0-2.8). NH residents were less likely to go out for enjoyment (aRR, 0.6; 95% CI, 0.5-0.8 for maintaining; aRR, 0.6; 95% CI, 0.4-1.0 for starting) and keep attending religious services (aRR, 0.7; 95% CI, 0.6-0.9). Black, Hispanic, and residents of other race or ethnicity were much less likely to start going out for enjoyment (aRR, 0.3; 95% CI, 0.1-0.8).

CONCLUSIONS AND RELEVANCE: This cohort study found that LTCF entry generally promoted community participation and reduced socialization. Benefits may be less likely among men, NH entrants, and residents of racial and ethnic minority groups.},
}

@article {pmid40758256,
year = {2025},
author = {Sharma, A and Nb, K},
title = {Dose-dependent effects of Arimoclomol in ALS: insights from a network meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40758256},
issn = {1590-3478},
}

@article {pmid40757593,
year = {2024},
author = {Orsini, M and Pinto, WBVR and Sgobbi, P and Oliveira, ASB},
title = {PRKAG2 Variant, Motor Neuron Disease, and Parkinsonism: Fortuitous Association or a Potentially Underestimated Pathophysiological Mechanism?.},
journal = {Muscles (Basel, Switzerland)},
volume = {3},
number = {3},
pages = {235-241},
doi = {10.3390/muscles3030021},
pmid = {40757593},
issn = {2813-0413},
abstract = {A 72-year-old Brazilian woman presented with a 4-year history of rest tremors of the hands, followed by slowness of movement, and a diagnosis of idiopathic Parkinson's disease. She was started on dopamine agonists with significant improvement. After three years, she complained about slowly progressive dysphagia, dysphonia, quadriparesis, and cramps and fasciculations. A neurological examination disclosed distal-dominant quadriparesis, dysarthria, atrophy and fasciculation of the tongue, global brisk tendon reflexes, fasciculations, bilateral ankle clonus, and moderate spasticity of the lower limbs. She had also palpitations, dyspnea, and one episode of paroxysmal atrial fibrillation. Electrocardiography revealed a short PR interval, a widened QRS complex, and the delta wave, suggestive of Wolff-Parkinson-White syndrome. Brain and spine MR imaging, a cerebrospinal fluid analysis, and general serum lab exams were unremarkable. Needle electromyography disclosed chronic denervation involving cervical, thoracic, lumbosacral, and bulbar levels associated with acute denervation, including positive sharp waves, fasciculations, and fibrillation potentials. This patient fulfilled the diagnostic criteria for amyotrophic lateral sclerosis associated with parkinsonism. A broad next-generation sequencing-based panel disclosed the presence of the novel heterozygous variant c.1247C > T (p.Pro416Leu) in the PRKAG2 gene (NM_016203.4). Clinicians must be aware of the possibility of PRKAG2 variants in complex clinical scenarios associating cardiac arrhythmia, preexcitation syndromes, hypertrophic cardiomyopathy, motor neuron disease, and parkinsonism.},
}

@article {pmid40757018,
year = {2025},
author = {Kato, N and Suzuki, R and Kaneko, H and Horimoto, Y},
title = {Effects of telerehabilitation on physical function and activities of daily living in patients with amyotrophic lateral sclerosis: a scoping review.},
journal = {Journal of physical therapy science},
volume = {37},
number = {8},
pages = {427-434},
pmid = {40757018},
issn = {0915-5287},
abstract = {[Purpose] This study aimed to clarify the effects of telerehabilitation on physical function and activities of daily living in patients with amyotrophic lateral sclerosis through a literature review. [Participants and Methods] We conducted a scoping review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews reporting guidelines. The PubMed, Scopus, Web of Science, and ProQuest databases were searched. Study design, type of interventions, telerehabilitation methods, adherence, effectiveness, adverse events, and patient satisfaction were extracted from the selected literature. [Results] Four case-series and one case-control study were identified. The interventions included respiratory muscle training (two studies), aerobic exercise, stretching, and comprehensive physical therapy (one study each). Various modalities were used, including videoconferencing, on-demand instructional videos, and real-time monitoring of vital signs using wearable devices. No serious adverse events were reported in any study. The dropout rate was 0-21%, and the compliance rate was 90%, indicating high adherence. Improvements in respiratory function and ADL were observed following respiratory rehabilitation. Patient satisfaction with telerehabilitation was high. [Conclusion] Telerehabilitation may improve adherence, respiratory function, and activities of daily living in patients with amyotrophic lateral sclerosis. However, its effects on other aspects of physical function remain unclear. Further high-quality studies are needed to establish evidence-based practices.},
}

@article {pmid40755012,
year = {2025},
author = {Chen, S and Xu, C and Liu, C and Li, J and Ke, S and Lu, Y and Huang, Y and Chen, J and Lin, F and Huang, H and Zou, Z},
title = {Immune checkpoint changes correlate with the progression and prognosis of amyotrophic lateral sclerosis.},
journal = {Annals of medicine},
volume = {57},
number = {1},
pages = {2540023},
doi = {10.1080/07853890.2025.2540023},
pmid = {40755012},
issn = {1365-2060},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/blood/diagnosis ; Male ; Female ; Middle Aged ; Prognosis ; Disease Progression ; CD4-Positive T-Lymphocytes/immunology/metabolism ; Aged ; Biomarkers/blood ; *Programmed Cell Death 1 Receptor/blood/immunology ; Neurofilament Proteins/blood ; Adult ; Case-Control Studies ; Flow Cytometry ; *Immune Checkpoint Proteins/blood ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) urgently requires robust biomarkers for early diagnosis and prognostic stratification. This study aims to investigate the diagnostic and prognostic potential of membrane-bound and soluble immune checkpoint molecules in ALS pathogenesis.

METHODS: In the present study at Fujian Medical Union Hospital, 72 participants (46 ALS and 26 healthy controls [HC]) underwent flow cytometry analysis of PD-1 expression in CD4[+] T cells and its subsets. A second cohort (n = 93, 44 ALS, 30 HC and 19 ALS mimics [Mimics]) was evaluated using Luminex technology for 14 serum immune checkpoint molecules. A single-molecule array was used to screen the neurofilament light chain (NFL) in serum.

RESULTS: Flow cytometry revealed elevated PD1 expression in CD4[+] T cells, particularly in Th9 and Th17 subsets (p < 0.05). ALS patients exhibiting a greater percentage of PD-1 in CD4[+] T cells showed accelerated functional decline. Serum analyses identified four elevated soluble checkpoints in ALS versus both HCs and Mimics (sPD-1/sBTLA/sCTLA-4/sCD27, p < 0.05), with sCD28/TIM-3 showing higher in ALS than in Mimics, and sGITR/sCD137/sIDO/sCD80/sLAG3/sPD-L2 elevating in ALS compared to HCs. Soluble TIM-3 correlated inversely with ALSFRS-R, while sPD-L1 demonstrated dual associations: negative with ALSFRS-R and positive with NFL (all p < 0.05).

CONCLUSIONS: Our research demonstrated a considerable increase in membrane-bound and soluble PD-1 in ALS patients, correlating with disease progression and worse prognosis. Furthermore, we explored 13 other immune checkpoint molecules. Collectively, these molecules may be implicated in peripheral immune mechanisms underlying ALS pathogenesis. While baseline PD-1 levels show some association with prognosis, their elevation potentially indicates an unfavorable course.},
}

Humans
*Amyotrophic Lateral Sclerosis/immunology/blood/diagnosis
Male
Female
Middle Aged
Prognosis
Disease Progression
CD4-Positive T-Lymphocytes/immunology/metabolism
Aged
Biomarkers/blood
*Programmed Cell Death 1 Receptor/blood/immunology
Neurofilament Proteins/blood
Adult
Case-Control Studies
Flow Cytometry
*Immune Checkpoint Proteins/blood

@article {pmid40754996,
year = {2025},
author = {Stam, R},
title = {Low frequency magnetic field exposure and neurodegenerative disease: systematic review of animal studies.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/15368378.2025.2540435},
pmid = {40754996},
issn = {1536-8386},
abstract = {Epidemiological studies have found an association between occupational exposure to low frequency magnetic fields and the occurrence of motor neuron disease and Alzheimer's disease. No association has been found for Parkinson's disease and the evidence for multiple sclerosis is insufficient. Animal models studying the effects of low frequency magnetic fields on neurodegenerative disease induction or progression could provide more evidence on causation and the underlying mechanisms. A systematic search and review was conducted of peer-reviewed research articles involving animal experiments on the effects of low frequency magnetic field exposure on behavioural and neuroanatomical outcomes relevant for neurodegenerative diseases in humans. Firstly, experimental studies in naive animals do not support a causal relationship between exposure to low frequency magnetic fields and the induction of neuropathology relevant for Alzheimer's disease, but the number of studies relevant for motor neuron disease, multiple sclerosis and Parkinson's disease is too limited to draw conclusions. Secondly, experimental studies in existing animal models for neurodegenerative disease support a therapeutic (beneficial) effect of low frequency magnetic field treatment on behavioural and neuroanatomical abnormalities relevant for dementia (including Alzheimer's disease), multiple sclerosis and Parkinson's disease and no effect on disease progression in models relevant for motor neuron disease.},
}

@article {pmid40754251,
year = {2025},
author = {Sepulveda, M and MartinezTraub, F and Ojeda, P and Mella, J and Ojeda, J and Pinto, C and Diaz, R and Rozas, P and Sepulveda, C and Kerr, B and Morales, V and Saaranen, M and Ruddock, L and Medinas, DB and Henriquez, JP and Hetz, C},
title = {Expression of amyotrophic lateral sclerosis associated protein disulfide isomerase A3 D217N variant recapitulates early morphological alterations at the neuromuscular junction.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107045},
doi = {10.1016/j.nbd.2025.107045},
pmid = {40754251},
issn = {1095-953X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by neuromuscular connectivity decline followed by motoneuron loss. Altered proteostasis is suggested as a transversal pathogenic mechanism, notably involving dysfunction at the level of the endoplasmic reticulum (ER). Protein disulfide isomerases (PDIs) are key enzymes that catalyze protein folding and disulfide bond formation in the ER. Importantly, PDIs function is disrupted in ALS. We previously identified mutations in the gene encoding PDIA3 (also known as Grp58 or ERp57) as risk factors for ALS, which were associated with altered neuromuscular junction (NMJ) organization when expressed in zebrafish, a phenotype recapitulated in PDIA3-null mice. Here, we generated a transgenic mouse line overexpressing the ALS-linked PDIA3 variant D217N and performed a comprehensive characterization of ALS-like features. The transgenic line exhibited moderate overexpression of mutant PDIA3[D217N], which led to morphological alterations at the NMJ resembling those observed in ALS models and patients, along with abnormal distribution of oxidative and glycolytic muscle fibers. However, mutant PDIA3[D217N] expression did not result in motor impairment, coordination deficits, or motoneuron loss. At the molecular level, we observed reduced expression of SV2 in the spinal cord, an important synaptic protein involved in NMJ function. Our findings further support the involvement of PDIA3 dysfunction as a risk factor in the emergence of early features of ALS.},
}

@article {pmid40753166,
year = {2025},
author = {Rothstein, JD and Keeley, O and Warlick, C and Miller, TM and Ly, CV and Glass, JD and Coyne, AN},
title = {Sporadic ALS induced pluripotent stem cell derived neurons reveal hallmarks of TDP-43 loss of function.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {7092},
pmid = {40753166},
issn = {2041-1723},
support = {NS132836//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Neurons/metabolism/pathology ; C9orf72 Protein/genetics/metabolism ; Nuclear Pore/metabolism/pathology ; Male ; Nuclear Pore Complex Proteins/metabolism/genetics ; Female ; Brain/metabolism/pathology ; Frontotemporal Dementia/genetics/metabolism/pathology ; Middle Aged ; },
abstract = {Nuclear loss and cytoplasmic buildup of the RNA-binding protein TDP-43 is a hallmark of ALS and related disorders. While studies using artificial TDP-43 depletion in neurons have revealed changes in gene expression and splicing, their relevance to actual patients remained unclear. Induced pluripotent stem cell (iPSC)-derived neurons (iPSNs) from 180 individuals, including controls, C9orf72 ALS/FTD, and sporadic ALS (sALS) patients were used to generate and analyze ~32,500 qRT-PCR data points across 20 genes which identified variable, time-dependent signatures of TDP-43 loss of function in individual lines. Notably, the same changes were also seen in postmortem brain tissue from the same patients, confirming that iPSNs accurately model disease. Inducing damage to the nuclear pore complex, specifically by reducing the nucleoporin POM121 in healthy iPSNs, was enough to replicate the molecular changes associated with ALS/FTD TDP-43 dysfunction. This directly links nuclear pore integrity to TDP-43-related pathology. Encouragingly, repairing nuclear pore injury in sALS iPSNs restored normal gene processing disrupted by TDP-43 loss. This study (1) provides a valuable population-scale resource for studying TDP-43 dysfunction in ALS, (2) confirms that patient-derived iPSNs closely reflect disease processes seen in the brain, and (3) demonstrates that targeting nuclear pore injury may offer a promising therapeutic strategy in ALS.},
}

Humans
*Induced Pluripotent Stem Cells/metabolism/pathology
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*DNA-Binding Proteins/metabolism/genetics
*Neurons/metabolism/pathology
C9orf72 Protein/genetics/metabolism
Nuclear Pore/metabolism/pathology
Male
Nuclear Pore Complex Proteins/metabolism/genetics
Female
Brain/metabolism/pathology
Frontotemporal Dementia/genetics/metabolism/pathology
Middle Aged

@article {pmid40753073,
year = {2025},
author = {Lv, G and Sayles, NM and Huang, Y and Mancinelli, C and McAvoy, K and Shneider, NA and Manfredi, G and Kawamata, H and Eliezer, D},
title = {Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {7121},
pmid = {40753073},
issn = {2041-1723},
support = {R01NS139141//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; RF1AG066493//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R35NS122209//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01NS134684//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; F31AG077836//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; F31HL154651//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; S10OD028556//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; S10OD016320//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; S10OD026974//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; S10RR027699//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P30CA016087//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; SF349247//Simons Foundation/ ; 961871-02//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; },
mesh = {Humans ; *Amyloid/metabolism/ultrastructure/chemistry/genetics ; *Mitochondrial Proteins/genetics/metabolism/chemistry/ultrastructure ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; Cryoelectron Microscopy ; *Transcription Factors/genetics/metabolism/chemistry/ultrastructure ; Mutation ; *Neurodegenerative Diseases/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/metabolism ; Models, Molecular ; Parkinson Disease/genetics/metabolism ; },
abstract = {Mitochondrial proteins CHCHD10 and CHCHD2 are mutated in rare cases of heritable FTD, ALS and PD and aggregate in tissues affected by these diseases. Here, we show that both proteins form amyloid fibrils and report cryo-EM structures of fibrils formed from their disordered N-terminal domains. The ordered cores of these fibrils are comprised of a region highly conserved between the two proteins, and a subset of the CHCHD10 and CHCHD2 fibril structures share structural similarities and appear compatible with sequence variations in this region. In contrast, disease-associated mutations p.S59L in CHCHD10 and p.T61I in CHCHD2, situated within the ordered cores of these fibrils, cannot be accommodated by the wildtype structures and promote different protofilament folds and fibril structures. These results link CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration and further suggest that fibril formation by the WT proteins could also be involved in disease etiology.},
}

Humans
*Amyloid/metabolism/ultrastructure/chemistry/genetics
*Mitochondrial Proteins/genetics/metabolism/chemistry/ultrastructure
*DNA-Binding Proteins/genetics/metabolism/chemistry
Cryoelectron Microscopy
*Transcription Factors/genetics/metabolism/chemistry/ultrastructure
Mutation
*Neurodegenerative Diseases/genetics/metabolism
Amyotrophic Lateral Sclerosis/genetics/metabolism
Frontotemporal Dementia/genetics/metabolism
Models, Molecular
Parkinson Disease/genetics/metabolism

@article {pmid40752076,
year = {2025},
author = {Mamangam, S and Brimson, JM},
title = {Rhodamine-B induces amyotrophic lateral sclerosis symptoms like -behaviours in zebrafish.},
journal = {Aquatic toxicology (Amsterdam, Netherlands)},
volume = {287},
number = {},
pages = {107515},
doi = {10.1016/j.aquatox.2025.107515},
pmid = {40752076},
issn = {1879-1514},
abstract = {Rhodamine B (RhB), often misused as a food adulterant, accumulates in the brain, causing oxidative stress and neurodegeneration. However, its detrimental effects on molecular mechanisms still require further investigation. The zebrafish is a model organism for studying neurodegeneration and neuropathology. We aimed to investigate the impacts of RhB on neuro-molecular and behaviours in Adult male zebrafish. Zebrafish were exposed to varying RhB concentrations of 0.25, 0.5, 1.0 μM and Rotenone (RoT) of 0.5 μM for 21 days. Behavioural assessments, including the mirror test, shoal preference test, T-maze and Y-maze tests, and novel tank test, were conducted to evaluate the impact of RhB on zebrafish behaviour. Furthermore, biochemical, neurochemical, and histopathological changes in the zebrafish brains were analysed. The neuronal behaviour patterns, such as reduced anxiety-like behaviour, time spent near or interacting with the mirror image, and cognitive dysfunction, were significantly affected by RhB in a time-dose-dependent manner when compared to those of control zebrafish. The glutathione reductase, catalase, lipid peroxidation, and reactive oxygen species levels were significantly increased, and acetylcholinesterase, glutathione peroxidase, superoxide dismutase, butyrylcholinesterase, serotonin, dopamine, and monoamine oxidase A and B were significantly reduced when exposed to RhB, when compared to those of control zebrafish. The C9orf72, btg2, fus, cfos, vgf, drd1b, npas4a, egr1, pax6a, vgf, ubb, atxn2, ier2a, tradbpa, tuba812 and grin1a mRNA levels were significantly upregulated. At the same time, sod1, bdnf, gabra1, and gabra2a were significantly down-regulated in the brain of RhB-exposed zebrafish compared to the control fish. These results suggested that RhB exposure can induce neurodegeneration in zebrafish mimicking Amyotrophic Lateral Sclerosis (ALS).},
}

@article {pmid40751692,
year = {2025},
author = {Trudel, P and Quesnel-Olivo, MH and Blais, M and Ramanathan, U and Dupré, N},
title = {ALS patients and PAD: description and comparison of patients from a neuromuscular clinic in Canada.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2025.2539894},
pmid = {40751692},
issn = {2167-9223},
abstract = {OBJECTIVES: In Canada, patients with ALS (PALS) who meet specific criteria can request Medical Assistance in Dying (MAiD), also known as Physician-Assisted Death (PAD). However, little is known about the characteristics of those patients. This study describes PALS who died of MAiD and compares them with patients who died from natural disease complications.

METHODS: A retrospective study of 209 consecutive PALS' electronic medical records was performed. Patients selected had follow-up at the CHU de Québec-Université Laval and died between January 2014 and April 2023. Sociodemographic and disease evolution data were collected. Fisher's exact test and Kolmogorov-Smirnov tests were used.

RESULTS: The analysis included 174 patients. MAiD PALS (N = 64) were mainly males (54.7%), of median age 67 years, in a relationship (68.7%), and parents of adult children (71.9%). Both cohorts had similar past medical histories of depressive disorders (15%, p > 0.999). MAiD PALS elected to use percutaneous endoscopic gastrostomy (PEG) feeding in 18.7% of cases compared to 28.2% of PALS who died of complications of ALS (p = 0.203). Palliative care teams were significantly more likely to be involved with PALS elected to request MAiD (86.6%, p = 0.023).

DISCUSSION: PALS who request MAiD share similar demographic and clinical characteristics with those who died from natural disease progression in our cohort. Trends toward differences were observed, namely, in the rate of disease progression, with PALS who requested MAiD more likely to be fast progressors than their counterparts, and in PEG feeding use with ALS MAiD patients less likely to request it. Palliative care involvement was more prevalent with MAiD PALS.},
}

@article {pmid40751342,
year = {2025},
author = {Corcia, P and Erazo, D and Amador, MDM and Beltran, S and Bernard, E and Blasco, H and Boutoleau-Bretonniere, C and Bruneteau, G and Camdessanche, JP and Camu, W and Cassereau, J and Choumert, A and Codron, P and Cintas, P and De La Cruz, E and Danel, V and Desnuelle, C and Eyraud, N and Esselin, F and Fauret, AL and Lefilliatre, M and Fleury, MC and Genestet, S and Grapperon, AM and Guy, N and Jacquin-Piques, A and Beauvais, K and Lautrette, G and Le Masson, G and Mathis, S and Piegay, AS and Pittion-Vouyovitch, S and Sauleau, P and Soriani, MH and Vershueren, A and Mouzat, K and Guissart, C and Couratier, P and Vourc'h, P},
title = {Prevalence of SOD1 and C9orf72 Variants Among French ALS Population: The GENIALS Study.},
journal = {European journal of neurology},
volume = {32},
number = {8},
pages = {e70302},
doi = {10.1111/ene.70302},
pmid = {40751342},
issn = {1468-1331},
support = {//Biogen/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; C9orf72 Protein ; Superoxide Dismutase-1/genetics ; France/epidemiology ; Female ; Male ; Middle Aged ; Aged ; Adult ; *Proteins/genetics ; Prevalence ; *Superoxide Dismutase/genetics ; Age of Onset ; Genetic Variation ; },
abstract = {RATIONALE: Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease in which genetics plays a central role for both familial and sporadic ALS cases. Systematic genetic analysis for all ALS patients is recommended at the time of diagnosis, leading to an early proposal of specific genetic therapy. Currently, C9orf72 is considered the most frequently mutated gene in ALS. Patients with a SOD1 pathogenic or probably pathogenic variants (ACMG classification) are eligible for SOD1 antisense oligonucleotide therapy.

OBJECTIVE: To determine the frequency of SOD1 variants and C9orf72 G4C2 repeats in a French ALS population and to describe genotype-phenotype relationships.

MATERIAL AND METHODS: One thousand incident ALS patients were enrolled from 22 ALS centers in France and followed up for 12 months. Epidemiological, familial history, neurological data, and genetic status were collected.

MAIN RESULTS: C9orf72 G4C2 repeats and SOD1 variants were observed in 7.6% and 1.6%, respectively. Fifty percent of SOD1 patients and 51% of C9orf72 patients had sporadic ALS. Fifteen different SOD1 variants were identified within the five exons and one intron. C9orf72 patients had a significantly younger age at onset and a trend toward a faster progression compared to non-expanded C9orf72 patients. Moreover, among the non-SOD1 non-C9orf72 population, patients with at least one C9orf72 copy with two G4C2 repeats had a shorter disease duration.

CONCLUSION: This study confirms SOD1 variants low frequency in the French population and highlights the more rapid disease progression observed in patients carrying C9orf72 expansions. These findings underscore the importance of systematic genetic screening at diagnosis.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/epidemiology
C9orf72 Protein
Superoxide Dismutase-1/genetics
France/epidemiology
Female
Male
Middle Aged
Aged
Adult
*Proteins/genetics
Prevalence
*Superoxide Dismutase/genetics
Age of Onset
Genetic Variation

@article {pmid40750781,
year = {2025},
author = {Arnold, J and Pathak, P and Jin, Y and Pont-Esteban, D and McCann, CM and Lehmacher, C and Bonadonna, JP and Lewko, T and Burke, KM and Cavanagh, S and Blaney, L and Rishe, K and Cole, T and Paganoni, S and Lin, D and Walsh, CJ},
title = {Personalized ML-based wearable robot control improves impaired arm function.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {7091},
doi = {10.1038/s41467-025-62538-8},
pmid = {40750781},
issn = {2041-1723},
mesh = {Humans ; *Robotics/instrumentation/methods ; *Wearable Electronic Devices ; *Arm/physiopathology/physiology ; Male ; Biomechanical Phenomena ; Female ; Stroke Rehabilitation/instrumentation/methods ; Middle Aged ; Movement/physiology ; Adult ; Shoulder/physiopathology ; Aged ; Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation ; Stroke/physiopathology ; Range of Motion, Articular ; },
abstract = {Portable wearable robots offer promise for assisting people with upper limb disabilities. However, movement variability between individuals and trade-offs between supportiveness and transparency complicate robot control during real-world tasks. We address these challenges by first developing a personalized ML intention detection model to decode user's motion intention from IMU and compression sensors. Second, we leverage a physics-based hysteresis model to enhance control transparency and adapt it for practical use in real-world tasks. Third, we combine and integrate these two models into a real-time controller to modulate the assistance level based on the user's intention and kinematic state. Fourth, we evaluate the effectiveness of our control strategy in improving arm function in a multi-day evaluation. For 5 individuals post-stroke and 4 living with ALS wearing a soft shoulder robot, we demonstrate that the controller identifies shoulder movement with 94.2% accuracy from minimal change in the shoulder angles (elevation: 3.4°, depression: 1.7°) and reduces arm-lowering force by 31.9% compared to a baseline controller. Furthermore, the robot improves movement quality by increasing their shoulder elevation/depression (17.5°), elbow (10.6°) and wrist flexion/extension (7.6°) ROMs; reducing trunk compensation (up to 25.4%); and improving hand-path efficiency (up to 53.8%).},
}

Humans
*Robotics/instrumentation/methods
*Wearable Electronic Devices
*Arm/physiopathology/physiology
Male
Biomechanical Phenomena
Female
Stroke Rehabilitation/instrumentation/methods
Middle Aged
Movement/physiology
Adult
Shoulder/physiopathology
Aged
Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation
Stroke/physiopathology
Range of Motion, Articular

@article {pmid40750607,
year = {2025},
author = {Nógrádi, B and Molnár, K and Kristóf, R and Horváth, O and Huang, YT and Ridgway, Z and Elicegui, A and Fuertes-Alvarez, S and Alonso-Martin, S and Szebeni, GJ and Gémes, N and Ramadan, A and Smith, HL and Krizbai, IA and Patai, R and Siklós, L and Klivényi, P and Chaytow, H and Gillingwater, TH},
title = {The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {7053},
doi = {10.1038/s41467-025-62351-3},
pmid = {40750607},
issn = {2041-1723},
support = {2021/MNDS/RP/8430GILL//MND Scotland (Motor Neuron Disease Scotland)/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/metabolism/genetics ; *Receptors, CCR2/metabolism/genetics/immunology ; Animals ; *Chemokine CCL2/metabolism/immunology/genetics ; Humans ; Male ; *Neuromuscular Junction/pathology/metabolism/immunology ; Mice ; Muscle, Skeletal/pathology/metabolism/innervation/immunology ; Disease Models, Animal ; Macrophages/immunology/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Female ; Mice, Transgenic ; Leukocytes/immunology/metabolism ; },
abstract = {Systemic immune changes have been implicated in amyotrophic lateral sclerosis (ALS), but precise mechanisms and cellular targets remain unknown. Neuromuscular junction (NMJ) denervation is another major pathophysiological event in ALS, but it remains unclear whether immune system dysregulation contributes to this process. Here, we report leukocyte and macrophage infiltration in ALS patient-derived skeletal muscle biopsies. Immune cell infiltration was replicated across the hTDP-43, TDP-43[A315T] (male only) and TDP-43[M337V] mouse models, occurring from pre-symptomatic stages and targeted to NMJ-enriched muscle regions. Proteomic analysis implicated the CCL2-CCR2 axis as a driving factor. CCL2[+] cells were enriched around NMJs in hTDP-43 mice, and in ALS patient skeletal muscle. Local treatment with CCL2-neutralising antibodies or normal IgG antibodies in hTDP-43 mice reduced leukocyte infiltration and ameliorated NMJ denervation. These results demonstrate that the CCL2-CCR2 axis drives immune cell infiltration targeting NMJs in ALS, identifying a potential avenue for therapeutic intervention to prevent NMJ denervation.},
}

*Amyotrophic Lateral Sclerosis/immunology/pathology/metabolism/genetics
*Receptors, CCR2/metabolism/genetics/immunology
Animals
*Chemokine CCL2/metabolism/immunology/genetics
Humans
Male
*Neuromuscular Junction/pathology/metabolism/immunology
Mice
Muscle, Skeletal/pathology/metabolism/innervation/immunology
Disease Models, Animal
Macrophages/immunology/metabolism
DNA-Binding Proteins/genetics/metabolism
Female
Mice, Transgenic
Leukocytes/immunology/metabolism

@article {pmid40747856,
year = {2025},
author = {Guilfoyle, J and Fan, Y and SÁnchez-SoliÑo, O and Boiser, J and Vinikoor-Imler, L},
title = {Symptoms prior to diagnosis among a diverse patient population with amyotrophic lateral sclerosis In the USA.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2538599},
pmid = {40747856},
issn = {2167-9223},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) symptom onset is gradual and may include muscle weakness, dysarthria, dysphagia, and respiratory difficulties among others. The objective of this study is to describe sex and racial/ethnic variation in limb and bulbar symptom diagnoses before ALS diagnosis in the USA.

METHODS: This retrospective cohort study was conducted using Optum's de-identified Market Clarity Data with a patient identification period between January 2015 and December 2019. Cases were identified using ICD-9/10 codes and were required to have ≥3 years of continuous enrollment or EHR activity prior to diagnosis. Descriptive statistics of symptom frequency and onset were stratified by sex and race.

RESULTS: This study identified 7121 individuals with ALS, 3303 female (46%) and 3818 male (54%). Most identified as Non-Hispanic White (67.5%), followed by African American (6.6%), Hispanic (3.6%), and Asian (0.9%), with 21.4% missing race/ethnicity. In the 3 years before ALS diagnosis, 42.9% of subjects were diagnosed with ≥1 bulbar symptom, 74.5% with ≥1 limb symptom, and 34.6% with both. Females more likely to be diagnosed than males: any bulbar 47.1% versus 39.3%, (p < 0.0001), any limb 76.0% versus 73.2%, (p = 0.007), both 38.1% versus 31.6%, (p < 0.0001). Variation by race/ethnicity was observed for limb symptoms (p < 0.0001) and both bulbar and limb symptoms (p = 0.008), but not bulbar symptoms alone (p = 0.07). Symptom onset to ALS was longer for females and varied by race/ethnicity.

CONCLUSION: Females were more likely to present with bulbar and limb symptoms prior to ALS diagnosis and African American patients were more likely to present with limb symptoms than other race/ethnicities.},
}

@article {pmid40747386,
year = {2025},
author = {Arnold, WD and Castoro, R and Saxena, S},
title = {Innovations In Physical Medicine and Rehabilitation: Advances in the Diagnosis, Treatment, and Care of Amyotrophic Lateral Sclerosis.},
journal = {Missouri medicine},
volume = {122},
number = {3},
pages = {199-205},
pmid = {40747386},
issn = {0026-6620},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/rehabilitation ; *Physical and Rehabilitation Medicine/trends/methods ; Quality of Life ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that causes loss of upper and lower motor neurons, leading to muscle weakness and ultimately death. This review highlights recent advancements in Neuromuscular Medicine and Physical Medicine and Rehabilitation (PM&R), emphasizing innovations in the diagnosis, treatment, and care delivery for ALS. The field of PM&R emphasizes a multidisciplinary, patient-centered approach, incorporating advanced diagnostic tools, therapeutic strategies, adaptive equipment, and telerehabilitation to optimize function. Neuromuscular PM&R physicians play a key role in managing symptoms and maximizing functional independence. Current disease-modifying therapies include riluzole and edaravone which provide only modest benefits, but emerging gene therapies like tofersen for SOD1-related ALS offer promise for targeted treatment for genetic forms of ALS. Future advancements in regenerative therapies, biotechnologies, and digital health integration hold the potential to improve care and enhance the quality of life and functional independence of individuals living with ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/therapy/rehabilitation
*Physical and Rehabilitation Medicine/trends/methods
Quality of Life

@article {pmid40747225,
year = {2025},
author = {Li, J and Wang, W},
title = {Challenges of Klebsiella pneumoniae infections post-liver transplantation: Insights and future directions.},
journal = {World journal of hepatology},
volume = {17},
number = {7},
pages = {107213},
pmid = {40747225},
issn = {1948-5182},
abstract = {Klebsiella pneumoniae infections (KPIs), particularly carbapenem-resistant Klebsiella pneumoniae (CRKP), pose significant challenges in liver transplantation (LT) recipients, with high morbidity and mortality. Guo et al's study highlights risk factors, such as elevated day-one alanine aminotransferase levels and prolonged catheterization, and identifies polymyxin B and ceftazidime/avibactam as effective treatments. However, limitations like the absence of pre-transplant colonization data and host-pathogen interaction insights highlight the need for enhanced strategies. Future directions should include routine CRKP colonization surveillance, immune and genomic profiling, and the development of novel therapeutics. By integrating these approaches, we can improve the prevention, diagnosis, and treatment of KPIs in LT patients.},
}

@article {pmid40746751,
year = {2025},
author = {Sabetta, E and Rallmann, K and Bergquist, J and Taba, P and Pfaff, AL and Poudel, BH and Ferrari, D and Locatelli, M and Kõks, S},
title = {Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {250},
number = {},
pages = {10593},
pmid = {40746751},
issn = {1535-3699},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; *DNA Repeat Expansion/genetics ; Aged ; Adult ; *Sequence Analysis, DNA/methods ; High-Throughput Nucleotide Sequencing/methods ; Whole Genome Sequencing/methods ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associated to genetically inherited ALS yet, approximately 85%-90% of ALS cases are sporadic. Short tandem repeats expansions, have recently been found in clinically diagnosed ALS patients and are currently investigated as potential genetic biomarkers. In this paper we compare the investigation of pathological tandem repeat expansions on a group of ALS patients by comparing the standard short-read sequencing (SRS) technique with a long-read-sequencing (LRS) method which has recently become more accessible. Blood samples from 47 sporadic ALS cases were subjected to SRS by Illumina Whole Genome Sequencing. The genome-wide tandem repeat expansions were genotyped using GangSTR, while wANNOVAR was used for variant annotation. Uncertain cases were further explored using LRS. SRS identified pathological expansions in HTT, ATXN2, and CACNA1A genes in one patient, which were not confirmed with LRS. The latter identified large tandem repeat expansions in the C9orf72 gene of one patient that were missed by SRS. Our findings suggest that LRS should be preferred to SRS for accurate identification of pathological tandem repeat expansions.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
Male
Female
Middle Aged
*DNA Repeat Expansion/genetics
Aged
Adult
*Sequence Analysis, DNA/methods
High-Throughput Nucleotide Sequencing/methods
Whole Genome Sequencing/methods

@article {pmid40746624,
year = {2025},
author = {Kashyap, PV and Singh, D and Nair, A and Jaiswal, A and Pandey, V},
title = {Effect of Edaravone Therapy on Amyotrophic Lateral Sclerosis Functional Rating Score (ALS-FRS) in Patients of Amyotrophic Lateral Sclerosis (ALS) in Central India: A Retrospective Open Label Study.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531251357377},
pmid = {40746624},
issn = {0972-7531},
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons and is characterised by a diverse range of clinical manifestations. With the understanding of its pathophysiology, many treatments have emerged in last two decades. This study aims to evaluate the impact of intravenous Edaravone on Amyotrophy Lateral Sclerosis Functional Rating Scale (ALS-FRS) scores and patient survival outcomes of Amyotrophic Lateral Sclerosis patients in Central India.

METHODS: This retrospective study was conducted over a span of 2.5 years and included patients diagnosed with definitive or probable ALS, as per the revised El Escorial criteria. The effects of intravenous (IV) Edaravone on ALS-FRS-R scores were compared between two groups: the intervention group (patients who received IV Edaravone) and the non-intervention group (patients who did not receive IV Edaravone). Data collected included demographic details and ALS-FRS-R scores that were recorded at baseline after each treatment cycle, for a total six cycles. These scores were compared with those of the control group at the corresponding time points. Survival outcomes were also evaluated between the two groups and side effect profile of the drug was also noted.

RESULTS: Data of ALS patients (definitive and probable) were screened, and 62 patients were enrolled, of which 12 were excluded, thus there were 25 ALS patients in the intervention group and 25 patients in the non-intervention group. The two groups were matched for demographic parameters and the ALS-FRS scores were noted at the baseline at each cycle till 6 cycles and compared. It was inferred that the scores were not significant statistically (p > .001) among the two groups, nor did the survival rates vary significantly.

CONCLUSION: Intravenous Edaravone therapy had no beneficial effect on the ALS-FRS score in the intervention group when compared to the non-intervention group, nor did the survival rates improve. Keywords: Amyotrophic lateral sclerosis, Edaravone Therapy, ALS FRS Score.},
}

@article {pmid40746518,
year = {2025},
author = {Liu, QZ and Zeng, L and Sun, NZ},
title = {Radiomics for preoperative pancreatic ductal adenocarcinoma risk stratification: Cross-population validation, multidimensional integration, challenges, and future directions.},
journal = {World journal of radiology},
volume = {17},
number = {7},
pages = {110048},
pmid = {40746518},
issn = {1949-8470},
abstract = {This editorial critically evaluated Liu et al's recent retrospective analysis of 283 Chinese patients with resectable pancreatic ductal adenocarcinoma (PDAC) that validated a preoperative computed tomography-based risk scoring system originally developed in South Korea. The scoring system incorporated five parameters: (1) Tumor size; (2) Portal venous phase density; (3) Necrosis; (4) Peripancreatic infiltration; and (5) Suspected metastatic lymph nodes. While demonstrating satisfactory recurrence prediction capability without requiring complex technologies, thereby supporting clinical utility in Chinese populations, the study exhibited notable limitations. Most analyzed patients lacked neoadjuvant chemotherapy exposure, resulting in underrepresentation of low-risk subgroups. Additionally, the short follow-up duration potentially compromised long-term prognostic assessment. Contemporary advances in radiomics coupled with machine learning have enhanced multimodal data integration for PDAC management. However, clinical implementation continues to confront challenges including variability in imaging parameters, incomplete understanding of molecular underpinnings, and confounding treatment effects. Future investigations should prioritize developing multidimensional predictive frameworks that synergize radiographic, molecular, and clinical data. Prospective multicenter validation and artificial intelligence-powered real-time risk stratification systems represent essential steps to overcome current barriers in precision medicine translation, ultimately advancing personalized therapeutic strategies for PDAC.},
}

@article {pmid40745959,
year = {2025},
author = {Dogra, S and Kouznetsova, VL and Tsigelny, IF},
title = {Repurposing FDA-approved drugs for treatment of amyotrophic lateral sclerosis using machine learning.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2536027},
pmid = {40745959},
issn = {2167-9223},
abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons. Current medications are largely ineffective, associated with side effects, and hindered by a lack of agreement over treatment pathways. The time-intensive process and high costs further limit the development of therapeutics. Therefore, this research aimed to identify FDA-approved drugs that inhibit three proteins (Casein kinase 1, Protein tyrosine kinase 2, Ephrin type-A receptor 4) associated with ALS.

METHODS: A machine learning (ML) model was trained for each protein to identify an inputted compound as an active inhibitor of that protein. The FDA-approved drugs were then screened through these models, and 18 drugs were identified as likely inhibitors for all three proteins. The results were validated through protein-ligand docking of each drug to its respective protein(s).

RESULTS: Risperidone was the most active drug, with an average ML score of 1 and binding affinity of -8.9. The ML scores and binding affinities had a strong correlation, indicating reliability.

CONCLUSION: This research predicted multiple drugs that can simultaneously target many proteins involved in ALS, creating more effective treatment options at a lower cost. This procedure can be applied to efficiently discover drugs for other diseases in the future.},
}

@article {pmid40744617,
year = {2025},
author = {Kaspary, TE and Cutti, L and Turra, GM and Angonese, PS and Dos Santos, OD and Merotto, A},
title = {Conyza bonariensis resistance to glyphosate and ALS inhibitors involves target and non-target site resistance.},
journal = {Pesticide biochemistry and physiology},
volume = {213},
number = {},
pages = {106501},
doi = {10.1016/j.pestbp.2025.106501},
pmid = {40744617},
issn = {1095-9939},
mesh = {Glyphosate ; *Herbicide Resistance/genetics ; *Glycine/analogs & derivatives/pharmacology ; *Herbicides/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics/metabolism ; *Conyza/drug effects/genetics ; Mutation ; Plant Proteins/genetics/antagonists & inhibitors/metabolism ; },
abstract = {Herbicide resistance in Conyza bonariensis (hairy fleabane) poses a significant challenge to agricultural systems worldwide. The genetic variability and prolific seed production of this species contribute significantly to its adaptative potential and fast spread in the agricultural fields. This study aimed to investigate the mechanisms underlying multiple herbicide resistance to glyphosate and ALS inhibitors in C. bonariensis biotypes from Southern Brazil. Resistance factors exceeded 100 times for chlorimuron-ethyl and 49 times for glyphosate. DNA Sequencing revealed the target-site mutations Pro106Thr in the EPSPS gene conferring glyphosate resistance, and Pro197Arg and Trp574Leu in the ALS gene contributing to chlorimuron-ethyl resistance. Additionally, the resistance factor decreased at least 80 % for resistant biotypes after application of chlorimuron-ethyl following treatment with the P450 inhibitor malathion, which might indicate enhanced metabolism mediated by cytochrome P450 enzymes. Copy number variation and overexpression of ALS and EPSPS genes were not related to resistance. Biotype II carries the Pro197Arg mutation and exhibited cross-resistance to imazethapyr, diclosulam, bispyribac‑sodium, and flucarbazone‑sodium. Biotypes carrying the Trp574Leu mutation were resistant to imazethapyr, diclosulam and flucarbazone‑sodium but demonstrated varying resistance patterns to bispyribac‑sodium, highlighting the complexity of resistance mechanisms. These findings underscore the importance of understanding both target and non-target-site resistance mechanisms to develop effective management strategies, including herbicide rotation and molecular diagnostics, to mitigate the spread of herbicide-resistant C. bonariensis in agricultural systems.},
}

Glyphosate
*Herbicide Resistance/genetics
*Glycine/analogs & derivatives/pharmacology
*Herbicides/pharmacology
*Acetolactate Synthase/antagonists & inhibitors/genetics/metabolism
*Conyza/drug effects/genetics
Mutation
Plant Proteins/genetics/antagonists & inhibitors/metabolism

@article {pmid40744595,
year = {2025},
author = {Li, J and Zhang, Y and Li, L and Wei, S and Huang, Z and Chen, L and Huang, H},
title = {Expression of Echinochloa oryzoides CYP71A1 and GSTU23 catalyzes the metabolism of thiobencarb, thereby conferring resistance.},
journal = {Pesticide biochemistry and physiology},
volume = {213},
number = {},
pages = {106555},
doi = {10.1016/j.pestbp.2025.106555},
pmid = {40744595},
issn = {1095-9939},
mesh = {*Echinochloa/drug effects/genetics/metabolism/enzymology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology/metabolism ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Thiocarbamates/metabolism/pharmacology ; *Plant Proteins/genetics/metabolism ; *Glutathione Transferase/metabolism/genetics ; },
abstract = {Echinochloa oryzoides (Ard.) Fritsch. is a notorious and prevalent weed in paddy fields. Thiobencarb (TB), a thiocarbamate herbicide, is widely applied in paddy fields for the control of pre-emergence weeds. However, owing to the prolonged and large-scale usage of TB, certain Echinochloa oryzoides populations have evolved resistance to it. In this study, a population of Echinochloa oryzoides from a paddy field was suspected of being resistant to the TB herbicide. Notably, this population also displayed multiple resistance and cross-resistance to Acetolactate synthase (ALS), Acetyl-CoA carboxylase (ACCase), and hormone-based herbicides. The resistance to TB was partially reversed by 50.8 % and 44.7 % upon treatment with a glutathione S-transferase (GST) inhibitor (NBD-Cl) and a cytochrome P450 inhibitor (malathion), respectively. This confirmed that metabolic resistance was the predominant mechanism underlying the observed resistance. RNA-seq analysis uncovered the overexpression of CYP71A1 and GSTU23 in the resistant (R) population. This study is the first to screen and validate metabolic enzymes capable of effectively metabolizing TB in an Echinochloa oryzoides. Functional verification was conducted using a yeast in vitro expression system, which confirmed the metabolic capabilities of both CYP71A1 and GSTU23 genes towards TB. Collectively, these findings demonstrate that the overexpression of CYP71A1 and GSTU23 in the R population endows Echinochloa oryzoides with the evolutionary capacity to develop resistance to thiobencarb. This study has shed light on the resistance mechanisms of Echinochloa oryzoides to TB, thereby enhancing our understanding of its herbicide tolerance. Moreover, these results highlight the necessity for targeted strategies to control resistant populations, ultimately contributing to more effective and sustainable herbicide resistance management in agriculture.},
}

*Echinochloa/drug effects/genetics/metabolism/enzymology
*Herbicide Resistance/genetics
*Herbicides/pharmacology/metabolism
*Cytochrome P-450 Enzyme System/metabolism/genetics
*Thiocarbamates/metabolism/pharmacology
*Plant Proteins/genetics/metabolism
*Glutathione Transferase/metabolism/genetics

@article {pmid40744561,
year = {2025},
author = {Mora, G and Gil-Monreal, M and Osuna, MD and Vijayarajan, VBA and Montull, JM and Llenes, JM and Recasens, J and Cirujeda, A and Marí, AI and Torra, J},
title = {First case of triple resistance to EPSPS, ALS, and synthetic auxin herbicides in Bassia scoparia (L.) Voss in Europe.},
journal = {Pesticide biochemistry and physiology},
volume = {213},
number = {},
pages = {106529},
doi = {10.1016/j.pestbp.2025.106529},
pmid = {40744561},
issn = {1095-9939},
mesh = {*Herbicides/pharmacology ; *Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Herbicide Resistance/genetics ; *3-Phosphoshikimate 1-Carboxyvinyltransferase/antagonists & inhibitors/genetics/metabolism ; *Bassia scoparia/drug effects/genetics/enzymology ; *Indoleacetic Acids/pharmacology ; Plant Proteins/genetics/metabolism ; },
abstract = {Bassia scoparia (L.) Voss has evolved resistance to five herbicide modes of action (MoAs) worldwide, including multiple resistance to up to four MoAs. Seeds were collected from a putatively resistant B. scoparia population (GUI-R) that survived successive herbicide applications of synthetic auxins, acetolactate synthase (ALS), and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors in a no-till winter cereal field in Catalonia, Spain, in 2022, to assess resistance levels and mechanisms. Dose-response assays confirmed that GUI-R was 2-, 340-, 42.7-, and 60-fold more resistant to glyphosate, thifensulfuron, MCPA, and 2,4-D, respectively, based on plant weight, and 3.2-, 123-, 57.9-, and 32-fold more resistant based on plant survival. GUI-R showed cross-resistance to imazamox (46 % survival), but not to dicamba or fluroxypyr (100 % mortality), at the label rate. Preliminary studies using malathion pre-treatment, a cytochrome P450 inhibitor, reversed 2,4-D resistance in GUI-R at the label rate, resulting in a 97 % reduction in biomass. Molecular studies revealed that GUI-R has 4.9 additional copies of the EPSPS:ALS gene, with no known mutations and less shikimate accumulation than the susceptible population. ALS gene sequencing identified the Pro197Ser, Pro197Leu, and Trp574Leu mutations, along with a combined Pro197Ser + Trp574Leu mutation. In conclusion, EPSPS gene amplification and ALS mutations confer target-site resistance to glyphosate, thifensulfuron and imazamox in GUI-R. Resistance to 2,4-D and MCPA is probably driven by P450-mediated non-target-site resistance and further research is necessary to confirm mechanisms. This biotype represents the first case of glyphosate resistance in Europe for the species, as well as the first triple resistance.},
}

*Herbicides/pharmacology
*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism
*Herbicide Resistance/genetics
*3-Phosphoshikimate 1-Carboxyvinyltransferase/antagonists & inhibitors/genetics/metabolism
*Bassia scoparia/drug effects/genetics/enzymology
*Indoleacetic Acids/pharmacology
Plant Proteins/genetics/metabolism

@article {pmid39163164,
year = {2025},
author = {Raggi, A and Serretti, A and Ferri, R},
title = {The P300 component of the auditory event-related potential in adult psychiatric and neurologic disorders: a narrative review of clinical and experimental evidence.},
journal = {International clinical psychopharmacology},
volume = {40},
number = {5},
pages = {259-274},
doi = {10.1097/YIC.0000000000000566},
pmid = {39163164},
issn = {1473-5857},
mesh = {Humans ; *Event-Related Potentials, P300/physiology ; *Mental Disorders/physiopathology/diagnosis ; *Nervous System Diseases/physiopathology/diagnosis ; *Evoked Potentials, Auditory/physiology ; Adult ; Electroencephalography ; Neuropsychological Tests ; },
abstract = {The auditory P300 wave, also known as P3b, is an event-related potential component thought to reflect central information processes involved in stimulus evaluation or categorization. It is typically elicited using the oddball paradigm, which involves mixing low-probability target items with high-probability standard stimuli. Its latency is associated with the timing of cognitive processes such as stimulus evaluation and response preparation, while its amplitude is related to the amount of attentional resources engaged during the task. Despite decades of use in research settings, its application in clinical practice has been limited. Prolongation of latencies and reduction of amplitudes in the auditory P3b have been observed in both psychiatric and neurological conditions. This includes cases where traditional neuropsychological tests are challenging due to severe motor or speech dysfunctions, or in conditions characterized by subtle cognitive deficits. Additionally, specific laterality patterns in psychoses and a loss of P300 habituation in migraines have been described. The wealth of experimental evidence supports the use of this evoked potential, which can be elicited through a relatively simple paradigm, for objectively evaluating cognition in psychiatric and neurological patients, particularly in follow-up assessments. Therefore, the auditory P300 appears to be a valuable tool for monitoring the clinical course of patients with mental and neurological disorders in certain circumstances.},
}

Humans
*Event-Related Potentials, P300/physiology
*Mental Disorders/physiopathology/diagnosis
*Nervous System Diseases/physiopathology/diagnosis
*Evoked Potentials, Auditory/physiology
Adult
Electroencephalography
Neuropsychological Tests

@article {pmid40744389,
year = {2025},
author = {Nelson, VK and Begum, MY and Suryadevara, PR and Madhuri Kallam, SD and Panda, SP and Bodapati, A and Sanga, V and Bishoyi, AK and Ballal, S and Monsi, M and Walia, C and Prasad, GVS and Abomughaid, MM and Shukla, S and Chauhan, P and Jha, NK},
title = {Natural Bioactive Compounds as Modulators of Autophagy: A Herbal Approach to the Management of Neurodegenerative Diseases.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178003},
doi = {10.1016/j.ejphar.2025.178003},
pmid = {40744389},
issn = {1879-0712},
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine (polyQ), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) disease are a significant health concern that affects millions of people every year worldwide. The main pathological hallmark of various NDs is the formation of misfolded protein aggregation and accumulation of inclusion bodies. These protein aggregates are mainly responsible for producing toxic effects and initiating neuronal cell death, ultimately promoting various NDs. On the other hand, the patients suffering from these kinds of diseases live in impaired conditions, imposing a substantial financial burden on the family. However, the current treatment strategies can only offer temporary relief from the disease symptoms and can't reverse the disease completely. Hence, there is an urgent need for specific and novel drug treatment that can significantly eradicate NDs. Ubiquitin proteasome system (UPS) and autophagy are the two essential intracellular defensive mechanisms that are involved in clearing the protein aggregates, pathogens, and damaged organelles from the cytoplasm and maintaining protein homeostasis. Nevertheless, UPS is inefficient in removing some kinds of organelles and aggregating-prone proteins, specifically in neuronal and glial cells. Under this kind of circumstance, the autophagy mechanism plays a vital role in eliminating the accumulated protein aggregates and other toxic elements from the cytoplasm of the neuronal cells that initiate oxidative stress. However, in NDs, the autophagy function is impaired, and the protein aggregates can't be eliminated effectively. Hence, forced up-regulation of autophagy function by applying various external agents could be a potential therapeutic strategy to control NDs like AD, PD, HD, and ALS. In this review, we focused on different kinds of plant-derived compounds that induce autophagy. We also discussed the role of these plant-derived autophagy modulators in various NDs. In this way, the current review will be a standalone reference to the researchers working in this area.},
}

@article {pmid40741338,
year = {2025},
author = {Marek, A and Brož, B and Kriegelstein, M and Nováková, G and Hojcsková, J and Blechová, M and Žáková, L and Jiráček, J and Maletínská, L},
title = {Late-stage labeling of diverse peptides and proteins with iodine-125.},
journal = {Journal of pharmaceutical analysis},
volume = {15},
number = {7},
pages = {101198},
pmid = {40741338},
issn = {2214-0883},
abstract = {The preparation of specifically iodine-125 ([125]I)-labeled peptides of high purity and specific activity represents a key tool for the detailed characterization of their binding properties in interaction with their binding partners. Early synthetic methods for the incorporation of iodine faced challenges such as harsh reaction conditions, the use of strong oxidants and low reproducibility. Herein, we review well-established radiolabeling strategies available to incorporate radionuclide into a protein of interest, and our long-term experience with a mild, simple and generally applicable technique of [125]I late-stage-labeling of biomolecules using the Pierce iodination reagent for the direct solid-phase oxidation of radioactive iodide. General recommendations, tips, and details of optimized chromatographic conditions to isolate pure, specifically [125]I-mono-labeled biomolecules are illustrated on a diverse series of (poly)peptides, ranging up to 7.6 kDa and 67 amino acids (aa). These series include peptides that contain at least one tyrosine or histidine residue, along with those featuring disulfide crosslinking or lipophilic derivatization. This mild and straightforward late-stage-labeling technique is easily applicable to longer and more sensitive proteins, as demonstrated in the cases of the insulin-like growth factor binding protein-3 (IGF-BP-3) (29 kDa and 264 aa) and the acid-labile subunit (ALS) (93 kDa and 578 aa).},
}

@article {pmid40740926,
year = {2025},
author = {Ding, Y and Xing, YX and Sun, NZ},
title = {Managements of bile leakage after liver transplantation: Commentary on recent findings.},
journal = {World journal of gastrointestinal surgery},
volume = {17},
number = {7},
pages = {108148},
pmid = {40740926},
issn = {1948-9366},
abstract = {Bile leakage remains a formidable challenge in post-liver transplantation management, posing significant risks to patient outcomes and graft survival. This editorial provides a critical appraisal of the recent clinical study by Gu et al, which compared the efficacy of stent placement vs endoscopic nasobiliary drainage (ENBD) for treating post-transplant bile leaks. By retrospectively analyzing data from their institutional cohort of liver transplant recipients with bile leaks, the authors evaluated the therapeutic success rates and clinical outcomes between the stent and ENBD groups, with a focused discussion on the relative advantages of each approach. Gu et al demonstrated that both stent placement and ENBD were effective in managing post-transplant bile leaks, with comparable therapeutic outcomes. However, the study also recognized its limitations, such as the lack of an assessment of the impact of bile leak severity on outcome and the absence of long-term follow-up data. The editorial further highlights the pressing need for advancing research on long-term complications post-liver transplantation and underscores the pivotal role of clinical stratification and physician expertise in guiding therapeutic decisions. In summary, Gu et al's study enhances our understanding of mitigating post-transplant complications like bile leaks and offers evidence-based insights to refine clinical protocols. This commentary aims to contextualize current research trends and future directions in the field, advocating for sustained innovation and evidence-driven practice.},
}

@article {pmid40740556,
year = {2025},
author = {Mirenayat, MS and Fakharian, A and Valizadeh, M and Abedi, M and Sadeghi, S and Zahiri, R and Haghi Ashtiani, B and Masaebi, F and Zamani, B},
title = {Evaluation of Inspiratory Muscle Training Effect Compared With Diaphragmatic Breathing in Respiratory Parameters in Amyotrophic Lateral Sclerosis Patients: A Randomized Controlled Trial.},
journal = {Medical journal of the Islamic Republic of Iran},
volume = {39},
number = {},
pages = {37},
pmid = {40740556},
issn = {1016-1430},
abstract = {BACKGROUND: Many patients with amyotrophic lateral sclerosis (ALS) experience respiratory failure. The use of respiratory muscle training exercises can improve the respiratory function of these patients. This study aimed to evaluate the effect of inspiratory muscle training (IMT) on respiratory muscle function in ALS patients.

METHODS: In the current randomized controlled clinical trial study, 22 patients were randomly divided into intervention (n = 11) and control groups (n = 11). In the control group, patients used only chest-opening training and diaphragm exercises. Patients in the intervention group used IMT in addition to controlled exercises (chest opening training and diaphragm exercises). Respiratory function by spirometry and monitoring of maximum inspiratory and expiratory pressure, functional capacity with a 6-minute walk test, and arterial blood gases were also assessed by ABG analysis at baseline and after 8 weeks. A comparative analysis of variables was performed with a student t-test, considering type 1 error (α = 0.05) using SPSS 27 software.

RESULTS: The indexes included maximal inspiratory pressure (PImax) (P = 0.000) and maximal expiratory pressures PEmax (P = 0.002). The strength of breathing muscles index (S-index) (P = 0.002) had a significant increase before and after rehabilitation in both groups (P ˂ 0.05). In intergroup analysis, the only factor with a significant increase was PImax (P = 0.019).

CONCLUSION: The use of IMT, along with chest opening training and diaphragm exercises, can cause a relative improvement of the respiratory muscles' function indexes, especially PImax in ALS patients. More clinical trials are required.},
}

@article {pmid40740433,
year = {2025},
author = {Shahim, P and AlQahtani, A and Kokkinis, AD and Kazmi, N and Ezuma-Ngwu, M and Misra, J and Harmison, G and Benoit, N and Jones, M and Howe, E and Schindler, AB and Joe, GO and Grunseich, C},
title = {CSF and blood neuronal injury biomarkers in spinal bulbar muscular atrophy and amyotrophic lateral sclerosis 4.},
journal = {Brain communications},
volume = {7},
number = {4},
pages = {fcaf275},
pmid = {40740433},
issn = {2632-1297},
abstract = {Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis 4 (ALS4) are two forms of motor neuron disease characterized by clinically slow disease progression. Based on the current limited human studies, the contribution of central nervous neurodegeneration to these diseases and the rate of clinical progression is unclear. Neuronal proteins glial fibrillary acidic protein (GFAP), neurofilament light (NfL) chain, or Total-tau measured in either cerebrospinal fluid or blood could serve as sensitive markers of neurodegeneration. We studied 56 adult participants (32 SBMA, 7 ALS4, and 17 controls) who were enrolled at the National Institutes of Health, of whom 22 (10 SBMA, 7 ALS4, and 5 controls) underwent paired CSF and serum sampling, and of whom 6 participants were assessed longitudinally up to 24 months from initial visit. An additional 7 controls completed CSF sampling only. CSF GFAP, NfL chain, and Total-tau correlated with corresponding levels in serum (r = 0.74, r = 0.47, and r = 0.70, respectively). CSF GFAP was increased in patients with SBMA (median, 8840 pg/mL, interquartile range (IQR) 5780-10489) as compared to controls (median, 5315 pg/mL, IQR 1822-6657; P = 0.029) but not compared with ALS4 (median, 5015 pg/mL, IQR 3172-9803; P = 0.31). Patients with SBMA had increased concentrations of CSF NfL chain (median, 719 pg/mL, IQR 483-773) as compared to ALS4 (median, 307 pg/mL, IQR 187-629; P = 0.034) or controls (median, 395 pg/mL, IQR 307-497; P = 0.024). In contrast, serum concentrations of either biomarker did not differ significantly between SBMA, ALS4, or controls. Higher CSF GFAP and NfL chain levels were associated with lower SBMA Functional Rating Scale scores (r = -0.49 and r = -0.42, respectively). Over the course of 24 months, the average change in SBMA Functional Rating Scale was -0.83 points, while the changes in CSF GFAP and NfL chain were progressive (increased 1.4-fold and 1.3-fold, respectively). Our data suggest that SBMA patients have increased concentrations of CSF GFAP and NfL chain as compared to ALS4 and controls, and higher levels of these biomarkers are associated with disease severity. Importantly, these results indicate that SBMA is associated with progressive neurodegeneration and that either CSF GFAP or NfL chain may be useful for patient stratification and monitoring treatment effects in clinical trials.},
}

@article {pmid40740123,
year = {2025},
author = {Giacomelli, E and Scirocco, E and Higgins, M and Pilja, A and Paganoni, S and Ho, D},
title = {Research access barriers in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2025.2539900},
pmid = {40740123},
issn = {2167-9223},
abstract = {As the general population ages, amyotrophic lateral sclerosis (ALS) incidence and prevalence are expected to rise, and the barriers that limit participation in ALS clinical research studies may increase. In this report, we highlight key challenges and available resources for accessing clinical research. We emphasize the importance of education and engagement among individuals with ALS and their families, clinicians, and researchers. Addressing accessibility and fostering trust in ALS research participation is essential to advance treatments for this devastating disease. We propose practical strategies to overcome participation barriers, including decentralized trial models, remote participation options, and expanded outreach through patient navigators, advisory committees, and digital tools. Strengthening partnerships among individuals with ALS, caregivers, researchers, ALS organizations, regulators, and industry, will help align research efforts with community needs and accelerate therapeutic development.},
}

@article {pmid40740086,
year = {2025},
author = {Ghazali, L and Hamid, SSA and Mohamad, H and Aziz, A},
title = {Clinical review of laryngomalacia in a tertiary hospital.},
journal = {The Medical journal of Malaysia},
volume = {80},
number = {4},
pages = {443-447},
pmid = {40740086},
issn = {0300-5283},
mesh = {Humans ; *Laryngomalacia/diagnosis/epidemiology/therapy/classification ; Male ; Female ; Retrospective Studies ; Tertiary Care Centers ; Infant ; Severity of Illness Index ; Infant, Newborn ; },
abstract = {INTRODUCTION: Laryngomalacia is the most common cause of stridor in infants, with severity ranging from mild to severe forms. Accurate classifications of severity is essential for guiding management and improving outcomes.

MATERIAL AND METHODS: We conducted a retrospective study of paediatric patients under two years of age diagnosed with laryngomalacia at a tertiary referral centre between January 2010 and December 2020. Data collected included demographic details, clinical presentation, comorbidities, endoscopic findings, treatment, and follow-up duration. Severity was classified using a symptoms-based scoring system by Shah et al, while laryngomalacia types were determined according to Olney et al's endoscopic classification. Association between severity, endoscopic findings, comorbidities and treatment choice were analysed using logistic regression.

RESULTS: A total of 148 patients were included (59.49% male). Mild, moderate, and severe laryngomalacia were observed in 45.27%, 35.14%, and 19.59% of patients, respectively. Type 3 laryngomalacia, identified via endoscopy, was significantly associated with severe disease (p<0.001). Comorbidities, particularly gastroesophageal reflux disease, cardiac, pulmonary, syndromic, neurological conditions and synchronous airway lesions, were significantly linked to higher severity (p<0.05). A strong association was found between severity and treatment: moderate cases had 89.6 times, and severe cases 133.3 times, the odds of receiving surgical intervention compared to mild cases (p<0.001).

CONCLUSION: Mild laryngomalacia was most prevalent, but severity increased with specific comorbidities and endoscopic findings. Objective symptom scoring and endoscopic classification are valuable for assessing severity and guiding appropriate management in laryngomalacia.},
}

Humans
*Laryngomalacia/diagnosis/epidemiology/therapy/classification
Male
Female
Retrospective Studies
Tertiary Care Centers
Infant
Severity of Illness Index
Infant, Newborn

@article {pmid40739673,
year = {2025},
author = {Zheng, X and Yuan, W and Li, L and Ma, H and Zhu, M and Li, X and Feng, X},
title = {Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to tackle central nervous system diseases: role as a promising approach.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {690},
doi = {10.1186/s40001-025-02937-1},
pmid = {40739673},
issn = {2047-783X},
mesh = {Humans ; *Proprotein Convertase 9/metabolism/genetics ; *PCSK9 Inhibitors/therapeutic use ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; },
abstract = {Atherosclerosis-associated disease (ASD) represents a complex pathological condition, characterized by the formation of atherosclerotic plaques within the arterial walls, encompassing cholesterol depositions, which is primarily attributed to elevated levels of low-density lipoprotein-cholesterol (LDL-C). A log-linear association between the absolute magnitude of LDL-C exposure and ASD risk has been widely studied. High levels of LDL-C have been acknowledged as the predominant culprit. The previous research findings have demonstrated that PCSK9 inhibitors (PCSK9i) can remarkably diminish the risk of ASD. The current research has primarily focused on the relevance of PCSK9 to the cardiovascular system and lipid metabolism; however, an increasing body of evidence shows that PCSK9 is pivotal in pathogenic processes in other organ systems. Yet, PCSK9's impact on the brain is complex and not fully clarified, although several recent studies emphasize a putative role of its impact on various neurodegenerative disorders. Among neurological disorders, not only stroke but neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, alcohol use disorder (AUD), amyotrophic lateral sclerosis(ALS), and Alzheimer's Disease (AD) are related to PCSK9. PCSK9 expression in brain is low but greatly upregulated in neurological disorders. Therefore, PCSK9 is a promising pathway for the treatment of central nervous diseases. This review comprehensively describes evidence from the previous research on the effects of PCSK9i on the central nervous system, with a focus on the clinical potential of PCSK9i. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop treatments for the neurological diseases based on PCSK9i.},
}

Humans
*Proprotein Convertase 9/metabolism/genetics
*PCSK9 Inhibitors/therapeutic use
*Central Nervous System Diseases/drug therapy/metabolism
Animals

@article {pmid40738791,
year = {2025},
author = {Roy, A and Dawson, VL and Dawson, TM},
title = {From metabolism to mind: The expanding role of the GLP-1 receptor in neurotherapeutics.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00712},
doi = {10.1016/j.neurot.2025.e00712},
pmid = {40738791},
issn = {1878-7479},
abstract = {GLP-1 receptor agonists (GLP-1RAs), initially approved for diabetes and obesity, are now under investigation for neuroprotective effects in a range of neurological disorders. These agents, whose receptors are widely expressed in brain regions involved in cognition and metabolism, modulate neurotransmitter release and promote neurogenesis. While preclinical studies consistently demonstrate benefits in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), clinical trial outcomes have been variable, largely owing to heterogeneity in study populations and trial design. Newer agents, such as NLY01 and tirzepatide, are under development to enhance central nervous system penetration and efficacy. Although GLP-1RAs are generally safe in metabolic conditions, their use in neurological diseases requires careful monitoring and patient selection. Future directions include developing reliable biomarkers, implementing precision medicine strategies, and exploring the use of combination therapies to maximize therapeutic potential.},
}

@article {pmid40737511,
year = {2025},
author = {Turner, MR},
title = {Inverting the logic in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf276},
pmid = {40737511},
issn = {1460-2156},
}

@article {pmid40741286,
year = {2024},
author = {Garand, KLF and Malek, AM and Ambrocio, KR},
title = {Linking Oropharyngeal Swallowing Physiology and Functional Clinical Predictors in Amyotrophic Lateral Sclerosis.},
journal = {Perspectives of the ASHA special interest groups},
volume = {9},
number = {1},
pages = {282-291},
pmid = {40741286},
issn = {2381-4764},
abstract = {PURPOSE: We aimed to quantify oropharyngeal swallowing physiology in amyotrophic lateral sclerosis (ALS) and examine relationships between swallowing impairments and ratings of pulmonary function (forced vital capacity percent predicted, FVC % pre) and functional status (ALS Functional Rating Scale-Revised, ALSFRS-R).

METHOD: A retrospective analysis of swallowing-related data of persons with ALS (PALS) was completed. Their Modified Barium Swallow Impairment Profile component, Oral Total (OT), and Pharyngeal Total (PT) scores were compared with data from age- (±1 year) and sex-matched healthy controls retrieved from an archival normative data set using Mann-Whitney U tests. Relationships between PALS' OT and PT scores, FVC % pre, and ALSFRS-R were examined using Pearson product-moment correlations and multiple linear regression modeling.

RESULTS: Twenty-one PALS (12 women), with a mean age of 62.2 ± 9.9 years, were included in the analyses. Compared to healthy controls, PALS exhibited significantly worse function across 13 (76%) physiological swallowing components (all p < .05). OT and PT scores significantly differed between PALS and healthy controls (each p < .001), with higher scores (worse impairment) observed in the former. When adjusting for age and sex, FVC % pre was a significant predictor of OT score (p = .045). An inverse relationship was found with ALSFRS-R and OT score (p = .052). FVC % pre (p = .061) and ALSFRS-R (p = .54) did not significantly predict PT score.

CONCLUSIONS: PALS demonstrated swallowing impairments across oropharyngeal domains and the esophageal component. In our PALS cohort, FVC % pre was a useful clinical indicator of oral swallowing impairment.},
}

@article {pmid40737092,
year = {2025},
author = {Dargan, R and Mikheenko, A and Johnson, NL and Packer, BE and Li, Z and Craig, EJ and Como, CN and Sarbanes, SL and Bereda, C and Hao, Y and Mehta, PR and Keuss, M and Nalls, MA and Qi, YA and Weller, CA and Fratta, P and Ryan, VH},
title = {Altered mRNA transport and local translation in i3Neurons with RNA-binding protein knockdown.},
journal = {Nucleic acids research},
volume = {53},
number = {14},
pages = {},
doi = {10.1093/nar/gkaf709},
pmid = {40737092},
issn = {1362-4962},
support = {//Center for Alzheimer's and Related Dementias/ ; /AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; ZIAAG000547/HH/HHS/United States ; ZIAAG000534/HH/HHS/United States ; /NS/NINDS NIH HHS/United States ; Fi2GM142475/GM/NIGMS NIH HHS/United States ; Fi2GM146657/GM/NIGMS NIH HHS/United States ; },
mesh = {*RNA, Messenger/metabolism/genetics ; *Protein Biosynthesis ; Humans ; *RNA-Binding Proteins/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *RNA Transport ; Gene Knockdown Techniques ; Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurons/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; Neurites/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Transcriptome ; Frontotemporal Dementia/genetics/metabolism ; },
abstract = {Neurons rely on messenger RNA (mRNA) transport and local translation to facilitate rapid protein synthesis in processes far from the cell body. These processes allow precise spatial and temporal control of translation and are mediated by RNA-binding proteins (RBPs), including those associated with neurodegenerative diseases. Here, we use proteomics, transcriptomics, and microscopy to investigate the impact of RBP depletion on mRNA transport and local translation in induced pluripotent stem cell-derived neurons. We find thousands of transcripts enriched in neurites and that many of these transcripts are locally translated, possibly due to the shorter length of transcripts in neurites. Loss of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS)-associated RBPs TDP-43 and hnRNPA1 induce distinct alterations in the neuritic proteome and transcriptome. TDP-43 knockdown (KD) leads to slightly increased neuritic mRNA and translation, while hnRNPA1 loss has more moderate effects on local mRNA profiles, possibly due to compensation by hnRNPA3. These results highlight the crucial role of FTD/ALS-associated RBPs in mRNA transport and local translation in neurons and the importance of these processes in neuron health and disease.},
}

*RNA, Messenger/metabolism/genetics
*Protein Biosynthesis
Humans
*RNA-Binding Proteins/genetics/metabolism
*DNA-Binding Proteins/genetics/metabolism
*RNA Transport
Gene Knockdown Techniques
Heterogeneous Nuclear Ribonucleoprotein A1/genetics
Induced Pluripotent Stem Cells/metabolism/cytology
*Neurons/metabolism
Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism
Neurites/metabolism
Amyotrophic Lateral Sclerosis/genetics/metabolism
Transcriptome
Frontotemporal Dementia/genetics/metabolism

@article {pmid40736930,
year = {2025},
author = {Chen, X and Zhuang, J and Chen, Z and Liu, S and Xu, Y and Chen, C and Yi, J and Yu, F and Xie, B and He, F},
title = {The relationship between allostatic load levels and time to deterioration of health-related quality of life in non-small cell lung cancer patients.},
journal = {Journal of cancer survivorship : research and practice},
volume = {},
number = {},
pages = {},
pmid = {40736930},
issn = {1932-2267},
support = {grant number 2023J01093//Fujian Provincial Natural Science Foundation Project/ ; },
abstract = {BACKGROUND AND PURPOSE: Allostatic load (AL) significantly impacts patient outcomes. This study aimed to explore the association between AL levels and time to deterioration (TTD) of health-related quality of life (HRQoL) in non-small cell lung cancer (NSCLC) patients.

METHODS: A prospective study (May 2017-September 2022) included 362 NSCLC patients from The First Affiliated Hospital of Fujian Medical University. HRQoL was assessed using EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires, and AL-related biomarkers were collected. Univariate and multivariate Cox regression analyses evaluated the impact of AL on HRQoL TTD.

RESULTS: TTD events were most common in global health status (QL), physical functioning (PF), and dyspnea (LC-DY). Lower AL levels delayed TTD in emotional functioning (EF) (HR = 2.041, 95% CI: 1.404-2.969, P < 0.001), cognitive functioning (CF) (HR = 1.613, 95% CI: 1.082-2.403, P = 0.019), insomnia (SL) (HR = 1.553, 95% CI: 1.064-2.266, P = 0.022), constipation (CO) (HR = 2.114, 95% CI: 1.179-3.791, P = 0.012), and hemoptysis (LC-HA) (HR = 2.316, 95% CI: 1.037-5.172, P = 0.041). Multivariate analysis confirmed these findings, except for insomnia, which lost significance.

CONCLUSIONS: Lower AL levels delayed TTD in EF, CF, CO, and LC-HA, highlighting AL's role in preserving HRQoL in NSCLC patients.

HRQoL is critical for cancer survivors. This study underscores the importance of AL to improve HRQoL outcomes in NSCLC patients.},
}

@article {pmid40736059,
year = {2025},
author = {Zhao, Q and Zhao, Z and Zhao, G and Xue, L and Chen, L and Zhou, G and Liang, J and Qin, M and Hu, M},
title = {Effect of Defocus Incorporated Multiple Segments (Fog Vision +0.50 D) Combined With 0.01% Atropine on the Preclinical and Early Stages of Myopia in Children.},
journal = {Journal of pediatric ophthalmology and strabismus},
volume = {},
number = {},
pages = {1-12},
doi = {10.3928/01913913-20250530-04},
pmid = {40736059},
issn = {1938-2405},
abstract = {PURPOSE: To retrospectively analyze the efficacy of multi-zone positive optical defocus lenses (DIMS) + fog vision + 0.01% atropine for the treatment of children with preclinical and early stages of myopia.

METHODS: The axial length (AL) and refraction were analyzed at baseline and after 12 months of follow-up in 192 eyes treated with combined therapy. The success of treatment was defined as an annual AL growth rate within the physiological growth range and myopia progression of -0.50 diopters (D)/year or greater. Subgroup analysis was performed to investigate the percentage of treatment success in the overall population compared to the subgroups based on baseline AL and age.

RESULTS: Overall, the success rates were 87% and 93% for AL control and myopia control, respectively. Compared to before combined therapy, there was an increase in AL after treatment (boys: P < .001; girls: P < .001). The change in spherical equivalent (SE) was consistent with the change in AL, with both boys and girls showing an increase in SE after treatment, with a statistically significant difference in girls (boys: P = .059; girls: P = .001). There was no statistically significant difference in the percentage of treatment success in either boys or girls based on baseline AL and age subgroups compared to the overall population.

CONCLUSIONS: The treatment regimen of DIMS + fog vision + 0.01% atropine demonstrated significant control effects on myopia in preclinical and early stages of myopia in children across different genders, baseline ALs, and ages. Timely intervention is recommended once a tendency toward myopia is observed in children.},
}

@article {pmid40735987,
year = {2025},
author = {Ergin, AD},
title = {Nanotechnological Approaches for Mitochondrial Targeting in Neurodegenerative Diseases.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266397447250723073446},
pmid = {40735987},
issn = {1873-4294},
abstract = {OBJECTIVES: Mitochondria are dynamic organelles essential for energy metabolism and cellular homeostasis, playing critical roles in ATP production, calcium regulation, redox balance, and apoptosis. However, mitochondrial dysfunction is a central factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Given the essential role of mitochondria in neuronal survival, targeted therapeutic strategies that restore mitochondrial function have gained significant attention. This review explores the latest advances in mitochondrial-targeted therapies and their potential applications in neurodegenerative diseases.

METHODS: A comprehensive literature review was conducted on mitochondrial-targeted therapeutic strategies, with a focus on nanotechnology-based drug delivery systems. The analysis includes various nanoparticle-based approaches, such as liposomes, DQAsomes, and polymeric nanoparticles, which have demonstrated high biocompatibility, controlled drug release, and enhanced mitochondrial targeting efficiency. Additionally, mitochondria-penetrating peptides and delocalized lipophilic cations (DLCs) are discussed for their role in improving drug localization within mitochondria and overcoming biological barriers, including the blood-brain barrier (BBB).

RESULTS: Recent research shows the potential of mitochondrial-targeted antioxidants, peptides, and biocompatible nanocarriers in arranging mitochondrial dysfunction and protecting neurons from oxidative damage. Various nanoparticle-based drug delivery systems have demonstrated the ability to selectively target mitochondria, improving drug bioavailability, therapeutic efficacy, and neuroprotective outcomes in neurodegenerative diseases.

CONCLUSION: Mitochondria-targeted therapies provide promising avenues for disease-modifying treatments aimed at preserving neuronal integrity and delaying disease progression. The unique properties of nanoparticles, such as their ability to enhance drug stability, facilitate controlled release, and achieve precise mitochondrial localization, make them valuable tools for neurodegenerative disease therapy. Future research should focus on optimizing delivery systems, validating clinical applicability, and exploring interdisciplinary approaches to accelerate translation into effective treatments.},
}

@article {pmid40735897,
year = {2025},
author = {Leonardo, C and Bjorling, A and Chadwick, KA},
title = {Factors Associated With Type 1 Thyroplasty Revision: Insights From the TriNetX Database.},
journal = {The Laryngoscope},
volume = {},
number = {},
pages = {},
doi = {10.1002/lary.32478},
pmid = {40735897},
issn = {1531-4995},
abstract = {OBJECTIVES: Type 1 thyroplasty (T1T), or medialization laryngoplasty (ML), is a laryngeal framework surgery that corrects glottic insufficiency. Prior studies report revision rates of T1T from 5% to 40%, but factors influencing the need for revision have not been studied in detail. The objectives of this study were to determine the revision rate of T1T and identify patient factors associated with revision.

METHODS: Retrospective cohort study. Patients undergoing T1T (CPT 31591) were identified in TriNetX, a global collaborative network with data from over 128 million patients. The revision rate was determined by the percentage of patients undergoing a second T1T at least 30 days after the initial procedure. Patient factors (demographics, surgical history, and comorbidities) were compared between groups.

RESULTS: A total of 4029 patients underwent T1T; 323 (8.02%) patients underwent revision T1T. Patients undergoing revision were slightly older at initial surgery compared to those not requiring revision (63.5 vs. 61.2 years, p = 0.02), and more likely to be of White or American Native race. Comorbidities associated with revision include pulmonary diseases, neurological conditions, and mental health disorders. A history of thyroidectomy or tracheostomy was also associated with revision. Gender, geographic region, tobacco use, emphysema, Parkinson's disease, and amyotrophic lateral sclerosis were not associated with the need for revision T1T.

CONCLUSION: This is the first comprehensive analysis of factors associated with revision T1T using the TriNetX database. Certain demographic and patient factors may influence the likelihood of requiring revision T1T, potentially impacting patient selection and providing a basis for individualized preoperative patient counseling.

LEVEL OF EVIDENCE: Level III.},
}

@article {pmid40735390,
year = {2025},
author = {Liu, Y and Chen, G and Li, M and Li, M and Xie, D and Luo, Z},
title = {Development of long-acting riluzole transdermal patch against amyotrophic lateral sclerosis: Mechanistic insights into polyglyceryl-3 dioleate-enhanced drug release and skin permeation.},
journal = {International journal of pharmaceutics: X},
volume = {10},
number = {},
pages = {100363},
pmid = {40735390},
issn = {2590-1567},
abstract = {Patients with amyotrophic lateral sclerosis (ALS) often experience difficulty swallowing, making oral administration unsuitable for effective treatment. A transdermal drug delivery system (TDDS) offers a long-acting, non-invasive alternative for ALS therapy. In this study, a riluzole transdermal patch capable of sustained release over 72 h was developed. In vitro skin permeation and pharmacokinetic experiments were conducted to evaluate the impact of various factors-including drug loading, type and concentration of chemical penetration enhancers (CPEs), and type of pressure-sensitive adhesive-on riluzole absorption through the skin. The optimized patch formulation contained 17 % (w/w) riluzole and 10 % (w/w) polyglyceryl-3 dioleate (PGD), with an adhesive layer thickness of 111 μm. The final prescription penetration rate of riluzole was found to be 2.96 μg/(h·cm[2]). Optimized formulation displayed enhanced stability and prolonged pharmacokinetic performance (C max = 74.34 ± 13.62 ng/mL, MRT0-t = 34.91 ± 11.31 h). No significant skin irritation was observed. The role of PGD in the in vitro release and in vivo transdermal absorption of riluzole was thoroughly investigated. The results revealed that PGD not only reduced the interaction between riluzole and the pressure-sensitive adhesive, enhancing drug release but also increased the fluidity of skin lipids, leading to improved transdermal absorption. This study provides a comprehensive molecular-level understanding of PGD's effect on riluzole permeation, offering valuable insights for the rational selection of CPEs in the development of riluzole TDDS.},
}

@article {pmid40733876,
year = {2025},
author = {Wang, Q and Liu, Y and Zou, G and Liang, Z and Liu, H and Yang, BR and Qin, Z},
title = {Modeling light propagation for under-display sensing in a smartphone.},
journal = {Optics express},
volume = {33},
number = {15},
pages = {30847-30858},
doi = {10.1364/OE.565761},
pmid = {40733876},
issn = {1094-4087},
abstract = {Under-display sensing (UDS) is essential to achieve bezel-less smartphones (infinity display). However, light penetrating or reflected by the display panel is distorted, deteriorating UDS signals. Therefore, light propagation should be accurately modeled to analyze and optimize UDS. This study proposes a universal model that recognizes the light propagation mode using the Fresnel number. Under-display ambient light sensors (ALS), under-display cameras (UDC), and proximity sensors are identified to work in the geometric optics, Fraunhofer diffraction, and Fresnel diffraction regimes, respectively. A commercial smartphone is adopted to demonstrate the model's effectiveness and provide domain knowledge. First, regarding the angular response attenuation in under-display ALS, the geometric obstruction by the pixel layout is simulated after acquiring the display panel's microphotograph. Measured data agrees with the simulation with an error smaller than 10 degrees in the viewing angle's full width at half maximum. Next, the UDC is simulated using Fraunhofer diffraction to provide full-color pictures containing blurring caused by the pixel layout's diffraction, showing high similarity with photographs. Finally, Fresnel diffraction dominates the under-display proximity sensor, which utilizes a weakly collimated infrared beam. An approximate solution of the signal on the detector is a scaled Fraunhofer diffraction pattern whose magnification is determined by the sensor configuration. The source-detector orientation influences the background noise (the signal level when no user is present), which is simulated and compared with experimental data, providing an optimal orientation of 45 degrees. The gap between the sensor and the display panel is also investigated through simulation and experiment, demonstrating that Fresnel diffraction is more effective than geometric optics or Fraunhofer diffraction. The proposed model with solid experimental verification on a commercial smartphone can help rationally design UDS and provide insight into the light propagation problem in smartphones.},
}

@article {pmid40732891,
year = {2025},
author = {Hein, ZM and Arbain, MFF and Kumar, S and Mehat, MZ and Hamid, HA and Che Ramli, MD and Che Mohd Nassir, CMN},
title = {Intermittent Fasting as a Neuroprotective Strategy: Gut-Brain Axis Modulation and Metabolic Reprogramming in Neurodegenerative Disorders.},
journal = {Nutrients},
volume = {17},
number = {14},
pages = {},
doi = {10.3390/nu17142266},
pmid = {40732891},
issn = {2072-6643},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy ; *Fasting/physiology ; Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; *Neuroprotection ; Energy Metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Metabolic Reprogramming ; Intermittent Fasting ; },
abstract = {Intermittent fasting (IF) is emerging as a heterogeneous neurometabolic intervention with the possibility of changing the course of neurodegenerative diseases. Through the modulation of the gut-brain axis (GBA), cellular bioenergetics (or metabolic) reprogramming, and involvement in preserved stress adaptation pathways, IF influences a range of physiological mechanisms, including mitobiogenesis, autophagy, circadian rhythm alignment, and neuroinflammation. This review critically synthesises current preclinical and early clinical evidence illustrating IF's capability to supplement synaptic plasticity and integrity, reduce toxic proteins (proteotoxic) burden, and rehabilitate glial and immune homeostasis across models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The key players behind these effects are bioactive metabolites such as short-chain fatty acids (SCFA) and β-hydroxybutyrate (BHB), and molecular mediators such as brain-derived neurotrophic factor (BDNF). We feature the therapeutic pertinence of IF-induced changes in gut microbiota composition, immune response, and mitochondrial dynamics, and we discuss emerging approaches for merging IF into precision medicine frameworks. Crucial challenges include individual variability, protocol optimisation, safety in cognitively vulnerable populations, and the need for biomarker-guided, ethically grounded clinical trials. Finally, we propose IF as a scalable and flexible intervention that, when personalised and integrated with other modalities, may reframe neurodegeneration from a model of irreversible decline to one of modifiable resilience.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy
*Fasting/physiology
Gastrointestinal Microbiome/physiology
Animals
*Brain/metabolism
*Brain-Gut Axis/physiology
*Neuroprotection
Energy Metabolism
Brain-Derived Neurotrophic Factor/metabolism
Metabolic Reprogramming
Intermittent Fasting

@article {pmid40731193,
year = {2025},
author = {Turkbey, B and Schoots, IG and Haider, MA},
title = {Reply to Masatomo Kaneko, Vasileios Magoulianitis, Vinay Duddalwar, et al's Letter to the Editor re: Baris Turkbey, Henkjan Huisman, Andriy Fedorov, et al. Requirements for AI Development and Reporting for MRI Prostate Cancer Detection in Biopsy-naive Men: PI-RADS Steering Committee, Version 1.0. Radiology 2025;315:e240140.},
journal = {European urology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.eururo.2025.07.005},
pmid = {40731193},
issn = {1873-7560},
}

@article {pmid40730291,
year = {2025},
author = {Magdalena, R and Ferrada, L and Ramírez, E and Smith-Ghiglioto, JF and Salazar, K and Nualart, F},
title = {DEHYDROASCORBIC ACID IMPAIRS NEURITE GROWTH THROUGH RIPK1-ASSOCIATED CASPASE ACTIVATION.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.07.036},
pmid = {40730291},
issn = {1873-4596},
abstract = {Axonal and neurite loss is a common event in neurodegenerative diseases, such as Alzheimer's disease or amyotrophic lateral sclerosis, which are enhanced by oxidative damage and reactive oxygen species (ROS) production. In the central nervous system, vitamin C can be found as ascorbic acid (AA), its reduced form, or dehydroascorbic acid (DHA), its oxidized form. Vitamin C mainly acts as an antioxidant agent, and homeostasis in the brain is maintained through its recycling between neurons and astrocytes. However, DHA accumulation under pathophysiological conditions has been associated with changes in neuronal metabolism and necroptotic cell death through RIPK1 activation. Furthermore, recent studies show that DHA accumulation induces significant neurite loss; however, it is unknown whether this effect is associated with RIPK1 activation. Here, we show that DHA treatment on neurospheres (NE) in vitro induces significant neurite shortening and reduced branching, effects associated with early RIPK1 activation and inhibited through Necrostatin-1s and zVAD-FMK treatment, suggesting the activation of apoptotic mechanisms. Finally, we propose DHA, the oxidized form of vitamin C, impairs neurite growth through ripk1-associated caspase activation.},
}

@article {pmid40730054,
year = {2025},
author = {Zhao, J and Bai, J and Wang, H and Zhang, Y and Zhang, J and Zhu, Y and Pang, X and Chen, Z and Ling, L and Cheng, H and Li, M and Huang, X},
title = {Diagnostic value of EMG of sternocleidomastoid and trapezius in assessing bulbar lower motor neuron involvement in amyotrophic lateral sclerosis patients.},
journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology},
volume = {84},
number = {},
pages = {103040},
doi = {10.1016/j.jelekin.2025.103040},
pmid = {40730054},
issn = {1873-5711},
abstract = {The diagnostic value of needle electromyography (EMG) of sternocleidomastoid (SCM) and trapezius (TRA) in assessing bulbar lower motor neuron involvement (LMN) remained controversial. 203 sporadic amyotrophic lateral sclerosis (ALS) patients were enrolled to assess the correlation between EMG abnormalities in SCM and TRA and bulbar LMN involvement. Additionally, difference analysis and diagnostic consistency analysis of EMG abnormalities in GEN (genioglossus), SCM, and TRA were compared. Finally, separate effects of EMG abnormalities in GEN, SCM, and TRA on diagnostic gradings were examined according to the Awaji-Shima criteria. 22 (18.2 %) and 65 (53.7 %) patients without bulbar LMN involvement showed EMG abnormalities in SCM and TRA. In contrast, 19 (23.2 %) and 11 (13.4 %) patients with bulbar LMN involvement showed normal EMG results in SCM and TRA. Multivariate logistic regression analyses showed that both EMG abnormalities in SCM and TRA were correlated with bulbar LMN involvement (P < 0.001). SCM showed electrophysiological characteristics similar to GEN when compared to TRA. However, TRA (67.0 %) showed significantly higher rates of EMG abnormalities than SCM (41.9 %) and GEN (40.4 %) in the whole study population. Reclassified diagnostic gradings showed no significant difference when evaluating EMG abnormalities in individual muscles to indicate bulbar LMN involvement (P = 0.072). EMG abnormalities in SCM and TRA could not fully represent bulbar LMN involvement but were correlated with it. It's advisable to prioritise TRA as a better option when a patient cannot tolerate an EMG examination in the GEN. To enhance the diagnostic evaluation, an EMG examination of GEN could be served as the last choice.},
}

@article {pmid40730020,
year = {2025},
author = {Martins, AP and Mattos, AHB and Pupe, CCB and Martinez, ARM and Nucci, A and França, MC},
title = {The novel missense variant D40V causes a young adult presentation of ANXA11-related myopathy.},
journal = {Neuromuscular disorders : NMD},
volume = {53},
number = {},
pages = {105443},
doi = {10.1016/j.nmd.2025.105443},
pmid = {40730020},
issn = {1873-2364},
abstract = {Pathogenic variants in the ANXA11 gene, which encodes the calcium-dependent phospholipid ligand protein Annexin A11, have been recently associated with amyotrophic lateral sclerosis, frontotemporal dementia and/or muscle disease. ANXA11-related myopathy is characterized by slowly progressive adult-onset limb-girdle weakness combined with axial and facial muscle involvement. Here we expand the spectrum of ANXA11-related myopathy with the description of a 38-year-old Brazilian woman with prominent distal and bulbar manifestations combined with dropped head caused by the novel p.D40V ANXA11 variant. This report widens both the genotypic and phenotypic spectrum of ANXA11-related myopathy. It also points to the pathophysiological relevance of amino acid changes at the highly conserved 40th Annexin A11 residue.},
}

@article {pmid40728732,
year = {2025},
author = {Tuddenham, JF and Fujita, M and Lee, E and Nimmagadda, N and Khairallah, A and Harbison, C and Flowers, XE and Coronas-Samano, G and Maniatis, S and Daly, A and Schneider, JA and Teich, AF and Vonsattel, JPG and Sims, PA and Elyaman, W and Bradshaw, EM and Ostrow, LW and Phatnani, H and Shneider, NA and Bennett, DA and De Jager, PL and Przedborski, S and Menon, V and Olah, M},
title = {Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {10},
pmid = {40728732},
issn = {1432-0533},
support = {NS107442//National Institute of Health, USA/ ; AG057473//National Institute of Health, USA/ ; NS117583//National Institute of Health, USA/ ; CS-02018-191971//Chan-Zuckerberg Neurodegeneration Challenge Network/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/genetics/metabolism ; Humans ; *Spinal Cord/immunology/metabolism/pathology ; *Microglia/metabolism/immunology ; *Transcriptome ; Single-Cell Analysis ; *Brain/immunology/metabolism/pathology ; Female ; Male ; Middle Aged ; Aged ; },
abstract = {Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.},
}

*Amyotrophic Lateral Sclerosis/immunology/pathology/genetics/metabolism
Humans
*Spinal Cord/immunology/metabolism/pathology
*Microglia/metabolism/immunology
*Transcriptome
Single-Cell Analysis
*Brain/immunology/metabolism/pathology
Female
Male
Middle Aged
Aged

@article {pmid40728364,
year = {2025},
author = {Wang, M and Guo, X and Zhang, H and Zhang, N and Yin, T and Gao, Y and Kang, J and Hu, Y and Fan, D and Ye, S},
title = {Educational adjustments for the Chinese version of the Edinburgh Cognitive and Behavioral Screen (ECAS): establishing normative data.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2025.2539904},
pmid = {40728364},
issn = {2167-9223},
abstract = {BACKGROUND: The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a cognitive screening tool designed for patients with amyotrophic lateral sclerosis (ALS). It has been translated into various languages and used globally. This study aimed to establish normative data for the Chinese version of the ECAS to better serve the Mandarin population.

METHODS: We enrolled 358 healthy individuals from different regions of China, all of whom completed the ECAS, and 340 also completed the Mini-Mental State Examination (MMSE). The participants were categorized into six age groups and five education groups.

RESULTS: ECAS scores were found to be related to education level (p < 0.001). After Bonferroni correction for multiple comparisons, we determined that there were no significant differences in total ECAS scores between the junior middle school and senior middle school groups, leading to their combination into a single middle school group. We established cutoff values for the ECAS on the basis of education group. After adjusting for age, sex, and education level, a significant correlation was found between MMSE scores and total ECAS scores (p < 0.001), indicating a high level of consistency in the cognitive assessment.

CONCLUSION: We have established norms for the ECAS on the basis of education level, and the ECAS is highly consistent with the MMSE in the assessment of cognition. These norms will be instrumental in future clinical and follow-up work for Mandarin ALS patients.},
}

@article {pmid40727601,
year = {2025},
author = {Termkijwanich, P and Sanguanwit, P and Yuksen, C and Trakulsrichai, S and Sricharoen, P},
title = {Different Resuscitation Termination Criteria for Out of Hospital Cardiac Arrest; A Prognostic Accuracy Study.},
journal = {Archives of academic emergency medicine},
volume = {13},
number = {1},
pages = {e59},
pmid = {40727601},
issn = {2645-4904},
abstract = {INTRODUCTION: Termination of resuscitation (TOR) rules in out of hospital cardiac arrest (OHCA) varies across different healthcare settings and populations. This study aimed to externally validate ten TOR rules for predicting death before hospital admission among OHCA patients.

METHODS: A retrospective prognostic accuracy study analyzed 379 non-trauma OHCA patients (≥18 years) in Bangkok who were either treated by the emergency medical services (EMS) of Ramathibodi Hospital or transported to Ramathibodi's emergency department by another EMS provider (January 2010 - March 2023). The predictive performance of ten TOR rules (AHA-BLS, AHA-ALS, Korean Cardiac Arrest Research Consortium (KoCARC) rules I, II, and III, Goto's rule, Shihabashi's rule, the New Model I, Helsinki's, and Petrie's rule) in predicting death before hospital admission as well as false positive rates (FPRs) of rules at various resuscitation times were calculated and reported with 95% confidence interval (CI).

RESULTS: Among 379 OHCA patients, 308 (81.27%) died before hospital admission and 71 (18.73%) survived to discharge. The New model I demonstrated the most conservative predictive performance with sensitivity of 96.7% (95% CI: 93.0-98.8), NPV of 91.5% (95% CI: 82.5-96.8), and area under the curve (AUC) of 0.74 (95% CI: 0.70-0.79). The KoCARC III showed FPR of 2.8%. Based on the initial presenting criteria, the FPR varied at different resuscitation time points, with increasing FPR over 30 minutes. Among all rules, Helsinki's and AHA-BLS showed the highest FPRs (1.14 - 21.13 and 1.14 - 23.94, respectively) while the KoCARC TOR rules III demonstrated the most conservative consistency in maintaining a low FPR (0-2.82%) throughout time.

CONCLUSION: The KoCARC III demonstrated relatively high safety for TOR decisions in Bangkok's OHCA population, with the lowest FPR, and high sensitivity and NPV. TOR rules showed higher FPRs compared to previous studies. These findings should be interpreted with caution due to the retrospective design, potential selection bias, and EMS protocol changes over the 10-year study period.},
}

@article {pmid40727259,
year = {2025},
author = {Sun, W and Zhu, A and Chang, H and Xia, J and Gao, J and Zhang, Z and Chi, F and Zhu, Y and Bao, X},
title = {Causal associations and shared genetic etiology between neurodegenerative diseases and constipation.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251362469},
pmid = {40727259},
issn = {2542-4823},
abstract = {BACKGROUND: There is increasing evidence suggesting a correlation between neurodegenerative diseases (NDDs) and constipation; however, their genetic relationship and causal mechanisms remain inadequately elucidated.

OBJECTIVE: We aim to investigate the causal link and shared genetic basis between NDDs and constipation.

METHODS: We obtained summary statistics from large-scale genome-wide association studies, encompassing five NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), as well as constipation. The primary analysis employed five Mendelian randomization methods to evaluate causal effects, while linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) were utilized to investigate genetic correlations. Additionally, significant pleiotropic SNPs were identified using pleiotropic analysis under the composite null hypothesis (PLACO) and functional mapping and annotation (FUMA). Finally, enrichment analysis was conducted to explore the biological pathways associated with the identified pleiotropic genes.

RESULTS: MR analysis revealed a significant causal relationship between AD and an enhanced risk of constipation was demonstrated (OR = 1.043, 95% CI: 1.015-1.073, p = 0.003), while no causality was found between PD, MS, ALS, LBD, and the risk of constipation (p > 0.05). LDSC and HDL analysis revealed a significant positive genetic correlation between AD and constipation. Using PLACO combined with FUMA, we identified 30 overlapping pleiotropic loci, with pathway enrichment analysis revealing important biological pathways related to Aβ metabolism and processing, tau protein process, and the complement and coagulation cascades.

CONCLUSIONS: Our study indicates that AD is a contributing factor to constipation and uncovers the complex genetic mechanisms linking AD and constipation, which holds significant implications for diagnosis and treatment of both conditions.},
}

@article {pmid40726766,
year = {2025},
author = {Bingham, IN and Norel, R and Roitberg, EG and Peller, J and Trevisan, MA and Agurto, C and Merler, M and Shalom, DE and Aguirre, F and Embon, I and Taitz, A and Harris, D and Wright, A and Seaver, K and Sullivan, S and Green, JR and Ostrow, LW and Fraenkel, E and Berry, JD},
title = {Listener effort measures clinically meaningful change of dysarthria in amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {7},
number = {4},
pages = {fcaf232},
pmid = {40726766},
issn = {2632-1297},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease that can cause progressive bulbar dysfunction and dysarthria, resulting in reduced quality of life. Quantitative motor speech analysis can identify features of dysarthria that worsen with ALS progression but are not, inherently, clinically meaningful. Listener effort (LE) is a clinician-rated feature describing how much effort the listener needs to exert to understand the dysarthric speaker. This study investigated whether LE could act as a clinically meaningful measure of ALS dysarthria that could be used as an outcome measure in clinical trials. The Everything ALS Speech Study obtained longitudinal clinical information and speech recordings from 292 participants. In a subset of 125 participants, we measured speaking rate and three speech-language pathologists (SLPs) with expertise in ALS rated LE. We also built and tested a LE prediction algorithm to predict the SLPs' rating of LE. In addition, all speech recordings and associated clinical data are now being made available to ALS researchers via the Everything ALS portal. LE intra- and inter-rater reliability was very high (ICC 0.94-0.95). LE correlated with other measures of dysarthria at baseline and changed over time in participants with ALS (slope 0.77 pts/month, SE = 0.15, P < 0.001) but not controls (slope 0.005 pts/month, SE = 0.02, P = 0.807). The slope of LE progression was faster in people with bulbar onset than non-bulbar onset ALS (1.66 points/month versus 0.42 pts/month; P < 0.001) but was similar in all participants who had bulbar dysfunction at baseline, regardless of ALS site of onset (1.52 pts/month for bulbar onset versus 0.98 pts/month for non-bulbar onset with current bulbar involvement; P = 0.36). The LE prediction model predicted the true LE, with an average R [2] of 0.83 ± 0.07. Dysarthria is associated with decreased quality of life in people with ALS. Quantitative measures of dysarthria in ALS could be useful as ALS clinical trial outcome measures, providing insight into the progression of bulbar symptoms. Speaking rate quantifies progression but is variable across speaking stimuli, emotional states and contextual factors. LE is more inherently clinically meaningful, can be measured reliably by SLPs, changes quantitatively over time and is highly reproducible, thus may be useful as a clinical outcome assessment for ALS clinical trials. Furthermore, a LE prediction model is effective at predicting LE scores and should be validated on an external dataset.},
}

@article {pmid40726565,
year = {2025},
author = {Dukic, S and Govaarts, R and Hillebrand, A and de Visser, M and Seeck, M and McMackin, R},
title = {Novel approaches to EEG and MEG in motor neurone disease: IFCN Handbook Chapter.},
journal = {Clinical neurophysiology practice},
volume = {10},
number = {},
pages = {301-315},
pmid = {40726565},
issn = {2467-981X},
abstract = {Motor neurone diseases (MNDs) are increasingly being acknowledged as network disorders, with cortical dysfunction and degeneration extending beyond the motor cortex. Measures of this broader cortical pathophysiology are providing promising candidates in the search for diagnostic and prognostic biomarkers of the MNDs. Electroencephalography (EEG) and magnetoencephalography (MEG) offer a direct view of neural network activity by detecting changes in electromagnetic fields of the brain. Measurements based on EEG/MEG have often been overlooked in the search for MND biomarkers, largely due to their limited spatial resolution and the perceived challenges associated with noise in these signals. However, with recent developments in sensor technology and source reconstruction algorithms, alongside substantial improvement in pipelines that address noise, EEG/MEG-based measures can now be readily employed for spatiotemporally-precise, economical and non-invasive characterisation of cortical network pathophysiology in MNDs. Here, we provide an overview of how EEG/MEG signals have been employed to quantify neural network function in MND. We outline the advantages and limitations of these measurements, discuss the most clinically promising EEG/MEG studies of MNDs to date, and highlight future directions warranted to harness the full potential of these technologies for understanding and assessing MNDs.},
}

@article {pmid40726139,
year = {2025},
author = {Jin, X and Wang, X and Zheng, D and Yuan, P and Li, J and Qiu, T and Zhang, H and Chen, Y and Zhang, J and Wu, F and Liu, Q and Grecucci, A and Zhang, Y and Wang, J and Yi, X and Palaniyappan, L and Braden, BB},
title = {Disrupted Glucose Metabolism Covariance Network in Amyotrophic Lateral Sclerosis.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {7},
pages = {e70537},
doi = {10.1111/cns.70537},
pmid = {40726139},
issn = {1755-5949},
support = {U22A20377//National Natural Science Foundation of China/ ; 2024PT5109//The Scientific Research Program of FuRong Laboratory/ ; 2022LNJJ09//Project Program of National Clinical Research Center for Geriatric Disorders/ ; 2024ZZTS0954//Fundamental Research Funds for the Central Universities of Central South University/ ; CB-C2022//Fonds de Recherche du Québec - Santé/ ; },
abstract = {AIMS: This study aimed to characterize the topological changes in glucose metabolism covariance networks in amyotrophic lateral sclerosis (ALS).

METHODS: We assessed the interregional coordination of [18]F-FDG-PET data to examine topological alterations in individualized glucose metabolism covariance networks in 127 ALS patients compared to 128 healthy controls (HC).

RESULTS: Compared to HC, ALS patients showed reduced small-worldness (lower normalized clustering coefficient, higher normalized characteristic path length) and decreased global and local efficiency, suggesting impaired global integration and local segregation. These network metrics correlated with disease progression and motor function. Regionally, altered degree centrality affected motor and default mode networks, and related to GABAa and mGluR5 receptor expression. Transcriptomic associations further linked these changes to immune function, synaptic signaling, and protein regulation. Bidirectional shifts in connectivity strength were observed, with both increased connectivity and disease progression independently predicting reduced survival.

CONCLUSION: Our findings may provide valuable biomarkers for monitoring the progression of ALS and suggest potential mechanistic pathways for the development of innovative therapeutic strategies for this disorder.},
}

@article {pmid40725930,
year = {2025},
author = {He, Y and Ming, W and Tan, Y and Wang, Y and Wang, M and Li, H and Jiao, Z and Hou, Y},
title = {The effectiveness of cognitive behavioral therapy in patients with motor neuron disease: A systematic review.},
journal = {Medicine},
volume = {104},
number = {30},
pages = {e43597},
doi = {10.1097/MD.0000000000043597},
pmid = {40725930},
issn = {1536-5964},
mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; *Motor Neuron Disease/psychology/therapy ; Quality of Life ; Caregivers/psychology ; Anxiety/therapy/etiology ; Depression/therapy/etiology ; Treatment Outcome ; },
abstract = {BACKGROUND: Motor neuron disease (MND) is a neurodegenerative disorder that causes progressive loss of motor function. With limited disease-modifying drug therapies, cognitive behavioral therapy (CBT) has emerged as a key nonpharmacological intervention. This systematic review evaluated CBT's therapeutic potential across clinical domains to inform psychosocial care of patients with MND.

METHODS: Comprehensive searches were performed in PubMed, Web of Science, Cochrane Library, and Embase, from inception until February 2025. Two researchers independently screened the literature, extracted data, assessed study quality, and resolved disagreements via consensus or third-party consultation.

RESULTS: Five studies involving 561 patients were included. Compared with conventional care, CBT significantly improves patients' quality of life and psychological flexibility. However, the effects on caregiver burden and physical health were not statistically significant. CBT modalities included acceptance and commitment therapy, dialectical behavior therapy, rational-emotive behavior therapy, mindfulness cognitive therapy, and metacognitive training. Traditional CBT demonstrated superior efficacy in reducing anxiety and depression compared to acceptance and commitment therapy.

CONCLUSION: CBT effectively enhances psychological flexibility and quality of life and reduces anxiety and depression in patients with MND. The standardization of outcome measures requires improvement. High-quality randomized controlled trials are needed to further assess CBT's impact of CBT on caregiver burden and patients' physical health.},
}

Humans
*Cognitive Behavioral Therapy/methods
*Motor Neuron Disease/psychology/therapy
Quality of Life
Caregivers/psychology
Anxiety/therapy/etiology
Depression/therapy/etiology
Treatment Outcome

@article {pmid40725270,
year = {2025},
author = {Tahri, A and Niccolai, E and Amedei, A},
title = {Neurosteroids, Microbiota, and Neuroinflammation: Mechanistic Insights and Therapeutic Perspectives.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26147023},
pmid = {40725270},
issn = {1422-0067},
mesh = {Humans ; *Gastrointestinal Microbiome ; *Neuroinflammatory Diseases/metabolism/microbiology/therapy ; Animals ; *Neurosteroids/metabolism ; *Neurodegenerative Diseases/metabolism/microbiology ; Brain/metabolism ; Inflammation ; },
abstract = {The gut-brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management.},
}

Humans
*Gastrointestinal Microbiome
*Neuroinflammatory Diseases/metabolism/microbiology/therapy
Animals
*Neurosteroids/metabolism
*Neurodegenerative Diseases/metabolism/microbiology
Brain/metabolism
Inflammation

@article {pmid40725035,
year = {2025},
author = {Bordoni, M and Scarian, E and Viola, C and Dragoni, F and Di Gerlando, R and Rizzo, B and Diamanti, L and Gagliardi, S and Pansarasa, O},
title = {Impact of SOD1 Transcript Variants on Amyotrophic Lateral Sclerosis Severity.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26146788},
pmid = {40725035},
issn = {1422-0067},
support = {Ricerca Corrente 2022-2024//Italian Ministry of Health/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Middle Aged ; Male ; Female ; Aged ; Severity of Illness Index ; Disease Progression ; Leukocytes, Mononuclear/metabolism ; Cell Line, Tumor ; RNA, Messenger/genetics/metabolism ; Adult ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects motor neurons of people, leading to death. This pathology can be caused by mutations in different genes, including superoxide dismutase 1 (SOD1). Previous studies have pointed out the presence of two transcripts of SOD1, a short one and a long one. The aim of this study was the investigation of these two transcripts both in the SH-SY5Y cell line and in patients' peripheral blood mononuclear cells. We found that the shortest SOD1 transcript is upregulated under stress conditions in both the cellular model and the patients' cells. Moreover, we found a potential correlation between the short SOD1 transcript and the severity of the pathology, which also correlates with the age of patients. No correlation was found between SOD1 transcripts and the progression of the disease. These data suggest a toxic effect of short SOD1 transcripts in ALS patients, by affecting the severity of the pathology making it a possible biomarker for this disease. Interestingly, our data suggest that a short SOD1 transcript does not influence and drive disease progression. The finding of a biomarker will have suitable implications as indicators of disease severity and from the perspective of drug development.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology
*Superoxide Dismutase-1/genetics/metabolism
Middle Aged
Male
Female
Aged
Severity of Illness Index
Disease Progression
Leukocytes, Mononuclear/metabolism
Cell Line, Tumor
RNA, Messenger/genetics/metabolism
Adult

@article {pmid40724820,
year = {2025},
author = {Tomaszewska-Zaremba, D and Gajewska, A and Misztal, T},
title = {Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26146570},
pmid = {40724820},
issn = {1422-0067},
mesh = {Humans ; *Cannabinoids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy ; Central Nervous System/drug effects ; *Central Nervous System Diseases/drug therapy ; },
abstract = {Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS). Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases. The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.},
}

Humans
*Cannabinoids/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Animals
*Inflammation/drug therapy
Central Nervous System/drug effects
*Central Nervous System Diseases/drug therapy

@article {pmid40722336,
year = {2025},
author = {Balz, LT and Uttner, I and Weishaupt, J and Ludolph, AC and Taranu, D and Vardakas, I and Jung, S and Fangerau, T and Erhart, DK and Senel, M and Tumani, H and Lulé, DE},
title = {Quality of Life in Multiple Sclerosis Compared to Amyotrophic Lateral Sclerosis: Fatigue and Fast Disease Progression Interferes with the Ability to Psychosocially Adjust.},
journal = {Brain sciences},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/brainsci15070745},
pmid = {40722336},
issn = {2076-3425},
abstract = {Background/Objectives: Multiple sclerosis (MS) is a complex neurological disease that is associated with a broad spectrum of physical and psychological symptoms. Psychosocial adjustment (PSA) refers to the ability to cope with these challenges, which influence quality of life (QoL) and depressiveness in ways not yet fully understood. This study explores the relationship of PSA and disease-specific symptoms in MS, including fatigue, a prominent MS symptom. Additionally, PSA was compared to Amyotrophic Lateral Sclerosis (ALS) to disentangle the impact of disease trajectory on PSA. Methods: We interviewed 77 MS patients using patient-reported outcome measures on QoL and depression and compared them to 30 ALS patients. Confirmatory factor analysis and regression analysis were used to identify PSA indicators and predictors in MS, while t-tests assessed PSA differences across diseases. Results: Key PSA indicators in MS included physical (PQoL), mental (MQoL), and subjective (SQoL) quality of life, as well as depressiveness, with cognitive and motor fatigue emerging as significant predictors. MS patients had higher PQoL and SQoL and lower levels of depression compared to ALS patients, while both groups were comparable with regard to MQoL. Conclusions: PSA in MS is supported by high QoL and low depression levels, with fatigue being a significant predictor. Despite different disease trajectories, patients with MS and ALS showed comparable MQoL, indicating that both diseases similarly impact mental QoL, reflecting a partial overlap in psychosocial adjustment. Overall, psychosocial adjustment was more favorable in MS, likely due to its slower disease progression compared to ALS.},
}