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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CLINICAL TRIAL NUMBER: Not applicable.},
}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid40453434,
year = {2025},
author = {Voosala, S and Sandhya, M and Mathuranath, PS and Mahale, RR},
title = {Autoimmune Encephalitis Pattern on PET-MRI in a Patient with Amyotrophic Lateral Sclerosis.},
journal = {Indian journal of nuclear medicine : IJNM : the official journal of the Society of Nuclear Medicine, India},
volume = {40},
number = {1},
pages = {22-25},
pmid = {40453434},
issn = {0972-3919},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive primary motor neuron disorder whose etiology is a subject of debate even today. Interplay between multiple genetic and environmental factors and co-existent/antecedent infection, inflammation, and malignancy have all been hypothesized as potentially causative for this disease. Owing to its hybrid diagnostic capability, fluorodeoxyglucose positron emission tomography-magnetic resonance imaging is highly valuable in detecting varied autoimmune encephalitis patterns, one of which we report in a patient with ALS providing insight into autoimmunity as a potential etiology in the pathogenesis of this disease.},
}

@article {pmid40453369,
year = {2025},
author = {Slagt, C and Van Kuijk, SMJ and Bruhn, J and Van Geffen, GJ and Mommers, L},
title = {First Results of Our Local Practice Guide Used During the Late Phase of Resuscitation in Patients with Refractory VF in Out of Hospital Cardiac Arrest.},
journal = {Open access emergency medicine : OAEM},
volume = {17},
number = {},
pages = {203-213},
pmid = {40453369},
issn = {1179-1500},
abstract = {OBJECTIVE: Treatment of refractory ventricular fibrillation (rVF) is a clinical challenge. If rVF is still present after standard advanced life support (ALS) guideline care, including amiodaron administration, other therapeutic options might be necessary. Based on the available evidence and expertise, our Helicopter Emergency Medical Service (HEMS) team developed a local practice guide for the prolonged resuscitation of patients in rVF and implemented this as standard HEMS care in March 2022.

METHODS: This database study contains all patients treated with our local practice guide during out of hospital cardiac arrest (OHCA) with rVF beyond the fifth regular ALS shock-block. This local practice HEMS treatment algorithm consisted of, among others, cessation of epinephrine and alternating administration of esmolol and norepinephrine combined with enoximone. Data were derived from the HEMS database and the treating hospitals. Primary outcome was the return of spontaneous circulation. Secondary outcome was defined as survival to hospital discharge and cerebral performance. This outcome was compared to the literature to analyze for inferiority of treatment.

RESULTS: In a 21-month period, HEMS was 761 times deployed for OHCA. Nineteen patients were treated with the local practice guide, nine patients (47%) were admitted to hospital with return of spontaneous circulation. Median resuscitation time was 22min. Hospital survival with good neurology was achieved in 42% vs 17% as expected. Exact Clopper-Pearson and logistic regression analysis revealed non-inferiority of the local practice guide. Withholding epinephrine was achieved in 84% of patients. A total of 79% and 90% of patients received esmolol and norepinephrine/enoximone mixture, respectively. Alternative defibrillation positions were indicated in 18 patients but applied in only 6 (33%).

CONCLUSION: In patients with persisting VF despite prolonged advanced life support care, a multifaceted bundle of care approach shows promising results and warrants further research. Alternative drug administrations were found to be substantially easier to achieve compared to alternative defibrillation positions.},
}

@article {pmid40452868,
year = {2025},
author = {Labarre, A and Guitard, E and Tossing, G and Parker, JA},
title = {har-1/CHCHD10 mutations induce neurodegeneration and mitochondrial fragmentation in Caenorhabditis elegans.},
journal = {microPublication biology},
volume = {2025},
number = {},
pages = {},
pmid = {40452868},
issn = {2578-9430},
abstract = {CHCHD10 encodes a mitochondrial protein that plays a role in cristae morphology and oxidative phosphorylation, with mutations associated with neurodegenerative diseases, including the spectrum of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The Caenorhabditis elegans ortholog of CHCHD10 is har-1 , which can be used to model CHCHD10-related neurodegenerative diseases. We focused on two har-1 mutant strains: one featuring a 260 bp deletion (gk3124) and the other with a G73E point mutation (ad2155). Both har-1 mutants displayed progressive paralysis, degeneration of GABAergic motor neurons, and mitochondrial fragmentation. These strains may be valuable tools for investigating pathogenic mechanisms and therapeutic strategies for neurodegenerative diseases.},
}

@article {pmid40452867,
year = {2025},
author = {Labarre, A and Guitard, E and Tossing, G and Parker, JA},
title = {Suppression of har-1/CHCHD10 phenotypes for ALS-FTD therapy discovery.},
journal = {microPublication biology},
volume = {2025},
number = {},
pages = {},
pmid = {40452867},
issn = {2578-9430},
abstract = {Mutations in CHCHD10 are linked to a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The Caenorhabditis elegans orthologue of CHCHD10 is har-1 , and we investigated whether har-1 mutants could be used for therapeutic discovery in ALS-FTD. Our results show that the small molecule pioglitazone and the probiotic Lacticaseibacillus rhamnosus HA-114 can alleviate har-1 mutant phenotypes. These findings suggest that har-1 mutants are suitable for modifier screens and could be adapted for high-throughput drug screening and microbiome studies to aid in discovering therapies for ALS-FTD.},
}

@article {pmid40451302,
year = {2025},
author = {Thang, CJ and Garate, D and Sánchez-Feliciano, A and Barbieri, JS},
title = {Response to Cho et. al's "GLP-1 Receptor Agonist Use Is Associated with Increased Rates of Acne Vulgaris Diagnosis In Non-Diabetic Obese Women but Not Men: A Retrospective Cohort Study".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.03.102},
pmid = {40451302},
issn = {1097-6787},
}

@article {pmid40450587,
year = {2025},
author = {Mehta, P and Raymond, J and Nair, T and Han, M and Punjani, R and Larson, T and Berry, J and Mohidul, S and Xue, S and Horton, DK},
title = {Incidence of ALS in all 50 states in the United States, data from the National ALS Registry, 2012-2019.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2506448},
pmid = {40450587},
issn = {2167-9223},
abstract = {OBJECTIVE: To summarize amyotrophic lateral sclerosis (ALS) incidence in all 50 states and the District of Columbia from 2012 to 2019. In 2010, the Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated National ALS Registry (Registry) to determine the incidence and prevalence of ALS within the United States, characterize demographics, and identify potential risk factors. This is the first analysis of state-level ALS incidence estimates for all 50 states and the District of Columbia.

METHODS: ALS is not a notifiable disease in the United States. As such, the Registry identifies cases using existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration), and a secure web portal that identifies cases not included in the national databases. Confirmed and likely cases are deduplicated and counted as incident cases for the first year they are identified using a validated algorithm. Incident counts, incident rates, and rate ratios were then calculated.

RESULTS: State-level age-adjusted overall incidence rates for 2012 to 2019 ranged from 0.65 per 100,000 persons (Alaska) to 2.25 per 100,000 persons (Vermont), with an overall incidence of 1.44 per 100,000 persons in the United States. New England and the upper Midwest regions had higher incidence rates than national rates.

CONCLUSIONS: These findings summarize the incidence of ALS for all 50 states from 2012 to 2019. This is a continuing effort to identify ALS cases nationally. The establishment of the Registry allows for epidemiological analyses of ALS data and the assessment of potential risk factors.},
}

@article {pmid40450581,
year = {2025},
author = {Tokuda, E and Leykam, L and Zetterström, P and Brännström, T and Andersen, PM and Marklund, SL},
title = {Diverse effects of coexpression of human SOD1 variants on motor neuron disease.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddaf088},
pmid = {40450581},
issn = {1460-2083},
support = {56103-7002829//Västerbotten County Council/ ; 223-2808-12//Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen/ ; 223-1881-13//Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen/ ; 2.1.12-1605-14//Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen/ ; 2012.0091//Knut and Alice Wallenberg Foundation/ ; 2014.0305//Knut and Alice Wallenberg Foundation/ ; 2020.0232//Knut and Alice Wallenberg Foundation/ ; 2012-3167//Swedish Research Council/ ; 2017-03100//Swedish Research Council/ ; 2012-0262//Swedish Brain Foundation/ ; 2012-0305//Swedish Brain Foundation/ ; 2013-0279//Swedish Brain Foundation/ ; 2016-0303//Swedish Brain Foundation/ ; 2018-0310//Swedish Brain Foundation/ ; 2020-0353//Swedish Brain Foundation/ ; 2022-0309//Swedish Brain Foundation/ ; },
abstract = {Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most common mutation, D90A, disease can develop in both homozygous and, more rarely, in heterozygous individuals with unexplained differences in clinical presentation. There is mounting evidence that prion-like spread of SOD1 aggregation is the primary cause of the disease. Two different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and hSOD1WT, whereas hSOD1D90A transgenic mice form a distinct strain B in addition to A. To explore the effects of aggregate strain propensities when hSOD1 variants are coexpressed, we generated digenic hSOD1G85R/WT and hSOD1G85R/D90A mice. Coexpression of hSOD1WT considerably shortened the lifespan of hSOD1G85R mice to the extent expected from the neurotoxicities of the variants alone. In contrast, coexpression of hSOD1D90A had a minimal effect on survival, far smaller than expected. Moreover, time from onset to the end stage was markedly prolonged in the hSOD1G85R/D90A mice. Aggregation of hSOD1 developed concomitantly with motor neuron disease, and the aggregates contained large amounts of both coexpressed variants in both digenic models. Our findings suggest that hSOD1WT has high a capacity to coaggregate with mutants and enhance neurotoxicity. Such interactions may be restricted by differences in strain propensities, which may contribute to the primarily recessive inheritance associated with the hSOD1D90A mutation.},
}

@article {pmid40449058,
year = {2025},
author = {Zhang, Q and Ding, Y and Zhang, Y and Li, Q and Shi, S and Liu, Y and Chen, S and Wu, Q and Xu, X and Wu, F and Cheng, X and Niu, Q},
title = {Early cortical alterations and neuropsychological mechanisms in amyotrophic lateral sclerosis.},
journal = {NeuroImage. Clinical},
volume = {47},
number = {},
pages = {103809},
doi = {10.1016/j.nicl.2025.103809},
pmid = {40449058},
issn = {2213-1582},
abstract = {OBJECTIVE: This study investigates the characteristics of cortical structural and functional alterations in amyotrophic lateral sclerosis (ALS) patients and their modulation of emotional and cognitive functions, as well as to discuss their diagnostic value in early-stage ALS.

METHODS: Fifty-nine ALS patients (28 in ALS 1 and 31 in ALS 2, categorized using King's College Staging) and 31 healthy controls were evaluated using multiparametric MRI, motor and neuropsychological assessments, and serum neurofilament light chain (NfL) levels. Mediation analyses were performed to examine how cortical alterations influence the relationship between emotional and cognitive functions. Support vector machine (SVM) classification models were constructed to assess the diagnostic utility of differential cortical parameters.

RESULTS: ALS 1 patients exhibited increased cortical thickness (CT) and functional activity in the cingulate and frontotemporal regions, correlating with neuropsychological performance and NfL levels. Mediation analysis revealed that perigenual and frontotemporal functional activity significantly modulated the relationship between depressive symptoms and cognitive function. SVM classification showed that the combined altered regions with Amplitude of Low Frequency Fluctuations (ALFF) model achieved slightly better performance (AUC = 0.853, 95 %CI: 0.687-1.000, p < 0.001) compared to CT (AUC = 0.779, 95 %CI: 0.587-0.972, p < 0.001), although both models showed limited efficacy in differentiating between ALS 1 and ALS 2 groups.

CONCLUSIONS: Cortical structural and functional alterations in ALS mediate the impact of depression on cognitive function, offering insights into the neuropsychological mechanisms of the disease and potential biomarkers for early-stage diagnosis.},
}

@article {pmid40446958,
year = {2025},
author = {Yuan, L and Yang, Y and Guo, Y and Deng, H},
title = {Genetic architecture of amyotrophic lateral sclerosis: a comprehensive review.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jgg.2025.05.008},
pmid = {40446958},
issn = {1673-8527},
abstract = {Amyotrophic lateral sclerosis (ALS), one of the most prevalent neurodegenerative disorders, is pathologically characterized by the progressive degeneration of both upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 2-4 years post-diagnosis. ALS is categorized into familial ALS (FALS) and sporadic ALS, with FALS accounting for approximately 10% of ALS cases. As a genetically heterogeneous disease, ALS exhibits diverse inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked transmission, and genetic factors play pivotal roles in disease pathogenesis. To date, at least 34 disease-causing loci and 32 genes for ALS have been identified. The investigations of mutant protein products and the establishment of animal models have unraveled potential pathogenic pathways, offering insights into the mechanisms of neurodegeneration in ALS. This review focuses on ALS clinical characteristics, neuropathological features, causative loci/genes, genetic susceptibility factors, animal models, and pathogenic mechanisms, with particular attention to recent advances in genetic findings and pathogenic pathways of ALS. Elucidation of the genetic basis of ALS could provide the scientific foundation for personalized treatments to address this recalcitrant disease.},
}

@article {pmid40446399,
year = {2025},
author = {Holdom, CJ and Pilkar, R and Guo, CC and Eijk, RPAV and Sethi, N and Henderson, RD and Ngo, ST and Steyn, FJ},
title = {Identification of passive wrist-worn accelerometry outcomes for improved disease monitoring and trial design in motor neuron disease.},
journal = {EBioMedicine},
volume = {117},
number = {},
pages = {105779},
doi = {10.1016/j.ebiom.2025.105779},
pmid = {40446399},
issn = {2352-3964},
abstract = {BACKGROUND: Motor neuron disease (MND) leads to progressive functional decline, making reliable measures of disease progression critical for patient care and clinical trials. Current clinical outcome measures lack the ability to continuously and objectively track functional decline in daily life of patients with MND. This study assessed and validated wrist-worn accelerometry outcome measures for continuous monitoring in MND, with the potential to refine clinical trial outcomes.

METHODS: This longitudinal study included 95 patients with MND who wore an ActiGraph GT9X Link device on their non-dominant wrist for 8 days, with follow-up every 3-4 months. Accelerometer data were processed using ActiLife and GGIR. Joint models were used to simultaneously investigate the longitudinal change in ALS Functional Rating Scale-Revised (ALSFRS-R) scores and accelerometer-derived outcomes alongside their relationship with overall survival. Sample size estimates for clinical trials were generated using both accelerometer- and ALSFRS-R-based outcomes, and principal component analysis (PCA) explored outcome relationships.

FINDINGS: Accelerometer outcomes showed a slower rate of decline (-0.03 to -0.07 SD/month) compared to ALSFRS-R (-0.10 SD/month) and had stronger correlations with ALSFRS-R motor subdomains (partial r: 0.60-0.73). PCA revealed that longitudinal measures of accelerometry were distinct from the ALSFRS-R, highlighting the complementary nature of these measures. Peak 6-min activity predicted smaller clinical trial sample sizes for studies over 12 months. Accelerometer-derived outcomes were not significantly associated with survival.

INTERPRETATION: Wrist-worn accelerometry offers a practical solution for continuous monitoring in MND, complementing ALSFRS-R. Measures of peak performance, and specifically peak 6-min activity shows promise, potentially reducing sample sizes and improving disease tracking over longer duration studies. Further refinement and validation are needed to adopt actigraphy measures as clinical assessment outcomes.

FUNDING: This study was supported by Wesley Medical Research (2016-32), the Honda Foundation, Motor Neurone Disease Research Australia, and FightMND. CJH received a Higher Degree Research Scholarship from UQ. STN received support from the Scott Sullivan Fellowship (MND and Me Foundation/RBWH Foundation), a FightMND Mid-Career Fellowship, and the AIBN.},
}

@article {pmid40445869,
year = {2025},
author = {Moisseyev, R and Kostyukova, VS and Pozharskiy, AS and Mendybayeva, A and Gritsenko, D},
title = {First Report of Grapevine Yellow Speckle Viroids and Hop Stunt Viroid in Vitis vinifera in Kazakhstan.},
journal = {Plant disease},
volume = {},
number = {},
pages = {},
doi = {10.1094/PDIS-04-25-0798-PDN},
pmid = {40445869},
issn = {0191-2917},
abstract = {Grapevine viroids are the smallest pathogens affecting viticulture. Infected grapevines may show symptoms such as leaf yellowing, mottling, stunted growth, reduced fruit quality, and overall vine decline. Asymptomatic viroid infections in grapevines can still decrease grapevine productivity, thereby posing a hidden economic threat to viticulture (Wolpert et al., 1996; Wu et al., 2023). This study aimed to detect three widely distributed viroid species of the Pospiviroidae family: Grapevine yellow speckle viroid 1 (GYSVd-1), Grapevine yellow speckle viroid 2 (GYSVd-2), and Hop stunt viroid (HSVd). The study focused on grapevine (Vitis vinifera) cultivars 'Saperavi' and 'Rkatsiteli' cultivated in Kazakhstan. Three fields in Shirin village and one field in Tyulkubas village (each about 600 ha) in Almaty region were tested for the presence of viroids due to a decline in yield observed despite the negative tests for common viruses (past 3 years). Symptoms typical for viral infections were observed sporadically without a consistent pattern of infection. Total 17 samples from Shirin (July 2023) and 14 from Tyulkubas (June 2024) with visible symptoms were collected randomly. Validated primers were used to identify GYSVd-1 (mF/mR1, 250 bp) (Hajizadeh et al. 2012) GYSVd-2 (P1/P2, 375 bp) (Jiang et al. 2009) and HSVd (78P/83M, 312 bp) (Sano et al. 2001) using conventional RT-PCR. Among the analyzed samples, in Shirin village, 6 samples tested positive for GYSVd-1, 15 for GYSVd-2, and 15 for HSVd, including 2 positive for both HSVd and GYSVd-1. In Tyulkubas village, 2 samples were positive for GYSVd-1 and 12 for HSVd; GYSVd-1 positive samples als were positive for HSVd, including 8 positive for both HSVd and GYSVd-2 and 6 positive for three viroids. Amplicons for each viroid were further sequenced using the Sanger's method on ABI 3500 Genetic Analyser with BigDye v.3.1 kit and using MinION sequencer with the Rapid Barcoding Kit 96 V14 (Oxford Nanopore Technologies) according to the manufacturer's protocol. The obtained reads were mapped to reference sequences from GenBank-GYSVd-1 NC_001920.1, HSVd NC_001351.1, and GYSVd-2 MG780425.1-using Minimap v.2.2.0 with default parameters in Geneious software. Sequencing produced total 2253 reads for GYSVd-1 (average length 159 bp, range 42-296), 2095 for GYSVd-2 (203.6 bp, 49-578), and 1235 for HSVd (218.5 bp, 53-440). Of these, 947 (42.0%) were been mapped to GYSVd-1, 1778 (84.9%) to GYSVd-2, and 678 (54.9%) to HSVd. Genome coverage was 62.3% (GYSVd-1), 98.1% (GYSVd-2), and 73.8% (HSVd), with mean depths of 889X, 1282X, and 659X, respectively. Each viroid resulted a single contig corresponding to the target amplicon. No reads corresponding to other viral or bacterial agents have been identified. NCBI BLASTn search resulted total 141 hits with coverage 59-68% and identity 98.69-99.35% for GYSVd-1; 128 hits with coverage 82-100% and identity 97.59-100% for GYSVd-2; 157 hits with coverage 99-100% and identity 95.49-97.29%; no not-specific matches were identified for three viroids. The assembled viroid sequences obtained using nanopore sequencing have been uploaded into NCBI database (accessions PV341024-PV341026). Viroids GYSVd-1,2 and HSVd have been detected for the first time in Kazakhstan. The results indicate the need for further studies to estimate impact of these viroids on viticulture and lay a basis for their monitoring in the country.},
}

@article {pmid40443183,
year = {2025},
author = {Gonçalves, F and Teixeira, MI and Rego, F and Magalhães, B},
title = {The role of spiritual care management - Needs and resources in people with amyotrophic lateral sclerosis: Insights from a mixed-methods study.},
journal = {Palliative & supportive care},
volume = {23},
number = {},
pages = {e111},
doi = {10.1017/S1478951525000495},
pmid = {40443183},
issn = {1478-9523},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/therapy ; Male ; Female ; Middle Aged ; Aged ; Surveys and Questionnaires ; Qualitative Research ; Adult ; *Spirituality ; Psychometrics/methods/instrumentation ; *Spiritual Therapies/methods/standards ; },
abstract = {OBJECTIVES: To explore the spiritual needs and resources of People with Amyotrophic Lateral Sclerosis (PALS) at different stages of its trajectory and to characterize the experiences of the current state of the disease.

METHODS: A convergent mixed-methods study was conducted using qualitative and quantitative approaches. Participants were assessed using the clinical and sociodemographic data, ALSFRS-R (function assessment), and the GES Questionnaire to evaluate spiritual needs and resources. Data were collected through in-person or online interviews, transcribed and coded. The qualitative analysis was based on the content analysis method. Statistical analysis was performed using SPSS software. Both datasets were integrated during data analysis.

RESULTS: Twenty-four patients were interviewed, with a duration of the illness ranging from 1 year to 12 years. Participants were at different stages of functional dependence. Analyzing the open questions of the GES questionnaire, six categories were established related to the inner world of PALS: Concern, Nuisance, Help, Support, Safety, and Valorization. Contrary to what was hypothesized, no correlations were found between functionality and the spiritual dimensions. Spiritual needs and resources tend to vary with age, with younger ages presenting a more fragile spiritual dimension overall. Also, the intrapersonal and interpersonal dimension seems to play a central role in the lives of PALS. A negative correlation was identified between the feeling of connection to a supreme/transcendent reality and the level of educational qualifications.

SIGNIFICANCE OF RESULTS: Spirituality often provides crucial emotional support, meaning, and resilience during challenging times. Despite its importance, it is often overlooked in clinical settings. The study emphasizes the need for personalized, holistic care, which should include spiritual care support, regardless of the functional state, highlighting the importance of addressing both intrapersonal and interpersonal domains, resources and needs from early phases. Allowing to create a structured care plan that meets patients' individual spiritual needs, that can contribute to a better QoL and reduce suffering.},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology/complications/therapy
Male
Female
Middle Aged
Aged
Surveys and Questionnaires
Qualitative Research
Adult
*Spirituality
Psychometrics/methods/instrumentation
*Spiritual Therapies/methods/standards

@article {pmid40441800,
year = {2025},
author = {Mehmood, N and Riaz, A and Ghuffar, S and Anwaar, S and Jabeen, N and Shaheen, I and Qasim, M and Khan, SS and Rauf, M and Anwar, T and Qureshi, H and Abusalim, GS and Zaman, W and Ansari, MJ and Iqbal, R},
title = {Epidemiology and genetic characterization of Alternaria alternata causing leaf spot in Fragaria × ananassa.},
journal = {Fungal biology},
volume = {129},
number = {4},
pages = {101589},
doi = {10.1016/j.funbio.2025.101589},
pmid = {40441800},
issn = {1878-6146},
mesh = {*Fragaria/microbiology ; *Alternaria/genetics/isolation & purification/classification/pathogenicity ; *Plant Diseases/microbiology ; Phylogeny ; Pakistan/epidemiology ; Incidence ; DNA, Fungal/genetics/chemistry ; Prevalence ; Sequence Analysis, DNA ; Plant Leaves/microbiology ; DNA, Ribosomal Spacer/genetics/chemistry ; },
abstract = {Alternaria leaf spot (ALS), caused by Alternaria alternata, is a major disease threatening strawberry (Fragaria × ananassa) production globally, including in Pakistan. This study investigated the incidence and prevalence of ALS in key strawberry-producing regions of Pakistan and characterized the pathogen using morphological and molecular techniques. Surveys were conducted during the 2014-2015 and 2015-2016 seasons across 182 farms in Punjab, Khyber Pakhtunkhwa, and Islamabad. Disease prevalence was 100% across all regions, with incidence rates ranging from 17.25% in cooler Islamabad to 55% in Mardan, KPK. Pathogenicity tests confirmed A. alternata as the causal agent. Morphological traits and sequencing of the ITS and endoPG genes further validated its identity. Phylogenetic analysis showed close genetic relatedness to known A. alternata isolates. This is the first comprehensive report of ALS in strawberries in Pakistan, confirming A. alternata as the primary pathogen. The widespread occurrence and high incidence highlight the urgent need for effective control measures. Integrated disease management, including resistant cultivars and targeted fungicide use, is strongly recommended. Further research should investigate environmental factors influencing disease spread and severity to support long-term sustainable management of ALS in strawberry cultivation.},
}

*Fragaria/microbiology
*Alternaria/genetics/isolation & purification/classification/pathogenicity
*Plant Diseases/microbiology
Phylogeny
Pakistan/epidemiology
Incidence
DNA, Fungal/genetics/chemistry
Prevalence
Sequence Analysis, DNA
Plant Leaves/microbiology
DNA, Ribosomal Spacer/genetics/chemistry

@article {pmid40441681,
year = {2025},
author = {Sarasate, M and Córdoba-Izquierdo, A and Farrero, E and López-Lisbona, R and Díez-Ferrer, M and Trias-Sabrià, P and Plana, M and Povedano, M and Santos, S and Prats, E},
title = {Effect of Noninvasive Ventilation on the Upper Airway in Patients With Amyotrophic Lateral Sclerosis: The Role of Upper-Airway Endoscopy.},
journal = {Respiratory care},
volume = {},
number = {},
pages = {},
doi = {10.1089/respcare.12791},
pmid = {40441681},
issn = {1943-3654},
abstract = {Background: Upper-airway obstruction (UAO) in amyotrophic lateral sclerosis (ALS) may reduce the efficacy of noninvasive ventilation (NIV). NIV can cause or worsen this obstruction, further worsening the disease prognosis. This study aims to describe UAO in ALS patients using upper-airway endoscopy (UA-End) during spontaneous breathing (SB) and NIV and to evaluate the usefulness of UA-End in adjusting NIV parameters to correct any observed obstruction. Methods: This prospective study (2017-2019) involved subjects with ALS and indications for NIV. After optimizing ventilation following standardized procedures, an awake UA-End was performed, first during SB and then during NIV. Endoscopic assessments included identification of the site of UAO using the VOTE classification, assessment of vocal cords, and adjustments of NIV settings to correct any identified obstructions. Afterward, a post hoc analysis was conducted comparing gasometrical and nocturnal oximetry variables between the groups with and without NIV obstruction at 3 and 6 months. Results: In total, 25 subjects were enrolled. UAO was observed in 9 cases (37%) during SB, whereas 12 cases (50%) showed obstruction during NIV, 7 newly appearing. Hypopharyngeal constriction and backward movement of the epiglottis were the most frequent findings. Adjustments in NIV settings during endoscopy improved UAO in all but one case. Survival rates were similar after UA-End adjustments for subjects on NIV, both with and without UAO. Conclusions: This study is, to the best of our knowledge, the first to show the usefulness of UA-End in assessing and correcting UAO in subjects with ALS at NIV initiation. Furthermore, correction of such events through UA-End may have a positive impact on ventilation control and survival.},
}

@article {pmid40441157,
year = {2025},
author = {Das, T and Zaidi, FK and Farag, M and Ruff, KM and Mahendran, TS and Singh, A and Gui, X and Messing, J and Taylor, JP and Banerjee, PR and Pappu, RV and Mittag, T},
title = {Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2025.05.011},
pmid = {40441157},
issn = {1097-4164},
abstract = {Stress granules form via co-condensation of RNA-binding proteins (RBPs) containing prion-like low-complexity domains (PLCDs) with RNA molecules. Homotypic interactions among PLCDs can drive amyloid fibril formation that is enhanced by amyotrophic lateral sclerosis (ALS)-associated mutations. We report that condensation- versus fibril-driving homotypic interactions are separable for A1-LCD, the PLCD of hnRNPA1. These separable interactions lead to thermodynamically metastable condensates and globally stable fibrils. Interiors of condensates suppress fibril formation, whereas interfaces have the opposite effect. ALS-associated mutations enhance the stability of fibrils and weaken condensate metastability, thus enhancing the rate of fibril formation. We designed mutations to enhance A1-LCD condensate metastability and discovered that stress granule disassembly in cells can be restored even when the designed variants carry ALS-causing mutations. Therefore, fibril formation can be suppressed by condensate interiors that function as sinks. Condensate sink potentials are influenced by their metastability, which is tunable through separable interactions even among minority components of stress granules.},
}

@article {pmid40441139,
year = {2025},
author = {Workman, MJ and Lim, RG and Wu, J and Frank, A and Ornelas, L and Panther, L and Galvez, E and Perez, D and Meepe, I and Lei, S and Valencia, V and Gomez, E and Liu, C and Moran, R and Pinedo, L and Tsitkov, S and Ho, R and Kaye, JA and , and Thompson, T and Rothstein, JD and Finkbeiner, S and Fraenkel, E and Sareen, D and Thompson, LM and Svendsen, CN},
title = {Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.05.022},
pmid = {40441139},
issn = {1097-4199},
}

@article {pmid40440345,
year = {2025},
author = {Krull, F and Hosseini, S and Bleyer, M and Brenig, B},
title = {Findings from transcriptomics and immunohistochemistry indicate an autoimmune disease targeting brainstem inhibitory interneurons in bovine spastic paresis.},
journal = {PloS one},
volume = {20},
number = {5},
pages = {e0324633},
doi = {10.1371/journal.pone.0324633},
pmid = {40440345},
issn = {1932-6203},
mesh = {Animals ; Cattle ; *Brain Stem/metabolism/pathology/immunology ; *Interneurons/metabolism/pathology/immunology ; *Transcriptome ; *Cattle Diseases/genetics/immunology/pathology/metabolism ; *Autoimmune Diseases/veterinary/genetics/metabolism/pathology/immunology ; Immunohistochemistry ; Gene Expression Profiling ; *Muscle Spasticity/veterinary/genetics/immunology/pathology/metabolism ; Spinal Cord/metabolism/pathology ; },
abstract = {Bovine spastic paresis (BSP) is a progressive neuromuscular disease of unknown origin that causes persistent stiffness of the hind limbs. The symptoms are similar to those of human motor neuron diseases such as primary (PLS) or amyotrophic lateral sclerosis (ALS). BSP occurs worldwide in cattle production with an estimated prevalence of <1%. For Germany, this means that around 20,000 Holstein cattle are affected. BSP is generally considered a hereditary disease, but there is no prevention through breeding programs. As a result, BSP not only affects animal welfare but also leads to economic losses in milk and beef production. Here, we used transcriptomics to analyse the brainstem, spinal cord and affected gastrocnemius muscle tissue of eight animals affected by BSP and eight control animals from slaughterhouses to gain new insights into the molecular mechanisms underlying BSP. We found that the expression of several genes was significantly different in animals affected by BSP compared to control animals. Specific genes for inhibitory neurons were downregulated in the brainstems of the affected animals, namely CCK (cholecystokinin), NPY (neuropeptide Y), and SST (somatostatin). These inhibitory neurotransmitters influence cerebral movement control, among other processes. Furthermore, OOSP2 (oocyte secreted protein 2) was found to be significantly upregulated in the affected animals in all tissues. This expression could best be explained by the presence of T-follicular-helper cells which, through interleukin 21, can trigger a TH-2-dominated immune response and lead to autoimmune encephalitis. Further cases were sampled for confirmation and we detected cell infiltrates of activated microglia and T-cells in the brainstem using immunohistochemistry. Microglial foci were significantly more abundant in animals affected by BSP than control animals. We conclude that BSP is caused by an autoimmune reaction directed against inhibitory interneurons in the brainstem and is due to a combination of genetics and environmental influences. This may result in lost controlling influence on the upper motor neurons via extrapyramidal pathways and therefore triggers the specific symptoms of motor neuron disease.},
}

Animals
Cattle
*Brain Stem/metabolism/pathology/immunology
*Interneurons/metabolism/pathology/immunology
*Transcriptome
*Cattle Diseases/genetics/immunology/pathology/metabolism
*Autoimmune Diseases/veterinary/genetics/metabolism/pathology/immunology
Immunohistochemistry
Gene Expression Profiling
*Muscle Spasticity/veterinary/genetics/immunology/pathology/metabolism
Spinal Cord/metabolism/pathology

@article {pmid40439916,
year = {2025},
author = {Porel, P and Hunjan, G and Kaur, N and Sharma, V and Kaur, M and Mittal, Y and Kaur, R and Aran, KR},
title = {Unlocking the neuroprotective potential of peptide nucleic acids 5 (PNA5) in neurological diseases: molecular mechanisms to therapeutic approaches.},
journal = {Metabolic brain disease},
volume = {40},
number = {5},
pages = {213},
pmid = {40439916},
issn = {1573-7365},
mesh = {Humans ; *Peptide Nucleic Acids/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Blood-Brain Barrier/drug effects/metabolism ; },
abstract = {Peptide nucleic acids (PNAs) are synthetic nucleic acid analogues offering distinct structural and functional advantages over conventional RNA and DNA, positioning them as powerful molecules in molecular biology. Recently, PNAs have gained significant attention for their potential in the prevention and management of neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), spinal cord injury (SCI), depression, and anxiety. PNA5, a specific PNA variant, is highly expressed in neocortical association regions, particularly in primates, and plays a critical role in high-level cognitive functions such as reasoning, decision-making, and problem-solving. It can form stable, sequence-specific hybridizations with nucleic acids, resist nuclease degradation, and efficiently cross cellular membranes, making them ideal candidates for targeting disease-related genes in the brain. PNA5 has shown neuroprotective properties by improving cognitive function, reducing neuroinflammation, and preserving the integrity of the blood-brain barrier (BBB). Additionally, it supports critical processes such as neural migration, axon guidance, and synaptogenesis, which are vital for maintaining proper brain function. This review explores the mechanisms by which PNAs, particularly PNA5, exert therapeutic effects in neurological disorders. It highlights their role in gene modulation, protein regulation, and potential strategies for enhancing PNA delivery to the central nervous system (CNS) and its related disorders.},
}

Humans
*Peptide Nucleic Acids/therapeutic use/pharmacology
Animals
*Nervous System Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Blood-Brain Barrier/drug effects/metabolism

@article {pmid40439808,
year = {2025},
author = {Singh, H and Gupta, R and Gupta, M and Ahmad, A},
title = {Aging-induced alterations in microglial cells and their impact on neurodegenerative disorders.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {515},
pmid = {40439808},
issn = {1573-4978},
mesh = {Humans ; *Microglia/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Aging/pathology/metabolism ; Animals ; Brain/metabolism/pathology ; Cellular Senescence ; },
abstract = {Senescence causes deterioration in the functioning and physiology of an organism. Microglia, the standing resident immune brain cells transform from neuroprotective to neurotoxic with age. Rapid process motility and cellular migration of microglia in the developing brain, and other characteristics are regarded to be crucial for immunological defense and tissue repair. As they mature, microglia not only differ in their morphology but also in their functioning. However, the exact mechanism related to the atrophies caused by aged microglia or their role in neurodegenerative diseases is still uncertain. The aim of this updated review is to provide insights of how aging microglial cells change and how this influences the development of neurodegenerative diseases. As life expectancy rises, there is an increase in the accumulation of iron, ROS/NOS, protein misfolding and insufficient clearing of debris. This is attributed to the age-dependent alterations in the genes linked to energy metabolism, mitochondrial and lysosome function, and neuroinflammation. Aging microglia often shifts towards a pro-inflammatory state with a reduction of anti-inflammatory cytokines. Aging microglia fail to clear amyloid-beta plaques, accelerates tau-pathology and enhances the chronic neuroinflammation, exacerbating the α-synuclein aggregation. These changes significantly impacted the onset of various neurogenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease etc. However, it is important to note that these microglial aging effects might not be perceived as absolute, due to various limitations such as microglial heterogeneity, intercellular complexity across brain regions and variability in human aging owing to genetic and epigenetic variations. Regardless of this the future perspective of such insights are of immense relevance as novel therapeutic approaches can be formulated if the molecular and cellular mechanisms of aging microglial perturbations are understood. Future research should focus on restoring microglial homeostasis to mitigate the effects of aging on the brain and slowing the progression of neurodegenerative diseases.},
}

Humans
*Microglia/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
*Aging/pathology/metabolism
Animals
Brain/metabolism/pathology
Cellular Senescence

@article {pmid40438583,
year = {2025},
author = {Li, H and Peng, Y and Wu, Y and Chen, Y and Li, J and He, Y and Wang, H and Luo, C and Mo, Z},
title = {Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1541442},
pmid = {40438583},
issn = {1663-9812},
abstract = {BACKGROUND: Methamphetamine (MA) is one of the most harmful synthetic drugs, yet the mechanisms underlying its addiction and relapse remain incompletely understood. This study investigates how cardiomyocyte-derived exosomes carrying miRNAs facilitate heart-brain crosstalk and contribute to MA dependence.

MATERIALS AND METHODS: A conditioned place preference (CPP) model of MA dependence was established in rats. High-throughput sequencing were employed to identify candidate miRNAs in cardiac exosomes and brain tissues. Behavioral assessments, real-time PCR, nanoparticle tracking analysis, in vivo imaging, in vitro uptake assays, network pharmacology, and dual-luciferase reporter assays were used to explore the role of cardiomyocyte-derived exosomes in MA dependence.

RESULTS: MA induced significant CPP in rats. miR-181a-5p was markedly upregulated in cardiac exosomes and brain tissue, with higher levels observed in cardiac exosomes. In vivo biodistribution showed that cardiomyocyte-derived exosomes cross the blood-brain barrier and accumulate in the brain. In vitro uptake assays demonstrated that SH-SY5Y cells internalized these exosomes, leading to increased miR-181a-5p expression. Tail vein injections of miR-181a-5p-enriched exosomes enhanced MA CPP behavior in rats. Network pharmacology revealed 108 potential targets of miR-181a-5p, enriched in processes such as steroid biosynthesis, amide metabolism, and apoptosis, involving pathways related to the endoplasmic reticulum, MAPK signaling, and amyotrophic lateral sclerosis. Molecular docking identified stable interactions between MA and 12 targets, including HSP90B1, TNF, and MAP2K1, with miR-181a-5p binding to the 3'-UTR regions of these targets. Dual-luciferase assays confirmed the negative regulation of six targets by miR-181a-5p.

CONCLUSION: This study reveals that cardiomyocyte-derived exosomes transport miR-181a-5p, facilitating heart-brain crosstalk and exacerbating MA CPP behavior in rats. These effects are mediated through the regulation of key brain targets, including HSP90B1, TNF, and MAP2K1, providing new insights into the molecular mechanisms of MA addiction and potential therapeutic targets.},
}

@article {pmid40437235,
year = {2025},
author = {Modafferi, S and Farina, S and Esposito, F and Brandi, O and Di Salvio, M and Della Valle, I and D'Uva, S and Scarian, E and Cicio, G and Riccardi, A and Pisati, F and Garbelli, A and Santini, T and Pansarasa, O and Morlando, M and D'Ambrosi, N and Cozzolino, M and Cestra, G and d'Adda di Fagagna, F and Gioia, U and Francia, S},
title = {DNA damage response defects induced by the formation of TDP-43 and mutant FUS cytoplasmic inclusions and their pharmacological rescue.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
pmid = {40437235},
issn = {1476-5403},
support = {RIPREI2023_7c8ae10d783c//Istituto Superiore di Sanità (ISS)/ ; PRIN 2020 CXFL4T//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; MNESYS (PE0000006)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; CN00000041 CN3 RNA//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PNRR-CN3//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2021 DDR&ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; 2016 DDRNA&ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; 2021 DDR&ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; 2016 DDRNA&ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; DBA.AD005.225-NUTRAGE-FOE2021//Consiglio Nazionale delle Ricerche (National Research Council)/ ; DBA.AD005.225-NUTRAGE-FOE2021//Consiglio Nazionale delle Ricerche (National Research Council)/ ; Flagship Project Interomics//Consiglio Nazionale delle Ricerche (National Research Council)/ ; TELORNAGING-835103//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AIRC-IG(21762)//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; AIRC 5×1000//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; GGP17111//Fondazione Telethon (Telethon Foundation)/ ; POR FESR 2014-2020//Regione Lombardia (Region of Lombardy)/ ; Ricerca Corrente 2022 - 2024//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente 2022 - 2024//Ministero della Salute (Ministry of Health, Italy)/ ; },
abstract = {Formation of cytoplasmic inclusions (CIs) of TDP-43 and FUS, along with DNA damage accumulation, is a hallmark of affected motor neurons in Amyotrophic Lateral Sclerosis (ALS). However, the impact of CIs on DNA damage response (DDR) and repair in this pathology remains unprobed. Here, we show that CIs of TDP-43 and FUS[P525L], co-localizing with stress granules, lead to a dysfunctional DDR activation associated with physical DNA breakage. Inhibition of the activity of the DDR kinase ATM, but not of ATR, abolishes DDR signaling, indicating that DNA double-strand breaks (DSBs) are the primary source of DDR activation. In addition, cells with TDP-43 and FUS[P525L] CIs exhibit reduced DNA damage-induced RNA synthesis at DSBs. We previously showed that the two endoribonucleases DROSHA and DICER, also known to interact with TDP-43 and FUS during small RNA processing, contribute to DDR signaling at DSBs. Treatment with enoxacin, which stimulates DDR and repair by boosting the enzymatic activity of DICER, restores a proficient DDR and reduces DNA damage accumulation in cultured cells with CIs and in vivo in a murine model of ALS. In Drosophila melanogaster, Dicer-2 overexpression rescues TDP-43-mediated retinal degeneration. In summary, our results indicate that the harmful effects caused by TDP-43 and FUS CIs include genotoxic stress and that the pharmacological stimulation of the DNA damage signaling and repair counteracts it.},
}

@article {pmid40436457,
year = {2025},
author = {Peace, A and White, DA and Hackney, G and Bradburn, M and Norman, P and White, S and Al-Chalabi, A and Baird, W and Beever, D and Cade, J and Coates, E and Cooper, C and Ezaydi, N and Halliday, V and Maguire, C and Shaw, PJ and Stavroulakis, H and Waterhouse, S and Young, TA and McDermott, CJ and , },
title = {Randomised controlled trial with parallel process evaluation and health economic analysis to evaluate a nutritional management intervention, OptiCALS, for patients with amyotrophic lateral sclerosis: study protocol.},
journal = {BMJ open},
volume = {15},
number = {5},
pages = {e096098},
doi = {10.1136/bmjopen-2024-096098},
pmid = {40436457},
issn = {2044-6055},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/economics ; United Kingdom ; Randomized Controlled Trials as Topic ; Ireland ; Cost-Benefit Analysis ; Energy Intake ; Quality of Life ; Nutrition Therapy/methods ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating illness that leads to muscle weakness and death usually within around 3 years of diagnosis. People with ALS (pwALS) often lose weight due to raised energy requirements and symptoms of the disease presenting significant challenges to taking adequate oral diet, with those who lose more weight being at a greater chance of earlier death. There is also some evidence to suggest that a higher calorie diet may benefit the disease course in pwALS, but further research is needed.

METHODS AND ANALYSIS: Two armed, parallel group, superiority, open labelled, randomised controlled trial, with internal pilot, to assess the effectiveness of an early high calorie diet on functional outcomes in ALS, comprising two treatment arms: (1) standard care, (2) standard care with additional active management using the OptiCALS complex intervention to achieve a high calorie diet (initially randomised 1:1, then 1:2 following a protocol amendment). Using a food first approach, pwALS will be encouraged and supported to follow a diet that meets an individualised calorie target from food before prescribing oral nutritional supplements. 259 pwALS will be recruited from up to 20 ALS centres across the United Kingdom and Ireland and followed up for a period of 12 months. Primary outcome is functional change measured over 12 months, using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Secondary end points include measures of functional health, quality of life, calorie intake and weight, as well as time to gastrostomy and survival. A health economic analysis and process evaluation will also be undertaken. Participant recruitment is expected to complete in September 2025, and participant follow-up is expected to complete in September 2026. The results of this study are expected in March 2027.

ETHICS AND DISSEMINATION: The trial was approved by Greater Manchester-North West Research Ethics Committee, reference 20/NW/0334 on 8 September 2020. We will publish the study findings in peer-reviewed academic journals and present at local, national and international conferences where possible.

TRIAL REGISTRATION NUMBER: ISRCTN30588041.},
}

Humans
*Amyotrophic Lateral Sclerosis/diet therapy/economics
United Kingdom
Randomized Controlled Trials as Topic
Ireland
Cost-Benefit Analysis
Energy Intake
Quality of Life
Nutrition Therapy/methods

@article {pmid40436400,
year = {2025},
author = {Onder, F and Kumova, D and Ağın, A},
title = {[Carcinom-assoziierte Retinopathie im Zusammenhang mit Lungen- und Nierenzellkarzinom: Paraneoplastischer Sehverlust als Erstmanifestation].},
journal = {Klinische Monatsblatter fur Augenheilkunde},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2623-5813},
pmid = {40436400},
issn = {1439-3999},
}

@article {pmid40436373,
year = {2025},
author = {Vosough, M and Drees, F and Sieber, G and Stach, TL and Beisser, D and Probst, AJ and Boenigk, J and Schmidt, TC},
title = {Integrative Analysis of Nontargeted LC-HRMS and High-Throughput Metabarcoding Data for Aquatic Environmental Studies Using Combined Multivariate Statistical Approaches.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c00539},
pmid = {40436373},
issn = {1520-6882},
abstract = {Significant progress in high-throughput analytical techniques has paved the way for novel approaches to integrating data sets from different compartments. This study leverages nontarget screening (NTS) via liquid chromatography-high-resolution mass spectrometry (LC-HRMS), a crucial technique for analyzing organic micropollutants and their transformation products, in combination with biological indicators. We propose a combined multivariate data processing framework that integrates LC-HRMS-based NTS data with other high-throughput data sets, exemplified here by 18S V9 rRNA and full-length 16S rRNA gene metabarcoding data sets. The power of data fusion is demonstrated by systematically evaluating the impact of treated wastewater (TWW) over time on an aquatic ecosystem through a controlled mesocosm experiment. Highly compressed NTS data were compiled through the implementation of the region of interest-multivariate curve resolution-alternating least-squares (MCR-ALS) method, known as ROIMCR. By integrating ANOVA-simultaneous component analysis with structural learning and integrative decomposition (SLIDE), the innovative SLIDE-ASCA approach enables the decomposition of global and partial common, as well as distinct variation sources arising from experimental factors and their possible interactions. SLIDE-ASCA results indicate that temporal variability explains a much larger portion of the variance (74.6%) than the treatment effect, with both contributing to global shared space variation (41%). Design structure benefits include enhanced interpretability, improved detection of key features, and a more accurate representation of complex interactions between chemical and biological data. This approach offers a greater understanding of the natural and wastewater-influenced temporal patterns for each data source, as well as reveals associations between chemical and biological markers in an exemplified perturbed aquatic ecosystem.},
}

@article {pmid40433509,
year = {2025},
author = {Baek, SH and Tae, WS and Park, JW and Kim, BJ},
title = {Assessment of the glymphatic dysfunction in amyotrophic lateral sclerosis using the diffusion tensor imaging along the perivascular spaces index: a pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1570327},
pmid = {40433509},
issn = {1663-4365},
abstract = {BACKGROUND: The glymphatic system plays a critical role in clearing interstitial waste from the brain. Dysfunction of this system has been linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The diffusion tensor imaging-along the perivascular space (DTI-ALPS) index has emerged as a potential neuroimaging biomarker for evaluating glymphatic function. This study investigates whether glymphatic function differs in individuals with ALS compared to those with Parkinson's disease (PD) and normal controls (NCs), using the DTI-ALPS index.

METHODS: This study included 35 ALS patients, 35 age- and sex-matched PD patients, and 13 NCs. Diffusion tensor imaging (DTI) was conducted, and the DTI-ALPS index was calculated. Clinical assessments included demographic data, disease duration, cognitive status, and functional scales. Group comparisons and correlation analyses were performed to assess the relationship between the DTI-ALPS index and clinical parameters.

RESULTS: The ALS group exhibited a significantly lower right-side DTI-ALPS index than the NC group (p = 0.037), while no differences were observed between the ALS and PD groups. The DTI-ALPS index was negatively correlated with age in ALS and PD groups but showed no correlation with clinical measures in the ALS group. Women in the ALS group had a significantly higher DTI-ALPS index than in men.

CONCLUSION: Glymphatic dysfunction may contribute to the pathogenesis of ALS, as evidenced by a reduced DTI-ALPS index compared to NCs. However, its clinical relevance and specificity for ALS remain uncertain. Further studies with larger cohorts are warranted to validate these findings.},
}

@article {pmid40432760,
year = {2025},
author = {Simkin, RL and Rhymes, ER and Lang, Q and Birsa, N and Sleigh, JN},
title = {Dissection and Whole-Mount Immunofluorescent Staining of Mouse Hind Paw Muscles for Neuromuscular Junction Analysis.},
journal = {Bio-protocol},
volume = {15},
number = {10},
pages = {e5315},
pmid = {40432760},
issn = {2331-8325},
abstract = {The neuromuscular junction (NMJ) is a peripheral synaptic connection between a lower motor neuron and skeletal muscle fibre that enables muscle contraction in response to neuronal stimulation. NMJ dysfunction and morphological abnormalities are commonly observed in neurological conditions, including amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, and spinal muscular atrophy. Employing precise and reproducible techniques to visualise NMJs in mouse models of neuromuscular disorders is crucial for uncovering aspects of neuropathology, revealing disease mechanisms, and evaluating therapeutic approaches. Here, we present a method for dissecting the deep lumbrical and flexor digitorum brevis (FDB) muscles of the mouse hind paw and describe the process of whole-mount immunofluorescent staining for morphological analysis of NMJs. Similar whole-mount techniques have been applied to other muscles, such as the diaphragm; however, dense connective tissue in adult samples often impedes antibody penetration. Moreover, large hind limb muscles, including the gastrocnemius and tibialis anterior, are commonly used to examine NMJs but require embedding and cryosectioning. These additional steps increase the complexity and duration of the protocol and can introduce sectioning artefacts, including transection of NMJs and disruption of morphology. Using small hind paw muscles enables whole-mounting, which completely eliminates the requirement for embedding and cryosectioning. As a result, the entire neuromuscular innervation pattern can be visualised, allowing a more accurate assessment of NMJ development, denervation, and regeneration in mouse models of neurological disease and nerve injury, which can be applied across all postnatal ages. Key features • Small muscles of the mouse hind paw, i.e., lumbrical and FDB muscles, can be rapidly dissected for whole-mount immunofluorescent analysis without the need for cryosectioning. • This protocol allows visualisation of the entire neuromuscular innervation pattern using axonal (anti-tubulin βIII), pre-synaptic (anti-synaptophysin), and post-synaptic (α-bungarotoxin) markers. • Whole-mount immunofluorescence of hind paw muscles enables assessment of developmental, degenerative, and regenerative phenotypes in young and adult mice across disease and injury models. • High-throughput analysis can be performed using NMJ-Analyser or NMJ-morph to evaluate diverse morphological features of the NMJ.},
}

@article {pmid40431734,
year = {2025},
author = {Kim, DH and Kim, JH and Jeon, MT and Kim, KS and Kim, DG and Choi, IS},
title = {The Role of TDP-43 in SARS-CoV-2-Related Neurodegenerative Changes.},
journal = {Viruses},
volume = {17},
number = {5},
pages = {},
doi = {10.3390/v17050724},
pmid = {40431734},
issn = {1999-4915},
support = {25-BR-02-03//Korea Brain Research Institute/ ; },
mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *COVID-19/complications/metabolism/virology/pathology ; *SARS-CoV-2/physiology ; *Neurodegenerative Diseases/metabolism/virology/pathology/etiology ; Virus Replication ; Animals ; },
abstract = {The coronavirus disease 2019 (COVID-19) pandemic has been linked to long-term neurological effects with multifaceted complications of neurodegenerative diseases. Several studies have found that pathological changes in transactive response DNA-binding protein of 43 kDa (TDP-43) are involved in these cases. This review explores the causal interactions between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and TDP-43 from multiple perspectives. Some viral proteins of SARS-CoV-2 have been shown to induce pathological changes in TDP-43 through its cleavage, aggregation, and mislocalization. SARS-CoV-2 infection can cause liquid-liquid phase separation and stress granule formation, which accelerate the condensation of TDP-43, resulting in host RNA metabolism disruption. TDP-43 has been proposed to interact with SARS-CoV-2 RNA, though its role in viral replication remains to be fully elucidated. This interaction potentially facilitates viral replication, while viral-induced oxidative stress and protease activity accelerate TDP-43 pathology. Evidence from both clinical and experimental studies indicates that SARS-CoV-2 infection may contribute to long-term neurological sequelae, including amyotrophic lateral sclerosis-like and frontotemporal dementia-like features, as well as increased phosphorylated TDP-43 deposition in the central nervous system. Biomarker studies further support the link between TDP-43 dysregulation and neurological complications of long-term effects of COVID-19 (long COVID). In this review, we presented a novel integrative framework of TDP-43 pathology, bridging a gap between SARS-CoV-2 infection and mechanisms of neurodegeneration. These findings underscore the need for further research to clarify the TDP-43-related neurodegeneration underlying SARS-CoV-2 infection and to develop therapeutic strategies aimed at mitigating long-term neurological effects in patients with long COVID.},
}

Humans
*DNA-Binding Proteins/metabolism/genetics
*COVID-19/complications/metabolism/virology/pathology
*SARS-CoV-2/physiology
*Neurodegenerative Diseases/metabolism/virology/pathology/etiology
Virus Replication
Animals

@article {pmid40431070,
year = {2025},
author = {Trebol-Aizpurua, E and Eceiza, MV and Jimenez-Martinez, C and Marí, AI and Royuela, M and Zabalza, A and Gil-Monreal, M},
title = {Resistance to Amino Acid Biosynthesis Inhibiting-Herbicides in Amaranthus palmeri Populations from Aragon (Spain).},
journal = {Plants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/plants14101505},
pmid = {40431070},
issn = {2223-7747},
support = {2020 117723-RB-I00//Spanish Ministry of Science and Innovation/ ; PhD fellowship//Basque Government/ ; Investigo programme//Public University of Navarre-Government of Navarre/ ; postgraduate research fellowship (call 2024)//Sociedad Española de Malherbología/ ; },
abstract = {Amaranthus palmeri is a highly problematic agricultural weed due to its rapid growth, high seed production, and strong tendency to develop herbicide resistance. In Spain, the initial colonization of A. palmeri began in 2007, when populations were detected at various locations in the province of Lleida (Catalonia). Since then, new infestations have been reported in other regions of the country, primarily infesting maize fields. Although resistance to glyphosate or to acetolactate synthase (ALS) inhibitors has been documented in several populations from Catalonia and Extremadura, little is known about the resistance profile of populations from Aragon. The main objective of this study was to characterize the putative resistance of five populations from Aragon to 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors (glyphosate) and ALS inhibitors (nicosulfuron and imazamox). Sensitivity to both mechanisms of action was measured by root growth in vertical plates and shikimate accumulation for glyphosate. Target-site resistance was evaluated by analyzing EPSPS and ALS gene copy numbers and ALS gene mutations. The populations showed high variability, with no multiple resistance detected. The Bujaraloz population showed moderate resistance to glyphosate due to EPSPS gene amplification. In three populations, mutations in the ALS gene conferring resistance were detected. The Trp574Leu mutation was detected in approximately half of the individuals from the Albelda, Tamarite de Litera, and Caspe populations. In the latter, the Pro197Thr mutation was also present. This study reveals significant genetic variability within each population and provides evidence for the spread of herbicide resistance across different regions of Spain.},
}

@article {pmid40430989,
year = {2025},
author = {Li, Z and Sun, X and Yu, S and Sun, H and Lian, L and Peng, X and Jin, T and Liu, W and Wang, H},
title = {Baseline Sensitivity of Echinochloa crus-galli (L.) P.Beauv. and Leptochloa chinensis (L.) Nees to Flusulfinam, a New 4-Hydroxyphenylpyruvate Dioxygenase (HPPD)-Inhibiting Herbicide in Rice, in China.},
journal = {Plants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/plants14101425},
pmid = {40430989},
issn = {2223-7747},
support = {ZR2024QC067//Shandong Provincial Natural Science Foundation/ ; 32202353//National Natural Science Foundation of China/ ; 2021CXGC010811//Key R&D Program of Shandong Province, China/ ; 2023YFD1400501//National Key R&D Program of China/ ; },
abstract = {Flusulfinam is a 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide applied post-emergence (POST) to control Echinochloa crus-galli (L.) P.Beauv., Leptochloa chinensis (L.) Nees, Digitaria sanguinalis (Linn.) Scop. and other annual weeds in directly seeded and transplanted paddy fields in China, registered in September 2024. Notably, compared with other HPPD inhibitors in rice, flusulfinam exhibits consistently high safety in both japonica and indica rice varieties. Meanwhile, flusulfinam has no target-site cross-resistance with traditional acetolactate synthase (ALS)-inhibiting, acetyl-CoA carboxylase (ACCase)-inhibiting, and auxin herbicides. Moreover, as the only heterocyclic-amide-structured herbicide in the HPPD inhibitors, it poses a low risk of metabolic cross-resistance with the other HPPD inhibitors, making it a promising candidate for managing herbicide-resistant weeds in rice fields. In this study, the baseline sensitivity to flusulfinam of E. crus-galli and L. chinensis in paddy fields in China was established using dose-response assays between June and October 2023. Thirty-nine populations of E. crus-galli and forty-three populations of L. chinensis, collected from rice fields across various major rice-producing regions in China, exhibited susceptibility to flusulfinam. The GR50 values ranged from 0.15 to 19.39 g active ingredient (a.i.) ha[-1] for E. crus-galli and from 7.82 to 49.92 g a.i. ha[-1] for L. chinensis, respectively, far below the field recommended rate of flusulfinam. Meanwhile, the GR50 values of E. crus-galli and L. chinensis to flusulfinam were both distributed as a unimodal curve, with baseline sensitivity (GR50b) of 6.48 g a.i. ha[-1] and 22.38 g a.i. ha[-1], respectively. The SI50 value showed 129.27-fold and 6.38-fold variability in flusulfinam sensitivity among the 39 E. crus-galli field populations and 43 L. chinensis filed populations, while the variability declined to 2.99-fold and 2.23-fold when the SI50b value was used. This study substantiated the efficacy of flusulfinam against E. crus-galli and L. chinensis in Chinese paddy fields and furnished a benchmark for monitoring temporal variations in the susceptibility of field populations of E. crus-galli and L. chinensis to flusulfinam.},
}

@article {pmid40429802,
year = {2025},
author = {Carnaroli, M and Deriu, MA and Tuszynski, JA},
title = {Computational Search for Inhibitors of SOD1 Mutant Infectivity as Potential Therapeutics for ALS Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {10},
pages = {},
doi = {10.3390/ijms26104660},
pmid = {40429802},
issn = {1422-0067},
mesh = {*Superoxide Dismutase-1/genetics/chemistry/antagonists & inhibitors/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; *Mutation ; Protein Multimerization ; },
abstract = {Familial amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons. Among the main genetic causes of ALS, over 200 mutations have been identified in the Cu/Zn superoxide dismutase (SOD1) protein, a dimeric metalloenzyme essential for converting superoxides from cellular respiration into less toxic products. Point mutations in SOD1 monomers can induce protein misfolding, which spreads to wild-type monomers through a prion-like mechanism, leading to dysfunctions that contribute to the development of the disease. Understanding the structural and functional differences between the wild-type protein and its mutated variants, as well as developing drugs capable of inhibiting the propagation of misfolding, is crucial for identifying new therapeutic strategies. In this work, seven SOD1 mutations (A4V, G41D, G41S, D76V, G85R, G93A, and I104F) were selected, and three-dimensional models of SOD1 dimers composed of one wild-type monomer and one mutated monomer were generated, along with a control dimer consisting solely of wild-type monomers. Molecular dynamics simulations were conducted to investigate conformational differences between the dimers. Additionally, molecular docking was performed using a library of ligands to identify compounds with high affinity for the mutated dimers. The study reveals some differences in the mutated dimers following molecular dynamics simulations and in the docking of the selected ligands with the various dimers.},
}

*Superoxide Dismutase-1/genetics/chemistry/antagonists & inhibitors/metabolism
*Amyotrophic Lateral Sclerosis/genetics/drug therapy
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
*Mutation
Protein Multimerization

@article {pmid40429767,
year = {2025},
author = {Bokulic Panichi, L and Stanca, S and Dolciotti, C and Bongioanni, P},
title = {The Role of Oligodendrocytes in Neurodegenerative Diseases: Unwrapping the Layers.},
journal = {International journal of molecular sciences},
volume = {26},
number = {10},
pages = {},
doi = {10.3390/ijms26104623},
pmid = {40429767},
issn = {1422-0067},
mesh = {Humans ; *Oligodendroglia/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism/etiology ; Animals ; Myelin Sheath/metabolism/pathology ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis/motor neuron disease, and multiple sclerosis, are characterized by progressive loss of neuronal structure and function, leading to severe cognitive, motor, and behavioral impairments. They pose a significant and growing challenge due to their rising prevalence and impact on global health systems. The societal and emotional toll on patients, caregivers, and healthcare infrastructures is considerable. While significant progress has been made in elucidating the pathological hallmarks of these disorders, the underlying cellular and molecular mechanisms remain incompletely understood. Increasing evidence implicates oligodendrocytes and their progenitors-oligodendrocyte progenitor cells (OPCs)-in the pathogenesis of several NDs, beyond their traditionally recognized role in demyelinating conditions such as MS. Oligodendrocytes are essential for axonal myelination, metabolic support, and neural circuit modulation in the central nervous system. Disruptions in oligodendrocyte function and myelin integrity-manifesting as demyelination, hypomyelination, or dysmyelination-have been associated with disease progression in various neurodegenerative contexts. This review consolidates recent findings on the role of OPCs in NDs, explores the concept of myelin plasticity, and discusses therapeutic strategies targeting oligodendrocyte dysfunction. By highlighting emerging research in oligodendrocyte biology, this review aims to provide a short overview of its relevance to neurodegenerative disease progression and potential therapeutic advances.},
}

Humans
*Oligodendroglia/metabolism/pathology
*Neurodegenerative Diseases/pathology/metabolism/etiology
Animals
Myelin Sheath/metabolism/pathology

@article {pmid40429496,
year = {2025},
author = {Watt, NA and Hockley, N and Armitage, JA},
title = {Exploring the Risk: Peripheral Retinal Degenerations in Young Australian Adults.},
journal = {Journal of clinical medicine},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/jcm14103501},
pmid = {40429496},
issn = {2077-0383},
abstract = {Background/Objectives: Peripheral retinal degenerations (PRDs) are structural anomalies in the outer regions of the retina, typically emerging in adolescence and early adulthood. Early detection is crucial, as some PRDs can lead to sight-threatening complications, such as retinal detachment, if left unmanaged. Due to a paucity of research regarding PRDs and their association with axial length (AL) and refractive error (RE) in young Australian adults, this study aimed to investigate the prevalence of PRDs in this population and establish whether AL and RE could help predict the likelihood of PRD occurrence. Methods: A cross-sectional study was conducted on a mixed population (n = 221) of Australian adults aged 18 to 40. Demographic data, RE, AL, and a series of ultra-widefield (UWF) retinal images were obtained from participants' undilated eyes using the Zeiss Clarus[TM] 500. Results: The overall PRD prevalence was 8.15% (n = 442 eyes). Binary logistic regression revealed that a longer AL was a more significant factor in increasing the risk of PRD development across all myopia classifications compared to emmetropia than RE. The likelihood of a PRD was 50% at an AL of 26.9 mm and -6.50D of myopia, and 95% at 29.6 mm and -11.00D. Conclusions: PRD prevalence was lower than reported in other global studies, perhaps reflecting the diverse ethnic makeup of the cohort. While our study supports the conventional understanding that longer ALs, and high myopia are key risk factors for developing a PRD, it also provides new insights into the likelihood of detecting a PRD at a given AL or RE in a mixed population. This information is crucial for eye care practitioners, enabling early identification of at-risk individuals and screening for PRDs that may increase the risk of retinal detachment.},
}

@article {pmid40428860,
year = {2025},
author = {Laucius, O and Drūteika, J and Vanagas, T and Balnytė, R and Radžiūnas, A and Vaitkus, A},
title = {Ultrasonography of the Vagus Nerve for ALS Patients: Correlations with Clinical Data and Dysfunction of the Autonomic Nervous System.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {5},
pages = {},
doi = {10.3390/medicina61050902},
pmid = {40428860},
issn = {1648-9144},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnostic imaging ; Male ; Female ; *Vagus Nerve/diagnostic imaging/physiopathology ; Middle Aged ; Aged ; Ultrasonography/methods ; *Autonomic Nervous System/physiopathology ; Prospective Studies ; Cohort Studies ; },
abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons, leading to the rapid decline of motor function. In recent years, dysfunction of the autonomic nervous system (ANS) has also been increasingly recognized as a contributing factor in various neurodegenerative diseases, including ALS. This study is the second publication from our ALS research cohort at Kaunas Clinics. Our previous work examined ultrasonographic changes in the phrenic nerve as a supplementary diagnostic approach for ALS. Materials and Methods: In the present study, we investigated ultrasonographic alterations of the vagus nerve within the same ALS cohort, aiming to explore correlations with ANS involvement. We performed high-resolution ultrasonography of the vagus nerve (VN), collected clinical data, conducted heart rate monitoring, and evaluated respiratory function. Results: We prospectively included 32 ALS patients meeting "Gold Coast" criteria and 64 age- and sex-matched control patients. The average onset of ALS was 57.97 ± 9.22 years, and the duration of the disease was15.41 ± 9.04 months. For ALS patients, we found significantly reduced vagus nerve cross-sectional area (CSA) at the level of the carotid artery bifurcation bilaterally compared to controls (right VN 1.86 ± 0.21 vs. 2.07 ± 0.18 mm[2], p < 0.001; left VN 1.69 ± 0.21 vs. 1.87 ± 0.21 mm[2], p < 0.001). Reduced values of the left VN positively correlated with the reduced values of FEV1% and sO2. Conclusions: Our findings revealed a significant bilateral reduction in vagus nerve size in ALS patients compared to controls, suggesting that vagal atrophy may serve as a potential marker of autonomic dysfunction in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnostic imaging
Male
Female
*Vagus Nerve/diagnostic imaging/physiopathology
Middle Aged
Aged
Ultrasonography/methods
*Autonomic Nervous System/physiopathology
Prospective Studies
Cohort Studies

@article {pmid40428407,
year = {2025},
author = {Škarica, M and Acsadi, G and Živković, SA},
title = {Pontocerebellar Hypoplasia Type 1 and Associated Neuronopathies.},
journal = {Genes},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/genes16050585},
pmid = {40428407},
issn = {2073-4425},
mesh = {Humans ; *Olivopontocerebellar Atrophies/genetics/pathology ; *Cerebellar Diseases/genetics/pathology ; },
abstract = {Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders.},
}

Humans
*Olivopontocerebellar Atrophies/genetics/pathology
*Cerebellar Diseases/genetics/pathology

@article {pmid40428327,
year = {2025},
author = {Papapanagiotou, AP and Alvanou, MV and Giantsis, IA and Vasilakoglou, I and Eleftherohorinos, IG},
title = {Characterization of the Giant Foxtail's (Setaria faberi) ALS Gene and Its Enhanced Metabolism-Based Cross-Resistance to Nicosulfuron and Rimsulfuron.},
journal = {Genes},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/genes16050505},
pmid = {40428327},
issn = {2073-4425},
mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Sulfonylurea Compounds/pharmacology ; *Herbicide Resistance/genetics ; *Pyridines/pharmacology ; Herbicides/pharmacology ; *Setaria Plant/genetics/drug effects/enzymology ; *Plant Proteins/genetics/metabolism ; Zea mays/genetics/drug effects ; },
abstract = {BACKGROUND: Weed herbicide resistance is a serious problem in crop protection globally. Giant foxtail (Setaria faberi R.A.N. Herrm.) populations cannot be controlled by acetolactate synthase (ALS)-inhibiting herbicides in a few corn (Zea mays L.) monoculture fields.

METHODS: Five putative resistant giant foxtail populations, originating from corn monoculture fields in northeastern Greece, were evaluated for possible evolution of ALS-inhibitor resistance (nicosulfuron, rimsulfuron). The resistance ratio, the underlying resistance mechanism, and its impact on competitive ability against corn were studied.

RESULTS: The whole-plant rate-response assays showed that these populations were resistant (R) to the sulfonylureas nicosulfuron and rimsulfuron, but susceptible (S) to imidazolinone imazamox, triketone 4-hydroxyphenylpyruvate dioxygenase inhibitor tembotrione, and acetyl-CoA carboxylase inhibitor cycloxydim. The sequencing of the ALS gene did not reveal the presence of resistance-associated point mutations, indicating that the resistance was probably not target-site mediated. This was confirmed by the application of piperonyl butoxide two hours before nicosulfuron application, which reversed the resistance in all R giant foxtail populations, supporting the evidence of enhanced metabolism-mediated resistance. The competition study between corn and R or S giant foxtail populations indicated no stable trend reduction in corn traits, suggesting that the resistance mechanism was not associated with the competitive ability of the R populations. The novel ALS genotype in S. faberi, characterized for the first time and submitted to the GenBank database with accession number PV016837, indicated a closer genetic relationship with the S. viridis ALS gene than with S. italica.

CONCLUSIONS: Five giant foxtail populations have evolved metabolism-based resistance to the ALS-inhibiting herbicides nicosulfuron and rimsulfuron.},
}

*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors
*Sulfonylurea Compounds/pharmacology
*Herbicide Resistance/genetics
*Pyridines/pharmacology
Herbicides/pharmacology
*Setaria Plant/genetics/drug effects/enzymology
*Plant Proteins/genetics/metabolism
Zea mays/genetics/drug effects

@article {pmid40428092,
year = {2025},
author = {Vaccarino, F and Quattrocchi, CC and Parillo, M},
title = {Susceptibility-Weighted Imaging (SWI): Technical Aspects and Applications in Brain MRI for Neurodegenerative Disorders.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {12},
number = {5},
pages = {},
doi = {10.3390/bioengineering12050473},
pmid = {40428092},
issn = {2306-5354},
abstract = {Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) sequence sensitive to substances that alter the local magnetic field, such as calcium and iron, allowing phase information to distinguish between them. SWI is a 3D gradient-echo sequence with high spatial resolution that leverages both phase and magnitude effects. The interaction of paramagnetic (such as hemosiderin and deoxyhemoglobin), diamagnetic (including calcifications and minerals), and ferromagnetic substances with the local magnetic field distorts it, leading to signal changes. Neurodegenerative diseases are typically characterized by the progressive loss of neurons and their supporting cells within the neurovascular unit. This cellular decline is associated with a corresponding deterioration of both cognitive and motor abilities. Many neurodegenerative disorders are associated with increased iron accumulation or microhemorrhages in various brain regions, making SWI a valuable diagnostic tool in clinical practice. Suggestive SWI findings are known in Parkinson's disease, Lewy body dementia, atypical parkinsonian syndromes, multiple sclerosis, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, hereditary ataxias, Huntington's disease, neurodegeneration with brain iron accumulation, and chronic traumatic encephalopathy. This review will assist radiologists in understanding the technical framework of SWI sequences for a correct interpretation of currently established MRI findings and for its potential future clinical applications.},
}

@article {pmid40427878,
year = {2025},
author = {Batterman, SA and Islam, MK and Jang, DG and Feldman, EL and Goutman, SA},
title = {Life Course Exposure to Cyanobacteria and Amyotrophic Lateral Sclerosis Survival.},
journal = {International journal of environmental research and public health},
volume = {22},
number = {5},
pages = {},
doi = {10.3390/ijerph22050763},
pmid = {40427878},
issn = {1660-4601},
support = {1R01NS127188-04D4/NH/NIH HHS/United States ; 1K23ES027221-02D2/NH/NIH HHS/United States ; 3P30ES017885-03D3/NH/NIH HHS/United States ; 1R01ES030049-03A3/NH/NIH HHS/United States ; (no number)//Scott L. Pranger ALS Clinic Fund/ ; (no number)//NeuroNetwork for Emerging Therapies/ ; (no number)//Andrea and Lawrence Wolfe Brain Health Initiative/ ; (no number)//Robert and Katherine Jacobs Environmental Health Initiative Fund/ ; (no number)//Coleman Therapeutic Discovery Fund/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/mortality/epidemiology ; Humans ; *Cyanobacteria ; *Environmental Exposure ; *Microcystins/toxicity ; Middle Aged ; *Harmful Algal Bloom ; Female ; Male ; Aged ; Adult ; },
abstract = {Cyanobacterial harmful algal blooms (cyanoHABs) occur worldwide and can cause ingestion and inhalation exposure to microcystin and other potent toxins. This study develops life course exposure measures for cyanobacteria for application in population studies and then associates these measures with the survival of individuals with amyotrophic lateral sclerosis (ALS). The exposure measures utilize an individual's residence history, date of disease onset, and satellite data from the Cyanobacteria Assessment Network. Residence duration for selected exposure windows referenced to disease onset date was used to weight cyanobacteria concentrations in water bodies within 0.25 to 10 km of each residence. Different concentration metrics, buffer sizes, and exposure windows were evaluated. The 2.5 and 5 km buffers best balanced the likelihood and plausibility of exposure while still resolving exposure contrasts. Over their lifetime, most study participants lived within 5 km of cyanobacteria blooms, and the exposure was associated with up to 0.89 years shorter survival, with significant interactions for individuals reporting swimming, fishing, and private wells. Our findings suggest a new and modifiable risk factor for ALS survival, and a need to confirm exposures and epidemiological findings. These cyanoHAB exposure estimates can facilitate population studies that can discover new relationships with neurodegenerative and other diseases.},
}

*Amyotrophic Lateral Sclerosis/mortality/epidemiology
Humans
*Cyanobacteria
*Environmental Exposure
*Microcystins/toxicity
Middle Aged
*Harmful Algal Bloom
Female
Male
Aged
Adult

@article {pmid40427436,
year = {2025},
author = {Minuti, A and Raffaele, I and Scuruchi, M and Lui, M and Muscarà, C and Calabrò, M},
title = {Role and Functions of Irisin: A Perspective on Recent Developments and Neurodegenerative Diseases.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/antiox14050554},
pmid = {40427436},
issn = {2076-3921},
support = {Current Research Funds 2025 (RRC-2025-23686388)//Ministero della Salute/ ; },
abstract = {Irisin is a peptide derived from fibronectin type III domain-containing protein 5 (FNDC5) and is primarily produced by muscle fibers under the regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) during exercise. Irisin has been the subject of extensive research due to its potential as a metabolic regulator and its antioxidant properties. Notably, it has been associated with protective actions within the brain. Despite growing interest, many questions remain regarding the molecular mechanisms underlying its effects. This review summarizes recent findings on irisin, highlighting its pleiotropic functions and the biological processes and molecular cascades involved in its action, with a particular focus on the central nervous system. Irisin plays a crucial role in neuron survival, differentiation, growth, and development, while also promoting mitochondrial homeostasis, regulating apoptosis, and facilitating autophagy-processes essential for normal neuronal function. Emerging evidence suggests that irisin may improve conditions associated with non-communicable neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Given its diverse benefits, irisin holds promise as a novel therapeutic agent for preventing and treating neurological diseases.},
}

@article {pmid40426973,
year = {2025},
author = {Ivantsik, O and Exarchos, TP and Vrahatis, AG and Vlamos, P and Krokidis, MG},
title = {Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights.},
journal = {Biomedicines},
volume = {13},
number = {5},
pages = {},
doi = {10.3390/biomedicines13051146},
pmid = {40426973},
issn = {2227-9059},
support = {TAEDR-0535850.//This work was partially supported by the European Union-Next Generation EU, Greece 2.0 Na-tional Recovery and Resilience Plan Flagship program TAEDR-0535850./ ; },
abstract = {Protein functionality depends on its proper folding, making protein misfolding crucial for the function of proteins and, by extension, cells and the whole organism. Increasing evidence supports the role of protein misfolding in the pathogenesis of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive disease diagnosed at a prevalence of 5 cases per 100,000, with approximately 2-3 patients per 100,000 diagnosed each year. To date, there is no cure, and the disease usually leads to death within 2 to 5 years from diagnosis. There are two types of the disorder: familial ALS (fALS), accounting for approximately 10% of cases, and sporadic (sALS), accounting for the remaining 90%. The hallmark of ALS, regardless of type, is the protein aggregates found in patients' tissues. This suggests that the disruption of proteostasis plays a critical role in the development of the disease. Herein, we stress the distinct factors that lead to protein misfolding and aggregate formation in ALS. Specifically, we highlight several triggering factors affecting protein misfolding, namely mutations, errors in the processes of protein production and trafficking, and failures of folding and chaperone machinery. Gaining a deeper understanding of protein aggregation will improve our comprehension of disease pathogenesis and potentially uncover new therapeutic approaches.},
}

@article {pmid40426848,
year = {2025},
author = {Spargo, TP and Iacoangeli, A and Ryten, M and Forzano, F and Pearce, N and Al-Chalabi, A},
title = {Modelling Population Genetic Screening in Rare Neurodegenerative Diseases.},
journal = {Biomedicines},
volume = {13},
number = {5},
pages = {},
doi = {10.3390/biomedicines13051018},
pmid = {40426848},
issn = {2227-9059},
abstract = {Importance: Genomic sequencing enables the rapid identification of a breadth of genetic variants. For clinical purposes, sequencing for small genetic variations is considered a solved problem, while challenges remain for structural variants, given the lower sensitivity and specificity. Interest has recently risen among governing bodies in developing protocols for population-wide genetic screening. However, usefulness is constrained when the probability of being affected by a rare disease remains low, despite a positive genetic test. This is a common scenario in neurodegenerative disorders. The problem is recognised among statisticians and statistical geneticists but is less well-understood by clinicians and researchers who will act on these results, and by the general public who might access screening services directly without the appropriate support for interpretation. Observations: We explore the probability of subsequent disease following genetic screening of several variants, both single nucleotide variants (SNVs) and larger repeat expansions, for two neurological conditions, Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), comparing these results with screening for phenylketonuria, which is well-established. The risk following a positive screening test was 0.5% for C9orf72 in ALS and 0.4% for HTT in HD when testing repeat expansions, for which the test had sub-optimal performance (sensitivity = 99% and specificity = 90%), and 12.7% for phenylketonuria and 10.9% for ALS SOD1 when testing pathogenic SNVs (sensitivity = 99.96% and specificity = 99.95%). Subsequent screening confirmation via PCR for C9orf72 led to a 2% risk of developing ALS as a result of the reduced penetrance (44%). Conclusions and Relevance: We show that risk following a positive screening test result can be strikingly low for rare neurological diseases, even for fully penetrant variants such as HTT, if the test has sub-optimal performance. Accordingly, to maximise the utility of screening, it is vital to prioritise protocols with very high sensitivity and specificity, and a careful selection of markers for screening, giving regard to clinical interpretability, actionability, high penetrance, and secondary testing to confirm positive findings.},
}

@article {pmid40426669,
year = {2025},
author = {Eisen, A},
title = {Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy.},
journal = {Brain sciences},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/brainsci15050498},
pmid = {40426669},
issn = {2076-3425},
abstract = {Amyotrophic lateral sclerosis (ALS/MND) is considered a uniquely human complex neurodegenerative disorder, presenting with a variety of clinical phenotypes, which include frontotemporal dementia [...].},
}

@article {pmid40426231,
year = {2025},
author = {Bergh, S and Casadei, N and Gabery, S and Simonsson, O and Duarte, JMN and Kirik, D and Nguyen, HP and Petersén, Å},
title = {TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {119},
pmid = {40426231},
issn = {2051-5960},
mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Hypothalamus/pathology/metabolism ; Mice, Transgenic ; Mice ; Humans ; Neurons/pathology/metabolism ; Male ; Orexins/metabolism ; Hypothalamic Hormones/metabolism ; Melanins/metabolism ; Pituitary Hormones/metabolism ; Oxytocin/metabolism ; *Behavior, Animal/physiology ; Disease Models, Animal ; },
abstract = {TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin. We aimed to investigate whether there is a casual link between the effects of TDP-43 in the hypothalamus and the development of neuropathology, as well as changes in metabolism and behavior. We generated an adeno-associated viral (AAV) vector expressing human TDP-43 under the neuronal-specific synapsin promoter, which was injected bilaterally into the hypothalamus of wild-type FVB/N mice. TDP-43 overexpression resulted in hypothalamic pathology in a dose-dependent fashion replicating clinical pathology with hypothalamic atrophy and loss of hypocretin-, MCH- and oxytocin-expressing neurons. Nuclear and cytoplasmic inclusions of TDP-43 were found in the hypothalamus. Mice overexpressing TDP-43 in the hypothalamus developed metabolic dysregulation with hyperglycaemia independent of food intake. Additionally, mice overexpressing TDP-43 in the hypothalamus exhibited reduced motor activity and nesting ability, suggesting the development of an apathy-like phenotype. Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior. These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies.},
}

Animals
*DNA-Binding Proteins/metabolism/genetics
*Hypothalamus/pathology/metabolism
Mice, Transgenic
Mice
Humans
Neurons/pathology/metabolism
Male
Orexins/metabolism
Hypothalamic Hormones/metabolism
Melanins/metabolism
Pituitary Hormones/metabolism
Oxytocin/metabolism
*Behavior, Animal/physiology
Disease Models, Animal

@article {pmid40424919,
year = {2025},
author = {Yamazaki, H and Takamatsu, N and Matsubara, T and Tani, M and Fukushima, K and Yoshida, T and Osaki, Y and Oki, R and Fujita, K and Nodera, H and Izumi, Y},
title = {Evaluation of the diagnostic performance of brachial plexus ultrasound in amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {175},
number = {},
pages = {2110741},
doi = {10.1016/j.clinph.2025.2110741},
pmid = {40424919},
issn = {1872-8952},
abstract = {OBJECTIVE: This study aimed to assess the diagnostic performance of brachial plexus cross-sectional area (BP-CSA) measured by nerve ultrasound (NUS) for differentiating amyotrophic lateral sclerosis (ALS) from controls.

METHODS: A retrospective, cross-sectional study was conducted including patients with ALS and control patients who underwent NUS evaluation of the BP-CSA and the cervical nerve root CSA (C-CSA). Reference values for BP-CSA were built using reference cohort. Receiver operating characteristic curve analysis was performed in independent discovery and validation cohorts to assess the diagnostic performance of BP-CSA.

RESULTS: A total of 244 patients (114 ALS and 130 controls) were included. BP-CSA significantly correlated with body weight (coefficient = 0.50, p < 0.001). After adjusting for body weight, BP-CSA values were significantly lower in patients with ALS than controls (p < 0.001). Adjusted BP-CSA showed superior diagnostic performance compared to C-CSA, with area under the curve values of 0.75 (95 % CI: 0.64-0.86) and 0.78 (95 % CI: 0.68-0.88) in the discovery and validation cohorts, respectively.

CONCLUSIONS: BP-CSA, when adjusted for body weight, shows reliable performance in diagnosing ALS.

SIGNIFICANCE: This study highlights the clinical value of BP-CSA as a potential ALS diagnostic biomarker and underscores its superiority over cervical nerve root measurements.},
}

@article {pmid40424855,
year = {2025},
author = {Mrkela, M and Rodrigues, M and Naidoo, S and Devaux, JBL and Kirk, SE and Vinnakota, C and Buchanan, CM and Mulroy, D and Fraser, H and Jacobsen, JC and Wyatt, H and Drake, K and Parker, E and Potter, H and Henden, L and McCann, EP and Williams, KL and Henders, AK and Roxburgh, RH and Scotter, EL},
title = {The genetics of motor neuron disease in New Zealand.},
journal = {Journal of the neurological sciences},
volume = {474},
number = {},
pages = {123472},
doi = {10.1016/j.jns.2025.123472},
pmid = {40424855},
issn = {1878-5883},
abstract = {Motor neuron disease (MND) is a group of adult-onset neurodegenerative diseases characterised by progressive motor neuron degeneration, of which amyotrophic lateral sclerosis (ALS) is the most common. MND is clinically heterogeneous with complex etiology, caused by or associated with over 40 different genes and multiple environmental risk factors. New Zealand has one of the highest global incidence and mortality rates of MND, however the reasons are unknown. We sought to identify the frequencies of genetic variants in known MND-linked genes among people with MND in New Zealand. We enrolled 184 participants: 149 with a clinical diagnosis of MND (128 sporadic, 21 familial) and 35 clinically unaffected but at-risk individuals. Participants' DNA was screened for genetic variation in 46 MND-associated genes using Sanger sequencing, Illumina SNP microarray, repeat-primed PCR for C9orf72, and an Invitae gene panel. Clinical phenotypes mirrored European trends: males and spinal-onset cases had earlier disease onset. Thirty-three participants (17.9%) carried known pathogenic variants: 24 had C9orf72 repeat expansions, and 9 had pathogenic SOD1 variants (p.(Ile114Thr) and p.(Glu101Gly)). All New Zealand SOD1 p.(Ile114Thr) cases (n = 4) were distantly related to each other and to over 30 Australian cases with the same variant. Variants of interest were found in 14 participants with the splicing variants DCTN1:c.279+1G>C and ATP13A2:c.2412G>A, p.(Lys804=) subject to further study. Notably, 48.4% of pathogenic variants were in pre-symptomatic, unaffected individuals with family history, highlighting the importance of offering cascade testing and symptom surveillance for families, particularly as gene-specific treatments emerge.},
}

@article {pmid40422218,
year = {2025},
author = {Saxena, S and Arnold, WD},
title = {Current Challenges in Elucidating ALS Disease Mechanisms and Therapeutic Advances.},
journal = {Cells},
volume = {14},
number = {10},
pages = {},
pmid = {40422218},
issn = {2073-4409},
mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology/genetics ; },
abstract = {As a researcher and a physician working together to combat amyotrophic lateral sclerosis (ALS), we are acutely aware of both the urgent need for innovation and the persistent divide between laboratory discoveries and clinical care [...].},
}

Animals
Humans
*Amyotrophic Lateral Sclerosis/therapy/pathology/genetics

@article {pmid40422183,
year = {2025},
author = {Verde, EM and Secco, V and Ghezzi, A and Mandrioli, J and Carra, S},
title = {Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.},
journal = {Cells},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/cells14100680},
pmid = {40422183},
issn = {2073-4409},
support = {SUMOsolvable//AriSLA/ ; AHA MCA 2022//Giovanni Armenise-Harvard Foundation and AirAlzh/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/metabolism/pathology/genetics ; *Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Animals ; Protein Processing, Post-Translational ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share common genes and pathomechanisms and are referred to as the ALS-FTD spectrum. A hallmark of ALS-FTD pathology is the abnormal aggregation of proteins, including Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), and dipeptide repeat proteins resulting from C9orf72 hexanucleotide expansions. Genetic mutations linked to ALS-FTD disrupt protein stability, phase separation, and interaction networks, promoting misfolding and insolubility. This review explores the molecular mechanisms underlying protein aggregation in ALS-FTD, with a particular focus on TDP-43, as it represents the main aggregated species inside pathological inclusions and can also aggregate in its wild-type form. Moreover, this review describes the protective mechanisms activated by the cells to prevent protein aggregation, including molecular chaperones and post-translational modifications (PTMs). Understanding these regulatory pathways could offer new insights into targeted interventions aimed at mitigating cell toxicity and restoring cellular function.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics
*DNA-Binding Proteins/metabolism/genetics
*Frontotemporal Dementia/metabolism/pathology/genetics
*Protein Aggregates
*Protein Aggregation, Pathological/metabolism
Animals
Protein Processing, Post-Translational

@article {pmid40421380,
year = {2025},
author = {Park, S and Park, SK and Blair, P and Liebman, SW},
title = {An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases.},
journal = {Microbial cell (Graz, Austria)},
volume = {12},
number = {},
pages = {119-130},
pmid = {40421380},
issn = {2311-2638},
abstract = {TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1∆ aah1∆ yeast model of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from liquid-like droplets toward a more amyloid-like state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like droplets rather than amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1∆ aah1∆ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine and TDP-43 fiber interactions as seen for other heterologous fibers. This work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.},
}

@article {pmid40420932,
year = {2025},
author = {Farsakoury, R and Nashwan, AJ},
title = {Revitalizing upper blepharoplasty: Preserving volume.},
journal = {World journal of clinical cases},
volume = {13},
number = {15},
pages = {100563},
pmid = {40420932},
issn = {2307-8960},
abstract = {Blepharoplasty is a frequently performed aesthetic surgery today aimed at enhancing eyelid appearance and correcting age-related changes. The traditional method of subtraction blepharoplasty, which involved removing fat and excess skin, is now considered outdated. This letter explores Gorgy et al's commentary on Miotti et al's study, highlighting a shift in upper eyelid blepharoplasty towards a more conservative, volume-preserving approach. The study systematically reviewed 10 publications, including three retrospective studies, five comparative studies, and two clinical trials. It emphasizes the trend towards preserving the patient's natural anatomy and focusing on enhancement rather than alteration. However, the study's limitations, such as the lack of long-term comparative research, a relatively small sample size, and a single-center design, indicate that further research with extended follow-up is necessary to validate the safety and effectiveness of these techniques. The focus is increasingly on preserving and augmenting volume in upper blepharoplasty rather than removing tissue.},
}

@article {pmid40420561,
year = {2025},
author = {Harkey, BA and Distefano, S and Pagliaro, JA and Heyd, L and Chase, M and Igne, C and Yu, H and Sherman, AV and Dagostino, D and Tustison, E and Changkuon, G and Hall, M and Kittle, G and Connolly, MR and Giacomelli, E and Scirocco, E and Berry, JD and Babu, S and Shefner, J and Macklin, EA and Chibnik, LB and De Mattos, A and Drake, K and Kamp, C and McGarry, A and Torti, M and Small, C and Bulat, A and Cudkowicz, ME and Paganoni, S and , },
title = {Operational Development and Launch of an Adaptive Platform Trial in Amyotrophic Lateral Sclerosis: Processes and Learnings From the First Four Regimens of the HEALEY ALS Platform Trial.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28442},
pmid = {40420561},
issn = {1097-4598},
support = {//Sean M. Healey and AMG Center/ ; //Tackle ALS/ ; //ALS Finding a Cure/ ; //The ALS Association/ ; //ALS ONE/ ; //The Arthur M. Blank Family Foundation/ ; //Muscular Dystrophy Association/ ; //UCB/ ; //Biohaven Pharmaceuticals Inc/ ; //Clene Nanomedicine/ ; //Prilenia Therapeutics/ ; },
abstract = {INTRODUCTION/AIMS: Platform trials present several advantages over traditional interventional clinical trials. Here, we provide a detailed description of the operational framework of the HEALEY ALS Platform Trial.

METHODS: Platform-level procedures for regulatory oversight, safety, and site management were developed prior to trial launch. Central vendors and a single Institutional Review Board (sIRB) were used. An Investigational New Drug (IND) application was submitted for the master protocol, and each regimen was added as an amendment.

RESULTS: The HEALEY ALS Platform Trial was launched in 2020. Fifty-four geographically diverse sites from the Northeast ALS Consortium (NEALS), all highly experienced in ALS care and research, were selected. Three investigational products were selected to launch concurrently at the start of the trial as individual regimens. A fourth investigational product was selected and added to the trial after the initial launch. The Master Protocol and the first three regimens (Regimens A-C) were sIRB approved in 120 days. sIRB amendment for Regimen D was approved in 21 days. Enrollment for regimens A-C was completed in 15 months, whereas Regimen D was completed in 11 months from the start of enrollment. Results of all regimens were available within approximately 2 years from the initial trial launch.

DISCUSSION: The HEALEY ALS Platform Trial capitalized on the benefits of the platform approach, including an adaptable operational infrastructure, concurrent enrollment into four distinct regimens, and an accelerated start-up time for a new regimen added after initial trial launch.},
}

@article {pmid40419749,
year = {2025},
author = {Monteiro Neto, JR and de Souza, GF and Dos Santos, VM and de Holanda Paranhos, L and Ribeiro, GD and Magalhães, RSS and Queiroz, DD and Eleutherio, ECA},
title = {SOD1, A Crucial Protein for Neural Biochemistry: Dysfunction and Risk of Amyotrophic Lateral Sclerosis.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40419749},
issn = {1559-1182},
support = {201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
abstract = {Neurons are very susceptible to oxidative stress. They are the major consumers of oxygen in the brain, which is used to provide energy through oxidative phosphorylation, the major source of reactive oxygen species (ROS). In addition, compared to other tissues, neurons have lower levels of catalase and glutathione and increased susceptibility to lipid peroxidation due to the elevated levels of unsaturated fatty acids. These characteristics increasingly emphasize the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) to maintain neuronal redox homeostasis. In the last decade, SOD1 gained additional roles which are also important to the metabolism of neurons. SOD1 controls the production of ROS by the electron transport chain, activates the expression of genes involved in the protection against oxidative stress, and regulates the shift from oxidative to fermentative metabolism involved in astrocyte-neuron metabolic cooperation. Furthermore, impaired interaction between the phosphatase calcineurin and SOD1 seems to result in TDP-43 hyperphosphorylation, the main proteinopathy found in amyotrophic lateral sclerosis (ALS) patients. However, this enzyme is ubiquitously expressed, mutated, and damaged forms of SOD1 cause disease in motor neurons. In this review, we discuss the pivotal functions of SOD1 in neuronal biochemistry and their implications for ALS.},
}

@article {pmid40417702,
year = {2025},
author = {Hoang, K and Prayotamornkul, S and Kuo, CY and Jang, H and Shi, L},
title = {Optical imaging of metabolic dynamics in ALS under methionine regulation.},
journal = {Journal of biomedical optics},
volume = {30},
number = {Suppl 2},
pages = {S23906},
pmid = {40417702},
issn = {1560-2281},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; *Methionine/metabolism/pharmacology ; Humans ; *Optical Imaging/methods ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; Spectrum Analysis, Raman/methods ; Cytochromes c/metabolism ; Imaging, Three-Dimensional ; Oxidation-Reduction ; },
abstract = {SIGNIFICANCE: Excessive reactive oxygen species (ROS) in dysfunctional mitochondria, combined with inefficient antioxidant defenses, can drive amyotrophic lateral sclerosis (ALS) progression. L-methionine (Met) can neutralize ROS by modulating metabolism and activating antioxidants; however, its impact on ALS remains unknown.

AIM: We aim to investigate the influence of excess Met on cellular metabolism and ROS accumulation and its role in ALS using multimodal optical imaging techniques.

APPROACH: We applied deuterium oxide-probed stimulated Raman scattering imaging to study metabolic changes of lipids, proteins, and cytochrome c and two-photon excitation fluorescence imaging to assess mitochondrial redox state (nicotinamide adenine dinucleotide and flavin adenine dinucleotide ratio) in ALS cellular models under excess Met treatment. With three-dimensional (3D) image reconstruction, we investigated morphological changes of lipid droplets (LDs) and stress granules (SGs) in ALS models.

RESULTS: Excess Met not only promoted syntheses of lipids and unsaturated lipid membranes but also reduced protein synthesis, cytochrome c oxidation, and oxidative stress. Moreover, 3D image reconstruction showed that LDs increased in volume and number to promote cellular repair, whereas SGs decreased in volume but increased in number in response to reduced cellular stress.

CONCLUSIONS: Excess Met offers a protective mechanism against oxidative stress and promotes cellular repair in ALS.},
}

*Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging
*Methionine/metabolism/pharmacology
Humans
*Optical Imaging/methods
Mitochondria/metabolism
Reactive Oxygen Species/metabolism
Oxidative Stress
Spectrum Analysis, Raman/methods
Cytochromes c/metabolism
Imaging, Three-Dimensional
Oxidation-Reduction

@article {pmid40417478,
year = {2024},
author = {Marchal, N and Janes, WE and Earwood, JH and Mosa, ASM and Popescu, M and Skubic, M and Song, X},
title = {Integrating Multi-sensor Time-series Data for ALSFRS-R Clinical Scale Predictions in an ALS Patient Case Study.},
journal = {AMIA ... Annual Symposium proceedings. AMIA Symposium},
volume = {2024},
number = {},
pages = {788-797},
pmid = {40417478},
issn = {1942-597X},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Monitoring, Ambulatory/methods ; Pilot Projects ; },
abstract = {Clinical tools for tracking functional decline in amyotrophic lateral sclerosis (ALS) rely on in-clinic guided assessments, such as the gold standard ALS Functional Rating Scale Revised (ALSFRS-R) instrument, thus limiting the frequency of collection and potentially delaying needed treatments. As such, ALS clinicians may miss subtle yet critical shifts inpatient health -pointing to the needfor objective and continuous capturing of day-to-day functional status. In-home health sensors could supplement clinical instruments with more frequent, quantitative measurements as early indicators of change. Using the XGBoost regressor in base learning, we explore interpolation techniques for aligning monthly ALSFRS-R assessment targets with high frequency sensor-based health features. We evaluated 9 interpolation models, which demonstrate superior prediction of ALSFRS-R scores compared to traditional clinical scale estimates based on linear slope. This pilot work provides a practical approach of modeling mixed-frequency data and shows the potential of using sensor-based health estimates as sensitive prognostic markers.},
}

*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology
Humans
*Monitoring, Ambulatory/methods
Pilot Projects

@article {pmid40415670,
year = {2025},
author = {Uskun, E and Turkmenel, N and Kutluhan, S},
title = {Cross-cultural adaptation and psychometric evaluation of a Turkish version of the Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2507177},
pmid = {40415670},
issn = {2167-9223},
abstract = {Objective: This study aimed to evaluate the validity and reliability of the Turkish version of the Amyotrophic Lateral Sclerosis Specific Quality of Life Instrument Short Form (ALSSQOL-SF), a quality-of-life scale originally developed by Simons et al., for Turkish Amyotrophic Lateral Sclerosis (ALS) patients. Methods: Using a rigorous six-step translation process, the scale was adapted without altering any items to maintain linguistic and cultural equivalence. The study included 100 patients diagnosed with ALS, aged 18 years and older, and native Turkish speakers. Results: Psychometric evaluations revealed strong content validity (CVI: 100%) and high internal consistency (Cronbach's alpha: 0.86 for the overall scale, 0.74-0.95 for subscales). Item-total correlation coefficients, except for three items, exceeded 0.20, and removing these items did not improve the scale's reliability, preserving the scale's integrity. Construct validity was supported by significant correlations with the Short Form 12 Health Survey Questionnaire (SF-12) and ALS Functional Rating Scale Revised (ALSFRS-R), confirming the scale's ability to assess physical and mental health in ALS patients. Exploratory factor analysis showed a 6-factor structure consistent with the original structure. Conclusion: Turkish version of ALSSQOL-SF (ALSSQOL-SF-Tr) is a reliable and valid instrument for assessing the quality of life in Turkish ALS patients. Its application in clinical and research settings can help evaluate patient needs and improve disease management.},
}

@article {pmid40415381,
year = {2025},
author = {Pretalli, JB and Vernerey, D and Evrard, P and Pozet, A and Clairet, AL and Benoist, S and Karoui, M and Cotte, E and Heyd, B and Lakkis, Z and , },
title = {Intraoperative indocyanine green fluorescence angiography in colorectal surgery to prevent anastomotic leakage: A single-blind phase III multicentre randomized controlled trial (FLUOCOL-01/FRENCH 21/GRECCAR 19 intergroup trial).},
journal = {Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland},
volume = {27},
number = {5},
pages = {e70119},
doi = {10.1111/codi.70119},
pmid = {40415381},
issn = {1463-1318},
support = {PHRC-K-20-044//Programme Hospitalier de Recherche Clinique-Cancer/ ; //French Ministry of Health/ ; },
mesh = {Humans ; *Indocyanine Green ; *Anastomotic Leak/prevention & control/etiology ; *Fluorescein Angiography/methods ; Single-Blind Method ; *Intraoperative Care/methods ; Anastomosis, Surgical/adverse effects/methods ; Multicenter Studies as Topic ; Female ; Male ; *Colorectal Neoplasms/surgery ; Randomized Controlled Trials as Topic ; Coloring Agents ; Clinical Trials, Phase III as Topic ; France ; Colon/surgery/blood supply ; Colorectal Surgery/methods ; },
abstract = {AIM: Anastomotic leak (AL) is a major problem in colorectal surgery, and its prevention is crucial for patient safety. The scientific literature shows that optimal anastomotic perfusion is essential for anastomotic healing. However, in cases of left colon or rectal cancer requiring high vessel ligation for oncological reasons, anastomotic blood supply relies mainly on the pericolic arterial arcades. Consequently, assessing anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green might be relevant to reduce the risk of AL. Although evidence of its positive impact on the risk of AL is growing in the literature, most studies are descriptive prospective cohorts or retrospective comparative series with controversial findings. Furthermore, no other studies specifically address left-sided colon or high rectal tumours. FLUOCOL-1 is a large multicentre randomized controlled trial (RCT) that aims to demonstrate that assessing anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green will reduce ALs in left-sided or high anterior resections with intraperitoneal anastomosis METHOD: FLUOCOL-1 is a French multicentre, single-blind, randomized, two-arm, phase III superiority clinical trial. Patients will be randomized in a 1:1 ratio to either the intervention group (FLUO+) or the control group (FLUO-). A total of 1010 patients will be randomized. The primary endpoint is the occurrence of an AL within 90 days postsurgery. AL is defined as any anastomotic dehiscence with leakage into the pelvic cavity diagnosed by imaging or surgical exploration, or any isolated pelvic organ-space infection with no evidence of fistula, as defined by the International Study Group of Rectal Cancer.

DISCUSSION: Prevention of AL is one of the most important questions to be addressed in colorectal surgery. The FLUOCOL-1 multicentre RCT described herein aims to demonstrate that assessment of anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green will reduce ALs in certain resections with intraperitoneal anastomosis.},
}

Humans
*Indocyanine Green
*Anastomotic Leak/prevention & control/etiology
*Fluorescein Angiography/methods
Single-Blind Method
*Intraoperative Care/methods
Anastomosis, Surgical/adverse effects/methods
Multicenter Studies as Topic
Female
Male
*Colorectal Neoplasms/surgery
Randomized Controlled Trials as Topic
Coloring Agents
Clinical Trials, Phase III as Topic
France
Colon/surgery/blood supply
Colorectal Surgery/methods

@article {pmid40414828,
year = {2025},
author = {Kim, MS and Yoo, SH and Kim, KH and Cho, B and Lee, SY},
title = {Telemedicine Experiences of People Living with Amyotrophic Lateral Sclerosis at Home in South Korea.},
journal = {Yonsei medical journal},
volume = {66},
number = {6},
pages = {366-373},
doi = {10.3349/ymj.2024.0145},
pmid = {40414828},
issn = {1976-2437},
support = {RS-2021-KH120239//Patient-Centered Clinical Research Coordinating Center (PACEN)/Korea ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Republic of Korea ; *Telemedicine ; Middle Aged ; Female ; Male ; Aged ; Cross-Sectional Studies ; Retrospective Studies ; Home Care Services ; },
abstract = {PURPOSE: Telemedicine is advantageous in providing medical care to patients with mobility difficulties. This single-center study aimed to report on the provision of video televisits to people living with amyotrophic lateral sclerosis (pALS, ALS) who were registered with a home-based medical care (HBMC) team in a tertiary hospital in South Korea.

MATERIALS AND METHODS: A retrospective cross-sectional study was conducted for pALS provided with video televisits by the HBMC team between July 2020 and February 2023. The patients' demographics, disease status, mobility level, and supportive care equipment were investigated. The main issues discussed at televisits were investigated.

RESULTS: During the 32-month study period, video televisits were provided to 69 (81.2%) of the 85 pALS registered with the HBMC team. Their median (interquartile range) age was 66 (57-71) years, and 66.7% were aged 60 years or older. At the time of the televisits, 71.0% were non-ambulatory and 27.5% were at an assisted ambulatory level. Furthermore, 82.6% were receiving nutritional support with a nasogastric or gastrostomy tube, and 78.3% had received either non-invasive positive pressure ventilation (43.5%) or tracheostomy invasive ventilation (34.8%). Common issues addressed on televisits were disease-related symptoms (100%), management of supportive care equipment (92.8%), acute health issues (52.2%), and advance care planning (ACP) including goal of care discussion (14.5%).

CONCLUSION: Video telemedicine is feasible for pALS, including older adults with limited mobility due to muscle weakness or reliance on various supportive care equipment. Video televisits allow for a variety of discussions, ranging from acute health issues to ACP.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy
Republic of Korea
*Telemedicine
Middle Aged
Female
Male
Aged
Cross-Sectional Studies
Retrospective Studies
Home Care Services

@article {pmid40414644,
year = {2025},
author = {Manusha, S and Varsha, N and Varshini, R and Sivamani, Y and Pokkuluri, KS and Elayaperumal, S},
title = {Altered microbiome influence on the enteric neuromuscular system in amyotrophic lateral sclerosis (ALS).},
journal = {International review of neurobiology},
volume = {180},
number = {},
pages = {95-123},
doi = {10.1016/bs.irn.2025.04.006},
pmid = {40414644},
issn = {2162-5514},
mesh = {*Amyotrophic Lateral Sclerosis/microbiology/physiopathology ; Humans ; *Gastrointestinal Microbiome/physiology ; *Enteric Nervous System/physiopathology/microbiology ; *Dysbiosis/physiopathology ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease marked by the degeneration of motor neurons, leading to muscle weakness and paralysis. While the cause of ALS is uncertain, research indicates that changes in the gut microbiome may influence the disease's progression. This chapter explores how alterations in gut microbiota affect the enteric neuromuscular system (ENS) in ALS. In ALS patients, disrupted gut microbiota are linked to the brain-gut axis, impacting both gastrointestinal function and neuronal health. Studies show that microbial changes are associated with inflammation, immune instability, and neurodegeneration, which exacerbate the disease. Gastrointestinal issues like constipation and dysphagia in ALS are tied to ENS dysregulation. Understanding the connections between the gut microbiome, ENS, and central nervous system (CNS) may lead to novel therapies targeting neurodegeneration and microbial dysbiosis in ALS.},
}

*Amyotrophic Lateral Sclerosis/microbiology/physiopathology
Humans
*Gastrointestinal Microbiome/physiology
*Enteric Nervous System/physiopathology/microbiology
*Dysbiosis/physiopathology
Animals

@article {pmid40414240,
year = {2025},
author = {Suzuki, N and Nishiyama, A and Ebihara, S and Aoki, M},
title = {Jacifusen for FUS-ALS: molecular effects and clinical outcomes in a case series.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(25)01038-4},
pmid = {40414240},
issn = {1474-547X},
}

@article {pmid40414239,
year = {2025},
author = {Shneider, NA and Harms, MB and Korobeynikov, VA and Rifai, OM and Hoover, BN and Harrington, EA and Aziz-Zaman, S and Singleton, J and Jamil, A and Madan, VR and Lee, I and Andrews, JA and Smiley, RM and Alam, MM and Black, LE and Shin, M and Watts, JK and Walk, D and Newman, D and Pascuzzi, RM and Weber, M and Neuwirth, C and Da Cruz, S and Soriano, A and Lane, R and Henry, S and Mathews, J and Jafar-Nejad, P and Norris, D and Rigo, F and Brown, RH and Miller, S and Crean, R and Bennett, CF},
title = {Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(25)00513-6},
pmid = {40414239},
issn = {1474-547X},
abstract = {BACKGROUND: Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA, previously shown to delay neurodegeneration in a mouse model and potentially slow functional decline in a first-in-human study. Here, we sought to further evaluate use of jacifusen as a treatment for FUS-ALS.

METHODS: This expanded access programme was conducted through a series of single-patient investigational new drug applications at five sites (four hospitals in the USA and one in Switzerland). Participants carried a FUS variant and had clinical evidence of motor neuron disease onset or electrophysiological abnormalities, if not a diagnosis of ALS. Participants were ineligible if chronically ventilated with tracheostomy. Enrolled sequentially, participants received serial intrathecal injections of jacifusen over 2·8-33·9 months. Based on multiple ascending doses of jacifusen (from 20 mg to 120 mg), successive protocols were modified as safety and other data were acquired, with the last participants enrolled receiving 120 mg doses monthly from the start of their treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and standard cerebrospinal fluid (CSF) metrics. Concentration of neurofilament light chain (NfL) in CSF was used as a biomarker of axonal injury and neurodegeneration, and the ALS Functional Rating Scale-Revised (ALSFRS-R) score was used as an overall measure of motor function. Biochemical analysis and immunohistochemical staining were done on post-mortem CNS tissues to quantify FUS protein expression and assess the burden of FUS pathology.

FINDINGS: Between June 11, 2019, and June 2, 2023, we recruited 12 participants (median age 26 years [range 16-45]; seven [58%] were female and five [42%] were male) into the expanded access programme. Transient elevations in cell counts or total protein concentration in CSF (six [50%] participants) were unrelated to treatment duration. The most common adverse events were back pain (six [50%]), headache (four [33%]), nausea (three [25%]), and post-lumbar puncture headache (three [25%]). Two participant deaths were recorded during the programme, both thought to be unrelated to the investigational drug. The concentration of NfL in CSF was reduced by up to 82·8% after 6 months of treatment. Although most participants had continued functional decline (as measured by ALSFRS-R) after starting treatment with jacifusen, one showed unprecedented, objective functional recovery after 10 months, and another remained asymptomatic, with documented improvement in electromyographic abnormalities. Biochemical and immunohistochemical analysis of CNS tissue samples from four participants showed reduced FUS protein levels and an apparent decrease in the burden of FUS pathology.

INTERPRETATION: The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial.

FUNDING: ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.},
}

@article {pmid40413670,
year = {2025},
author = {Montero-Odasso, M and Pieruccini-Faria, F and Black, SE and Binns, MA and Freedman, M and Grimes, DA and Hegele, RA and Haddad, SH and Lang, AE and Masellis, M and Mandzia, J and Beaton, D and Ramirez, J and Roberts, AC and McIlroy, W and Pasternak, SH and Zinman, L and Abrahao, A and Swartz, RH and Symons, S and Tan, B and Tartaglia, C and Son, S and Sakurai, R and Dilliott, A and Cornish, BF and Hezam, A and Strong, MJ and , and Bartha, R},
title = {Association between vascular risk factors burden and neurodegenerative diseases: results from ONDRI.},
journal = {Journal of neurology},
volume = {272},
number = {6},
pages = {418},
pmid = {40413670},
issn = {1432-1459},
mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Neurodegenerative Diseases/epidemiology/diagnostic imaging/pathology ; Risk Factors ; Middle Aged ; *White Matter/diagnostic imaging/pathology ; *Cerebrovascular Disorders/epidemiology/diagnostic imaging ; Cognitive Dysfunction/epidemiology/diagnostic imaging ; Aged, 80 and over ; Cohort Studies ; Ontario/epidemiology ; Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; },
abstract = {BACKGROUND: Vascular risk factors are common in older adults and contribute to brain damage, can manifest as increased white matter hyperintensities (WMH), and associated with future risk of stroke and dementia. However, their prevalence, effect across different neurodegenerative diseases, and association with WMH remains underexplored.

OBJECTIVE: To investigate the association between vascular risk burden, and brain white matter integrity, across five neurodegenerative conditions.

METHODS: Cross-sectional study including 520 participants from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) cohorts: 126 with amnestic Mild Cognitive Impairment/Alzheimer's Disease (MCI/AD), 53 with Frontotemporal Dementia (FTD), 161 with Cerebrovascular Disease (CVD), 140 with Parkinson's Disease (PD), and 40 with Amyotrophic Lateral Sclerosis (ALS), along with 41 cognitively healthy controls. A vascular risk index (VRI, range 0-5) assessed hypertension, diabetes, dyslipidemia, obesity (BMI ≥ 30), and smoking history. Macro (WMH volume) and micro (Diffusion tensor imaging) white matter integrity were evaluated using 3-Tesla MRI. Associations were analyzed using multinomial logistic regression and ANCOVA, adjusting for age, sex, education, and APOE ε4 allele status.

RESULTS: Vascular risk factors, particularly hypertension and hypercholesterolemia, were more prevalent in the disease cohorts than controls. A higher VRI was significantly associated with MCI/AD (1.5-fold, p = 0.05), FTD (1.7-fold, p =0 .02), and CVD (2.6-fold, p < 0.005) cohorts. High VRI was associated with reduced macro and microstructural white matter integrity in the pooled sample (macro: p = 0.005; micro: p = 0.003), and separately in CVD (macro: p = 0.04; micro: p = 0.002). APOE ε4 status only mildly attenuated these associations.

CONCLUSION: Vascular risk burden is prevalent in neurocognitive syndromes including MCI/AD, FTD and CVD, and impacts white matter integrity. Future studies are needed to explore if vascular risk management may mitigate the consequences of neurodegeneration in these clinical groups.},
}

Humans
Male
Female
Aged
Cross-Sectional Studies
*Neurodegenerative Diseases/epidemiology/diagnostic imaging/pathology
Risk Factors
Middle Aged
*White Matter/diagnostic imaging/pathology
*Cerebrovascular Disorders/epidemiology/diagnostic imaging
Cognitive Dysfunction/epidemiology/diagnostic imaging
Aged, 80 and over
Cohort Studies
Ontario/epidemiology
Magnetic Resonance Imaging
Diffusion Tensor Imaging

@article {pmid40413526,
year = {2025},
author = {Hawley, ZCE and Li, X and Bodnar, D and Gu, Y and Luo, Y and Ferretti, D and Sheehy, A and Driscoll, R and Zavodszky, MI and Cao, S and Isaza, I and Jandreski, L and Liu, Y and Carlile, T and Lo, SC and Grimard, A and Bourque, S and Utturkar, A and Desmarais, S and Arnold, HM and Huh, D and Guilmette, E and Kwon, DY},
title = {Viral-mediated knockdown of Atxn2 attenuates TDP-43 pathology and muscle dysfunction in the PFN1[C71G] ALS mouse model.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {116},
pmid = {40413526},
issn = {2051-5960},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Profilins/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Ataxin-2/genetics/metabolism ; Humans ; Spinal Cord/pathology/metabolism ; Gene Knockdown Techniques ; Muscle, Skeletal/pathology/metabolism ; Male ; Motor Neurons/pathology/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and muscle atrophy. Hyperphosphorylated aggregation of the RNA-binding protein, TDP-43, in the motor cortex and spinal cord are defining molecular features of ALS, suggesting TDP-43 dysfunction underlies disease pathogenesis. This phenomenon, however, has been difficult to recapitulate endogenously in animal models, impeding characterization of TDP-43 pathobiology in neurodegeneration. In this study, we report age-dependent accumulation of TDP-43 pathology in the spinal cord and progressive muscle-related deficits in transgenic mice expressing the ALS-associated PFN1[C71G] mutant protein. We show that transgenic neuronal expression of PFN1[C71G] induces early hyperphosphorylation of endogenous TDP-43 in the spinal cord that augments over time, preceding accumulation of insoluble non-phosphorylated TDP-43 and the manifestation of muscle denervation and motor dysfunction. Sustained knockdown of Atxn2 in the central nervous system (CNS) in pre-symptomatic PFN1[C71G] mice by AAV-driven expression of an artificial microRNA (AAV-amiR-Atxn2) reduces aberrant TDP-43 in the spinal cord, while delaying neurodegeneration and improving muscle and motor function. RNA-sequencing analysis of spinal cord samples from PFN1[C71G] mice and ALS donors show shared patterns of transcriptional perturbation, including a pro-inflammatory gene signature that is attenuated by AAV-amiR-Atxn2. Notably, impaired regulation of the PFN1[C71G] skeletal muscle transcriptome exceeds that of the spinal cord and is also improved by Atxn2 reduction in the CNS. Lastly, we find significant gene co-expression network homology between PFN1[C71G] mice and human ALS, with shared dysregulation of modules related to neuroinflammation and neuronal function and uncover novel hub genes that provide biological insight into ALS and potential drug targets that can be further investigated in this mouse model.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
*Profilins/genetics/metabolism
Mice, Transgenic
Disease Models, Animal
*DNA-Binding Proteins/metabolism/genetics
Mice
*Ataxin-2/genetics/metabolism
Humans
Spinal Cord/pathology/metabolism
Gene Knockdown Techniques
Muscle, Skeletal/pathology/metabolism
Male
Motor Neurons/pathology/metabolism

@article {pmid40413303,
year = {2025},
author = {Yang, W and Luo, Z and Tang, X and Guo, J and Chen, X and Dong, Y and Sun, YM and Fan, D and Xu, K and Chen, Y and Zhang, M},
title = {Protein Structure-based FUS Mutational Subtypes Are Associated With Protein Mislocalization in Amyotrophic Lateral Sclerosis Patients.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40413303},
issn = {1559-1182},
support = {32301018//National Natural Science Foundation of China/ ; 82071430, 82371878//National Natural Science Foundation of China/ ; 2021YFA1302200//National Key Research and Development Program of China/ ; 22ZR1466400//Shanghai Municipal Natural Science Foundation General Program/ ; },
abstract = {The mislocalization of RNA-binding proteins (RBPs) from nucleus to cytoplasm and the formation of aggregates are hallmarks of neurodegeneration. Amyotrophic lateral sclerosis (ALS) disease-causing mutations in the fused in sarcoma (FUS) gene, encoding an RNA-binding protein, cluster at the C-terminal proline/tyrosine-nuclear localization signal (PY-NLS) domain, which is crucial for mediating nucleus-cytoplasm translocation by binding to Transportin-1. However, the mechanisms underlying heterogeneous protein mislocalization and age at onset (AAO) of ALS cases carrying FUS PY-NLS mutations remain unclear. Here, we screened FUS mutations in 416 ALS patients, and identified 12 patients carrying four FUS mutations at the p.R521 locus of PY-NLS domain (p.R521P, p.R521C, p.R521G, p.R521H), exhibiting highly variable AAO (20-56 years). AlphaFold-2 predicted protein structures classified FUS p.R521 mutants into alpha-helix containing (p.R521C, p.R521H) and alpha-helix disrupted (p.R521P, p.R521G) subgroups. Isothermal titration calorimetry experiment showed that the FUS alpha-helix disrupted subgroup had a reduced binding affinity with transportin-1, which is essential for mediating the nucleus-cytoplasm translocation. Furthermore, immunofluorescence in HEK-293 T and SH-SY5Y cells revealed more protein mislocalization in the FUS alpha-helix disrupted subgroup compared to the alpha-helix containing subgroup. FUS mislocalization status is also significantly associated with ALS AAO. Finally, the alpha-helix structure based FUS-ALS subgroups exhibited significantly different AAO (P = 0.036) in our cohort, but not in a Chinese cohort including published dataset. In summary, we showed highly diverse phenotypes in ALS patients with FUS R521 mutants, and implicated a link between genetic mutation related C-terminal structure with the status of FUS protein mislocalization.},
}

@article {pmid40413059,
year = {2025},
author = {Lopes, AMDS and Giacomini, S and Ulahannan, A and Darnac, C and Bugeia, S and Gutknecht, G and Colomer-Lahiguera, S and Spurrier-Bernard, G and Latifyan, S and Addeo, A and Michielin, O and Eicher, M},
title = {Acceptability of an Electronic Patient-Reported Outcomes-Based Model of Care to Monitor Symptoms Related to Cancer Treatment with Immune Checkpoint Inhibitors: Results from the IePRO Randomized Controlled Trial.},
journal = {Seminars in oncology nursing},
volume = {},
number = {},
pages = {151903},
doi = {10.1016/j.soncn.2025.151903},
pmid = {40413059},
issn = {1878-3449},
abstract = {OBJECTIVES: This study analyzed the acceptability of an electronic patient-reported outcomes measures-based model of care (IePRO MoC) and the usability of its complementary ePROM mobile app to monitor and manage symptoms related to immune checkpoint inhibitors. In this MoC, symptoms reported by patients treated at an outpatient clinic were reviewed by oncology triage nurses who provided symptom management interventions by telephone.

METHODS: As part of a larger intervention trial (ClinicalTrials.gov.NCT05530187) we conducted an abductive, semantic thematic analysis through semistructured interviews of patients participating in the intervention arm. Acceptability was deduced from Sekhon et al's (2017) Theoretical Framework of Acceptability completed with inductively generated themes. Usability analysis was guided by the mHealth App Usability Questionnaire's domains by Zhoul et al (2019).

RESULTS: A total of 17 interviews were performed. The IePRO MoC was reported to be an acceptable intervention. Patients expressed feeling safe and empowered due to continuous monitoring and timely support from nurses. Personalized support motivated patients to use the MoC throughout treatment. Some questioned the predefined response options of the app, and the standardized approach regarding notifications and monitoring requirements. Despite high app usability, some expressed discomfort from being frequently reminded of their illness and being confronted with questions about their sexuality and other intimate themes.

CONCLUSIONS: The feedback loop between patients and nurses facilitated the acceptability of the IePRO MoC. The app's usability further facilitated adherence to the MoC. A more personalized approach regarding the frequency of assessments and the way symptoms are conveyed is recommended to decrease discomfort and support the implementation of similar MoCs in the future.},
}

@article {pmid40412392,
year = {2025},
author = {Yan, X and Kuster, D and Mohanty, P and Nijssen, J and Pombo-García, K and Garcia Morato, J and Rizuan, A and Franzmann, TM and Sergeeva, A and Ly, AM and Liu, F and Passos, PM and George, L and Wang, SH and Shenoy, J and Danielson, HL and Ozguney, B and Honigmann, A and Ayala, YM and Fawzi, NL and Dickson, DW and Rossoll, W and Mittal, J and Alberti, S and Hyman, AA},
title = {Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2025.04.039},
pmid = {40412392},
issn = {1097-4172},
abstract = {Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.},
}

@article {pmid40412267,
year = {2025},
author = {Tian, H and Huang, N and Chen, C and Yu, H and Ge, C},
title = {Flavor profiles and genetic basis differences of Lacticaseibacillus paracasei isolates from different isolations in fermented milk.},
journal = {International journal of food microbiology},
volume = {440},
number = {},
pages = {111274},
doi = {10.1016/j.ijfoodmicro.2025.111274},
pmid = {40412267},
issn = {1879-3460},
abstract = {Lacticaseibacillus paracasei from diverse traditional fermented foods exhibit unique flavor profiles in dairy products. In this study, 101 Lacticaseibacillus isolates were categorized into four distinct classes, with those originating from fermented dairy products demonstrating the highest flavor diversity. Multivariate statistical analyses identified diacetyl, acetoin, and 2-nonanone as key volatile compounds characterizing ketone-type isolates. Further examination of two ketone-type isolates and one non-ketone-type isolate, isolated from kurut, sour porridge, and Huangjiu mash respectively, revealed their specific abilities to produce ketones, lactones, and alcohols. Genome comparison of ketone-type and non-ketone-type L. paracasei isolates revealed disparities in the cit gene cluster, als, and but genes within the citrate metabolic pathway. These findings provide novel insights into the flavor diversity and help identify potential key genes involved in flavor formation in L. paracasei isolates, thereby facilitating the application of L. paracasei isolates in fermented dairy products.},
}

@article {pmid40411682,
year = {2025},
author = {Jain, S and Das, D and Mukherjee, A and Roy, I},
title = {Inhibition of PolyGA Dipeptide Repeat Protein Aggregation by Nucleic Acid Aptamers in C9 Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Models.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40411682},
issn = {1559-1182},
support = {BT/PR30896/BRB/10/1747/2018//Department of Biotechnology/ ; },
abstract = {Hexanucleotide (GGGGCC) repeat expansion in non-coding region of C9ORF72 is the main genetic cause of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Gain of toxic function, via RNA or proteins, or loss of function via haploinsufficiency, are probable mechanisms of disease progression. Expanded GGGGCC repeat codes for dipeptide repeat (DPR) proteins which form inclusions in the brain. Among all the dipeptides, aggregates formed by polyGA sequence are the most toxic. In this work, inhibition of aggregation of polyGA DPRs using aptamers has been explored as a therapeutic strategy to delay disease progression. Target-specific, high-affinity RNA aptamers were selected against monomeric (GA)30. Selected aptamers showed significant inhibition of aggregation of (GA)30 in vitro. Inhibitory RNA sequences were seen to form typical secondary structures which was missing in a non-inhibitory sequence. Some of the RNA aptamers showed increased solubilisation of DPRs formed by (GA)30 and (GA)60 in a neuronal cell model of ALS-FTD. Decreased aggregation was accompanied by lower oxidative stress and improved cell survival. Importantly, expression level of one of the markers of autophagy was significantly enhanced in the presence of aptamers, explaining lower aggregation observed in these cells. Thus, aptamers may be developed as potential therapeutic agents in C9 ALS-FTD.},
}

@article {pmid40411245,
year = {2025},
author = {Giacobbe, A and Hiana, J and Wang, O and Benatar, M and Wicks, P and Mascias Cadavid, J and Jhooty, S and McDermott, C and Pattee, G and Bertorini, T and Heiman-Patterson, T and Ratner, D and Barkhaus, P and Carter, G and Jackson, C and Denson, K and Brown, A and Armon, C and Sun, Y and Nguyen, A and Bedlack, R and Li, X},
title = {ALSUntangled #79: alpha-lipoic acid.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/21678421.2025.2507166},
pmid = {40411245},
issn = {2167-9223},
abstract = {Alpha-lipoic acid (ALA) is a naturally occurring fatty acid. It serves as an essential cofactor for enzymatic reactions in mitochondrial energy production, is a potent antioxidant and has anti-inflammatory effects, which are plausible mechanisms in slowing ALS progression. In ALS preclinical studies, ALA slowed motor function decline and improved survival. There were self-reported cases of improved muscle strength in ALS patients when ALA was taken with numerous additional supplements, making it difficult to discern its efficacy. One small, 6-month open-label study showed improved quality of life, fatigue, and mood after participants took it with B vitamins and amino acids for the first 3 months. So far, no clinical trials have been published in people living with amyotrophic lateral sclerosis (PALS). Given the insufficient clinical data, we cannot endorse ALA and will support more research on its efficacy in slowing ALS progression.},
}

@article {pmid40409555,
year = {2025},
author = {Ma, G and Ruan, X and Yang, B and Li, N and Su, D and Sun, S and Chen, S and Xu, K and Ying, Z and Wang, H},
title = {Abnormal regulation of membrane-less organelles contributes to profilin1-associated ALS.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110259},
doi = {10.1016/j.jbc.2025.110259},
pmid = {40409555},
issn = {1083-351X},
abstract = {Profilin 1 (PFN1) is a key cytoskeletal protein that regulates actin dynamics by incorporating monomeric actin into linear filaments. PFN1 deletion or mutations have been linked to numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the contribution of PFN1 to neurodegenerative pathologies is poorly understood. Recent studies have implicated the role of aberrant cellular membrane-less organelles (MLOs) in neurodegenerative pathogenesis. Here, we demonstrate that PFN1 is involved in the assembly of MLOs, including Cajal bodies and Stress granules. Specifically, depletion of PFN1 leads to abnormal Cajal body accumulation and accelerated maturation into a gel-like state, consequently dysregulating snRNP biogenesis and impairing pre-mRNA splicing efficiency in both neuronal and non-neuronal cells. Similarly, we show that PFN1 knockdown accelerates the assembly of Stress granules in stressed cells. Furthermore, we demonstrate that the ALS-linked PFN1-C71G mutant exhibits a loss of function in the context of MLO biogenesis. We further reveal that the PFN1 deficiency-induced Cajal body dysregulation, but not Stress granule assembly, is caused by cellular actin filament depolymerization. Importantly, the actin filament agonist CN04 rescues Cajal body properties in PFN1-depleted cells. Taken together, our findings shed light on the role of PFN1 in MLO biogenesis and suggest its involvement in neurodegenerative pathogenesis.},
}

@article {pmid40409351,
year = {2025},
author = {Collins, K and Hoellein, A},
title = {Undifferentiated Myopathies.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2025.05.026},
pmid = {40409351},
issn = {1555-7162},
}

@article {pmid40409314,
year = {2025},
author = {, and , },
title = {Safety and efficacy of trehalose in amyotrophic lateral sclerosis (HEALEY ALS Platform Trial): an adaptive, phase 2/3, double-blind, randomised, placebo-controlled trial.},
journal = {The Lancet. Neurology},
volume = {24},
number = {6},
pages = {500-511},
doi = {10.1016/S1474-4422(25)00173-5},
pmid = {40409314},
issn = {1474-4465},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Trehalose/therapeutic use/adverse effects/administration & dosage ; Double-Blind Method ; Male ; Female ; Middle Aged ; Aged ; Adult ; Disease Progression ; Treatment Outcome ; *Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Edaravone/therapeutic use ; },
abstract = {BACKGROUND: Trehalose is a disaccharide that activates autophagy pathways in animal models of neurodegenerative diseases, with the potential to catalyse clearance of toxic, misfolded proteins in motor neurons and slow disease progression in amyotrophic lateral sclerosis (ALS). We aimed to evaluate the safety and efficacy of trehalose in individuals with ALS.

METHODS: The HEALEY ALS Platform Trial is a perpetual, adaptive, phase 2/3, randomised, double-blind, multi-regimen trial conducted at 60 geographically diverse sites in the USA. In the current regimen, adults with clinically possible, probable, laboratory-supported probable, or definite ALS, defined by the revised El Escorial criteria, were randomly allocated (3:1), stratified by use of edaravone and riluzole, to receive trehalose 0·75 g per kg intravenously weekly over 24 weeks, or matching placebo. The primary outcome was a composite of the relative rate of disease progression, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R), and survival over 24 weeks, estimated in a Bayesian shared-parameter model. The study included prespecified stopping rules for futility; interim analyses occurred every 12 weeks. The primary outcome was analysed according to the intention-to-treat principle in all participants in the trehalose group, the placebo group within the regimen, and placebo groups from other contributing regimens; the safety analysis population was comprised of all participants who initiated treatment. This study is registered with ClinicalTrials.gov, NCT05136885.

FINDINGS: Between Feb 21, 2022, and Feb 17, 2023, 1021 participants were screened for the platform trial and 171 were assigned to the trehalose regimen. Of these, 161 participants met eligibility criteria, with 120 randomly allocated to trehalose and 41 to regimen-specific placebo. 164 participants randomly allocated to placebo in other regimens were added for analysis (totalling 205 placebo recipients). The disease rate ratio for change in ALSFRS-R and survival was 0·87 (95% credible interval 0·665-1·102, posterior probability of superiority 0·877). Serious adverse events occurred in 19 (16%) participants in the trehalose group and three (7%) participants in the regimen-only placebo group, leading to premature discontinuations in 14 (12%) versus one (2%), respectively. Fatal treatment-emergent adverse events occurred in seven participants in the trehalose group and none in the regimen-only placebo group. No death was considered related to the trial drug. The most common cause of death was respiratory failure, consistent with the natural history of ALS.

INTERPRETATION: Trehalose was well tolerated but there was no evidence to suggest a difference in ALS disease progression compared with placebo in this study. No statistical benefit was seen in secondary clinical or biomarker measures, suggesting that trehalose at this dosage is unlikely to be efficacious for treatment of ALS.

FUNDING: AMG Charitable Foundation, Tackle ALS, the ALS Association, ALS Finding a Cure, the Muscular Dystrophy Association, ALS ONE, the Arthur M Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative, and other community fundraising initiatives and donors. Study drug and partial regimen-related funding was provided by Seelos.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
*Trehalose/therapeutic use/adverse effects/administration & dosage
Double-Blind Method
Male
Female
Middle Aged
Aged
Adult
Disease Progression
Treatment Outcome
*Neuroprotective Agents/therapeutic use
Riluzole/therapeutic use
Edaravone/therapeutic use