Journal of Molecular Neuroscience最新文献

{"title":"Genetic Abnormalities in Neurodevelopmental Disorders with Multidimensional Impairment","authors":"Cyril Hanin,&nbsp;Paloma Torres,&nbsp;Isabelle Millet,&nbsp;Joana Matos,&nbsp;Cora Cravero,&nbsp;Marianna Giannitelli,&nbsp;Anne-Sophie Pellen,&nbsp;Hugues Pellerin,&nbsp;Charline Grossard,&nbsp;Ingrid Zammouri,&nbsp;Astrid De Foucaud,&nbsp;Claudine Laurent-Levinson,&nbsp;David Cohen","doi":"10.1007/s12031-025-02424-6","DOIUrl":"10.1007/s12031-025-02424-6","url":null,"abstract":"<div><p>Objectives: Many children with neurodevelopmental disorders (NDD) show complex, multidimensional impairments meeting criteria for multiple NDD, yet remain “diagnostically homeless” as DSM-5 lacks a Multidimensional Impairment (MDI) category. We investigated the prevalence of genetic abnormalities in such complex NDD cases. Methods:Between 2017 and 2019, we diagnosed MDI in 666 patients. Among them, 122 (18%) underwent genetic assessment (DNA microarrays, karyotype, gene panels, FISH, FMR1 testing, exome/genome sequencing). We used univariate analyses and clustering to explore associations between clinical dimensions and genetic findings. Results: Genetic abnormalities were identified in 78 patients. Of these:</p><ol>\u0000 <li>\u0000 <span>(1)</span>\u0000 \u0000 <p>41 had known abnormalities usually linked to complex NDD (e.g., del22q11.2);</p>\u0000 \u0000 </li>\u0000 <li>\u0000 <span>(2)</span>\u0000 \u0000 <p>16 had mutations associated with severe ASD/ID (e.g., <i>GRIA3</i> on Xq25);</p>\u0000 \u0000 </li>\u0000 <li>\u0000 <span>(3)</span>\u0000 \u0000 <p>11 showed novel abnormalities not previously linked to NDD (e.g., duplication Xq21.1 including <i>POU3F4</i>);</p>\u0000 \u0000 </li>\u0000 <li>\u0000 <span>(4)</span>\u0000 \u0000 <p>10 had variants of uncertain significance.</p>\u0000 \u0000 </li>\u0000 </ol><p> Depending on classification, prevalence ranged from 47% (57/122, definite or predisposition) to 64% (78/122, including uncertain/possible pathogenic variants). Neither clinical dimensions nor severity clusters were associated with the presence of genetic abnormalities. Conclusion:Despite a referral bias toward severe cases, the high rate of genetic findings in this cohort underscores the need for more systematic genetic testing in complex NDD with multidimensional impairment.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145210844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can Oxidative Stress Biomarkers Differentiate Trichotillomania from Obsessive–Compulsive Disorder and Healthy Controls?","authors":"Yusuf Selman Çelik,&nbsp;Hande Günal Okumuş,&nbsp;Meryem Kaşak,&nbsp;Göktuğ Okyar,&nbsp;Barışcan Çimen,&nbsp;Yusuf Öztürk,&nbsp;Ayşegül Efe,&nbsp;Özcan Erel","doi":"10.1007/s12031-025-02428-2","DOIUrl":"10.1007/s12031-025-02428-2","url":null,"abstract":"<div><p>This study investigated oxidative stress biomarkers in differentiating trichotillomania (TTM), obsessive–compulsive disorder (OCD), and healthy controls (HC), focusing on thiol-disulfide homeostasis, total oxidant status (TOS), total antioxidant status (TAS), and ischemia-modified albumin (IMA). A total of 68 adolescent females aged 10–18 were recruited and divided into three groups: TTM (n = 24), OCD (n = 21), and HC (n = 23). Oxidative stress biomarkers were assessed through blood analyses, including measurements of thiol-disulfide homeostasis, TOS, TAS, and IMA. Blood analyses revealed that TTM patients had significantly lower native and total thiol levels, a reduced native/total thiol ratio, and elevated disulfide levels compared to OCD and HC (p &lt; 0.01). ROC analysis indicated that the native thiol/total thiol ratio effectively distinguished TTM from both HC and OCD with high accuracy. These findings reveal distinct oxidative stress patterns in TTM and OCD, with disrupted thiol-disulfide homeostasis in TTM and elevated oxidative burden in OCD. The discriminative power of the native thiol/total thiol ratio suggests molecular-level differences, which may inform the etiopathogenesis of TTM and support the development of targeted treatment strategies.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Neural Network-Based Risk Prediction of Glioblastoma Multiforme Recurrence","authors":"Disha Sushant Wankhede,&nbsp;Aniket K. Shahade,&nbsp;Priyanka V. Deshmukh,&nbsp;Akshay Manikjade,&nbsp;Makrand Shahade,&nbsp;Pritam H. Gohatre,&nbsp;Kanchan Tidke","doi":"10.1007/s12031-025-02412-w","DOIUrl":"10.1007/s12031-025-02412-w","url":null,"abstract":"<div><p>This study aims to develop and evaluate deep neural network (DNN) models for accurately predicting the recurrence risk of glioblastoma multiforme (GBM) to enhance individualized treatment strategies and improve patient outcomes. This study implemented DNN architectures optimized using a hybrid differential evolution neural network (HDE-NN) framework to forecast GBM recurrence risk, particularly in patients at advanced disease stages. The models were trained and validated on a multimodal dataset comprising genomic profiles, imaging-derived metrics, and longitudinal clinical records from 780 GBM patients. Data were sourced from The Cancer Genome Atlas (TCGA) and institutional repositories. Performance was benchmarked against conventional machine learning models, including support vector machines (SVM), random forests (RF), and standard DNNs. The models were implemented in Python. The proposed HDE-optimized DNN achieved an accuracy of 94%, precision of 92%, recall of 90%, F1 score of 91%, and an AUC-ROC of 0.96. These metrics significantly outperformed baseline models, with improvements of 6–12% across evaluation criteria. Confidence intervals (95%) were computed via tenfold cross-validation, confirming statistical robustness. This research introduces a high-performance and generalizable deep learning framework for GBM recurrence prediction. By incorporating multi-source clinical and genomic data, the model demonstrates superior predictive capacity over traditional methods. These findings support the integration of AI-driven tools into GBM care workflows to improve prognosis assessment and personalize therapeutic interventions.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinocerebellar Ataxia Type 1 (SCA1) Cell Models Display Widespread Mitochondrial and Extra-Nuclear Alterations","authors":"Dane Ford-Roshon,&nbsp;Madison Dudek,&nbsp;Ada Glynn,&nbsp;Abigale Glasman,&nbsp;Jaden York,&nbsp;Emily Lawrence,&nbsp;Donna Nguyen,&nbsp;Lindsay Shinn,&nbsp;Georgia Berry,&nbsp;Lily Kendall,&nbsp;Jennifer Bonner,&nbsp;Austin Ferro,&nbsp;Sarita Lagalwar","doi":"10.1007/s12031-025-02425-5","DOIUrl":"10.1007/s12031-025-02425-5","url":null,"abstract":"<div><p>Ataxin-1 (ATXN1) is a nuclear-cytoplasmic shuttling protein, which, when expanded in its polyglutamine coding stretch, causes the progressive neurodegenerative disease Spinocerebellar Ataxia Type 1 (SCA1). While the role of nuclear ATXN1 as a repressor of transcription and regulator of splicing is well studied, its potential cytoplasmic role is more ambiguous. We previously demonstrated mitochondrial dysfunction- including altered respiration and enhanced oxidative stress- is associated with early SCA1 pathogenesis in mice. Moreover, intervention with the electron transport chain substrate succinic acid ameliorated Purkinje cell atrophy and cerebellar behavioral deficits. We now hypothesize that mitochondrial dysfunction in SCA1 may be at least partially due to cytoplasmic interactions between ATXN1 and mitochondria, rather than a result of mutant ATXN1’s altered nuclear function. In order to characterize the extent of mitochondrial dysfunction due to mutant ATXN1, we turned to cerebellar-derived Daoy cells which endogenously express human wild type ATXN1. Our SCA1 Daoy model stably over-express phosphorylation-prone, nuclear-aggregating ATXN1[82]. Despite the short lifespan (~ 33 h), Daoy SCA1 cells reveal gross morphological, compositional, and physiological deficits. Conversely, expression in Daoy of a phosphorylation-resistant, cytoplasm-degradable, non-aggregating ATXN1 (ATXN1[82Q-A776]) selectively resulted in intermediate physiological phenotypes and altered mitochondrial protein composition. Finally, our meta-analysis of previously published data supports direct interactions between mutant polyglutamine-expanded ATXN1 and mitochondrial proteins involved in apoptosis, oxidative phosphorylation, composition, and transcription. Our data therefore suggest that irrespective of a disease context and ATXN1[82Q] nuclear aggregation, mitochondrial deficits occur. Overall, the results of this study show mutant ATXN1 can affect metabolic processes outside of its deleterious effect on transcription and splicing, and highlights its multifaceted and multicompartmental function.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-025-02425-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Investigation of the Levels of Serine Protease and Associated Molecules in Children with Autism Spectrum Disorder","authors":"Merve Yaylaci,&nbsp;Ozlem Dogan,&nbsp;Fatma Zehra Kirşan,&nbsp;Didem Behice Oztop","doi":"10.1007/s12031-025-02415-7","DOIUrl":"10.1007/s12031-025-02415-7","url":null,"abstract":"<div><p>This study aimed to elucidate the potential role of serine proteases and their associated regulatory molecules in the etiopathogenesis of autism spectrum disorder (ASD) and to assess their relationship with symptom severity and specific behavioral domains in children diagnosed with ASD. A cross-sectional design was employed, including 44 children aged 2 to 6 years with a confirmed diagnosis of ASD and 43 age- and sex-matched typically developing children as controls. Behavioral assessments were conducted using the Childhood Autism Rating Scale (CARS), the Autism Behavior Checklist (ABC), and the Repetitive Behavior Scale-Revised, Turkish Version (RBS-R-TV). Serum concentrations of motopsin, agrin, C-terminal agrin fragment (CAF), tissue plasminogen activator (tPA), neuroserpin, and plasminogen activator inhibitor-1 (PAI-1) were determined using enzyme-linked immunosorbent assay (ELISA). Serum levels of all analyzed molecules were significantly reduced in the ASD group compared to controls (<i>p</i> &lt; 0.05 for all). Although no significant associations were observed between total ASD severity scores and biomarker concentrations, notable correlations emerged between specific behavioral subdomains and select biomarkers. Motopsin levels exhibited a moderate positive correlation with the “imitation” subdomain of CARS and the “sensory” subdomain of ABC. Conversely, agrin levels demonstrated moderate inverse correlations with “listening response,” “taste–smell-touch response and use,” and “activity level” subdomains of CARS. PAI-1 levels showed a significant negative correlation with the “self-injurious behavior” subdomain of RBS-R-TV. The findings suggest that serine proteases and their modulators implicated in synaptic remodeling and neuroplasticity may contribute to the underlying neurobiological mechanisms of ASD. The observed domain-specific associations support the hypothesis that ASD comprises heterogeneous neurodevelopmental trajectories, and that peripheral biochemical markers reflecting these pathways may aid in the identification of ASD subtypes and guide personalized therapeutic strategies.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145210221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Higher Serum Aspartate May be Associated with Better Cognitive Function as Mediated by Reduced Aβ Accumulation in Frontal and Temporal Lobes in Mild Cognitive Impairment","authors":"Sarraa Ahmad Qahtan,&nbsp;Ali Fawzi Al-Hussainy,&nbsp;Vimal Arora,&nbsp;M. M. Rekha,&nbsp;Mayank Kundlas,&nbsp;Kattela Chennakesavulu,&nbsp;Mehul Manu,&nbsp;Jasur Rizaev,&nbsp;Sada Ghalib Taher,&nbsp;Mariem Alwan,&nbsp;Mahmood Jawad,&nbsp;Hiba Mushtaq","doi":"10.1007/s12031-025-02418-4","DOIUrl":"10.1007/s12031-025-02418-4","url":null,"abstract":"<div><p>Aspartate, a key excitatory neurotransmitter, has shown conflicting links to cognitive disorders like Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Given its role in brain function, studying its relationship with amyloid-beta (Aβ) accumulation may provide important insights into these conditions. This study is the first to examine the link between serum aspartate levels, Aβ accumulation in key brain regions, and cognitive function (via ADAS-Cog) across cognitively normal (<i>n</i> = 113), MCI (<i>n</i> = 283), and AD (<i>n</i> = 24) participants. The results showed significant increases in Aβ accumulation across all brain regions from CN to MCI and AD groups (overall <i>p</i> &lt; 0.001; pairwise <i>p</i> ≤ 0.001). In individuals with MCI, elevated aspartate levels were inversely associated with Aβ accumulation in the frontal (<i>β</i> = − 0.122, <i>p</i> = 0.041) and temporal regions (<i>β</i> = − 0.128, <i>p</i> = 0.032), but this relationship was lost after adjusting for age, gender, education, handedness, and ApoE ɛ4, ɛ3, and ɛ2 genotypes. Further analysis identified age and ApoE ɛ4, ɛ3 status as key modifiers of the aspartate–Aβ relationship in MCI. Mediation analysis revealed that higher serum aspartate levels were associated with better cognitive function, potentially mediated by reduced Aβ accumulation in the frontal (<i>β</i> = − 0.037) and temporal lobes (<i>β</i> = − 0.043) in MCI, but this effect disappeared after adjusting for demographic factors and ApoE genotypes. Overall, higher serum aspartate levels may be associated with reduced Aβ accumulation and improved cognitive outcomes in MCI, with age and ApoE genotypes acting as key confounders.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Glutamatergic Excitotoxicity on the Differentiation of Cerebellar Neural Stem Cells","authors":"Grinev Egor,&nbsp;Shuvaev Andrey,&nbsp;Khilazheva Elena,&nbsp;Belozor Olga,&nbsp;Teplyashina Elena,&nbsp;Shuvaev Anton","doi":"10.1007/s12031-025-02426-4","DOIUrl":"10.1007/s12031-025-02426-4","url":null,"abstract":"<div><p>The adult cerebellum retains a small Sox2/prominin-1 NSC pool whose fate is shaped by developmental cues and the glutamatergic milieu. We argue that glutamate excitotoxicity is the dominant negative regulator of this niche and Purkinje cell survival because it forms self-reinforcing loops. Spillover activates extrasynaptic GluN2B/2D-NMDARs, silencing CREB/PI3K–Akt and driving sustained <span>(Ca^{2+})</span> influx; mitochondria translate this load into mPTP opening and ROS bursts, creating a <span>(Ca^{2+})</span>–ROS feedback that accelerates death. Oxidative stress and energy failure also depress EAAT1/2 clearance, elevating glutamate and re-activating eNMDARs. Loss of Purkinje cells withdraws Sonic Hedgehog support, shrinking the proliferative granule-precursor pool—another vicious cycle. A countervailing axis (synaptic GluN2A/2C and BDNF/TrkB) is muted by extrasynaptic drive. Cerebellar neurospheres model these gradients and readouts. We outline a triple strategy to break the loops: selective eNMDAR blockade, EAAT enhancement, and Sonic Hedgehog restoration.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluoxetine HCl-Loaded Nanostructured Lipid Carriers for Nose-to-Brain Delivery: Optimization and Synergistic Role of Saffron Oil","authors":"Avinash R. Tekade,&nbsp;Prasad V. Kadam,&nbsp;Manoj K. Aswar,&nbsp;Anil B. Gaikwad,&nbsp;Rohit B. Shinde,&nbsp;Snehal S. Kharade","doi":"10.1007/s12031-025-02411-x","DOIUrl":"10.1007/s12031-025-02411-x","url":null,"abstract":"<div><h3>Objectives</h3><p>Depression is a widespread psychiatric condition marked by ongoing sadness, disinterest, insomnia, and thoughts of self-harm. Fluoxetine HCl (FH) is a frequently prescribed antidepressant; however, it has low oral bioavailability (28%) due to significant first-pass metabolism and has side effects such as low blood pressure, gastrointestinal discomfort, and blurred vision. This research aimed to create and assess a novel intranasal nanostructured lipid carrier (NLC) system for FH, utilizing saffron oil (SO) as a functional lipid to enhance brain delivery while minimizing systemic side effects.</p><h3>Methods</h3><p>FH-NLCs were prepared using the high-pressure homogenization and ultrasonication method and was optimized based on particle size, PDI, Drug loading and entrapment efficiency.</p><h3>Results</h3><p>The observed mean particle size of FH-NLCs is 117.3 nm, PDI 0.219, and ZP -44.76 mV which were ideal for nose-to-brain delivery. The optimized formulation showed high drug loading and entrapment efficiency. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) confirmed a uniform morphology, while X-ray diffraction (XRD) and differential scanning calorimetry (DSC) indicated partial amorphization of the drug within the lipid matrix. The in vitro drug release exhibited a sustained profile without burst release, adhering to Korsmeyer-Peppas kinetics, which showed non-fickian diffusion Super Case II Transport (n = 1.14). Ex vivo permeation studies on goat nasal mucosa revealed significantly enhanced nasal mucosal permeability compared to the FH solution, indicating the permeation-enhancing properties of SO. Histopathological assessments confirmed the formulation's safety for nasal application. The pharmacodynamic evaluations demonstrated a synergistic antidepressant effect between FH and SO, thereby supporting improved therapeutic efficacy.</p><h3>Conclusion</h3><p>The intranasal delivery of FH through SO-based NLCs offers a promising approach for direct brain targeting, potentially enhancing clinical outcomes in depression while reducing systemic side effects of FH.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on “Impact of AOC1 and HNMT Variants on the Therapeutic Outcomes of a Histamine Reducing Diet in Autism Spectrum Disorder”","authors":"Rafia Raza,&nbsp;Arooba Khan","doi":"10.1007/s12031-025-02422-8","DOIUrl":"10.1007/s12031-025-02422-8","url":null,"abstract":"<div><p>Kadiyska et al. recently investigated the impact of a histamine-reducing diet in children with autism spectrum disorder (ASD), with attention to potential modifying effects of AOC1 and HNMT gene variants. Although the study poses an important question, several design limitations may affect the certainty of its conclusions. The dietary intervention removed not only foods high in histamine but also gluten, dairy, sugar, and other items. Such broad restrictions can influence health and behavior on their own. This makes it difficult to determine whether the reported improvements were specifically the result of reduced histamine. The histamine cut-off chosen for participant selection was not explained or tied to clinical standards, which makes reproducibility less clear. In addition, some of the genetic results rested on very small numbers, at times a single child, reducing confidence in their reliability. Finally, histamine levels were not re-measured after the intervention, and the developmental outcomes were not fully explained in terms of clinical significance. Stronger evidence will require controlled diets, standardized thresholds, larger cohorts, and outcomes relevant to daily life.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron and Ferritin Dyshomeostasis Intersect with Sex, Age, and Disease Severity in Amyotrophic Lateral Sclerosis","authors":"Xiaoge Xie,&nbsp;Peng Wu,&nbsp;Ting Wen,&nbsp;Rui Jia,&nbsp;Ronghua Zhang,&nbsp;Fangfang Hu,&nbsp;Jiaoting Jin,&nbsp;Xing Qin,&nbsp;Qiao Yi Chen","doi":"10.1007/s12031-025-02416-6","DOIUrl":"10.1007/s12031-025-02416-6","url":null,"abstract":"<div><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor neurons. Due to heterogeneity in both cause and clinical phenotype, accuracy of diagnosis and efficacy of treatment remain challenging. An evolving body of evidence point to the importance of the “gene-time-environment” hypothesis in ALS onset and progression. Despite extensive research, understanding of the complex environmental risk factors remains fragmented. In this study, we comprehensively analyzed the associations between trace elements, biochemical signatures, and modifiable risk factors among ALS patients stratified by age, sex, type of onset, disease severity, and progression. Specifically, we investigated blood concentrations of cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), and iron (Fe) levels in 121 participants. Moreover, we examined the associations between trace metals, biochemical indicators including serum ferritin (SF), blood glucose, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), cerebrospinal fluid (CSF) cell count, CSF total protein, as well as history of hypertension, hazardous chemical exposure, drinking, and smoking in ALS patients. Specifically, we report that high Fe levels were found in male and spinal-onset patients. Moreover, high serum ferritin was positively associated with age of onset, blood iron and glucose, as well as high disease severity. Results from this study highlight the complex characteristics of ALS and provide new insight for understanding the intricate relationship between disease phenotype, metal homeostasis, and modifiable risk factors.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}