Annals of Clinical and Translational Neurology最新文献

{"title":"Lesion Location and Functional Connections Reveal Cognitive Impairment Networks in Multiple Sclerosis.","authors":"Alessandro Franceschini, Paolo Preziosa, Paola Valsasina, Damiano Mistri, Monica Margoni, Federica Esposito, Massimo Filippi, Maria A Rocca","doi":"10.1002/acn3.70199","DOIUrl":"https://doi.org/10.1002/acn3.70199","url":null,"abstract":"<p><strong>Objective: </strong>Cognitive impairment, fatigue, and depression are common in multiple sclerosis (MS), potentially due to disruption of regional functional connectivity caused by white matter (WM) lesions. We explored whether WM lesions functionally connected to specific brain regions contribute to these MS-related manifestations.</p><p><strong>Methods: </strong>A total of 596 MS patients underwent 3T brain MRI acquisition, neurologic assessment, and neuropsychological evaluation (Brief Repeatable Battery, Modified Fatigue Impact Scale [MFIS], and Montgomery-Åsberg Depression Rating Scale [MADRS]). Voxel-wise lesion probability maps were compared between subgroups based on cognition, fatigue, or depression. Lesion distributions were linked to a brain functional connectivity atlas to map lesion network associations. Lesion network maps (LNMs) were then compared among subgroups (p < 0.05, FWE-corrected).</p><p><strong>Results: </strong>One hundred twenty-six (27.2%) MS patients were cognitively impaired and showed significantly more widespread WM lesions, more strongly functionally connected to bilateral hippocampi, thalami, cerebellum, and occipital cortices (corrected-p < 0.05) than cognitively preserved patients. Lesion networks were similar for impaired processing speed/attention. Verbal memory deficits were associated with WM lesions connected to parahippocampi, temporal pole, and cerebellum (corrected-p ≤ 0.05), while verbal fluency deficits involved connections to thalami, putamen, caudate nuclei, anterior cingulate cortex, and cerebellum (corrected-p ≤ 0.05). No significant lesion distribution or network connectivity differences were found in patients with visual memory deficits, fatigue (MFIS ≥ 38, 184/493 [37.3%]) or depression (MADRS > 9, 192/495 [38.8%]).</p><p><strong>Interpretation: </strong>Regional WM lesions disrupting connections to the hippocampus, thalamus, cerebellum, and temporo-occipital cortices contribute to cognitive impairment, but not fatigue or depression. LNM may clarify mechanisms underlying cognitive deficits in MS.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scoliosis Surgery in a Patient With Advanced Friedreich's Ataxia-It Is Not Too Late.","authors":"Kathrin Reetz, Stella A Lischewski, Jörg B Schulz, Maximilian Praster, Miguel Pishnamaz, Imis Dogan, Sandro Romanzetti, Ravi Dadsena, Kerstin Konrad, Thomas Clavel, Vera Jankowski, Joachim Jankowski, Oliver Pabst, Nikolaus Marx, Julia Moellmann, Malte Jacobsen, Katharina Marx-Schütt, Juergen Dukart, Simon Eickhoff, Ralf-Dieter Hilgers","doi":"10.1002/acn3.70219","DOIUrl":"https://doi.org/10.1002/acn3.70219","url":null,"abstract":"<p><p>Friedreich's ataxia is a multisystem disorder with scoliosis being the most common non-neurological manifestation. While scoliosis surgery is typically performed in adolescent, ambulatory patients, few data exist on surgical outcomes in patients with advanced disease. We present a 38-year-old woman with late-stage Friedreich's ataxia and pronounced thoracolumbar scoliosis (Cobb angle 48°) causing severe pain and limited sitting tolerance. After posterior corrective spondylodesis (T4-ilium), she reported marked improvements in pain, sitting tolerance, function, and quality of life in the SF-36 questionnaire. This case highlights the potential for substantial clinical and functional benefits from scoliosis surgery in patients with advanced Friedreich's ataxia.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Assessment of Upper Limb Ataxia Using a Virtual Reality-Based Evaluation System.","authors":"Masayuki Sato, Takayuki Abe, Sho Aoki, Setsuki Tsukagoshi, Yasushi Yuminaka, Yoshio Ikeda","doi":"10.1002/acn3.70215","DOIUrl":"https://doi.org/10.1002/acn3.70215","url":null,"abstract":"<p><strong>Objective: </strong>Cerebellar ataxia impairs coordination and balance, reducing quality of life. Conventional clinical scales, including the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS), are widely used to assess ataxia but are limited by subjectivity and inter-rater variability. Therefore, we aimed to develop a virtual reality-based system to objectively and quantitatively assess upper limb ataxia.</p><p><strong>Methods: </strong>A \"virtual nose-finger test\" was implemented using a head-mounted display, in which participants performed repetitive reaching tasks. Six parameters were measured: four spatial (subtracted length, trajectory ratio, terminal trajectory length, and maximum overshoot distance) and two temporal (required time and movement speed). These parameters were compared across groups, correlated with clinical scales, and analyzed for diagnostic accuracy using receiver operating characteristic curves. Motor adaptation was assessed using parameter changes across trials.</p><p><strong>Results: </strong>Ninety-five participants were recruited: 39 with cerebellar ataxia, 30 controls, and 26 with Parkinsonian disorders. Participants with ataxia exhibited significantly greater spatial deviations and temporal variability than other groups did. Trajectory ratio, required time, and movement speed variability coefficient significantly correlated with clinical ataxia scores. The system demonstrated high diagnostic accuracy from the receiver operating characteristic analyses, and participants with ataxia showed different motor adaptations by compensating for spatial errors through reduced movement speed.</p><p><strong>Interpretation: </strong>This virtual reality-based system enables objective, quantitative, portable, and ambulatory-independent evaluation of upper limb ataxia, enhancing its feasibility in clinical and research settings and its potential as a biomarker for cerebellar ataxia.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Diverse Neuromuscular Spectrum of VPS13A Disease.","authors":"Anne Buchberger, Evamaria Riedel, Marie Hackenberg, Alexander Mensch, Stefanie Beck-Woedl, Joohyun Park, Tobias B Haack, Bernhard Haslinger, Jan Kirschke, Holger Prokisch, Andreas Hermann, Christian Mawrin, Adrian Danek, Benedikt Schoser, Kevin Peikert, Marcus Deschauer, Isabell Cordts","doi":"10.1002/acn3.70198","DOIUrl":"https://doi.org/10.1002/acn3.70198","url":null,"abstract":"<p><strong>Objective: </strong>VPS13A disease (chorea-acanthocytosis) is a rare neurodegenerative disorder caused by biallelic variants in VPS13A, typically presenting with hyperkinetic movement disorders, while neuromuscular signs are often mild. The aim of the project was to investigate the frequency and severity of neuromuscular impairment in VPS13A disease.</p><p><strong>Methods: </strong>We systematically assessed the neuromuscular involvement in six patients with VPS13A disease. Our evaluation included genetic and clinical data, blood tests, electrophysiological studies, muscle MRI, and tissue samples from muscle and nerve.</p><p><strong>Results: </strong>Age at clinical onset was 14 to 38 years (median: 37.5). Age at onset of paresis was 27 to 29 years (median: 29). Initial symptoms included seizures (5/6), hyperkinesia (2/6), and muscle weakness (1/6). Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6). Nine VPS13A variants were detected, including a novel copy-neutral inversion. Phosphocreatine kinase was elevated in all cases (498-12,420 U/L; median of highest values: 2230 U/L). Nerve conduction studies revealed sensorimotor axonal neuropathy. Electromyography showed chronic neurogenic changes with high amplitudes, polyphasic potentials, and reduced interference patterns (6/6). Muscle MRI displayed fatty atrophy, most prominently in the calves (5/5). Muscle histology indicated neurogenic and myopathic changes. Electron microscopy of mitochondria and respiratory chain analysis showed no specific pathological findings.</p><p><strong>Interpretation: </strong>Our findings emphasize the underrecognized neuromuscular spectrum in VPS13A disease, ranging from subclinical signs to severe paresis and sometimes preceding the hyperkinesia that gave rise to the historical term of chorea-acanthocytosis. A comprehensive understanding of the phenotype is crucial for early diagnosis and appropriate management of VPS13A disease.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nationwide Characterization of MFN2-Related CMT in 176 Japanese Patients: Clinical and Genetic Insights.","authors":"Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Chikashi Yano, Takahiro Hobara, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima","doi":"10.1002/acn3.70218","DOIUrl":"https://doi.org/10.1002/acn3.70218","url":null,"abstract":"<p><strong>Background: </strong>Mitofusin 2 (MFN2) is a major causative gene for axonal Charcot - Marie - Tooth disease type 2A (CMT2A), with a wide phenotypic spectrum. Comprehensive large - scale genotype - phenotype association studies are essential for understanding disease pathogenesis and improved clinical management.</p><p><strong>Methods: </strong>We conducted a nationwide retrospective study of 176 Japanese patients with genetically confirmed pathogenic or likely pathogenic MFN2 variants encompassing clinical, electrophysiological, and genetic characterization.</p><p><strong>Results: </strong>MFN2 was the second most frequent causative gene among 1211 genetically diagnosed inherited peripheral neuropathy cases in Japan. A total of 76 MFN2 variants were identified, including nine novel likely pathogenic variants. Disease onset occurred at a mean age of 11.1 years, with distal motor weakness and tibialis anterior involvement as prominent features. Sensory symptoms were present in ~60% of patients and were more common in cases with longer disease duration. Central and systemic features, including pyramidal signs, optic atrophy, and vocal cord paralysis, were also observed. Electrophysiological studies revealed a predominantly axonal sensorimotor pattern, with relatively preserved upper limb conduction and marked lower limb abnormalities. Importantly, 24 patients (16%) were non-ambulatory, with earlier onset and greater weakness. Domain-based analysis further revealed that variant location may influence age at onset.</p><p><strong>Conclusion: </strong>This large-scale study highlights the genetic and clinical diversity of MFN2-related CMT in Japan. Our findings confirm a motor-dominant, length-dependent axonal neuropathy with additional sensory and systemic features in some cases. These results emphasize the importance of early diagnosis, genotype-informed care, and long-term follow-up in managing MFN2-related CMT.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth Differentiation Factor 15 Elevation in the Central Nervous System Is Associated With Failure to Thrive in Alexander Disease.","authors":"Tracy L Hagemann, Michelle M Sonsalla, Cora Luzinski, Fernando Zacahua, David A Harris, Dudley W Lamming, Albee Messing","doi":"10.1002/acn3.70209","DOIUrl":"https://doi.org/10.1002/acn3.70209","url":null,"abstract":"<p><strong>Objective: </strong>Alexander disease (AxD) is a severe neurodegenerative disorder caused by gain-of-function mutations in the gene for GFAP, which lead to protein aggregation and a primary astrocytopathy. Symptoms vary, but failure to thrive (FTT) and frequent emesis are common and cause significant morbidity. Here we investigate GDF15, a member of the TGFβ superfamily, which regulates energy balance and appetite, as a potential mediator of FTT in AxD.</p><p><strong>Methods: </strong>In this study, we use the Gfap^+/R237H rat model (R237H), in which pups fail to gain weight after weaning and become frail and impaired as they mature, to assess muscle atrophy, energy expenditure, and feeding behavior in AxD. We measure GDF15 in brain and cerebrospinal fluid (CSF), assess activation of its receptor GFRAL in area postrema neurons, and use GFAP suppression to correlate FTT phenotypes with GDF15 expression. Finally, we measure GDF15 in patients with AxD.</p><p><strong>Results: </strong>R237H rats show reduced lean and fat mass and muscle atrophy despite reduced energy expenditure, and at an early age exhibit pica and anorexia. GDF15 is expressed by R237H rat astrocytes and is elevated in brainstem and CSF, but not in plasma. Neurons expressing GFRAL, a mediator of GDF15-induced appetite suppression, are activated in the area postrema. Suppression of GFAP using antisense oligonucleotides normalizes weight gain and GDF15 levels in brainstem and CSF. In human AxD, GDF15 is elevated in CSF, but not in blood.</p><p><strong>Interpretation: </strong>GDF15 is associated with FTT in AxD and provides both a target and useful biomarker for the development of future therapeutics.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosome Proteomics of SOD1^D90A Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker.","authors":"Mukesh Gautam, Ali Laith, Aslihan Gunel, Melda Yilmaz, Nazli Basak, Halil Idrisoglu, P Hande Ozdinler","doi":"10.1002/acn3.70208","DOIUrl":"https://doi.org/10.1002/acn3.70208","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss.</p><p><strong>Objective: </strong>Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations.</p><p><strong>Methods: </strong>Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1^D90A mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay.</p><p><strong>Results: </strong>Father, Son, and Daughter are at different disease stages and carry the SOD1^D90A mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1^D90A mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA.</p><p><strong>Interpretation: </strong>Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Study of Salivary Biomarkers in the Definition of Clinico-Molecular Progression of Parkinson's Disease.","authors":"Maria Ilenia De Bartolo, Daniele Belvisi, Matteo Costanzo, Claudia Caturano, Francesco Emanuele Bellomi, Carolina Cutrona, Flavia Aiello, Giorgio Leodori, Massimo Marano, Romina Mancinelli, Antonella Conte, Giovanni Fabbrini, Alfredo Berardelli, Giorgio Vivacqua","doi":"10.1002/acn3.70178","DOIUrl":"https://doi.org/10.1002/acn3.70178","url":null,"abstract":"<p><strong>Objectives: </strong>In our previous study, we investigated in de novo PD patients salivary biomarkers targeting different molecular pathways, including alpha-synuclein (a-syn), tau pathology, autophagy (MAPLC3beta), and inflammation (TNFalpha). Here, we aimed to investigate longitudinal changes in these salivary biomarkers with the goal of assessing their dynamic changes over time and their predictive value for clinical progression.</p><p><strong>Methods: </strong>A clinical and molecular 4-year follow-up (T1) was conducted on 43 PD patients of our previously molecularly characterized cohort of de novo PD patients (T0). Salivary levels of oligomeric and total a-syn, pS199-tau, total-tau, activated MAP-LC3beta, and TNFalpha were quantified using ELISA. Clinical assessments included motor and non-motor symptom scales. The Wilcoxon test was used to verify molecular and clinical variations from T0 to T1; regression analysis to determine whether salivary biomarkers at T0 could predict clinical progression and Spearman's correlations to explore correlations between changes in molecular biomarkers and clinical scores.</p><p><strong>Results: </strong>Oligomeric a-syn and MAPLC3beta dramatically decrease, while total a-syn, phosphorylated-tau, total-tau, and TNFalpha exhibited significantly higher levels from T0 to T1. Oligomeric and total a-syn, phosphorylated and total-tau at baseline predicted motor progression, while TNFalpha predicted non-motor worsening. Significant correlations were found for MAPLC3beta, phosphorylated tau, and TNFalpha with motor and non-motor scores, while no correlations emerged between a-syn species and clinical scores both at T0 and T1.</p><p><strong>Interpretation: </strong>Salivary biomarkers dynamically reflect PD progression and predict long-term clinical outcomes. These findings support the use of saliva as a noninvasive, accessible source for predicting and monitoring disease progression in PD.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics.","authors":"Gregorio A Nolasco, Mònica Roldán, Yalda Jamshidi, Ioannis Georvasilis, Rocío Jadraque Rodríguez, Reza Boostani, Ali Shoeibi, Lluís Armengol, Anna Codina, Ehsan Ghayoor Karimiani, Cristina Hernando-Davalillo, Loreto Martorell, María Luisa Ramírez Almaraz, Jordi Muchart, Carlos Ortez, Andrés Nascimento, Roser Urreizti, Daniel Natera-de Benito, Mercedes Serrano","doi":"10.1002/acn3.70206","DOIUrl":"https://doi.org/10.1002/acn3.70206","url":null,"abstract":"<p><strong>Objective: </strong>Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders marked by spasticity and lower limb weakness. The most common type, SPG4, is usually autosomal dominant and caused by SPAST gene variants, typically presenting as pure HSP. We describe five individuals from three unrelated families who meet the clinical criteria for cerebral palsy and carry biallelic SPAST variants. We aim to increase the clinical and genetic understanding of SPAST-related disorders and explore the underlying abnormal cellular mechanisms.</p><p><strong>Methods: </strong>We performed comprehensive phenotyping and genetic analysis. In silico and functional studies were conducted using confocal microscopy on fibroblast cultures derived from carriers of the biallelic SPAST variants, a monoallelic SPAST variant, and a healthy control.</p><p><strong>Results: </strong>Individuals exhibited early-onset complex HSP with a diverse range of encephalopathy severity, spasticity, and neuronoaxonal involvement, occasionally leading to the diagnosis of cerebral palsy. Whole-exome sequencing identified homozygous and compound heterozygous SPAST variants. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient-derived fibroblasts, supporting the pathogenicity of the variants.</p><p><strong>Interpretation: </strong>We provide the first evidence of biallelic inheritance in SPAST-related disorders, supported by functional analysis, expanding the clinical spectrum to include moderate-to-severe early-onset encephalopathy. Our findings emphasize the importance of genetic diagnosis in cerebral palsy for prognosis, counseling, and personalized therapy. The identified variants reveal the genetic complexity of SPAST-related disease and suggest a threshold effect of spastin levels in phenotypic variation. Cellular mechanisms such as mitochondrial dynamics and membrane morphology may contribute to pathogenesis and warrant further investigation.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered Dynamic Functional Network Connectivity in Post-Stroke Aphasia.","authors":"Guihua Xu, Yongsheng Wu, Junyu Qu, Rui Zhu, Wenwen Xu, Jiaxiang Xin, Dawei Wang","doi":"10.1002/acn3.70194","DOIUrl":"https://doi.org/10.1002/acn3.70194","url":null,"abstract":"<p><strong>Objective: </strong>Previous studies examining post-stroke aphasia (PSA) patients via resting-state functional magnetic resonance imaging (rs-fMRI) have predominantly focused on static functional connectivity. In contrast, the current investigation aims to elucidate the alterations in dynamic functional network connectivity (dFNC) among PSA patients.</p><p><strong>Methods: </strong>We recruited 40 PSA patients and 41 age-, gender-, and education-matched normal controls (NCs). The participants underwent rs-fMRI and the Western Aphasia Battery (WAB) test. Independent component analysis (ICA) was used to identify resting-state networks (RSNs), and dFNC was constructed using a sliding window technique followed by k-means clustering to classify distinct dynamic network states. We compared the dFNC differences between the PSA and NC groups and examined their relationships with clinical outcomes.</p><p><strong>Results: </strong>The dynamic analysis identified 4 distinct dFNC states: state 1 (modular network state), state 2 (pan-network hyperconnectivity state), state 3 (intra-network coordinated state), and state 4 (sparse connectivity state). Notable group differences were observed: compared with NCs, the PSA group demonstrated significantly reduced connectivity within the language network (LN) and increased connectivity between the cerebellar network (CN) and the default mode network (DMN) in state 3; significantly reduced connectivity changes within the LN and between the LN and executive control network (ECN) / CN were noted in state 4. Additionally, fraction time and mean dwell time in the modular network state were positively correlated with the WAB score.</p><p><strong>Interpretation: </strong>Alteration in dFNC could serve as a sensitive biomarker toward language impairment in PSA patients, with implications for diagnostic assessment and therapeutic intervention planning.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}