Annals of Clinical and Translational Neurology最新文献

{"title":"Mechanical Thrombectomy for TRACE-III-Eligible Patients With Ischemic Stroke: A Multicenter Retrospective Study Compared to TRACE-III and TIMELESS Trials","authors":"Chongyang Huang,&nbsp;Yanru Liu,&nbsp;Jiangang Zhang,&nbsp;Sheng Guan,&nbsp;Tao Quan,&nbsp;Zhen Chen,&nbsp;Xiaojie Fu,&nbsp;Sen Wei,&nbsp;Kaihao Han,&nbsp;Xiaoan Zhou,&nbsp;Chengcheng Zhu,&nbsp;Edgar Samaniego,&nbsp;Yueqi Zhu,&nbsp;Haowen Xu","doi":"10.1002/acn3.70107","DOIUrl":"10.1002/acn3.70107","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The results of the TRACE-III trial demonstrated that tenecteplase (TNK) might be comparable to TNK combined with mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke within 4.5 to 24 h of onset, as tested in the TIMELESS trial. We aimed to evaluate the safety and effectiveness of MT alone in TRACE-III-eligible patients in routine clinical settings, comparing the results of both trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective multicenter cohort study involved consecutive patients who underwent MT alone at three stroke centers between March 2021 and July 2024. Only those meeting the inclusion and exclusion criteria of TRACE-III were included. Safety, clinical, and imaging outcomes were compared with the TRACE-III and TIMELESS trial data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>336 TRACE-III-eligible patients were enrolled in our cohort. MT alone had a higher percentage of patients with a modified Rankin scale (mRS) score of 0–2 at 90 days (58.9%) compared to the TNK group in TRACE-III, TNK and placebo groups in TIMELESS (43.6%, 46.0%, and 42.4%, respectively; all <i>p</i> &lt; 0.01). Additionally, MT achieved a higher rate of early-stage reperfusion (86.0%) compared to the TRACE-III TNK, TIMELESS TNK, and TIMELESS placebo groups (27.9%, 76.7%, and 63.9%; all <i>p</i> &lt; 0.05). The mRS 0–1 at 90 days, incidence of symptomatic intracerebral hemorrhage, and mortality at 90 days were 36.0%, 5.4%, and 14.9%, respectively, similar to those in the three groups (all <i>p</i> &gt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>In clinical practice, MT can achieve higher rate of early-stage reperfusion and tended to yield better functional outcomes than intravenous TNK, with similar safety, in TRACE-III-eligible patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"12 9","pages":"1886-1893"},"PeriodicalIF":3.9,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.70107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Iron Measurements in the Basal Ganglia of NBIA Patients Using QSM: Insights From a Tertiary Center.","authors":"Özge Uygun, Alpay Özcan, Fuat Kaan Aras, Evrim Bozdemir, Sibel Uğur İşeri, Murat Gültekin, Nihan Hande Akçakaya, Orkhan Mammadov, Gülay Kır, Dilek İnce Günal, Neşe Tuncer, Fatma Betül Özdilek, Banu Özen Barut, Ercan Köse, Hülya Apaydın, Asuman Ali, Sultan Çağırıcı, Pınar Topaloğlu, Alp Dinçer, Zuhal Yapıcı","doi":"10.1002/acn3.70161","DOIUrl":"https://doi.org/10.1002/acn3.70161","url":null,"abstract":"<p><strong>Objective: </strong>Neurodegeneration with brain iron accumulation (NBIA) comprises rare genetic disorders characterized by predominantly extrapyramidal symptoms and iron deposition in the basal ganglia. Conventional magnetic resonance imaging (MRI) detects qualitative changes but cannot accurately quantify iron accumulation. Quantitative susceptibility mapping (QSM) allows precise in vivo quantification of iron, providing insight into the pathophysiology of the disease.</p><p><strong>Methods: </strong>We studied 27 genetically confirmed NBIA patients and 11 age-matched healthy controls using susceptibility-weighted imaging (SWI) on a 3 Tesla MRI scanner. Basal ganglia regions of interest (ROIs) were manually delineated and QSM values were extracted.</p><p><strong>Results: </strong>Sixteen NBIA patients and 11 controls were analyzed. QSM showed significantly higher iron in the globus pallidus (GP) (p = 0.008), with PKAN patients showing a 2.5-fold increase in GP iron (p = 0.001). MPAN patients showed 2.5 times higher iron in both GP and substantia nigra (SN). A GP iron level > 0.1133 ppm increased the likelihood of PKAN 18-fold. Atypical PKAN cases had 2.5 times higher SN iron levels compared to classic cases.</p><p><strong>Interpretation: </strong>QSM is a sensitive and noninvasive tool for detecting and quantifying iron accumulation in NBIA. The GP consistently showed the highest susceptibility values across subtypes, emphasizing its significant role in disease pathology. Distinct patterns of iron deposition in different NBIA subtypes may reflect subtype-specific mechanisms with diagnostic and therapeutic relevance. Age-related susceptibility changes were found to be significant, reinforcing the need to account for age when interpreting QSM data. More importantly, QSM may serve as a candidate biomarker for longitudinal disease monitoring in future clinical trials targeting disease-modifying therapies in NBIA.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858722","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":"Cytokine, Chemokine, and Neurofilament Light Chain Signatures in LGI1 Autoimmune Encephalitis.","authors":"Albert Aboseif, Georgios Mangioris, Binxia Yang, Vanessa K Pazdernik, Jeffrey W Britton, Divyanshu Dubey, Eoin P Flanagan, Sarosh R Irani, Gregory S Day, Charles L Howe, A Sebastian López-Chiriboga, Andrew McKeon, John R Mills, Yahel Segal, Michel Toledano, Ivana Vodopivec, Sean J Pittock, Anastasia Zekeridou","doi":"10.1002/acn3.70158","DOIUrl":"https://doi.org/10.1002/acn3.70158","url":null,"abstract":"<p><strong>Objectives: </strong>To investigate the value of cytokine, chemokine, and neurofilament light chain (NfL) concentrations in predicting relapse risk, chronic epilepsy, and functional impairment in LGI1 autoimmune encephalitis (AE).</p><p><strong>Methods: </strong>Cytokines/chemokines (IL-1-beta, IL-2, IL-4, IL-5, IL-6, IL-8/CXCL8, IL-10, IL-12p70, IL-13, IL-17A, GM-CSF, TNF-alpha, IFN-gamma, CXCL9, CXCL10, CXCL13, BAFF) and NfL concentrations were measured in CSF and paired serum from LGI1-AE patients evaluated at Mayo Clinic (01/2015-02/2024), using a multiplex immunoassay system (ELLA, Bio-Techne) and correlated with clinical outcomes. A laboratory-based cohort of LGI1-IgG-positive patients and control cohorts, including patients with mixed non-inflammatory disorders (MNID), Alzheimer's disease (AD), and temporal lobe epilepsy (TLE) were analyzed.</p><p><strong>Results: </strong>Forty-four patients with LGI1-AE were included; 29 (66%) were male, with a median age of 68.5 years (range, 8-85). Median time from symptom onset to CSF sampling was eight months (IQR, 3-17); 19/42 (45%) experienced a clinical relapse and 27% developed chronic epilepsy. Serum IL-6, serum and CSF IL-8/CXCL8, and IL-17A were higher in LGI1-IgG positive patients than MNID (p < 0.05). TLE cytokine/chemokine profiles were similar to LGI1 AE; AD patients had lower serum IL-6 and CSF IL-8/CXCL8 (p = 0.04; p = 0.01), and higher serum IL-17A and GM-CSF (p = 0.004; p = 0.01) than LGI1-AE. Higher CSF IL-6 and IL-8/CXCL8 in LGI1-AE associated with clinical relapse (p < 0.05) and higher CSF NfL associated with chronic epilepsy (p = 0.01).</p><p><strong>Conclusion: </strong>Elevations in IL-6, IL-8/CXCL8, and IL-17A were identified in this LGI1-AE cohort. CSF IL-6, IL-8/CXCL8, and NfL levels are potential prognostic biomarkers for risk of relapse and chronic epilepsy in LGI1-AE.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803014","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":"Reply to Letter: \"Real-World Clinical Experience With Serum MOG and AQP4 Antibody Testing by Live Versus Fixed Cell-Based Assay\".","authors":"Yana Said, Eoin P Flanagan, Elias S Sotirchos","doi":"10.1002/acn3.70169","DOIUrl":"https://doi.org/10.1002/acn3.70169","url":null,"abstract":"","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803016","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":"ICU-EEG Pattern Detection by a Convolutional Neural Network.","authors":"Giulio Degano, Hervé Quintard, Andreas Kleinschmidt, Nikita Francini, Oana E Sarbu, Pia De Stefano","doi":"10.1002/acn3.70164","DOIUrl":"https://doi.org/10.1002/acn3.70164","url":null,"abstract":"<p><strong>Objective: </strong>Patients in the intensive care unit (ICU) often require continuous EEG (cEEG) monitoring due to the high risk of seizures and rhythmic and periodic patterns (RPPs). However, interpreting cEEG in real time is resource-intensive and heavily relies on specialized expertise, which is not always available. This study introduces a lightweight convolutional neural network (CNN) to automatically detect key EEG patterns, including seizures and RPPs.</p><p><strong>Methods: </strong>We classified time-frequency spectrograms of EEG data from the Harmful Brain Activity Classification challenge, including 1950 patients. We tested our model on a subset of this dataset and a small independent cohort of ICU patients with epileptic seizures from the Geneva University Hospital.</p><p><strong>Results: </strong>Our model showed good performance metrics on the open-source data with an AUROC score of 93% for SZ, 91% for lateralized PD, 94% for generalized PD, 87% for lateralized RDA, 89% for generalized RDA, and 88% for others. The evaluation with the Geneva University Hospital dataset also demonstrated strong temporal detection capabilities, showing an false positive rate (FPR) of 22%, 20%, and 21% at 50 s, 30 s, and 20 s before seizure onset, and a true positive rate (TPR) of 76%, 84%, and 89% at 20 s, 30 s, and 50 s after seizure onset.</p><p><strong>Interpretation: </strong>This study presents a lightweight CNN model capable of detecting critical EEG patterns in ICU patients with minimal preprocessing. Moreover, the model's design provides reliable detection of ICU-EEG epileptic patterns shortly after their onset. These features underscore the model's potential to enhance timely EEG monitoring in resource-limited and advanced clinical contexts.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797713","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":"Exploring if Longitudinal Changes on PET Imaging Can Serve as a Biomarker for Stiff Person Syndrome Spectrum Disorders.","authors":"Munther M Queisi, Samantha N Roman, Mohammad S Sadaghiani, Lilja B Solnes, Scott D Newsome","doi":"10.1002/acn3.70145","DOIUrl":"https://doi.org/10.1002/acn3.70145","url":null,"abstract":"<p><strong>Objective: </strong>To identify metabolic patterns in the brain and musculoskeletal system of stiff person syndrome spectrum disorders (SPSD) patients over time using PET imaging and evaluate the impact of immune therapy on metabolic activity as a surrogate for treatment response.</p><p><strong>Methods: </strong>This observational study at the Johns Hopkins SPS Center of Excellence included adults (≥ 18 years) diagnosed with classic SPS, partial SPS, SPS plus, or PERM, who were treated from 2009 to 2023. Participants underwent at least two whole-body and/or dedicated brain PET scans. Brain PET analysis utilized NeuroQ v3.8 software to generate standardized Z-scores for 47 distinct brain regions, assessed by expert nuclear medicine radiologists. Patient demographics, antibody types, immune therapies, and symptomatic treatments were assessed.</p><p><strong>Results: </strong>Eighteen patients met inclusion criteria (10 SPS plus, 6 classic SPS, 2 PERM), with a mean age of 50.7 (SD 8.5) years; 77.8% were female and 50.0% were Black/African American. Hypermetabolic activity and hypometabolism were both seen over time in the brain and the musculoskeletal system. Two patients starting immune therapy in between PET scans demonstrated improvement in brain but not body PET findings.</p><p><strong>Interpretation: </strong>The study findings indicate that PET imaging abnormalities are present over time and appear to have regional patterns that are common among phenotypes. Additionally, starting immune therapy between scans appears to correlate with stabilization or improvement in brain PET abnormalities, though this was less clear in body PET scans. PET scans have the potential to be an imaging biomarker in SPSD, but future studies are needed to validate this.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797712","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":"Translating a Preclinically Tested 15 Hz rTMS Protocol to Humans With Chronic Spinal Cord Injury: A Safety and Feasibility Study.","authors":"Nabila Brihmat, Mehmed B Bayram, Morgan Paine, Janelle Carnahan, Jian Zhong, Xiaofei Guan, Guang H Yue, Soha Saleh, Gail F Forrest","doi":"10.1002/acn3.70154","DOIUrl":"https://doi.org/10.1002/acn3.70154","url":null,"abstract":"<p><strong>Objectives: </strong>Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation strategy with a demonstrated potential to reinforce the residual pathways after a spinal cord injury (SCI). A preclinically tested high-frequency (15 Hz) rTMS (15 Hz rTMS) protocol was shown to induce corticospinal tract axon regeneration growth and sprouting, resulting in improved voluntary motor control and performance. In a translational perspective, we aimed to investigate the safety and feasibility of the 15 Hz rTMS paradigm as an adjunct therapeutic intervention in individuals with chronic SCI.</p><p><strong>Method: </strong>We thus investigated the effects of a 15-day repeated protocol consisting of 15 Hz rTMS followed by task-specific hand motor training in 7 individuals with chronic cervical SCI. 15 Hz rTMS targeted the weaker wrist extensor muscle, based on participant- and day-specific resting motor threshold, motor responses, and maximum tolerability. Safety, feasibility, neurophysiological, and clinical functional outcomes were measured at different times of the therapeutic protocol.</p><p><strong>Results: </strong>The therapeutic stimulation protocol was delivered mostly as designed except with regard to stimulation intensity and duration and was overall tolerable without major serious effects. Preliminary neuroplastic and functional benefits revealed by corticospinal excitability and intracortical inhibition modulation and clinical improvements were noted and were still observable at follow-up times.</p><p><strong>Interpretation: </strong>This study confirms that an intervention combining 15 Hz rTMS and task-specific motor training is feasible, tolerable, and has the potential to induce neuroplastic changes and improve function in individuals with chronic cervical SCI. This feasibility study, in parallel with previous reports in able-bodied individuals, warrants further investigation of the adapted 15 Hz rTMS protocol in individuals at an earlier stage post-injury and to confirm efficacy in a larger and controlled study trial.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793026","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":"Long-Term Temporal Profile of Motor Recovery After Intracerebral Hemorrhage.","authors":"Yan Zheng, Fu-Xin Lin, Ling-Yun Zhuo, Jian-Cai Chen, Xin Ge, Xiang-Lin Chen, Xue-Jiao Wang, Zhi-Gang Yao, You-Liang Tong, Bo Xie, Bai-Hai Guo, Zhao-Sheng Sun, Zhi-Hua Tian, Ping Qiu, Xin-Ru Lin, Qiu He, Shu-Na Huang, Ke Ma, Fang-Yu Wang, Huang-Cheng Shang-Guan, Wen-Hua Fang, Deng-Liang Wang, Ying Fu, Yuan-Xiang Lin, De-Zhi Kang","doi":"10.1002/acn3.70124","DOIUrl":"https://doi.org/10.1002/acn3.70124","url":null,"abstract":"<p><strong>Objective: </strong>Limited data is available to describe the temporal profile of long-term recovery over 1 year after the stroke in patients with spontaneous intracerebral hemorrhage (ICH).</p><p><strong>Methods: </strong>A registered multicentral cohort was conducted to consecutively include non-herniated supratentorial ICH patients from November 2013 to January 2023. Eligible patients received follow-ups at the time of 3 months, 6 months, 1 year, and each year after the enrollments until death or the study termination. The outcome of motor recovery was assessed with the dichotomy of independent standing ability. Analyses were performed to investigate the associated factors, recovery rates, and temporal profile.</p><p><strong>Results: </strong>Of 1624 eligible responses, 105 (6.5%) regained motor recovery beyond 1 year after the stroke. The motor recovery course decreased with time and continued until 44 months, with 1-year and long-term cumulative recovery rates of 71.3% (95% CI: 69.0%-73.5%) and 80.2% (95% CI: 78.0%-82.5%), respectively. Moreover, the onset age, ICH location, larger ICH, and peripheral hematomal edema (PHE), intraventricular extension, GCS score, and admission hospital tier were independent factors on the motor outcome (all p < 0.05). However, the older age (aHR = 0.97/year, 95% CI: 0.95-0.98, p < 0.001) was identified as the only hazard factor for future recovery in patients who were incapable of recovery within 1 year.</p><p><strong>Interpretation: </strong>The poststroke recovery was ongoing beyond 1 year until about 3 years after the onset, and those with delayed motor recovery accounted for about 10% of ultimately recovered patients.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787898","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":"Commentary on \"The Impact of Diabetes and Metabolic Syndrome Burden on Pain, Neuropathy Severity and Fiber Type\".","authors":"Majid Khalilizad, Ebrahim Hejazian, Mohammad Barary, Mostafa Javanian, Soheil Ebrahimpour","doi":"10.1002/acn3.70151","DOIUrl":"https://doi.org/10.1002/acn3.70151","url":null,"abstract":"","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937173","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":"Central Dysmyelination in SSADH-Deficient Humans and Mice.","authors":"Itay Tokatly Latzer, Henry H C Lee, Edward Yang, Cesar Alves, Mariarita Bertoldi, Caitlyn Fung, Spencer V Steele, Eren Kule, Zijie Jin, Alexander Rotenberg, Jean-Baptiste Roullet, Phillip L Pearl","doi":"10.1002/acn3.70148","DOIUrl":"https://doi.org/10.1002/acn3.70148","url":null,"abstract":"<p><strong>Objectives: </strong>Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder characterized by an accumulation of γ-aminobutyric (GABA). In addition to its synaptic role as an inhibitory neurotransmitter, GABA also plays an important role in myelination. We aimed to investigate the relationship between GABA and myelination abnormalities in SSADHD patients and the mouse model.</p><p><strong>Methods: </strong>Brain MRIs performed on 44 individuals (23 with SSADHD and 21 healthy controls) were independently reviewed by two neuroradiologists and scored using a disease-specific myelination scoring system. Inter-rater reliability (IRR) was assessed by the intraclass correlation coefficient. Myelination scores of SSADHD individuals were correlated with clinical, biochemical, magnetic resonance spectroscopy, and genetic data. Additionally, we investigated the expression of myelin-related genes in a mouse SSADHD model.</p><p><strong>Results: </strong>Dysmyelination in SSADHD patients was overall mild, but significantly greater than in healthy controls (p < 0.001). In SSADHD patients, lower myelination scores were significantly correlated with younger age (R = 0.775, p < 0.001) and higher plasma GABA (R = -0.722, p < 0.001) and γ-hydroxybutyric acid (GHB) (R = -0.683, p = 0.001). In SSADH-deficient mice, there was reduced expression of genes encoding myelin basic protein (p = 0.001), myelin-associated oligodendrocyte basic protein (p = 0.001), and mitochondrial aspartate transporter (p = 0.025).</p><p><strong>Interpretation: </strong>Excessive GABA and GHB, which characterize SSADHD and are further pronounced in younger SSADHD individuals, may account for delayed oligodendrocyte maturation and altered myelination dynamics in this disorder. Studying the properties of dysmyelination in this unique disorder enhances our understanding of GABA's mediating role on myelination and may contribute to monitoring disease progression and managing other white-matter neurological disorders.</p><p><strong>Trial registration: </strong>NCT03758521.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751922","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}