Annals of Clinical and Translational Neurology最新文献

{"title":"The Road Not Taken: Misclassifying an Anti-Seizure Medication as a Failure.","authors":"Christopher N Henry, Daniel M Goldenholz","doi":"10.1002/acn3.70139","DOIUrl":"https://doi.org/10.1002/acn3.70139","url":null,"abstract":"<p><strong>Objective: </strong>To quantify how often anti-seizure medications (ASMs) appear ineffective yet provide benefit when considering seizure frequency (SF) variability.</p><p><strong>Methods: </strong>We used the CHOCOLATES seizure diary simulator to generate 100,000 patient seizure diaries that reflect natural SF variation in a heterogeneous population. Medication effect was modeled as a 20% average SF reduction (standard deviation 10%). We identified how many patients with an observed ≥ 25% SF increase (apparent worsening) actually had a true ≥ 10% SF reduction (vs. no medication), and how many with an observed ≥ 50% SF reduction (apparent responders) would have shown < 0% reduction if not taking the ASM. We also quantified how many individuals who had apparent worsening were actual worsening (> 0% SF increase vs. no medication).</p><p><strong>Results: </strong>Simulations closely matched real-world ASM trials, showing a median SF reduction of 36% with ASM versus 17% with placebo; 35% of patients on ASM achieved ≥ 50% SF reduction versus 20% on placebo. Apparent worsening occurred in 12%; among these, 76% were true improvers. Of the apparent responders, 12% were true nonresponders. Only 4% of the individuals with apparent worsening truly worsened compared to no medication.</p><p><strong>Interpretation: </strong>SF variability can lead to significant misclassification of ASM benefit. Many patients labeled as having \"failed\" an ASM trial were likely receiving meaningful benefit and may warrant reconsideration of the medication. Prospective clinical studies are needed to determine how best to account for SF variability and refine the interpretation of treatment response in epilepsy management.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681695","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":"Real-World Comparison of High-Efficacy Versus Non-High-Efficacy Therapies in Multiple Sclerosis.","authors":"Sarmad Al-Araji, Marcello Moccia, Alessia Bianchi, Charmaine Yam, Weaam Hamed, Suraya Mohamud, Alan J Thompson, Frederik Barkhof, Ahmed T Toosy, Olga Ciccarelli","doi":"10.1002/acn3.70130","DOIUrl":"https://doi.org/10.1002/acn3.70130","url":null,"abstract":"<p><strong>Objective: </strong>The choice of the first disease modifying treatment (DMT) in multiple sclerosis (MS) is a topic of great interest, and whether high-efficacy DMTs should be the first choice remains debated. We compared treatment outcomes (no evidence of disease activity [NEDA] and its components) between treatment-naïve relapsing-remitting MS (RRMS) patients commencing high-efficacy therapies (HET) and non-high-efficacy therapies (non-HET), using propensity score matching.</p><p><strong>Methods: </strong>This is an observational prospective study of two real-world, single-centre, longitudinal cohorts: (1) Relapsing-remitting MS (RRMS) patients initiated dimethyl fumarate, fingolimod, glatiramer acetate and natalizumab between 2002 and 2020; (2) RRMS patients initiated ocrelizumab between 2019 and 2021. We selected treatment-naïve patients and had at least 2 years of follow-up. We compared the two groups at years 1 and 2 using Cox and Logistic regression models as appropriate.</p><p><strong>Results: </strong>After propensity score matching, we included 448 patients: 110 HET and 338 non-HET. The probability of losing NEDA was 57% and 39% lower in the HET group at year 1 and 2 (HR = 0.43; 95% CI = 0.35, 0.52; p < 0.01 and HR = 0.61; 95% CI = 0.45, 0.84; p < 0.01, respectively). The probability of relapse in the HET group was 94% and 71% lower at year 1 and 2 (OR = 0.06; 95% CI = 0.01, 0.28; p < 0.01 and OR = 0.29; 95% CI = 0.10, 0.84; p < 0.02, respectively). The EDSS in the HET group was 30% and 18% lower at year 1 and 2 (Coeff = -0.30; 95% CI = -0.42, -0.18; p < 0.01 and Coeff = -0.16; 95% CI = -0.34, 0.02; p < 0.09, respectively). The probability of MRI activity in the HET group was 82% lower at year 1 (OR = 0.18; 95% CI = 0.04, 0.86; p < 0.03).</p><p><strong>Interpretation: </strong>This study demonstrated that treatment-naïve RRMS patients should be considered for high-efficacy therapies based on a greater suppression of disease activity at 2 years.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648068","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":"Fixel-Based Analysis of Diffusion Imaging as a Quantitative Marker of Disease State in Spinocerebellar Ataxia","authors":"David J. Arpin,&nbsp;S. H. Subramony,&nbsp;the READISCA Consortium,&nbsp;David E. Vaillancourt,&nbsp;Tetsuo Ashizawa,&nbsp;Alexandra Durr,&nbsp;Thomas Mareci,&nbsp;Thomas Klockgether,&nbsp;Jennifer Faber,&nbsp;Henry L. Paulson,&nbsp;Gülin Öz,&nbsp;Matthew R. Burns","doi":"10.1002/acn3.70116","DOIUrl":"10.1002/acn3.70116","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Spinocerebellar ataxias (SCAs) are a group of genetically heterogeneous neurodegenerative diseases causing progressive deterioration and reduced quality of life. Therapeutic advances have been limited by a lack of sensitive anatomic, functional, or diffusion imaging-based biomarkers. This study aimed to identify white matter differences in the brains of preataxic and early-stage SCA1 and SCA3 mutation carriers using diffusion magnetic resonance imaging data from a multisite trial setting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Fixel-based analysis was used to estimate microscopic fiber density, macroscopic fiber-bundle cross-section, and a combined fiber density and fiber-bundle cross-section measure within 45 cerebral and cerebellar tracts. Multivariate ANOVAs compared controls (<i>n</i> = 16), pre-ataxic (<i>n</i> = 10 SCA1, <i>n</i> = 24 SCA3), and ataxic patients (<i>n</i> = 14 SCA1, <i>n</i> = 36 SCA3). Clinical variables were correlated with fixel metrics and receiver operating characteristic analyses identified white matter tracts sensitive to distinguishing controls from pre-ataxic SCA1 and SCA3.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found widespread white matter deficits in pre-ataxic and ataxic patients compared to controls with regard to fiber density, fiber-bundle cross-section, and combined measures, all of which were associated with clinical measures of ataxia severity. We also found the combined fiber density and fiber-bundle cross-section measure from cerebellar tracts distinguished controls from pre-ataxia with high sensitivity and specificity for both SCA1 (receiver operating characteristic area under the curve = 0.96) and SCA3 (area under the curve = 0.97). The receiver operating characteristic analyses revealed that cerebellar tracts resulted in greater area under the curve than cortico-spinal and transcallosal tracts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These results demonstrate that fixel metrics offer sensitive disease-specific measures of early SCA disease state that correlate with standard clinical measures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>Clinical Trial Readiness for SCA1 and SCA3 (READISCA), NCT03487367. https://clinicaltrials.gov/ct2/show/NCT03487367.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"12 9","pages":"1846-1857"},"PeriodicalIF":3.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.70116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641317","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":"NMDAR-Antibody Encephalitis Diagnosed With Primary Central Nervous System Lymphoma: A Case Series","authors":"Soo Hyun Ahn,&nbsp;Cynthea Prima,&nbsp;Tae Min Kim,&nbsp;Soon-Tae Lee,&nbsp;Kon Chu","doi":"10.1002/acn3.70090","DOIUrl":"10.1002/acn3.70090","url":null,"abstract":"<p><i>N</i>-methyl-D-aspartate receptor-antibody encephalitis (NMDAR encephalitis) is one of the most common forms of autoimmune encephalitis, with a paraneoplastic relationship described in approximately 38%. Primary central nervous system lymphoma (PCNSL) is a rare hematologic malignancy that is not often considered as the underlying neoplasm in this autoimmune disease. We report three cases of suspected NMDAR encephalitis diagnosed in the context of PCNSL. Our cases highlight clinical features to suspect the coexistence of these two rare conditions and demonstrate the potential role PCNSL can play as the paraneoplastic source condition.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"12 9","pages":"1913-1918"},"PeriodicalIF":3.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937138","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":"Cognitive Resilience in Apolipoprotein ε4 Carrier Women Predicted by Neuron-Derived Extracellular Vesicles.","authors":"Apostolos Manolopoulos, Maja Mustapic, Carlos Nogueras-Ortiz, Francheska Delgado-Peraza, Krishna A Pucha, Pamela J Yao, Joseph Blommer, Michael P Vreones, William York, De' Larrian Knight, Stephen R Rapp, Aladdin H Shadyab, JoAnn E Manson, Ramon Casanova, Robert B Wallace, Luigi Ferrucci, Susan M Resnick, Dimitrios Kapogiannis","doi":"10.1002/acn3.70143","DOIUrl":"https://doi.org/10.1002/acn3.70143","url":null,"abstract":"<p><strong>Objective: </strong>The Apolipoprotein (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD); however, many ε4 carriers remain cognitively intact into old age. Leveraging plasma neuron-derived extracellular vesicles (NDEVs), we sought to identify biomarkers of cognitive resilience and their interplay with APOE genotype.</p><p><strong>Methods: </strong>In this case-control study nested within the Women's Health Initiative (WHI), we analyzed 1130 plasma samples from 676 women in the WHI Memory Study (WHIMS)/Long Life Study (LLS), with APOE ε4 or ε3/ε3 genotypes. At baseline, all participants were cognitively intact and at LLS visit, 13-17 years later, were classified as still cognitively intact (resilient) or having become impaired at age > 80 or ≤ 80 years. We isolated NDEVs using immunoaffinity capture for the neuronal marker L1CAM and quantified AD pathogenic proteins (Aβ₄₂, total Tau, p181-Tau), insulin signaling (pSer312-IRS-1), TNFR1/NFκB pathway mediators and targets, and mitochondrial Complex V. Linear mixed models assessed group differences, adjusting for NDEV yield, age, and education, with FDR correction.</p><p><strong>Results: </strong>No group differences were found for Aβ₄₂, Tau proteins, or pS312-IRS-1. Resilient ε4 carriers had higher baseline levels of phosphorylated TNFR1, NFκB, c-Myc, and FADD than ε4 carriers who eventually developed impairment at > 80 or ≤ 80 years. Additionally, resilient ε4 carriers had higher baseline Complex V levels than ε4 carriers impaired at age > 80.</p><p><strong>Interpretation: </strong>Augmented neuronal TNFR1/NFκB signaling and Complex V levels may promote cognitive resilience in ε4 carrier women. Boosting these mechanisms may have preventive and therapeutic potential against cognitive decline in this high-risk population.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641315","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":"Comparative Effect of Standard Versus Extended Interval Dosing of Rituximab or Ocrelizumab in Multiple Sclerosis.","authors":"Nabil K El Ayoubi, Fares Fahd, Hani Tamim, Salem Hannoun, Mark Bal, Elham El-Hallak, Samia J Khoury","doi":"10.1002/acn3.70142","DOIUrl":"https://doi.org/10.1002/acn3.70142","url":null,"abstract":"<p><strong>Objective: </strong>We aimed to investigate the comparative effectiveness of standard versus personalized extended interval dosing of anti-CD20 therapy on clinical and sub-clinical outcomes in multiple sclerosis.</p><p><strong>Methods: </strong>Clinical information was collected prospectively on Research Electronic Data Capture. Patients with age ≥ 18 years old, confirmed diagnosis of multiple sclerosis, treatment with B-cell depleting drug (Rituximab and Ocrelizumab), and minimum follow-up of 12 months with at least 3 clinical visits and at least 3 infusions of medication were included and divided into an extended interval dosing group, a standard interval dosing group, and a converters group who switched from standard to extended interval dosing. Retinal measures were obtained using spectral domain Optical Coherence Tomography. Magnetic resonance imaging acquisitions were performed in two centers using a standardized conventional imaging protocol for multiple sclerosis.</p><p><strong>Results: </strong>Patients had a median clinical follow-up of 3.5 (0.44-7.3) years, retinal OCT follow-up of 2.6 (1.4) years, and MRI follow-up of 2.6 (1.1) years. Annualized changes in clinical measures, retinal measures, and brain volumetric measures were similar between the 3 groups. Multivariate regression analyses also showed no differences.</p><p><strong>Interpretation: </strong>We found no differences in clinical or sub-clinical outcomes between patients treated with standard interval dosing, patients converting from standard to extended interval dosing, and patients on extended interval dosing of B-cell depleting drugs.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641316","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":"Associations of Stroke With Risk of Epilepsy: Results From the Atherosclerosis Risk in Communities (ARIC) Study.","authors":"Jiping Zhou, Asma A Ladak, Connor A Law, Michelle C Johansen, Anny Reyes, Silvia Koton, Sean Kelly, Jeubin Huang, Kamakshi Lakshminarayan, Rebecca F Gottesman, Emily Johnson, Andrea L C Schneider","doi":"10.1002/acn3.70144","DOIUrl":"https://doi.org/10.1002/acn3.70144","url":null,"abstract":"<p><strong>Objective: </strong>To estimate the risk of epilepsy associated with stroke in a community-based cohort, with consideration of stroke type, number, and severity.</p><p><strong>Methods: </strong>Data from 15,100 Atherosclerosis Risk in Communities (ARIC) Study participants without stroke at baseline (1987-1989) were analyzed through 12/31/2022. Adjudicated stroke events were modeled as time-varying exposures. Epilepsy was defined using International Classification of Diseases Ninth/Tenth Revisions codes. Adjusted Fine and Gray proportional hazards models were used to estimate the risk of epilepsy associated with stroke.</p><p><strong>Results: </strong>At baseline, the mean age of participants was 54 years, 55% were female, and 26% were of Black race. Over a median of 27 years, 1553 incident all-cause strokes occurred. The risk of epilepsy was higher among individuals with versus without incident stroke (HR = 1.75, 95% CI = 1.50-2.04). There was evidence for interaction by age (p-interaction = 0.03) whereby the risk of epilepsy associated with stroke was higher among individuals with younger versus older baseline age. Compared to no stroke, the point estimate for the risk of epilepsy associated with subarachnoid hemorrhage (HR = 2.94, 95% CI = 1.67-5.17) was higher than that for the risk of epilepsy associated with ischemic stroke (HR = 1.65, 95% CI = 1.40-1.94) and hemorrhagic stroke (HR = 1.47, 95% CI = 0.95, 2.27). The risk of epilepsy was similar by the number of incident strokes but was greater with increasing ischemic stroke severity.</p><p><strong>Interpretation: </strong>The risk of epilepsy was increased after an incident stroke. This work identifies high-risk subgroups, including younger individuals, individuals with subarachnoid hemorrhage, and individuals with more severe ischemic strokes, who may benefit from closer clinical monitoring for seizures/epilepsy after a stroke.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641314","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":"Discovery and Treatment of Action Potential-Independent Myotonia in Hyperkalemic Periodic Paralysis.","authors":"Chris Dupont, Adam Deardorff, Murad Nawaz, Andrew A Voss, Mark M Rich","doi":"10.1002/acn3.70134","DOIUrl":"https://doi.org/10.1002/acn3.70134","url":null,"abstract":"<p><strong>Objective: </strong>Hyperkalemic periodic paralysis (hyperKPP) is characterized by attacks of transient weakness. A subset of hyperKPP patients suffers from transient involuntary contraction of muscle (myotonia). The goal of this study was to determine mechanisms causing myotonia in hyperKPP.</p><p><strong>Methods: </strong>Intracellular electrophysiology, single-fiber Ca²⁺ imaging, and whole muscle contractility studies were performed in a mouse model of hyperKPP.</p><p><strong>Results: </strong>Myotonia in hyperkPP was caused by both involuntary myogenic action potentials (AP myotonia) lasting less than 5 min and action potential-independent myotonia (non-AP myotonia) lasting over 1 h. Non-AP myotonia was caused by prolonged subthreshold depolarization and elevated intracellular Ca²⁺ in the absence of action potentials. Treatment with dantrolene effectively mitigated non-AP myotonia, suggesting that the source of Ca²⁺ was the sarcoplasmic reticulum. Although non-AP myotonia occurred in the absence of action potentials, Na⁺ channel blockers were effective as therapy.</p><p><strong>Discussion: </strong>We propose myotonia in hyperKPP occurs via two mechanisms: (1) suprathreshold depolarization triggering action potentials that are detectable with EMG and (2) sustained subthreshold depolarization resulting in Na⁺ overload and Ca²⁺ leak from the sarcoplasmic reticulum. Notably, clinical diagnostics such as EMG cannot detect the second mechanism as it occurs in the absence of action potentials. Currently, only a minority of patients with hyperKPP are treated with Na⁺ channel blockers and none are treated with dantrolene. Our data suggest hyperKPP patients, as well as patients with a number of other neuromuscular disorders, may benefit from trials of these therapies, even if they do not have myotonia detectable clinically or by EMG.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625091","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 MSA Atrophy Index (MSA-AI): An Imaging Marker for Diagnosis and Clinical Progression in Multiple System Atrophy","authors":"Paula Trujillo,&nbsp;Kilian Hett,&nbsp;Amy Cooper,&nbsp;Amy E. Brown,&nbsp;Jessica Iregui,&nbsp;Manus J. Donahue,&nbsp;M. Erik Landman,&nbsp;Italo Biaggioni,&nbsp;Margaret Bradbury,&nbsp;Cynthia Wong,&nbsp;David Stamler,&nbsp;Daniel O. Claassen","doi":"10.1002/acn3.70106","DOIUrl":"10.1002/acn3.70106","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Reliable biomarkers are essential for tracking disease progression and advancing treatments for multiple system atrophy (MSA). In this study, we propose the MSA Atrophy Index (MSA-AI), a novel composite volumetric measure to distinguish MSA from related disorders and monitor disease progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Seventeen participants with an initial diagnosis of probable MSA were enrolled in the longitudinal bioMUSE study and underwent 3T MRI, biofluid analysis, and clinical assessments at baseline, 6, and 12 months. Final diagnoses were determined after 12 months using clinical progression, imaging, and fluid biomarkers. Ten participants retained an MSA diagnosis, while five were reclassified as either Parkinson disease (PD, <i>n</i> = 4) or dementia with Lewy bodies (DLB, <i>n</i> = 1). Cross-sectional comparisons included additional MSA cases (<i>n</i> = 26), healthy controls (<i>n</i> = 23), pure autonomic failure (<i>n</i> = 23), PD (<i>n</i> = 56), and DLB (<i>n</i> = 8). Lentiform nucleus, cerebellum, and brainstem volumes were extracted using deep learning-based segmentation. Z-scores were computed using a normative dataset (<i>n</i> = 469) and integrated into the MSA-AI. Group differences were tested with linear regression; longitudinal changes and clinical correlations were assessed using mixed-effects models and Spearman correlations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MSA patients exhibited significantly lower MSA-AI scores compared to all other diagnostic groups (<i>p</i> &lt; 0.001). The MSA-AI effectively distinguished MSA from related synucleinopathies, correlated with baseline clinical severity (<i>ρ</i> = −0.57, <i>p</i> &lt; 0.001), and predicted disease progression (<i>ρ</i> = −0.55, <i>p</i> = 0.03). Longitudinal reductions in MSA-AI were associated with worsening clinical scores over 12 months (<i>ρ</i> = −0.61, <i>p</i> = 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The MSA-AI is a promising imaging biomarker for diagnosis and monitoring disease progression in MSA. These findings require validation in larger, independent cohorts.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"12 9","pages":"1823-1833"},"PeriodicalIF":3.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635790","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":"BCS1L-Associated Disease: 5′-UTR Variant Shifts the Phenotype Towards Axonal Neuropathy","authors":"Rotem Orbach,&nbsp;Nunziata Maio,&nbsp;Russell J. Butterfield,&nbsp;A. Reghan Foley,&nbsp;Sarah Silverstein,&nbsp;Yan Li,&nbsp;Katherine Chao,&nbsp;Tanya J. Lehky,&nbsp;Abigail Potticary,&nbsp;Tracey A. Rouault,&nbsp;Sandra Donkervoort,&nbsp;Carsten G. Bönnemann","doi":"10.1002/acn3.70108","DOIUrl":"10.1002/acn3.70108","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To investigate the consequences of a pathogenic missense variant (c.838C&gt;T; p.L280F) and a 5′-UTR regulatory variant (c.-122G&gt;T) in <i>BCS1L</i> on disease pathogenesis and to understand how regulatory variants influence disease severity and clinical presentation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Deep phenotyping, research-based whole genome sequencing, biochemical characterization of identified variants, and studies in patient-derived fibroblast cultures were applied to uncover the underlying genetic cause and molecular defects in siblings with a genetically uncharacterized complex neurologic condition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Genome sequencing identified a paternally inherited missense variant (c.838C&gt;T; p.L280F) and a maternally inherited 5′-UTR variant (c.-122G&gt;T) in <i>BCS1L</i> in two affected siblings. Although the missense variant disrupts complex III assembly, the 5′-UTR variant allows residual wild-type <i>BCS1L</i> expression, likely mitigating disease severity. Biochemical studies in patient-derived fibroblasts confirmed the pathogenicity of both variants and demonstrated a moderate in vitro response to a coenzyme Q10 analog.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study expands the clinical spectrum of <i>BCS1L</i>-related disorders to include a comparatively milder phenotype with central and peripheral nervous system involvement. Our findings demonstrate that the 5′-UTR variant modulates disease severity by enabling residual wild-type <i>BCS1L</i> expression, partially mitigating the pathogenic effects of the missense variant. These insights underscore the importance of evaluating both protein coding and regulatory variants in mitochondrial disease diagnostics and pathogenesis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"12 9","pages":"1834-1845"},"PeriodicalIF":3.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.70108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635789","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}