Annals of Clinical and Translational Neurology最新文献

{"title":"NOTCH2NLC Repeat Expansions in Parkinsonian Disorders: Clinical and Neuroimaging Characteristics.","authors":"Han-Lin Chiang, Kang-Yang Jih, Cheng-Tsung Hsiao, Fu-Pang Chang, Justus Chunyu Chen, Yi-Chu Liao, Yih-Ru Wu, Yi-Chung Lee","doi":"10.1002/acn3.70147","DOIUrl":"https://doi.org/10.1002/acn3.70147","url":null,"abstract":"<p><strong>Objective: </strong>Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by NOTCH2NLC GGC repeat expansions, with heterogeneous clinical manifestations, including parkinsonism. Recent studies have identified NOTCH2NLC repeat expansions in patients with Parkinson's disease (PD) and atypical parkinsonism (aPM), suggesting a potential genetic contribution. However, it remains unclear whether such cases represent NIID-related parkinsonism or typical PD. To address this, we screened NOTCH2NLC repeat expansions in a parkinsonian cohort and analyzed associated clinical and neuroimaging features.</p><p><strong>Methods: </strong>We examined 1017 unrelated patients with PD, 115 with aPM, 11 with multiple system atrophy, six with progressive supranuclear palsy, three with dementia with Lewy bodies, and 321 healthy controls. NOTCH2NLC GGC repeat expansions were detected using repeat-primed PCR and amplicon length analysis. Clinical data and neuroimaging findings were comprehensively reviewed.</p><p><strong>Results: </strong>Pathological NOTCH2NLC repeat expansions were identified in four patients with aPM and none with PD or in controls, with significantly higher frequency in aPM than in PD. An additional affected family member was also identified. All five patients showed clinical or neuroimaging features suggestive of NIID, including white matter hyperintensities in the paravermis and/or corticomedullary junction, curvilinear hyperintensities on diffusion-weighted imaging. Skin biopsies in two patients revealed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and fibroblasts. No patient responded well to levodopa. TRODAT scans revealed normal findings in three patients, symmetric dopaminergic deficits in one, and asymmetric deficits in another.</p><p><strong>Interpretation: </strong>NOTCH2NLC repeat expansions appear to be more frequently associated with aPM with NIID-like features than with typical PD.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705872","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":"Multimodal Autonomic Biomarkers Predict Phenoconversion in Pure Autonomic Failure.","authors":"S Koay, E Vichayanrat, F Bremner, F Valerio, R Mackenzie, G Chiaro, G Ingle, P McNamara, L Watson, J N Panicker, M P Lunn, C Mathias, V Iodice","doi":"10.1002/acn3.70140","DOIUrl":"https://doi.org/10.1002/acn3.70140","url":null,"abstract":"<p><strong>Background: </strong>Pure autonomic failure (PAF) presents with autonomic failure without other neurological features. A third develop central neurological features, fulfilling criteria for multiple system atrophy (MSA) and Lewy body diseases (LBD), including Parkinson's disease and Dementia with Lewy bodies. We hypothesized multimodal autonomic biomarkers would identify differences between PAF, MSA, and LBD, and predict phenoconversion in patients presenting with PAF.</p><p><strong>Methods: </strong>This observational cohort study included 391 alpha-synucleinopathy patients evaluated with cardiovascular autonomic testing, plasma noradrenaline, pupillometry, autonomic symptom, and quality-of-life questionnaires. PAF patients were monitored for the emergence of central neurological features. Logistic regression modeling was used to identify autonomic biomarkers at initial assessment that predicted future phenoconversion.</p><p><strong>Results: </strong>Patients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD. 50/194 (26%) with PAF phenoconverted to MSA or LBD after a median of 13 years, with normal pupils, heart rate response to deep breathing ≥ 10 bpm, and supine plasma noradrenaline ≥ 200 pg/mL predicting future phenoconversion to MSA or LBD, with younger age at presentation and higher supine plasma noradrenaline levels associated with conversion to MSA.</p><p><strong>Conclusion: </strong>In patients presenting with PAF, normal pupillary function and supine plasma noradrenaline levels with intact cardiovagal responses were red flags for future phenoconversion. Younger patients with higher supine plasma noradrenaline levels were more likely to convert to MSA rather than LBD. A non-invasive multimodal autonomic assessment can help differentiate between alpha-synucleinopathies and predict phenoconversion from PAF to MSA or LBD.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688455","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":"Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features.","authors":"Laura Llansó, Igor Stevanovski, Germán Morís, Roger Collet-Vidiella, Alba Segarra-Casas, Lidia González-Quereda, Benjamín Rodríguez-Santiago, Pia Gallano, Rodrigo Alvarez, Ana Vesperinas, Rosa Blanco, Beatriz San-Millán, Carmen Navarro, Isabel Illa, Gianina Ravenscroft, Ira W Deveson, Eduard Gallardo, Montse Olivé","doi":"10.1002/acn3.70146","DOIUrl":"https://doi.org/10.1002/acn3.70146","url":null,"abstract":"<p><strong>Objective: </strong>We aim to describe and characterize two unrelated Spanish families suffering from an autosomal dominant autophagic vacuolar myopathy caused by repeat expansions in PLIN4.</p><p><strong>Methods: </strong>We evaluated the clinical phenotype and muscle imaging, and performed a genetic workup that included exome sequencing, muscle RNAseq, and long-read genome sequencing. Muscle pathology was assessed by means of histochemistry, electron microscopy, PLIN4, p62, LC3, and NBR1 immunofluorescence and/or western blotting. Detailed characterization of autophagic vacuoles was performed.</p><p><strong>Results: </strong>Patients presented around the age of 30 with mild proximal weakness followed by prominent distal weakness in lower legs, eventually spreading to other muscle groups. Muscle biopsies showed unique pathological features characterized by numerous rimmed vacuoles that displayed sarcolemmal features and were located beneath the sarcolemma and within the cytoplasm. Ultrastructural studies showed autophagic vacuoles, replications, and loops of the basal lamina and tubulofilamentous sarcoplasmic inclusions. p62 and NBR1 co-localized with PLIN4 at the sarcolemma and vacuoles. LC3 immunoreactivity and other lysosomal markers were increased at the vacuoles. Targeted long-read sequencing of PLIN4 in affected individuals revealed a single expanded allele of 39 × 99 bp repeats in family 1 and of 37 × 99 bp repeats in family 2.</p><p><strong>Interpretation: </strong>We characterize two new families suffering from an autosomal dominant myopathy carrying repeat expansions in PLIN4. Subsarcolemmal p62 expression is a powerful although nonspecific marker of this disease. No correlation between the size of the expansion and clinical severity can be clearly established. PLIN4 expansions should be considered in the diagnosis of autosomal dominant vacuolar myopathies, especially when sarcolemmal features are present.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688456","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":"Continuous Monitoring of Bladder Dysfunction in People With Multiple Sclerosis: Wearables for the Bladder.","authors":"Valerie J Block, Shane Poole, Leah McIntyre, Nikki Sisodia, Chelyn Park, Gabby Joseph, Michelle E Van Kuiken, Anne M Suskind, Riley Bove","doi":"10.1002/acn3.70112","DOIUrl":"https://doi.org/10.1002/acn3.70112","url":null,"abstract":"<p><strong>Background: </strong>Bladder dysfunction affects over 85% of people with multiple sclerosis (PwMS), yet current assessment methods are limited to periodic in-clinic evaluations or subjective patient reports, failing to capture real-world symptom fluctuations.</p><p><strong>Objectives: </strong>To evaluate the feasibility and validity of using a novel remote bladder ultrasound device for home monitoring of bladder dysfunction in PwMS, comparing remote measurements with standard clinical assessments.</p><p><strong>Methods: </strong>Twenty-two women with MS participated in this 3-month pilot study. Participants were asked to use the wearable ultrasound device at home for at least 3-5 days a month. Remote device measurements were compared with standard clinical data for post-void residual (rPVR vs. cPVR) and urinary frequency (rFrequency vs. 3-day bladder diary frequency). Agreement between measures was assessed using Bland-Altman analyses and correlation coefficients.</p><p><strong>Results: </strong>Participants were middle-aged (mean 51.5 years; SD 9.3) with mild-moderate disability (median EDSS 4.0) and mostly relapsing MS (72.7%). Study retention was high (86.4%; 19/22), with mean device utilization of 14.1 days. Good agreement was seen between rPVR and cPVR (mean difference = 32.1 mL, SD = 38.6; 95% limits of agreement: -43.6, 107.9). The rFrequency measure also demonstrated a strong correlation with patient-reported frequency (ICC = 0.81, Pearson's r = 0.793, p = 0.002). Visualization of remote monitoring data revealed substantial day-to-day variability in bladder symptoms not captured by traditional assessments.</p><p><strong>Conclusion: </strong>This pilot study demonstrates the feasibility and preliminary validity of using wearable ultrasound technology for remote monitoring of bladder dysfunction in PwMS. The ability to capture real-world symptom variations could transform assessment and management approaches, enabling more personalized and responsive care strategies.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688454","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":"Amyotrophic Lateral Sclerosis as a Multistep Process in the United States: A Population-Based Study.","authors":"Jasmine Berry, Jaime Raymond, Theodore Larson, D Kevin Horton, Moon Han, Theresa Nair, Ammar Al-Chalabi, Paul Mehta","doi":"10.1002/acn3.70096","DOIUrl":"https://doi.org/10.1002/acn3.70096","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease that typically results in death within 3-5 years from symptom onset. However, little is known about the environmental exposures, clinical aspects, or social determinants of health factors that may be associated with the disease. Multistep modeling has been previously applied to cancer research, demonstrating a linear relationship between logs of incidence and age. This method may help to understand the mechanisms involved in the development of ALS in the United States (e.g., environmental exposures, genetic mutations). We aim to assess whether ALS is a multistep process among patients enrolled in the largest ALS registry in the world-the United States' National ALS Registry.</p><p><strong>Methods: </strong>Incident ALS cases, defined as confirmed and likely, cases between 2012 and 2019 were obtained from the National ALS Registry. Age-standardized incidence was calculated for all cases and by sex. The log incidence of ALS was regressed against the log of age (years) at case determination, on average, for each year and by sex.</p><p><strong>Findings: </strong>Between 2012 and 2019, there was a mean of 5253 incident ALS cases (confirmed or likely) per year. We identified a linear relationship between the log of the average incidence and log age overall (r² = 0.99), for men (r² = 0.99), and for women (r² = 0.98). The incidence slope estimates were 4.8 (95% CI: 4.4-5.1) overall, 4.7 (95% CI: 4.4-5.1) for men, and 5.0 (95% CI: 4.5-5.5) for women.</p><p><strong>Interpretation: </strong>The linear relationships observed overall, for men, and for women are consistent with a multi-step process. The slope estimates, on average, are approximately 5.0, which suggests that the development of ALS is a six-step process. Further investigation of these steps can elucidate potential risk factors and treatments for ALS.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688453","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":"A Novel C19orf47-AKT2 Chimeric RNA Generated by Cis-Splicing of Adjacent Genes Is Associated With Glioblastoma Prognosis.","authors":"Zihan Wang, Bowen Ni, Kezhi Wu, Qi Zhang, Jinglin Guo, Runwei Yang, Ziyu Wang, Guozhong Yi, Guanglong Huang, Minyi He, Yimin Xu, Yawei Liu","doi":"10.1002/acn3.70125","DOIUrl":"https://doi.org/10.1002/acn3.70125","url":null,"abstract":"<p><strong>Objective: </strong>Malignant gliomas pose significant therapeutic challenges. This study aimed to identify and characterize a novel chimeric RNA in glioma and assess its clinical and functional significance for precision treatment.</p><p><strong>Methods: </strong>The C19orf47-AKT2 chimeric RNAs were identified through RNA sequencing and validated by polymerase chain reaction. Their expression in tumor core and peritumoral tissues was quantified and compared via quantitative polymerase chain reaction, whereas their prognostic significance in glioblastoma was assessed using Kaplan-Meier analysis. The formation mechanism was investigated through genomic analysis, and western blotting was performed to assess fusion protein translation. The CCK-8 assay was performed to assess the chimeras' effect on glioma proliferation.</p><p><strong>Results: </strong>C19orf47-AKT2 chimeric RNAs were detected in 88.9% (144/162) of glioma core tissues, significantly higher than in peritumoral tissues (65.2%, 30/46, p < 0.001). Quantitative analysis showed no significant expression difference between variants in peritumoral tissues, but the C19orf47e9-AKT2e2 variant was significantly more abundant in tumor core tissues. High expression of this variant correlated with poor prognosis in glioblastoma patients. Mechanistically, C19orf47-AKT2 chimeras were generated via cis-splicing of adjacent genes, without DNA rearrangement. Although Western blot confirmed the translation of C19orf47e9-AKT2e3 into a fusion protein in 293 T cells, no endogenous fusion protein was detected in glioblastoma tissues or cells. Functional assays demonstrated that downregulation of C19orf47-AKT2 chimeras significantly suppressed the proliferation of patient-derived glioblastoma cells.</p><p><strong>Interpretation: </strong>This study identifies novel C19orf47-AKT2 chimeras formed through cis-splicing, which might function as noncoding RNAs to promote glioblastoma proliferation. These chimeras may serve as potential prognostic markers and therapeutic targets in gliomas.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688452","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 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, S H Subramony, David E Vaillancourt, Tetsuo Ashizawa, Alexandra Durr, Thomas Mareci, Thomas Klockgether, Jennifer Faber, Henry L Paulson, Gülin Öz, Matthew R Burns","doi":"10.1002/acn3.70116","DOIUrl":"https://doi.org/10.1002/acn3.70116","url":null,"abstract":"<p><strong>Objective: </strong>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><p><strong>Methods: </strong>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 (n = 16), pre-ataxic (n = 10 SCA1, n = 24 SCA3), and ataxic patients (n = 14 SCA1, n = 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><p><strong>Results: </strong>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><p><strong>Interpretation: </strong>These results demonstrate that fixel metrics offer sensitive disease-specific measures of early SCA disease state that correlate with standard clinical measures.</p><p><strong>Trial registration: </strong>Clinical Trial Readiness for SCA1 and SCA3 (READISCA), NCT03487367. https://clinicaltrials.gov/ct2/show/NCT03487367.</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":"144641317","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":"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}