medRxiv : the preprint server for health sciences · 2026
The United States CADASIL Consortium: Baseline Findings from a Natural History Study.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Paulsen Jane S, Bockholt H Jeremy, Adams William H, Burks Deven K, Majersik Jennifer J, Salloway Stephen P, Lee Songmi, Fornage Myriam, Joyce Cara, Elliott Jamie L, Huey Edward D, Caruso Megan R, Jayadev Suman, Biller José, Lutsep Helmi L, Doyle Sara J, Liebeskind David S, Eklund Kelsey, Naqvi Imama A, Salardini Arash, Seshadri Sudha, Hinman Jason D, Krishnamurthy Lisa C, Fischer Barbara L, Geschwind Michael D, United States CADASIL Consortiusm
Аннотация
BACKGROUND AND OBJECTIVES: Vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID.
METHODS: Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education.
RESULTS: Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14- 17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34).
DISCUSSION: The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.
METHODS: Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education.
RESULTS: Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14- 17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34).
DISCUSSION: The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.