Year: 2026
Type: preprint
Study design: Observational Study
Abstract: 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.
Source: medRxiv
Authors: Jane S. Paulsen, H. Jeremy Bockholt, William H. Adams, Deven K. Burks, Jennifer J. Majersik, Stephen P. Salloway, Songmi Lee, Myriam Fornage, Cara Joyce, Jamie L. Elliott, Edward D. Huey, Megan R. Caruso, Suman Jayadev, José Biller, Helmi L. Lutsep, Sara J. Doyle, David S. Liebeskind, Kelsey Eklund, Imama A. Naqvi, Arash Salardini, Sudha Seshadri, Jason D. Hinman, Lisa C. Krishnamurthy, Barbara L. Fischer, Michael D. Geschwind, the United States CADASIL Consortiusm
Institutions: University of Wisconsin–Madison, Georgia Institute of Technology, Emory University, Georgia State University, Center for Translational Research in Neuroimaging and Data Science, Loyola University Chicago, The University of Texas Health Science Center at Houston, University of Washington, Oregon Health & Science University, The University of Texas at San Antonio Health Science Center, University of Southern California, University of Colorado Anschutz, University of San Francisco, University of California, Los Angeles, University of California, San Francisco
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G3294506581, Unraveling the earliest phases of vascular cognitive impairment and dementia using CADASIL--a monogenic form of small vessel cerebrovascular disease, Cerebrovascular reactivity as a VCID biomarker in CADASIL, Non-Invasive MRI Markers to Elicit the Role of Vascular Disease in CADASIL Compared to Normal Aging
OpenAlex ID: W7214010052
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