Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Study
Unraveling the Early Phases of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)
5 other identifiers
observational
660
1 country
12
Brief Summary
This is an observational study to better understand the risk factors and progression of CADASIL, a leading cause of vascular cognitive impairment and dementia (VCID). 575 participants will be enrolled and can expect to be on study for up to 5 years.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for all trials
Started Jun 2022
Longer than P75 for all trials
12 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
June 3, 2022
CompletedFirst Submitted
Initial submission to the registry
December 12, 2022
CompletedFirst Posted
Study publicly available on registry
January 10, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 1, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
August 1, 2027
January 15, 2026
January 1, 2026
5 years
December 12, 2022
January 14, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (7)
Performance Measured by Change in Cognitive Executive Function Composite Z-Score
A composite Cognitive Executive Function Score will be reported based on data from two electronic assessments (Favorites and Match). Favorites tests both episodic and associative memory and consists of 2 learning trials followed by an immediate recall trial, 10 minute delayed recall, and delayed recognition trials. The Match assessment tests the processing speed and executive functions. The primary performance metric is the total correct score in 2 minutes. Scores are reported on a continuous scale with greater values indicating better performance. Demographically adjusted regression based z score for Favorites Total Recall and Match Total Correct are calculated to produce the composite score.
baseline and 36 months
Change in total brain volume between baseline and 36 months
MRI structural integrity is measured using available analytic packages as well as newly validated outcome measures from the investigator's imaging core. MRI outcomes will reflect changes in the total brain volume from two time points. Less volumes will reflect greater brain loss and greater change over time will suggest a more rapid rate of progression.
baseline and 36 months
Change in total cerebral spinal volume between baseline and 36 months
MRI structural integrity is measured using available analytic packages as well as newly validated outcome measures from the investigator's imaging core. MRI outcomes will reflect changes in the total cerebral spinal fluid volume from two time points. Less volumes will reflect greater brain loss and greater change over time will suggest a more rapid rate of progression.
baseline and 36 months
Percent change in brain connectivity from baseline to 36 months
MRI functional integrity is measured using available analytic packages as well as newly validated outcome measures from the investigator's imaging core. MRI outcomes will reflect the strength of connectivity among different areas of the brain. Levels of connectivity will be associated with cognitive performances. Greater connectivity is associated with better cognition.
baseline and 36 months
Change in Neurofilament Light (Nfl)
Blood will be analyzed using validated assays to measure the amount of NfL. Greater levels of NfL reflect worsened brain atrophy and change over time will demonstrate worsening over time.
baseline and 36 months
Change in World Health Organization Disability Assessment Schedule (WHODAS) Score
Functional capacity is assessed using the WHODAS instrument. The measure consists of 12 items and allows responses on a 5-point scale for each item, the total possible range of scores is converted to 0-100 where 0 is no disability and 100 is full disability. The change in total WHODAS score from baseline to 36 months will show the rate of progression in loss of capacity.
baseline and 36 months
Change in CADASIL Severity Score
CADASIL severity is determined using established disease-specific scales involving the frequency, severity, and duration of clinical signs and symptoms of CADASIL. The CADASIL scale is a 12-item scale of CADASIL symptoms and signs. Each item is given a weighted score according to a large sample of patients in Europe. A summary of all items is the total CADASIL score which can range from 0-25. Higher scores represent greater CADASIL severity. Change in total score from baseline to 36 months is used to measure the rate of symptomatic worsening or improvements over time.
baseline and 36 months
Secondary Outcomes (5)
Age of Disease Onset
baseline
NOTCH3 variant characteristics
baseline
Frequency of NOTCH2 CADASIL Genetic Variations associated with VCID
baseline
Polygenic Risk Score (PRS)
baseline
Statistical Analysis of Risk Factors that Modify Clinical Meaningful Outcomes
baseline
Study Arms (4)
Non-Carrier Cohort
About 100 participants who are at-risk, healthy family members with No NOTCH3 Mutation and no symptoms or signs of cognitive decline.
Pre-Symptomatic NOTCH3 Cohort
About 133 participants who are pre-symptomatic, at-risk, and healthy (with verified NOTCH3 mutation) family members with no symptoms.
Symptomatic NOTCH3 Cohort - No Functional Decline
About 134 participants who are symptomatic (with verified NOTCH3 mutation) family members and no functional decline (e.g., mild cognitive impairment (MCI) with premorbid functional levels maintained).
Symptomatic NOTCH3 Cohort - Functional Decline
About 133 participants who are symptomatic family members with a verified NOTCH3 CADASIL mutation and evidence of functional decline consistent with early dementia.
Interventions
Participants will experience * Neurocognitive Tests and Self-Report Measures * Clinical Interviews * Neurological Exam * MRI screening at baseline, 18 months, 36 months * Fasted Blood draw
Eligibility Criteria
The study will enroll a total of 500 participants with a CADASIL family history who have had a genetic test for a NOTCH3 variant. All ethnicities, sexes and ages throughout the adult lifespan will be recruited. CADASIL research participants will be recruited across the earlier part of the disease spectrum from pre-symptomatic (no symptoms or signs) through the prodromal phase (having symptoms and signs without significant functional decline) to varying levels of early dementia or mild to moderate functional impairment.
You may qualify if:
- Must be at least 18 years old
- Positive NOTCH3 genetic testing; OR a positive skin biopsy; OR a willingness to have a NOTCH3 genetic test completed prior to enrolling AND are at-risk for, or diagnosed clinically with, CADASIL
- Willing to commit to three in-person visits (a baseline visit, an 18-month follow-up, and a 36-month follow-up) and to remote visits as needed by phone, email, mail or internet
- Willing to provide documentation of all current medications to study team
- a. All medications will be allowed throughout the course of study. Documentation of medications will be used for analyses to assess potential impact of medications on study outcomes.
- Willing and able to undergo an MRI scan and blood draw at each in-person visit
- Must have a designated "study companion"
- a. A "study companion" is someone who knows the participant well (has greater than or equal to 3 hours/month of contact with the CADASIL participant) and can provide additional information to the study team (either remotely or in-person).
- A functional capacity less than 4 on the Modified Rankin Scale
- \. Must meet same criteria as CADASIL participants, EXCEPT have negative NOTCH3 genetic testing
You may not qualify if:
- History of severe learning disability, intellectual disability, or other neurological disease or event not attributable to CADASIL
- History of serious alcohol or drug abuse within the past year
- Unwilling to undergo NOTCH3 genetic testing if there is no test on file
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (12)
University of California
Los Angeles, California, 90095, United States
University of California
San Francisco, California, 94143, United States
University of Colorado
Denver, Colorado, 80204, United States
Georgia State University Research Foundation
Atlanta, Georgia, 30303, United States
Loyola University
Chicago, Illinois, 60660, United States
Columbia University
New York, New York, 10027, United States
Oregon Health & Science University
Portland, Oregon, 97239, United States
Brown University
Providence, Rhode Island, 02912, United States
University of Texas Health Science Center
Houston, Texas, 77030, United States
University of Texas
San Antonio, Texas, 78249, United States
University of Utah
Salt Lake City, Utah, 84112, United States
University of Washington
Seattle, Washington, 98195, United States
Related Links
Biospecimen
60 milliliter blood draw
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Jane S Paulsen, PhD
University of Wisconsin, Madison
- PRINCIPAL INVESTIGATOR
Michael D Geschwind, MD
University of California, San Francisco
Central Study Contacts
Study Design
- Study Type
- observational
- Observational Model
- CASE CONTROL
- Time Perspective
- PROSPECTIVE
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
December 12, 2022
First Posted
January 10, 2023
Study Start
June 3, 2022
Primary Completion (Estimated)
June 1, 2027
Study Completion (Estimated)
August 1, 2027
Last Updated
January 15, 2026
Record last verified: 2026-01
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF, CSR
- Time Frame
- De-identified data will be shared with the research community one year following the end of the research study.
- Access Criteria
- Data sharing will be granted to persons with appropriate scientific and professional expertise to advance knowledge of CADASIL.
All clinical research data collected as part of this study will be stored in a designated NIH database such as the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) NIA Genetic and for sharing with approved researchers worldwide. Summaries of studies and the contents of measured variables as well as original study document text are generally available to the public, while access to individual-level data including phenotypic data tables and genotypes require varying levels of authorization. Data to be de-identified such that the identities of data subjects cannot be readily ascertained or otherwise associated with the data by the repository staff or secondary data users.