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.
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
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
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.
Case-control
Prospective
Study Procedures
Other interventionParticipants will experience * Neurocognitive Tests and Self-Report Measures * Clinical Interviews * Neurological Exam * MRI screening at baseline, 18 months, 36 months * Fasted Blood draw
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.
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.
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.
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.
Age of Disease Onset
Date of disease onset is determined by family and medical history and self-, proxy- and clinician-reported symptoms and signs. Earlier disease onset will suggest worsened burden for the participant.
NOTCH3 variant characteristics
There are various methods used to define the NOTCH3 variations: Specific mutations are documented in available databases and hypothesis testing will include those with and without a cysteine residue and the location of variant as determined by the 34 epidermal growth factor-like repeat domains (EGFrs). Participants will gene mutations in exons 1-6 are expected to demonstrate worsened cognition, MRI abnormality, biofluid NfL marker, functional capacity and symptomatic severity than participants having gene mutation in exons 7-34.
Frequency of NOTCH2 CADASIL Genetic Variations associated with VCID
All mutations in the NOTCH3 CADASIL gene will be characterized and the frequency of each mutation will be tallied. Gene mutations that are present for the most participants will be determined.
Polygenic Risk Score (PRS)
Polygenic risk scores (PRS) for cerebral small vessel disease and dementia will be derived for each participant. We will derive PRSs for phenotypes in the data, such as worsened white matter hyperintensities or disabling headache. The best-fit PRS for each phenotype will be used to address how the PRS may impact the association of NOTCH3 canonical mutations with clinical, neuroimaging, and fluid markers of CADASIL and whether PRSs will add information to a predictive risk model to inform management of CADASIL.
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University of Wisconsin, Madison
Lead sponsor
National Institute on Aging (NIA)
Collaborator
