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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) Study

Recruiting
Conditions
CADASIL
Interventions
Other: Study Procedures
Registration Number
NCT05677880
Lead Sponsor
University of Wisconsin, Madison
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.

Detailed Description

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic vascular dementia. Individuals with CADASIL are destined to develop vascular cognitive impairment and dementia (VCID), which can be studied in pre-symptomatic and prodromal disease stages to detect the earliest changes in biological fluids, neuroimaging, and the emerging phenotype of symptomatic VCID.

The objective of the proposed research is to exploit an autosomal dominant vascular dementia as a model to investigate specific features of VCID and to examine interactions with risk factors impacting the aging life course.

The study will enroll a total of 575 participants with a CADASIL family history who have had a genetic test for a NOTCH3 variant. Participants will complete: a clinical interview, a neurological exam, neurocognitive and behavior assessments, MRI, and a blood draw at each study visit. Participants will complete 3 in-person visits in total as part of this study: baseline, visit 2 (18 months after baseline), visit 3 (36 months after baseline). Additional contact will occur by phone, mail, email or the internet as needed and will be referred to as "remote visits".

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
575
Inclusion Criteria

Not provided

Exclusion Criteria
  1. History of severe learning disability, intellectual disability, or other neurological disease or event not attributable to CADASIL
  2. History of serious alcohol or drug abuse within the past year
  3. Unwilling to undergo NOTCH3 genetic testing if there is no test on file

Study & Design

Study Type
OBSERVATIONAL
Study Design
Not specified
Arm && Interventions
GroupInterventionDescription
Pre-Symptomatic NOTCH3 CohortStudy ProceduresAbout 133 participants who are pre-symptomatic, at-risk, and healthy (with verified NOTCH3 mutation) family members with no symptoms.
Non-Carrier CohortStudy ProceduresAbout 100 participants who are at-risk, healthy family members with No NOTCH3 Mutation and no symptoms or signs of cognitive decline.
Symptomatic NOTCH3 Cohort - No Functional DeclineStudy ProceduresAbout 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 DeclineStudy ProceduresAbout 133 participants who are symptomatic family members with a verified NOTCH3 CADASIL mutation and evidence of functional decline consistent with early dementia.
Primary Outcome Measures
NameTimeMethod
Change in World Health Organization Disability Assessment Schedule (WHODAS) Scorebaseline and 36 months

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.

Change in CADASIL Severity Scorebaseline and 36 months

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.

Change in total brain volume between baseline and 36 monthsbaseline 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.

Performance Measured by Change in Cognitive Executive Function Composite Z-Scorebaseline and 36 months

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 cerebral spinal volume between baseline and 36 monthsbaseline 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 monthsbaseline and 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.

Change in Neurofilament Light (Nfl)baseline and 36 months

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.

Secondary Outcome Measures
NameTimeMethod
Statistical Analysis of Risk Factors that Modify Clinical Meaningful Outcomesbaseline

Lifestyle risk factors for VCID (e.g., inactivity, obesity, heavy alcohol use, smoking, SES) and comorbid health conditions (e.g., hypertension, hyperlipidemia, hypercholesterolemia, atrial fibrillation, diabetes) may contribute to disease outcomes.

Age of Disease Onsetbaseline

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 characteristicsbaseline

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 VCIDbaseline

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)baseline

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.

Trial Locations

Locations (11)

University of California

🇺🇸

San Francisco, California, United States

University of Colorado

🇺🇸

Denver, Colorado, United States

Georgia State University Research Foundation

🇺🇸

Atlanta, Georgia, United States

Loyola University

🇺🇸

Chicago, Illinois, United States

Columbia University

🇺🇸

New York City, New York, United States

Oregon Health & Science University

🇺🇸

Portland, Oregon, United States

Brown University

🇺🇸

Providence, Rhode Island, United States

University of Texas Health Science Center

🇺🇸

Houston, Texas, United States

University of Texas

🇺🇸

San Antonio, Texas, United States

University of Utah

🇺🇸

Salt Lake City, Utah, United States

University of Washington

🇺🇸

Seattle, Washington, United States

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