Clinical trial NCT05677880: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) Study
Official title: Unraveling the Early Phases of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: CADASIL
Keywords: neurodegeneration
dementia
cognitive impairment
NOTCH3
vascular dementia
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2023-01-10
Enrollment: 575
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 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.

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".

Eligibility criteria: Inclusion Criteria for CADASIL Participants:

1. Must be at least 18 years old
2. 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
3. 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
4. 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.
5. Willing and able to undergo an MRI scan and blood draw at each in-person visit
6. 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).
7. A functional capacity less than 4 on the Modified Rankin Scale

Inclusion Criteria for Healthy Controls (HC):

1. Must meet same criteria as CADASIL participants, EXCEPT have negative NOTCH3 genetic testing

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

Primary outcomes:
measure: Performance Measured by Change in Cognitive Executive Function Composite Z-Score
timeFrame: baseline and 36 months
measure: Change in total brain volume between baseline and 36 months
timeFrame: baseline and 36 months
measure: Change in total cerebral spinal volume between baseline and 36 months
timeFrame: baseline and 36 months
measure: Percent change in brain connectivity from baseline to 36 months
timeFrame: baseline and 36 months
measure: Change in Neurofilament Light (Nfl)
timeFrame: baseline and 36 months
measure: Change in World Health Organization Disability Assessment Schedule (WHODAS) Score
timeFrame: baseline and 36 months
measure: Change in CADASIL Severity Score
timeFrame: baseline and 36 months
Secondary outcomes:
measure: Age of Disease Onset
timeFrame: baseline
measure: NOTCH3 variant characteristics
timeFrame: baseline
measure: Frequency of NOTCH2 CADASIL Genetic Variations associated with VCID
timeFrame: baseline
measure: Polygenic Risk Score (PRS)
timeFrame: baseline
measure: Statistical Analysis of Risk Factors that Modify Clinical Meaningful Outcomes
timeFrame: baseline
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California
state: California
city: San Francisco
country: United States
facility: University of California
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Atlanta
country: United States
facility: Georgia State University Research Foundation
state: Georgia
city: Chicago
country: United States
facility: Loyola University
state: Illinois
city: New York City
country: United States
facility: Columbia University
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Providence
country: United States
facility: Brown University
state: Rhode Island
city: Houston
country: United States
facility: University of Texas Health Science Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Wisconsin, Madison
name: Jane S Paulsen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Michael D Geschwind, MD
role: PRINCIPAL_INVESTIGATOR
References: