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

Sponsor

University of Wisconsin, Madison (Other)

Overall Status

Recruiting

CT.gov ID

NCT05677880

Collaborator

National Institute on Aging (NIA) (NIH)

500

Enrollment

Locations

Anticipated Duration (Months)

41.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an observational study to understand better the risk factors and progression of a leading cause of vascular cognitive impairment and dementia (VCID). 500 participants will be enrolled and can expect to be on study for up to 5 years.

Condition or Disease	Intervention/Treatment	Phase
CADASIL	Other: Study Procedures

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 500 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 and will be referred to as "remote visits".

Study Design

Study Type:

Observational

Anticipated Enrollment :

500 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Unraveling the Early Phases of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Actual Study Start Date :

Jun 3, 2022

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

Jan 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
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.	Other: Study Procedures Participants will experience Neurocognitive Tests and Self-Report Measures Clinical Interviews Neurological Exam MRI screening at baseline, 18 months, 36 months Fasted Blood draw
Pre-Symptomatic NOTCH3 Cohort About 133 participants who are pre-symptomatic, at-risk, and healthy (with verified NOTCH3 mutation) family members with no symptoms.	Other: Study Procedures Participants will experience Neurocognitive Tests and Self-Report Measures Clinical Interviews Neurological Exam MRI screening at baseline, 18 months, 36 months Fasted Blood draw
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).	Other: Study Procedures Participants will experience Neurocognitive Tests and Self-Report Measures Clinical Interviews Neurological Exam MRI screening at baseline, 18 months, 36 months Fasted Blood draw
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.	Other: Study Procedures Participants will experience Neurocognitive Tests and Self-Report Measures Clinical Interviews Neurological Exam MRI screening at baseline, 18 months, 36 months Fasted Blood draw

Outcome Measures

Primary Outcome Measures

Performance Measured by Change in Cognitive Executive Function Composite Z-Score [baseline 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 brain volume between baseline and 36 months [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 [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 [baseline 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.
Change in World Health Organization Disability Assessment Schedule (WHODAS) Score [baseline 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 Score [baseline 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.

Secondary Outcome Measures

Age of Disease Onset [baseline]
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 [baseline]
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 [baseline]
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.
Statistical Analysis of Risk Factors that Modify Clinical Meaningful Outcomes [baseline]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria for CADASIL Participants:

Age at least 18 years old
Positive NOTCH 3 genetic testing
Willing to commit to three in-person visits (baseline and 18-month follow-up and 36-month follow-up) as well as remote visits by phone, email, mail or internet.
No unstable comorbidities (i.e., receiving stable treatment) that could affect neurological/psychiatric function
All medications will be allowed although the protocol will mandate documentation of medications and our analyses will particularly assess potential impact of medications on outcomes (i.e., sedation of abnormal movements).
Able to undergo an MRI scan and blood draw at each visit
A companion who knows the participant well (>= 3 hours/month of contact) and can provide additional information (either remotely or in-person).

Inclusion Criteria for Healthy Controls (HC)

Will meet same criteria as CADASIL participants except
Negative NOTCH3 genetic testing

Exclusion Criteria:

Evidence of unstable (not stable or treated for at least 3 months) medical or psychiatric illness (including substance abuse)
History of severe learning disability, mental retardation, or other central nervous system (CNS) disease or event not attributable to CADASIL (e.g., seizures, additional neurological diagnoses)
History of serious alcohol or drug abuse within the past year

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California	Los Angeles	California	United States	90095
2	University of California	San Francisco	California	United States	94143
3	University of Colorado	Denver	Colorado	United States	80204
4	Georgia State University Research Foundation	Atlanta	Georgia	United States	30303
5	Emory University	Atlanta	Georgia	United States	30322
6	Loyola University	Chicago	Illinois	United States	60660
7	Columbia University	New York	New York	United States	10027
8	Oregon Health & Science University	Portland	Oregon	United States	97239
9	Brown University	Providence	Rhode Island	United States	02912
10	University of Texas Health Science Center	Houston	Texas	United States	77030
11	University of Utah	Salt Lake City	Utah	United States	84112
12	University of Washington	Seattle	Washington	United States	98195