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Natural History Study of CADASIL

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT05072483
Recruitment Status : Recruiting
First Posted : October 11, 2021
Last Update Posted : March 16, 2023
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:


CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy) is a genetic disorder. It causes narrowing of the small blood vessels and can lead to strokes and dementia. Researchers want to monitor people with CADASIL over time.


To learn more about how CADASIL affects a person s blood vessels over time.


Adults ages 18 and older who have CADASIL, and healthy volunteers.


Participants will be screened with a medical record review.

Participants will have 4 study visits over 9 years. Visits will last 6 8 hours per day, for 2 4 days.

Participants will give blood and urine samples. They will have an electrocardiogram to record their heart s electrical activity. They will fill out a family tree. They will have tests that measure mental abilities like memory and attention. They may have a skin biopsy. They may have a lumbar puncture.

Participants will have an eye exam. Their pupils will be dilated. They will receive a dye via intravenous (IV) line. Pictures will be taken of their eyes.

Participants will have an imaging scan of their brain. They may receive a contrast agent via IV.

Participants blood flow and blood vessel flexibility will be measured. In one test, a probe will be pressed against the skin of the their wrist, neck, and groin. In another test, they will hold one arm still while a microscope makes videos of the blood flow through a fingernail. In another test, they will perform light exercise or other activities while wearing an elastic band around their head or probes placed on their arm or leg.

Healthy volunteers will complete some of the above tests.

Condition or disease
Cardiovascular Disease Arterial Stiffness Germline Mutation in the NOTCH 3 Gene Pathogenesis of CADASIL Clinical Phenotype of CADASIL

Detailed Description:

Study Description:

This is a disease discovery/natural history protocol. We will enroll 100 CADASIL subjects to perform in-depth prospective and retrospective evaluations for research purposes. Some evaluations will be compared to healthy controls.


Primary Objective: This study will examine the pathogenesis and progression of CADASIL through comprehensive evaluations, and molecular studies on biospecimens collected from affected individuals.

Secondary Objective: Comprehensive evaluations will be used to investigate variability of the genotype and clinical phenotype of CADASIL during the study period.

Exploratory Objective: Healthy controls may be used for comparison for some of the research testing where data on normal values is lacking. Healthy controls will not be used to establish normal range values but for qualitative comparison with CADASIL population.

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Study Type : Observational
Estimated Enrollment : 140 participants
Observational Model: Case-Control
Time Perspective: Other
Official Title: Natural History Study of CADASIL
Actual Study Start Date : April 18, 2022
Estimated Primary Completion Date : June 1, 2034
Estimated Study Completion Date : June 1, 2041

Healthy controls
Healthy controls for exploratory analyses, where the measurements were not commonly performed previously in other populations, for qualitative comparison with CADASIL population
Subjects with CADASIL
Adult genetically-confirmed patients with a wider range of CADASIL disease duration and debility

Primary Outcome Measures :
  1. This study will examine the pathogenesis of CADASIL through comprehensive clinical evaluations and molecular studies on biospecimens collected under this protocol from affected individuals. [ Time Frame: 13 years ]
    To study the pathogenesis of CADASIL and obtain clinical evaluations and biospecimens from affected cohorts to identify underlying disease mechanism(s).

Secondary Outcome Measures :
  1. Clinical evaluations will be used to investigate variability of clinical phenotype during the study period. [ Time Frame: 20 years ]
    To use Clinical evaluations to investigate variability of clinical phenotype during the study period. These studies will serve as baseline evaluations for future studies on the identification of underlying disease mechanism(s) and potential therapeutic approaches.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
We will follow 100 subjects with CADASIL (80 new CADASIL subjects and up to 20 CADASIL subjects previously enrolled in our pilot study, if they would like to participate in this study as well) and up to 40 healthy controls male and female, ages 18-100. Should anyone from the original patient cohort decide not to participate in this new study, additional patients will be recruited in order to meet our goal of having 100 CADASIL subjects enrolled in the study.

Eligibility for this study may be determined based on information collected under other NHLBIapproved protocols, outside records and patient report. In order to be eligible to participate in this study, an individual must meet criteria 1 & 2 and either criteria 3 or 4:

  1. Stated willingness to comply with all study procedures and availability for the duration of the study.
  2. Male or female, aged 18 to 100 years (inclusive).
  3. Established diagnosis of CADASIL or NOTCH3 mutations, as determined by genetic testing.
  4. Healthy controls.


An individual who meets any of the following criteria will be excluded from participation in this study:

  1. Pregnancy or nursing at time of consent.
  2. Subjects who lack capacity to consent and don't have a legally authorized representative.
  3. Subjects who decline to provide samples for blood and/or tissue studies.
  4. Subjects who do not speak English.
  5. Subjects whose scans or examinations show unexpected brain conditions (outside of CADASIL) which would interfere with interpretation of testing.
  6. Subjects unable to undergo an MRI scan or subjects meeting the following criteria:

    • Subjects who have internal non-MRI compatible metals (i.e., cardiac pacemaker, brain stimulator, shrapnel, surgical metal, clips in the brain or on blood vessels, cochlear implants, artificial heart valves or metal fragments in the eye) as these rendering an MRI unsafe
    • Subjects with ferromagnetic dental bridges or crowns (exclusion only for 7.0T)
    • Subjects unable to remain supine for the expected length of the MRI (i.e., up to 1 hour)
    • Subjects with uncontrolled head movements
    • Subjects who are claustrophobic for the expected length of the MRI (i.e., up to 1 hour) and claustrophobia cannot be controlled with anti-anxiety medication.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05072483

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Contact: Katherine Carney (301) 402-9841 katherine.carney@nih.gov
Contact: Manfred Boehm, M.D. (301) 435-7211 mb454z@nih.gov

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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Manfred Boehm, M.D. National Heart, Lung, and Blood Institute (NHLBI)
Additional Information:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT05072483    
Other Study ID Numbers: 10000413
First Posted: October 11, 2021    Key Record Dates
Last Update Posted: March 16, 2023
Last Verified: March 10, 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Biospecimen Procurement
Laboratory Research Specimens
progressive chronic hypoperfusion
progressive white matter degeneration, and debilitating dementia.
Additional relevant MeSH terms:
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Dementia, Multi-Infarct
Cardiovascular Diseases
Cerebral Infarction
Brain Infarction
Brain Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebral Small Vessel Diseases
Dementia, Vascular
Cerebral Arterial Diseases
Intracranial Arterial Diseases
Vascular Diseases
Genetic Diseases, Inborn
Pathologic Processes
Neurocognitive Disorders
Mental Disorders