CADASIL Disease Discovery

Completed

• Conditions: Cardiovascular Disease; Pathogenesis of CADASIL; Germline Mutation in the NOTCH 3 Gene; Arterial Stiffness; Clinical Phenotype of CADASIL

• Registration Number: NCT02821780
• Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Brief Summary

Cerebral autosomal dominant arteriopathy with subcortical infarct (CADASIL) is a lethal disease caused by a gene mutation that affects arteries in the brain. Symptoms include migraines, strokes, memory loss, and dementia. There are no treatments. Researchers want to study people who have CADASIL to learn more about it.

Objectives:

To learn more about CADASIL by studying people who have it.

Eligibility:

People ages 18-100 who were diagnosed with CADASIL in the past 5 years and can make their own decisions

Design:

Participants will be screened in another NIH protocol.

Participants will have 3 visits over 2 years. These may include:

* Physical exam

* Thinking and concentration tests

* Blood tests

* Skin biopsy: A small skin punch is removed from the arm or leg

* Eye exam and eye imaging tests

* Fluorescein angiogram: A catheter is placed in an arm vein. Dye is given through the catheter and travels

to the eyes.

* EndoPAT: A small clamp on the fingertip measures blood volume.

* Cardio-ankle vascular index (CAVI): Artery stiffness is tested with blood pressure cuffs on the arms and

legs. Soft electrodes on the skin measure heart signals.

* Brain MRI or MRA: They lie on a table that slides in and out of a tube that takes pictures. They may get

a contrast agent in their vein. It brightens the brain so researchers can see where blood flows.

* CT scan of the heart: They lie on a table that slides in and out of a machine that takes pictures.

* They get contrast dye injected through a catheter. They may get a medicine that makes their blood

vessels bigger or slows their heart rate.

Detailed Description

Small vessel diseases are conditions characterized by the narrowing of small arteries leading to an imbalance of blood supply upon demand. This results in a progressive chronic hypoperfusion with detrimental outcomes for the affected organ system and for the patient. Recent advances in genetic evaluation have identified several genetic variants causing cerebrovascular small vessel diseases. These diseases have common clinical presentation including recurrent strokes, progressive white matter degeneration, and debilitating dementia. The link between these pathologies is defects in the tunica media of arteries, which is composed mainly of vascular smooth muscle cells (vSMCs).

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy) is caused by mutations in NOTCH3. The disease is of slow onset, with initial clinical manifestations in the third and fourth decade of life, but progressive and fatal. Predominant clinical features include migraine with aura (atypical or isolated), strokes, memory loss, and multiple psychiatric symptoms including dementia. Currently, CADASIL is considered the most common hereditary subcortical vascular dementia, however, treatments are palliative, and there is little prospect of future therapies to directly address causation and block progression. We propose to characterize the etiology and natural history of CADASIL subjects through comprehensive clinical and molecular characterizations. Subjects will be seen at the National Institutes of Health (NIH) once a year for a period of 2 years (total of 3 visits).

Study Timeline

• Study First Submitted: 2016-06-29
• Study First Submitted QC: 2016-07-01
• Study First Posted: 2016-07-04
• Study Start: 2016-10-18
• Primary Completion: 2022-05-03
• Study Completion: 2022-05-03
• Status Verified: 2025-02-10
• Last Update Submitted: 2025-04-10
• Last Update Posted: 2025-04-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To study the pathogenesis of CADASIL through comprehensive clinical evaluations and molecular studies on biospecimens collected under this protocol from affected and unaffected cohorts (as reference biospecimens).	2 years	pathogenesis of CADASIL through comprehensive clinical evaluations and molecular studies on biospecimens

Secondary Outcome Measures

Name	Time	Method
Clinical evaluations will be used to determine whether disease progression can be assessed.	2 years	Therefore, we will perform a comprehensive clinical and molecular assessment to determine possible correlations between clinical phenotypes, histological biopsy read-outs, and molecular findings

Trial Locations

Locations (2)

Nationwide Children s Hospital; 🇺🇸 Columbus, Ohio, United States

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States