CADASIL Disease Discovery

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.

Study Overview

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

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 Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Male or female, age 18 to 100 years (inclusive). Established diagnosis of CADASIL, as determined by genetic testing, in early stages of disease (0-5 years after diagnosis) with mild or no cognitive impairment

Description

• INCLUSION CRITERIA:
• Male or female, age 18 to 100 years (inclusive).
• Established diagnosis of CADASIL, as determined by genetic testing, in early stages of disease (0-5 years after diagnosis) with mild or no cognitive impairment.
• Willing and able to comply with study requirements.

EXCLUSION CRITERIA:

• Subjects unable to give informed consent without requirement for a legally authorized representative
• Subjects who decline to provide samples for blood and/or tissue studies, or who do not consent to have samples stored for future research
• Pregnant women are excluded due to study procedures (pregnancy test will be done in females of childbearing age under other NHLBI-approved protocols the subject is consented to, up to 48 hours prior to consenting to this protocol).

• Subjects unable to undergo an MRI scan

  • 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.
• Subjects whose scans or examinations show unexpected brain conditions.
• Subjects who do not speak English

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	pathogenesis of CADASIL through comprehensive clinical evaluations and molecular studies on biospecimens	2 years

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Manfred Boehm, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2016
• Primary Completion (Actual): May 3, 2022
• Study Completion (Actual): May 3, 2022

Study Registration Dates

• First Submitted: June 29, 2016
• First Submitted That Met QC Criteria: July 1, 2016
• First Posted (Estimated): July 4, 2016

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: November 17, 2023

More Information

Terms related to this study

• Keywords: Stroke; Natural History; Biospecimen Procurement; Laboratory Research Specimens; progressive white matter degeneration, and debilitating dementia.; progressive chronic hypoperfusion
• Additional Relevant MeSH Terms: Mental Disorders; Ischemia; Pathologic Processes; Necrosis; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Brain Ischemia; Dementia; Infarction; Stroke; Brain Infarction; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Cerebral Small Vessel Diseases; Cerebral Infarction; Dementia, Vascular; Cardiovascular Diseases; CADASIL; Dementia, Multi-Infarct
• Other Study ID Numbers: 160132; 16-H-0132

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No