CADASIL Disease Discovery
Condition: Germline Mutation in the NOTCH 3 Gene; Cardiovascular Disease; Arterial Stiffness; Pathogenesis of CADASIL; Clinical Phenotype of CADASIL
MeSH terms: CADASIL; Dementia, Multi-Infarct; Cardiovascular Diseases
Study type: Observational

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).
    

Observational model: Cohort
Time perspective: Prospective
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
      
Keywords: Stroke; progressive white matter degeneration, and debilitating dementia.; progressive chronic hypoperfusion; Biospecimen Procurement; Laboratory Research Specimens; Natural History