CADASIL

What Causes CADASIL?

CADASIL is caused by an abnormal change (mutation) in a gene responsible for producing the Notch3 receptor protein. This protein is responsible for the proper function and survival of specialized blood vessel cells, and the mutation results in a deficiency of the vital protein. As a result, the cells slowly die, and when this happens in the brain, the symptoms of CADASIL develop.

Is CADASIL Hereditary?

In most cases, CADASIL is passed from parent to child when the parent carries the disease-causing NOTCH3 gene mutation. The disease is inherited in an autosomal dominant pattern, meaning that children may develop the disorder if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

In a small number of cases, the NOTCH3 mutation may occur spontaneously in someone who has no family history of CADASIL.

How Is CADASIL Detected?

Although some strokes associated with CADASIL may be mild, a stroke is a potentially life-threatening event that requires emergency medical attention. Brief episodes of numbness, weakness, or vision loss are urgent warning signs of a stroke. A transient ischemic attack (TIA), a “mini-stroke,” often precedes a more serious cardiovascular event.

The acronym FAST is a reminder to take symptoms seriously. Each letter in the word stands for one of the things to watch for if a stroke is suspected:

Face: Sudden weakness or drooping of the face and/or visual problems

Arm: Sudden weakness or numbness of one or both arms

Speech: Difficulty speaking and/or slurred speech

Time: Time saves the brain. The sooner treatment begins, the better the chances are for recovery. Dial 9-1-1 to call an ambulance right away.

How Is CADASIL Diagnosed?

To pinpoint the cause of a patient’s symptoms, doctors look for a pattern of symptoms, risk factors, and family history. The diagnostic process typically includes physical examinations, tests, a medical and family history review, and information gathered from caregivers or loved ones. Some diagnostic procedures may be used to differentiate CADASIL from other disorders with similar symptoms, including multiple sclerosis and Alzheimer’s disease.

Diagnostic steps may include:

• A physical exam. This exam aims to rule out specific physical conditions that could be causing the symptoms.
• Cognitive tests. These tests aim to measure the patient’s ability to think clearly, and they target cognitive functions such as memory, reasoning, language, attention, and orientation.
• Neurological tests. These tests measure the function of the patient’s nervous system. They evaluate functions such as balance, reflexes, memory, visual perception, and language.
• Brain scans. These tests, such as MRIs, CTs, and PET scans, look for changes in the patient’s brain.
• Genetic testing. These tests will look for the NOTCH3 mutation. Genetic testing is the most reliable way to distinguish CADASIL from similar disorders.

How Is CADASIL Treated?

CADASIL is not curable. To date, no treatments have proven effective at slowing the disorder’s progression or reversing its symptoms. Treatments are usually aimed at preventing future strokes to reduce the progression of brain damage. In addition, patients are encouraged to treat high blood pressure if it’s present and to quit smoking, as this is a significant risk factor for strokes.

Other treatments may focus on moderating CADASIL symptoms such as migraine and improving quality of life as the disease progresses.

Medications that may be recommended to treat symptoms of CADASIL include:

• Over-the-counter pain medications such as acetaminophen or NSAIDs for migraine pain
• Anti-convulsants or anti-depressants to prevent migraines
• Aspirin to decrease the risk of stroke
• Medications to treat high blood pressure or diabetes if necessary

Non-Drug Therapies

Non-drug therapies for treating dementia typically focus on making the sufferer’s environment as safe, comforting, and supportive as possible. For example, occupational therapy can be used to learn how to cope with the symptoms and progression of dementia, and modifications to the environment, such as increasing organization and decreasing distractions, can help the sufferer stay safe and calm.

How Does CADASIL Progress?

The most common types of dementia, including that caused by Alzheimer’s, Lewy body dementia, vascular dementia, and frontotemporal dementia, all get worse over time as the damage to the sufferer’s brain increases. Different types of dementia progress at different rates.

Dementia associated with CADASIL usually progresses slowly, but by age 65, most people with the disease will experience cognitive decline or significant dementia. Eventually, many people with the disease lose the ability to care for themselves or live independently.

How Is CADASIL Prevented?

There is no known way to prevent CADASIL. People with a family history of the disease should consult a genetic counselor to assess their risk if they are planning to have children.

CADASIL Caregiver Tips

Caring for someone with dementia is one of the most challenging responsibilities for any caregiver. Most caregivers are family members or loved ones. They are unprepared and untrained for the extremely difficult job of keeping the sufferer safe and as comfortable as possible as the disease progresses. If you’re responsible for taking care of a person living with dementia, keep these tips in mind:

• Learn as much as possible about the specific type of dementia to understand what you’re facing now and what you’re likely to face in the future as the disorder progresses.
• Be as involved as possible with the sufferer’s medical care so that you can ask questions of doctors and other healthcare professionals.
• Don’t hesitate to ask for help from other family members or friends.
• Take advantage of support services in your community, such as respite care, if they’re available.
• Don’t feel guilty if you feel frustrated or angry with the sufferer.
• Take time for yourself whenever possible, and don’t neglect your own emotional and physical needs.
• Find a support group for caregivers.

CADASIL Brain Science

The brain is the most blood-hungry organ in the body, with a constant need for oxygen and other nutrients delivered through the bloodstream. When starved of blood, the fragile brain is vulnerable to damage ranging from speech difficulties to paralysis. One in four patients dies from their stroke during the first several days or weeks. In the case of CADASIL, however, the strokes are not fatal, and damage to the brain is progressive.

CADASIL Research

Title: Neurologic Stem Cell Treatment Study (NEST)

Stage: Recruiting

Principal investigator: Jeffrey Weiss, MD 

MD Stem Cells

Coral Springs, FL

This is a human clinical study involving the isolation of autologous bone marrow-derived stem cells (BMSC) and transfer to the vascular system and inferior 1/3 of the nasal passages to determine if such treatment will improve neurologic function for patients with certain neurologic conditions.

Various clinical studies have registered with the National Institutes of Health (NIH) to study neurologic diseases and damage. There have also been several journal reports of the benefits of treatment with BMSC for diseases and damage to nervous tissue. The investigators hope to add to the volume of literature regarding the use of BMSC in those neurologic diseases and conditions identified as likely to respond to this treatment.

Intravenous administration of BMSC is a well-established approach to neurologic disease and injury, with much support for its effectiveness in the pre-clinical and clinical literature. BMSC and the associated bone marrow fraction are posited to have several different mechanisms by which they may potentially improve neurologic function. Regarding their ability to penetrate the blood-brain barrier for potential neuronal transdifferentiation and direct impact on the neurons and glial tissue within the brain, it should be remembered that within the diencephalon, there are specific circumventricular organs that lie in the wall of the third ventricle. These are noteworthy for a significantly diminished blood-brain barrier and glial limitans which facilitates their function of coordinating homeostatic mechanisms of the endocrine and nervous systems. Therefore the investigators believe the entry of BMSC may be facilitated in this area of the brain.

The NEST Study provides a treatment Arm 1, which combines intravenous BMSC with topical application of BMSC to the lower 1/3 of the nasal passages to introduce BMSC to the Central Nervous System (CNS). This is applied bilaterally to the inferior nasal conchas and meatuses. The Trigeminal Nerve, or 5th Cranial Nerve, is a paired, large sensory and motor nerve with multiple branches. It provides sensation to the surface and interior structures of the face including the nasal mucosa that lines the nose. The nerves of the Trigeminal Nerve providing sensation to this area converge and enter the brain at the level of the pons. There is documentation in the scientific literature that intranasal delivery of BMSC allows the BMSC to follow the pathways of the trigeminal nerve, facilitating entry into the parenchyma and cerebral spinal fluid (CSF) for effects on the CNS.

Title: Retina is a Marker for Cerebrovascular Heath

Stage: Recruiting

Principal investigator: Michelle Lin, MD, MPH 

Mayo Clinic in Florida

Jacksonville, FL

Cerebral small vessel disease (SVD), present in 80-94% of adults over age 65, increases the risk of stroke by 2-fold and dementia by 2.3-fold. There is currently no treatment to slow SVD progression. This study aims to test whether impaired cerebral and retinal vasoreactivity may serve as a biomarker for SVD progression, and to evaluate the safety and efficacy of cilostazol (an antiplatelet agent with vasodilatory and anti-inflammatory properties) for the treatment of SVD.

This is a prospective, observational nested pilot randomized controlled study to discover retinal biomarkers that would predict cerebral small vessel disease progression and evaluate the safety/efficacy of cilostazols in slowing SVD progression. Twenty CADASIL, 40 sWMD, 20 lobar CMB, and 20 age-matched healthy controls from the Mayo Clinic Florida Familial Cerebrovascular Disease Registry and neurology clinic will be recruited. All participants will undergo OCTA retinal scan, MRI-BOLD brain scan, cognitive battery evaluation, and blood sample at baseline and a 12-month follow-up visit. Key outcome measures are RVR, CVR, cognition, WMH volume, and CMB volume. The 40 patients diagnosed during routine clinical care with sWMD will be randomized in a 1:1 ratio to receive cilostazol 100mg bid (or 50 mg bid if taking medications known to affect the metabolism of cilostazol) or no cilostazol and followed for WMD progression, and secondarily for changes in cognition, RVR, and CVR.

Title: Natural History Study of CADASIL

Stage: Recruiting

Principal investigator: Manfred Boehm, MD 

National Institutes of Health Clinical Center

Bethesda, MD

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

This is a disease discovery/natural history protocol. Researchers 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 the variability of CADASIL’s genotype and clinical phenotype during the study period.

Exploratory Objective: Healthy controls may be used for comparison for some 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 the CADASIL population.