CADASIL

What is CADASIL?

CADASIL is a rare, usually inherited type of small vessel disease of the brain. CADASIL is an acronym, and stands for:

Cerebral 

Autosomal 

Dominant 

Arteriopathy with 

Subcortical 

Infarcts and 

Leukoencephalopathy 

Cerebral refers to the brain. Autosomal Dominant refers to the fact that it is a genetic disorder, with only one copy of the abnormal gene being needed to cause the condition. If one parent carries the changed gene, their child has a 1 in 2 chance of developing CADASIL. Arteriopathy means a disease that affects the arteries. Subcortical refers to the region of the brain below the cortex (the grey matter layer on the surface of the brain). Infarcts are small areas of tissue which have died due to inadequate blood supply. Leukoencephalopathy refers to diseases that affect the white matter of the brain.

CADASIL Symptoms

CADASIL causes a range of symptoms. Individuals with CADASIL usually notice these symptoms between the ages of 30 and 50, and they tend to develop slowly over many years. Symptoms may include:

• Stroke or transient ischemic attacks (TIAs, or ministrokes)
• Complex migraine or migraine with aura (migraine accompanied by sensory disturbances, e.g. visual or speech disturbances, fatigue, tingling)
• Cognitive decline (reduced ability to think clearly, problem solve, pay attention, etc). May eventually progress to dementia, specifically vascular dementia.
• Mood changes (depression, anxiety, irritability, apathy)
• Less common: Seizures or acute encephalopathy (CADASIL coma)

While these are the most common symptoms, not everyone experiences CADASIL in the same way. The types and severity of symptoms may be linked to the individual’s specific type of genetic variation but researchers are still trying to work out exactly what affects CADASIL presentation.

Causes of CADASIL

CADASIL is caused by a change to a gene known as NOTCH3. This gene is responsible for making a protein which helps in the function of vascular smooth muscle cells. When there is a genetic mutation in NOTCH3, this protein accumulates in the blood vessel walls which causes the walls to thicken and narrow. This impairs the movement of blood through the vessel and can lead to ischemic events such as stroke. 

CADASIL is inherited in an autosomal dominant pattern. In other words, if one parent carries the genetic mutation in NOTCH3, the risk of their children inheriting the mutation is 50%. 

It is possible to have CADASIL without this being inherited, i.e. a spontaneous mutation. However, this is rare. If you are concerned about the genetics of CADASIL, you can ask your doctor to refer you to a clinical genetics service. These services can provide you with counselling and explain the risks and implications of genetic testing. If based in Australia, click here for a link to accredited clinical genetics services.

Risk factors & protective factors

CADASIL typically occurs in the absence of traditional cardiovascular risk factors. That being said, the recommendation is to maintain a healthy lifestyle to reduce stroke risk which includes not smoking, avoiding excessive alcohol, monitoring blood pressure, preventing and treating diabetes, maintaining a healthy weight, and staying active. It is also recommended to maintain social connections and engage in mentally stimulating activities to help reduce dementia risk which includes partaking in new skills or activities, learning a language, doing a course, playing an instrument, completing puzzles or joining an interest group. 

CADASIL Diagnosis

Diagnosis of CADASIL is usually multi-faceted. It includes clinical presentation, i.e. assessing whether an individual has the predominant symptoms of CADASIL and/or family history. The doctor will usually request neuroimaging, typically an MRI of the brain which uses a magnetic field to create visualisations of the brain structures. MRI does not use radiation and is typically safe but if you have any implants or concerns, discuss this risk with your doctor. A brain MRI of someone with CADASIL often shows disturbance to the white matter which shows us as bright spots on one kind (T2-weighted) of MR images. This is usually in particular regions known as the anterior temporal lobe and external capsule but can be quite diffuse as the disease progresses. Commonly, individuals with CADASIL will also present with small bleeds in the brain.

Since there are a few conditions which look similar to CADASIL on brain MRI, CADASIL is usually confirmed using a genetic test and/or a skin biopsy. The genetic test involves standard blood collection, and this blood is then analysed for the presence of a NOTCH3 mutation. The skin biopsy involves taking a small skin sample from the upper arm (usually) using a punch. This sample is then observed using electron microscopy which allows for the identification of very small objects. In CADASIL, this technique indicates the presence of abnormal granular deposits indicating misfolded NOTCH3 protein.

Treatment & management of CADASIL

There is no cure or specific treatment for CADASIL. There are a number of research groups working on this, but it will likely be years before an effective treatment is rolled out.

Management usually focuses on symptoms and minimising stroke risk. This includes controlling for high blood pressure, high cholesterol and high glucose. Medications vary and while the recommendations typically coincide with reducing stroke risk, these are typically not tested in CADASIL specifically. Neurologists should be consulted in the management of this risk as the combination of some stroke-reducing strokes has been shown to increase risk of cerebral microbleeds in CADASIL.

Prognosis

In CADASIL, the age of symptom onset, severity and rate of disease progression varies person to person. Typically, if strokes recur, ability to function and cognition tend to worsen over time. Some of the progressive deficits can occur without strokes as well.

The position of the genetic variant within the domains of NOTCH3 is the strongest indicator we have for CADASIL severity. Individuals with genetic variants in the high risk domains showed greater white matter change on brain MRI, and had greater risk of stroke and greater disability. High risk domains included epidermal growth-factor-like repeats (EGFr) 1–6, 8, 11 and 26; the medium risk domains were EGFr 9, 10, 12–15, 17, 25, 27, 32; and the low risk domains were EGFr 16, 18–20, 23, 24, 28–31, 33. The remaining domains were undefined risk.

Frequently Asked Questions about CADASIL

What are the first symptoms of CADASIL?

The earliest symptoms of CADASIL typically appear between the ages of 30 and 50. The most common initial signs include migraine with aura (headaches accompanied by visual or sensory disturbances), strokes or transient ischemic attacks (TIAs or “mini-strokes”), and mood changes such as depression or irritability. As the condition progresses, individuals may experience cognitive difficulties such as problems with attention, memory, and decision-making. However, the onset and combination of symptoms can vary widely between individuals.

Is CADASIL a type of dementia?

CADASIL is not a form of dementia itself, but it can lead to mild cognitive impairment or dementia over time. The most common type associated with CADASIL is vascular dementia, which results from reduced blood flow and repeated small strokes affecting brain function. Cognitive decline can develop gradually, often following stroke episodes or as a result of ongoing small vessel damage in the brain. 

How quickly does CADASIL progress?

The progression of CADASIL varies greatly from person to person. Some individuals may experience only mild symptoms for many years, while others may face more rapid decline, particularly if recurrent strokes occur. Factors such as the specific type and location of the NOTCH3 genetic variant may influence the severity and speed of progression. In general, CADASIL is a slowly progressive condition, but its course can be unpredictable.

What should be avoided with CADASIL?

While CADASIL itself is genetic and not caused by lifestyle factors, certain measures can help minimise stroke risk and potentially slow progression. It is recommended to avoid smoking and excessive alcohol consumption, and manage high blood pressure or diabetes early and adequately. Activities or medications that increase the risk of bleeding or cerebral microbleeds should be discussed carefully with a healthcare provider, especially when managing stroke prevention strategies. Maintaining physical activity, mental stimulation, and social engagement, getting adequate sleep, treating depression if present, and keeping stress low may also be beneficial for brain health

Further reading

• Update on the Epidemiology, Pathogenesis, and Biomarkers of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy, Yamamoto et al. DOI: 10.3988/jcn.2023.19.1.12
• Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction, Hack et al. https://doi.org/10.1093/brain/awac486
• Prevalence of Fatigue and Associations With Depression and Cognitive Impairment in Patients With CADASIL, Jolly et al. DOI: 10.1212/WNL.0000000000213335
• Determining Clinical Disease Progression in Symptomatic Patients With CADASIL, Kaisaridi et al.  DOI: 10.1212/WNL.0000000000210193

Participate in ongoing Australian research

The AusCADASIL study is the only cohort study of CADASIL in Australia. It aims to characterise the major symptoms of CADASIL and use blood samples, MRI scans and ocular imaging to develop markers to monitor disease progression.
For more information contact auscadasil@unsw.edu.au or visit https://www.cheba.unsw.edu.au/research-projects/vascular-contributions-dementia-centre-research-excellence/auscadasil.