Research Advances In CADASIL
A new animal model for CADASIL
Although we know the genetic abnormality (mutation) which causes CADASIL, we are a long way from understanding how this abnormality results in the disease. If we could understand this link better, it might be possible to develop treatments which can delay onset of the disease. An important advance in this area has been made by a group of researchers in Paris led by Anne Joutel who have developed a new animal model of CADASIL. This involves introducing a typical CADASIL mutation into a mouse. The mouse developed a disease which is in many ways similar to human CADASIL including similar brain changes (deposition of NOTCH3 extracellular domain aggregates and granular osmiophilic material; GOM). The researchers were able to show that abnormalities in the regulation of blood flow within the brain appeared to be an early feature of the disease. This suggests that in some way CADASIL genetic mutations result in an inability of the blood vessels to regulate blood flow normally which could then lead to brain damage secondary to a shortage of blood (and oxygen) supply. Hopefully, this model will tell us many new things about the disease and may also allow us to investigate new treatments for the disease.
Reference: Joutel A, Monet-Leprêtre M, Gosele C, Baron-Menguy C, Hammes A, Schmidt S, Lemaire-Carrette B, Domenga V, Schedl A, Lacombe P, Hubner N. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest. 2010;120: 433-45. Click here for pdf
Common cardiovascular risk factors make CADASIL worse
This study describes 200 consecutive individuals with CADASIL who were seen at a specialised CADASIL service in London, UK. It provides a good description about which features are most common in the disease. The average age of assessment was 48 years and the average age at which symptoms first occurred was 34 years, although there was a wide age range. Migraine was the most common symptom affecting 75% of individuals. More than half of individuals had suffered a stroke and the average age of onset for this was 46 years. Importantly, this study demonstrated that common risk factors for stroke seemed to make CADASIL worse. For example, both high blood pressure and smoking were associated with an increased risk of stroke. This emphasizes how important it is to treat common cardiovascular risk factors in patients with CADASIL.
Reference: Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype; study in 200 consecutively recruited individuals. Stroke. 2010;41: 630-4. Click here for pdf
Do drugs which help Alzheimer’s Disease also help CADASIL?
The cholinesterase inhibitor drugs have been shown to improve memory in Alzheimer’s disease. They increase the level of a chemical in the brain called acetylcholine which is reduced in Alzheimer’s disease. It has been suggested that this chemical is also reduced in patients with cognitive impairment due to vascular disease, which CADASIL can cause. This study tested whether one of these drugs, called Donepezil, could improve memory and other thinking skills (cognition) in patients with CADASIL. The overall study was negative although there did appear to be a small effect on certain cognitive functions (which we refer to as executive function). However, this was small and did not seem to have a significant effect on an individual’s lifestyle.
This study is also important as it has shown that it is possible to carry out drug trials in CADASIL. Even though it is a rare disease, by collaborating across many countries and continents, it was possible to include a sufficient number of patients to answer this research question. Hopefully, we will be able to carry out further trials in the future when potentially useful drugs are discovered.
Reference: Dichgans M, Markus HS, Salloway S, Verkkoniemi A, Moline M, Wang Q, Posner H, Chabriat HS. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol. 2008 Apr; 7(4): 310-8. Click here for PubMed abstract