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 NOTCH3extracellular 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.