Areas of research

Study of patients with a mutation on the gene responsible for CADASIL

Prospective MRI and clinical study of a French cohort of patients with a mutation in the Notch3 gene responsible for CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy).

Starting date: 2003
Completion date: 2008

Principal Investigator: Prof. Hugues Chabriat – Neurology Unit – Lariboisière Hospital – Paris.

Rationale: CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the name given to an autosomal dominant disease of small cerebral arteries causing small deep infarctions. Using magnetic resonance imaging (MRI), it is possible to see extensive abnormalities in the white matter. Various mutations in the Notch3 gene located on chromosome 19 are responsible for the disease and its diagnosis can now be confirmed by a genetic test. It is a serious disease affecting young adults or middle-aged people, currently known to be present in approximately one hundred families in France. It develops for 10 to 40 years, eventually causing severe motor and cognitive disability. At present, there is no treatment available to stem the inevitable progress of the disease. The clinical phenotype and the development of CADASIL appears to vary from one individual to another with a course over several decades. Because of this, one crucial step is now to determine precise intermediate criteria that are reliable in clinical terms and/or in brain scans, for use in future therapeutic trials on the disease.

Objective: The aim of the research is to prospectively assess a cohort of 200 patients with a known mutation of the Notch3 gene in terms of their cognitive and motor skills and by means of MRI brain scans to determine the intermediate evolutive markers required for a future therapeutic trial. It will also determine the factors that allow for prognosis at different stage of the disease.

Design: Prospective cohort study with direct individual benefit.

Selection, inclusion of patients and carrying out of the study: After obtaining written informed consent, all symptomatic or asymptomatic adult patients willing to be monitored in the investigation centre and carrying a pathogenic mutation of the Notch3 gene will be included in the trial. We shall study the developmental profile of cognitive impairment and the loss of motor ability, the lesional charge in T1, T2 and Flair hypersignals and the temporal variation in the mean overall diffusivity of the water measured in the brain by magnetic resonance imaging. We shall study the influence of the type of mutation, gender, age and vascular risk factors on motor and cognitive impairment and on the changes observed in imaging over the period of observation. In particular, we shall assess the value of the imaging parameters and the serum markers of neuronal or glial impairment obtained on inclusion in the study, as a means of estimating the prognosis with regard to motor and cognitive impairment and MRI lesions.

Number of subjects: It was planned to include 200 patients in March 2007 and more than 200 patients were included in April 2009.

Expected results: The results of the research should enable us to identify those imaging parameters which vary most during the monitoring period and which are associated with a worsening clinical picture. They should also enable us to propose intermediate criteria that can be used in future therapeutic trials.