Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common heritable cause of vascular cognitive impairment and dementia (VCID). By working closely with CADASIL gene mutation carriers (individuals diagnosed with CADASIL), our research team will be able to study the earliest clinical, biofluid, and neuroimaging changes that lead to symptomatic VCID before these symptoms emerge in individuals. If the team works with a large enough group of CADASIL gene mutation carriers, we will learn important lessons about CADASIL that can be applied to other types of VCID, including sporadic or intermittent forms and mixed dementia syndromes with a vascular component. For this reason, we will establish the first longitudinal study in the United States where 400 CADASIL gene mutation carriers and 100 non-carrier controls (NC) will be observed several times over the course of five years at one of twelve study sites with established CADASIL clinics.
With the data from this longitudinal study, our research team will achieve two main objectives. First, the team will be able to characterize the initial presentation and course of clinical, neuroimaging, and fluid markers of participants diagnosed with CADASIL and to compare these diagnostic indications of disease with those from NC. This means that we will identify when markers in participants diagnosed with CADASIL diverge from those in NC and which measures indicate a worsening condition. On the basis of these measures, the team will refine how the stages of disease severity are assessed.
Second, the research team will be able to clarify genetic, health, and lifestyle factors which impact clinically meaningful outcomes in CADASIL by incorporating genetic tools, medical history, and lifestyle questionnaires in the study. This means that we will better understand how variant NOTCH3 mutations, risk-increasing behaviors, coexisting medical conditions, and Alzheimer’s disease markers influence the disease onset of CADASIL. Alongside these main objectives, the research team will apply disease modeling analytics (or the computational study of data or statistics) to the information collected and examine outcomes with experts from different fields to develop a model for CADASIL which is also more broadly applicable to VCID.