Unraveling the earliest phases of vascular cognitive impairment and dementia using CADASIL--a monogenic form of small vessel cerebrovascular disease

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Project Summary/Abstract The project addresses vascular contributions to cognitive impairment and dementia (VCID) using a design that exploits the enrollment of persons with the autosomal dominant gene for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Exploration of VCID by focusing on the rare heritable monogenic disorder, CADASIL, will advance knowledge of the full spectrum of vascular dementia from presymptomatic gene carriers through dementia and will facilitate an examination of mixed dementia in CADASIL participants also having AD. This research is novel from any other in its efforts to study a single-gene vascular dementia group throughout the life span in an effort to reduce vascular dementia heterogeneities selecting persons enriched for certain future vascular disease secondary to NOTCH3 gene mutation. CADASIL is caused by a mutation in the gene NOTCH3, which encodes a receptor protein. Although rare, CADASIL is the most common heritable cause (due to a single gene mutation) of vascular dementia. Many consider CADASIL to be a good single gene model of small vessel disease and vascular dementia. By improving our understanding of CADASIL and its progression, we will be better able to understand VCID as well as mixed dementias having both CADASIL and the most common sporadic dementia, Alzheimer's disease. This is particularly important because of the fact that many cases of Alzheimer's disease have co- occurring vascular dementia. More than 200 genetic variations in NOTCH3 have been identified, but it is not known which cause milder, or more severe, forms of VCID. Furthermore, among the NOTCH3 mutations known to cause CADASIL, and even within CADASIL families, there is wide variability in age at onset, disease progression, brain imaging abnormalities and presentation of symptoms. Some recent data reported by the CADASIL European Consortium suggests that patients with mutations in certain parts of NOTCH3 cause a more severe form of CADASIL than do mutations in other parts of the gene. It's also likely that variations in other genes influence the effect of NOTCH3 mutations on VCID. Unfortunately, no large cohort of CADASIL patients for clinical research has been organized in North America. Better understanding of the associations between clinical presentation, potential disease modifiers (i.e., risk factors) and NOTCH3, as well as other gene variations in a new cohort in the United States could improve understanding of the causes and severity contributions to various forms of small-vessel disease and vascular dementia. To accomplish this, we will recruit, characterize and follow longitudinally a cohort of 400 NOTCH3 variant/mutation carriers, plus 100 non- carriers as controls, from U.S. CADASIL families. Participants will be evaluated every 18 months with detailed neurological, cognitive, behavioral, functional, blood, genetic and brain MRI assessments. This study will provide critical information regarding CADASIL that will also advance understanding for the most common type of mixed dementias (viz., VCID and AD).