The Role of Hypertensive Vascular Disease in Brain Aging and Neurodegeneration

Brain aging, the phenomenon by which the passage of chronological time is associated with reduced brain volume, is important because it is regarded as a key component of increased dementia risk. The main purpose of this thesis is to present a model and supporting data that enhances knowledge of the underlying processes that drive brain aging and dementia risk. This has been done using structural and functional MRI scans from the Cardiovascular Health Study-Cognition Study (CHS-CS), a longitudinal community cohort study of elderly individuals that possesses extensive clinical and neuropsychological data. The model defended in this dissertation states that the relationship between older age and lower gray matter volume is not strictly a function of the passage of chronological time. Rather, older age is correlated with vascular diseases that themselves are a driving force behind brain aging. Most importantly, the three entities of aging, vascular disease, and neurodegeneration overlap in key strategic areas of the brain. Thus, a large factor behind dementia risk is that there are common brain areas that serve as sites of synergy by which age, vascular disease, and neurodegeneration can summate and thus amplify the risk for cognitive impairment and dementia. Using a whole brain method for analyzing structural MRI scans, we have found that the age and vascular disease, as reflected by white matter hyperintense lesions (WMHL) jointly affect areas of the brain known to be targeted by age and neurodegeneration and that they interact in these key strategic brain regions. Finally, results from perfusion MRI imaging will be reported showing that hypertension as the main predictor of lower regional cerebral blood flow. Taken together, these data will be interpreted to support the following model: structural and functional changes in an aging brain are modulated by hypertensive vascular disease. Additionally, the damage exerted by neurodegenerative processes on the brain is also modified by vascular disease. Finally, there are common strategic anatomical sites in which this synergy occurs and they include areas with important cognitive functions such as the hippocampus, cingulate gyrus, and precuneus. This model has several broad implications. First, it suggests that age related brain atrophy and perhaps even neurodegenerative atrophy itself can be reduced in magnitude if underlying vascular diseases are either prevented or better managed. Second, such a reduction in brain aging may lower risk for dementia by providing additional brain reserve. Third, key strategic brain regions provide a basis for further study and therapeutic targets