Prevalence and impact of cerebral anatomical variations: a risk factor for cognitive decline?

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PROJECT SUMMARY Optimal brain health requires effective cerebrovascular function, adequate perfusion, and highly responsive blood flow regulation. If any of these are compromised, there are negative implications for brain and cognitive health. Adults with cognitive impairment, including vascular dementia and Alzheimer’s disease, exhibit inadequate cerebral perfusion. There is a critical need for more research on the pathophysiology of cognitive decline in humans. This project investigates the connection between the cerebral vasculature, cerebral perfusion, and cognitive function in middle-aged and older adults. Our overarching hypothesis is that chronic hypoperfusion, resulting from a specific variation in cerebrovascular architecture, impacts cerebral blood flow, and increases the risk of cognitive impairment. Variations in cerebrovascular architecture likely influence the trajectory of age- related declines in cerebral blood flow and warrant further investigation. Our preliminary data, using state-of-the- art MRI, indicates that individuals with a specific cerebral anatomical variation have lower cerebral blood flow and reduced cerebrovascular function compared to controls with normal cerebral anatomy. Thus, the objectives of this application are to investigate vertebral artery hypoplasia (VAH), as a chronic model of hypoperfusion in humans, and determine the potential impact on brain health. For each aim, we will utilize existing MRI scans from a unique, risk-enriched cohort of middle-aged and older adults from the University of Wisconsin-Madison Alzheimer’s Disease Research Center (ADRC). This cohort has extensive longitudinal data on medical health, genetics, and cognitive biomarkers. We will use novel neuroimaging analysis techniques to identify differences in cerebrovascular anatomy and quantify cerebral blood flow in the following specific aims. In Aim 1 we will determine the prevalence of VAH in cognitively unimpaired and cognitively impaired adults in the Wisconsin ADRC cohort. In Aim 2 we will examine the impact of VAH on cerebral blood flow in cognitively unimpaired adults 55-70 years of age. In Aim 3 we will determine the impact of VAH on biomarkers of cognitive decline in cognitively unimpaired adults. This application will provide essential information to determine the potential of variations in cerebrovascular architecture as a novel risk factor for cognitive decline and support critical data for future studies evaluating the impact of chronic hypoperfusion on cognitive function and the risk of Alzheimer’s disease and other dementias. To achieve these aims, we will employ innovative MRI analysis in adults with distinct differences in cerebrovascular architecture. This approach aligns with recent NIH recommendations emphasizing the need for human studies to identify and confirm biomarkers of vascular processes related to cognitive impairment. Upon completion, we will have identified a unique cohort for future large-scale studies, understand the impact on cognitive health and determine whether cerebral anatomical variations are associated with an increase in risk for cognitive decline.