Cerebrovascular contributions to cognitive impairment in Lewy body dementias

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Project Summary / Abstract Cognitive decline in Lewy body dementias [Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB)] causes significant functional impairment and does not respond well to existing treatments. Perhaps the largest challenge for developing efficacious treatments in these diseases is the lack of objective biomarkers for early identification and stratification of PDD/DLB patients based on the location and extent of neuropathological processes. Cerebrovascular impairment may be an important factor to capture early in the disease course as there are numerous opportunities for intervention. However, there are several limitations of the prior research, including: 1) objective measurement of cerebrovascular functions, 2) evaluation of the frequency and consistency in subject specific cerebrovascular abnormalities, 3) examination of the impact of cerebrovascular dysfunction on clinical presentation, and 4) examination of the relationship between cerebrovascular dysfunction and AD plasma biomarkers. The current study addresses these gaps in the literature and leverages innovative magnetic resonance imaging measures, including: cerebrovascular reactivity (CVR), the ability of the arterioles and capillaries to dilate in response to a vasodilatory challenge, and arterial transfer time (ATT) - the travel time of labeled blood to the imaged tissue. This study is both clinically and methodologically innovative as we use state of the art multimodal imaging to quantify several aspects of cerebrovascular function and integrate biospecimen analyses to answer key clinical questions. Specifically, PDD (N = 20), DLB (N = 20), and healthy controls (HC, N = 20) matched on age and sex will be recruited to evaluate the sensitivity and specificity of novel relative to established MRI cerebrovascular biomarkers and frequency of abnormal cerebrovascular functions in patient groups (Aim 1). We will then evaluate the relationships between cerebrovascular abnormalities, AD plasma biomarkers, and cognitive symptoms (Aim 2). At the conclusion of this successful application, we will identify which cerebrovascular functions are altered in PDD/DLB, the frequency of cerebrovascular abnormalities in PDD/DLB, and the relationship between cerebrovascular abnormalities, AD plasma biomarkers, and cognitive outcomes. This information is crucial to developing interventions for these disorders as potentially cerebrovascular dysfunction may occur early and provide ample opportunity for intervention. Additionally, in line with the objectives outlined in PAS-19-392, this project will establish an initial cohort of Lewy body dementia patients that can be expanded through a competitive R01 application to evaluate longitudinal change in cerebrovascular functioning in Lewy body disease across the cognitive spectrum (e.g. in PD-MCI, prodromal DLB). As part of the current project, the PI will engage in professional development efforts through several local NIH Centers, enhancing opportunities for networking, collaboration, and retention in the field.