Cerebrovascular neuroimaging markers and abnormal brain aging

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PROJECT SUMMARY It is increasingly recognized that cerebrovascular dysfunction plays an important role in Alzheimer’s disease (AD) pathogenesis and cognitive decline, contributing to 70% of all dementias. Cerebral small vessel disease (SVD) often occurs (up to 80%) in those with Alzheimer’s disease (AD), but the current markers of SVD risk and progression are poor. Cerebrovascular reactivity (CVR) is a neuroimaging marker of vascular health which indicates of the ability of the brain vessels to respond to neuronal demand or a vasoactive stimulus, such as inhaled CO2. CVR shows promise as a marker of SVD and cognitive impairment, but some studies fail to see an association between CVR and markers of abnormal brain aging. Increasing evidence suggests that the time it takes for brain vessels to maximally respond to a stimulus, or CVRDELAY, may be a more sensitive of cerebrovascular health than CVR. Further, due to technical and physiological factors, CVR is often only quantified in the grey matter, and thus associations between white matter CVR and brain health are not well characterized. Rather than traditional CVR processing which assumes uniformly timed reactivity to CO2 across the entire brain parenchyma, we propose to use more novel time-delay processing to quantify CVR from hypercapnic normoxic challenge blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) data. The purpose of this proposal is to better understand if time-delay processed CVR metrics are associated with a faster longitudinal increase in SVD pathology and faster cognitive decline. In particular, we will assess (1) if impaired CVR and elevated CVRDELAY in the cerebral white matter relate a faster increase in white matter hyperintensities (WMHs) and enlarged perivascular spaces (ePVS) burden, and (2) if impaired CVR and elevated CVRDELAY in grey matter lobar regions of interest are related to faster longitudinal cognitive decline in specific cognitive domains. To fulfill the research aims of this F31 application, we will leverage exceptional resources from the Vanderbilt Memory & Alzheimer’s Center, Vanderbilt Memory & Aging Project, Vanderbilt University Institute of Imaging Science, Vanderbilt Advanced Computing Center for Research and Education, and the Vanderbilt Brain Institute. The candidate, Hudson Robb, will carry out the proposed research with the support of an interdisciplinary mentorship team, including experts in the neurobiology of Alzheimer’s disease and small vessel disease, geriatric neuropsychology, neuroscience, and brain MRI. The parallel training plan will provide the candidate with the necessary knowledge and skillset to complete the proposed research aims and develop into a successful neuroscientist working at the neurobiological intersection of SVD, AD, and cognitive impairment. Results from this research will offer crucial insight into associations between a relatively novel biomarker of vascular function and SVD and cognitive impairment.