Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel Disease

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Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel Disease Vascular cognitive impairment and dementia (VCID) is common in older adults and is a major public health risk. VCID affects the network of small blood vessels that supply all parts of the brain, resulting in cognitive decline. Clinical trials have been hampered by the lack of non- invasive tools to detect early stages of VCID. Consequently, innovative tools for the identification of early-stage VCID have become a major research priority. The blood-brain barrier (BBB) may be a key system affected early in the course of VCID. Recent advances in the development of a novel diffusion-weighted ASL (DW-ASL) sequence and post-processing analyses have made it possible to quantify water exchange rate across the BBB, a metric of BBB functioning. Our preliminary results using this novel sequence suggest that low water exchange across the BBB (low kw) is associated with high concentrations of plasma vascular inflammatory markers and poor cognitive performance, suggesting that it may represent an early marker of VCID. Longitudinal research is required to test this possibility. This proposal seeks to assess the accuracy of low kw as a predictor of subsequent neurocognitive declines. We will also test the possibility that low kw is associated with oxidative stress, assessed via cerebrospinal fluid (CSF) isoprostane levels. We propose to study 140 healthy older adults at baseline using DW-ASL, plasma inflammatory markers and CSF measures of isoprostanes, Aβ, p-tau and t-tau. In addition, structural neuroimaging measures will be obtained and quantified, including regional volumes, white matter hyperintensity (WMH) volumes, diffusion tensor imaging for quantification of regionally distributed white matter abnormalities and susceptibility weighted imaging for quantification of cerebral microbleeds. A subset of participants will complete the same neuroimaging and biofluid measures approximately 3 years later. We aim to identify the relationship between baseline BBB water exchange and subsequent WMH growth (Aim 1); cognitive declines (Aim 2) and biofluid indices of oxidative stress (Aim 3). The overall hypothesis we will test is that that low water exchange rate assessed with a novel DW-ASL sequence represents an early marker BBB dysfunction associated with later WMH growth, cognitive declines and oxidative stress.