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

Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel Disease Small vessel disease (SVD) is a major contributor to vascular cognitive declines and Alzheimer’s disease (AD). Preclinical stages of SVD can be present years before clinical symptomatology. Consequently, innovative tools for the identification of preclinical SVD have become a major research priority. The blood-brain barrier (BBB) may be a key biomarker of preclinical SVD and a critical structure mediating interactions between SVD and AD. Recent neuroimaging developments have made it possible to assess early-stage BBB dysfunction using a novel diffusion-weighted ASL (DW-ASL) scan. Our recent neuroimaging results suggest that low water exchange across the BBB (low kw) is a valid measure of vascular damage. Further our preliminary results indicate that low kw is associated with low executive task performance and functional connectivity in cognitively normal older adults. This proposal seeks to identify the impact of BBB dysfunction on neurocognitive networks over time and potential modifiers of BBB dysfunction. We will also define the interplay between BBB function and biomarkers of AD pathology on neurocognitive declines. We propose to study 140 healthy older adults using neuroimaging measures including DW-ASL, fMRI, cerebrospinal fluid (CSF) measures of Aβ, p- tau and t-tau and plasma inflammatory markers. Additional structural neuroimaging measures will include regional volumes, FLAIR imaging for quantification of WMH volumes and diffusion tensor imaging for quantification of regionally distributed white matter abnormalities. A subset of participants will complete the same CSF and imaging measures approximately 2.5 years later. We aim to (1) identify the impact of low BBB water exchange on neurocognitive functions; (2) demonstrate the utility of reduced BBB water exchange as a biomarker of preclinical SVD; and (3) identify factors that attenuate BBB dysfunction or its effects on cognition. We will test the hypothesis that low BBB water exchange is associated with subtle impairment in executive function and functional connectivity in cognitive normal older adults. We will also identify potential interactions between BBB dysfunction and accumulation of AD pathology on cognitive declines over time. Finally, we will test the hypothesis that specific reserve factors may offset the effects of BBB dysfunction on cognition, or attenuate its effects on cognition, via plastic brain reorganization of brain networks. Project Narrative Recent neuroimaging advances have made it possible to identify subtle reductions in blood- brain-barrier function in healthy older adults. This project will identify relations between a promising new biomarker of preclinical small vessel disease (SVD), cognition and brain connectivity patterns over time. Results from this project should improve the ability to identify participants for SVD clinical trials and monitor therapeutic efficacy.