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

> **NIH NIH RF1** · UNIVERSITY OF KENTUCKY · 2022 · $1,952,654

## Abstract

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.

## Key facts

- **NIH application ID:** 10369462
- **Project number:** 1RF1NS122028-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** BRIAN Timothy GOLD
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,952,654
- **Award type:** 1
- **Project period:** 2022-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369462

## Citation

> US National Institutes of Health, RePORTER application 10369462, Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel Disease (1RF1NS122028-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10369462. Licensed CC0.

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