# MR measured regional hypoxia as an early biomarker in cerebral small vessel disease

> **NIH NIH RF1** · WASHINGTON UNIVERSITY · 2020 · $3,443,971

## Abstract

Abstract
 In response to the growing societal burden of vascular and other AD related-dementias, NINDS has proposed
“Vascular Contributions to Cognitive Impairment and Dementia” (VCID) as a critical area of future research. VCID
is the second leading cause of dementia and a major contributor to Alzheimer’s disease, the leading cause of
dementia. VCID typically presents as progressive cognitive decline due to cerebral small vessel disease (CSVD).
Risk factors for disease at the patient-level are well-understood and include age, hypertension, cigarette
smoking, and diabetes. Furthermore, the end result of CSVD causing structural brain injury is well studied
including white matter hyperintensities (WMH) on FLAIR, disrupted white matter microstructure on diffusion
tensor imaging (DTI), lacunes, microbleeds, enlarged perivascular spaces, and atrophy. However, the link
between patient-level vascular risk factors and endpoint pathologies is missing. There is a knowledge gap in
the pathogenic mechanisms leading to CSVD progression and VCID. Indirect evidence suggests that ischemia
is a key contributors to CSVD, but direct evidence in humans is lacking. Here, we propose a causal pathway
linking vascular risk factors to, chronic ischemic-hypoxia, resulting in CSVD progression. We propose MR-
oxygen extraction fraction (MR-OEF) as a tissue-specific biomarkers of hypoxia-ischemia due to CSVD. We
postulate that MR-OEF can be used to understand CSVD pathogenesis such that targeted therapeutics can be
developed, and to select patients who are at high or early risk of CSVD progression. Our preliminary data show
that MR-OEF is elevated in the watershed region of older adults with WMH and correlates with WMH volume
and with disruption of white matter microstructure in normal appearing white matter (NAWM). Therefore, we
propose to determine: (1) the repeatability of watershed OEF measures, and the association between OEF and
burden of white matter injury in CSVD; (2) if regionally elevated OEF predicts NAWM tissue ‘at-risk’ for WMH
progression; (3) if baseline watershed OEF provides a patient biomarker to predict the progression of structural
impairment and cognitive decline at follow-up; and (4) which specific modifiable risk factors correlate with change
in watershed OEF across the study period.
 Given the aging society with increased duration of exposure to vascular risk factors, there is a critical need
to identify predictors of: (1) CSVD progression defined using sensitive neuroimaging endpoints and (2) cognitive
decline due to VCID. In this grant, we will serially image adults across a range of CSVD risk factors. We will test
the ability of these biomarkers to predict progression of WMH and disrupted white matter microstructure. With
successful completion of these aims, we will: 1) link specific hypoxia-ischemia to CSVD pathogenesis; 2)
determine the optimal threshold of the MR-OEF biomarker that identifies individuals at risk for CSVD progression,
enabling c...

## Key facts

- **NIH application ID:** 9960958
- **Project number:** 1RF1NS116565-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Hongyu An
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,443,971
- **Award type:** 1
- **Project period:** 2020-04-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960958

## Citation

> US National Institutes of Health, RePORTER application 9960958, MR measured regional hypoxia as an early biomarker in cerebral small vessel disease (1RF1NS116565-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9960958. Licensed CC0.

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