# Novel Biomarkers of Small Vessel Contributions to Vascular Cognitive Impairment and Dementia (VCID)

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $735,286

## Abstract

Small vessel disease (SVD) is thought to be among the most prevalent disorders of the central nervous system
and contributes a key mechanistic role in the syndrome of vascular cognitive impairment and dementia (VCID).
A major challenge in the investigation of cerebral SVD is that small vessel integrity cannot be visualized in vivo.
Instead, MRI lesions, most notably white matter hyperintensities, currently provide the most widely accepted
biomarker of SVD. However, MRI white matter lesions represent downstream effects of SVD and further are
not specific to ischemic brain injury. Noninvasive imaging strategies capable of detecting mechanistically-
specific changes in small vessel structure or function would improve the identification and quantification of
small vessel contributions to cognitive impairment and dementia and serve as biomarkers for monitoring the
effects of therapeutic interventions in clinical trials.
As we show in preliminary data, recent developments in the spatial resolution and sensitivity of arterial spin
labeled (ASL) perfusion MRI now allow noninvasive quantification of cerebral blood flow (CBF) from the
periventricular white matter (PVWM), which is supplied by the terminal distributions of long arterioles much less
than 100 microns in diameter. PVWM-CBF accordingly represents a promising biomarker of small vessel
perfusion, allowing quantification of small vessel functional integrity without spatially resolving individual
arteries. Concomitantly, emerging optical methods such as optical coherence tomographic angiography
(OCTA) also allow small vessels and even capillaries to be rapidly noninvasively imaged in the human retina
using relatively inexpensive and increasingly widely available instrumentation. Both biomarkers hold the
potential to detect mechanistically specific changes in small vessel structural or functional integrity prior to the
development of brain lesions been formally established. However, while retina has been described as a
“window” to the brain, the relationship between OCTA measures of retina and brain structure and function has
yet to be adequately tested.
The overall goal of this proposal is to validate PVWM CBF and OCTA-derived microvascular density as bona
fide biomarkers of human small vessel structure for use in clinical research. We will investigate the biological
and technical determinants of PVWM CBF and OCTA-derived microvascular density, associate changes in
retinal microvasculature with brain WML and perfusion, and preliminarily show their predictive value in SVD by
correlating baseline measures with longitudinal changes in healthy and clinical cohorts. A multidisciplinary
team of investigators with expertise in neuroimaging, retinal imaging, cerebral blood flow physiology,
cerebrovascular disorders, aging, and dementia will collaborate to carry out this work.

## Key facts

- **NIH application ID:** 10201780
- **Project number:** 5R01NS111115-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JOHN A DETRE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $735,286
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201780

## Citation

> US National Institutes of Health, RePORTER application 10201780, Novel Biomarkers of Small Vessel Contributions to Vascular Cognitive Impairment and Dementia (VCID) (5R01NS111115-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201780. Licensed CC0.

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