# Characterization and validation of cerebrovascular reactivity (CVR) as a biomarker of vascular dementia in mouse models

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2021 · $465,301

## Abstract

Project summary/Abstract
 Small-vessel-related vascular cognitive impairment and dementia (VCID) is the second leading cause of
dementia in the United States. However, compared to other dementia types (e.g. amyloid and tau imaging in
Alzheimer's disease), validated imaging biomarkers for VCID are limited. Recent studies in humans suggested
that the brain's vasodilatory capacity, referred to as cerebrovascular reactivity (CVR), is one of the most
sensitive indicators of VCID. While human studies are important in demonstrating the utility of CVR in clinical
settings, animal models are invaluable for validating and characterizing this new biomarker. With appropriate
animal models, one can elucidate the mechanistic link between CVR and classical measures of
neuropathologic hallmarks of small vessel disease such as vessel density, vascular smooth muscle cells, and
endothelial cells. Additionally, animal models can be designed to have relatively pure mechanism and therefore
avoid confounding pathologies, which often occur in human patients of dementia. Therefore, the present
exploratory/developmental (R21) study will address the above scientific gap by characterizing and validating
CVR as a biomarker of VCID with mouse models. It should be noted that quantitative CVR techniques have not
been available in mouse, because of the difficulties in both the measurement of hemodynamic parameters and
quantification of vasoactive stimuli in small animals. Therefore, this application will first conduct systematic
development of CVR MRI technique in mice, followed by an application of the technique in two mouse models
of small vessel disease (SVD). The two models are complementary in that one is a classic genetic model of
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and
the other is an environmentally based model of hyper-homocysteinemia (HHcy) mice. This study has two
specific aims. Aim 1 is to develop a CVR MRI technique in mice. We will measure hemodynamic responses to
vasoactive challenge, the magnitude of which will yield an index of CVR. For the choice of vasoactive
challenge, we will use injection of acetazolamide as a vasodilative agent, the plasma concentration of which
will be quantified and used as an input function. For imaging readouts, both global and regional CVR methods
will be developed using advanced physiological MRI techniques. Dose-dependence of acetazolamide effects
will also be studied. Aim 2 is to characterize CVR impairment in a longitudinal study of SVD mouse models.
We will compare CVR with several histological measures, including total vessel density stained with collagen
IV, vascular smooth muscle cell density stained with Acta 2, and vascular endothelial proteins stained with
CD31. Regional CVR studies will focus on subcortical nuclei which are the most susceptible regions in human
SVD. We will also study the longitudinal time course of CVR and compare it to that of behavioral sc...

## Key facts

- **NIH application ID:** 10302475
- **Project number:** 1R21NS119960-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Zhiliang Wei
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $465,301
- **Award type:** 1
- **Project period:** 2021-07-15 → 2024-01-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10302475

## Citation

> US National Institutes of Health, RePORTER application 10302475, Characterization and validation of cerebrovascular reactivity (CVR) as a biomarker of vascular dementia in mouse models (1R21NS119960-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10302475. Licensed CC0.

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