# Pathophysiological mechanisms of hypoperfusion in mouse models of Alzheimer?s disease and small vessel disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $528,322

## Abstract

Project summary/Abstract
 Hypoperfusion is broadly reported as an important symptom of Alzheimer’s disease related dementia
(ADRD). Severity of cerebral blood flow (CBF) loss correlates with severity of cognitive deficit. However,
hypoperfusion is only one of the signs of microvascular dysfunction in ADRD and, in fact, may not be the most
sensitive or specific one. For example, in the recent NIH-funded MarkVCID Consortium study to identify the
most sensitive biomarkers of vascular contributions to cognitive impairment and dementia (VCID), CBF was
not selected as a candidate biomarker kit (despite proposed), whereas an index of vasodilatory function,
referred to as cerebrovascular reactivity (CVR), was selected. In AD, despite the widely reported observations
that there is hypoperfusion in posterior cingulate cortex and temporoparietal regions, some proposed this to be
an indirect effect attributed to metabolic abnormalities via metabolism-vascular coupling. Therefore, to
systematically understand the mechanism of hypoperfusion in ADRD, one needs to look beyond perfusion to
examine a suite of related vascular and metabolic parameters in the brain.
 Therefore, the central goal of this application is to conduct a multi-parametric study to fully characterize the
relationship between hypoperfusion and related vascular and metabolic underpinnings, separately in AD and
small vessel disease (SVD) mice, as they represent two leading causes of dementia and most prominently
linked to hypoperfusion. The proposed study in mouse models will parallel our ongoing efforts in human
participants, making this work having a strong translational relevance. Using novel MRI techniques, we will
measure CBF, cerebrovascular reactivity, oxygen extraction fraction, cerebral metabolic rate of oxygen, and
BBB permeability concomitantly, and compare them to behavior (e.g. novel object recognition) and histology
(e.g. smooth muscle cell density, tight-junction protein density) results (Aim 1). These multiple parameters will
be integrated into a mechanistic model, which is fully testable based on the experimental measures proposed.
The PI, an early stage investigator, is uniquely positioned to carry out this work because he has pioneered
several of these MRI techniques in mice over the past few years. The non-invasive nature of these techniques
(e.g. does not require skull thinning or contrast agents) also make them ideally suited for longitudinal studies
(Aim 2), which will allow the characterization of the temporal relationship between hypoperfusion (and related
vascular/metabolic parameters) and behavior outcomes. Two novel mouse models of Tau4RΔK-AP (replicating
tauopathy and amyloidosis of AD) and CADASIL (replicating vascular pathology of SVD) will be utilized, based
on the recent discovery of our collaborators. Taking together, we are in a unique position to make meaning
contributions to the understanding of hypoperfusion in ADRD.

## Key facts

- **NIH application ID:** 10841661
- **Project number:** 5R01AG081932-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Zhiliang Wei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $528,322
- **Award type:** 5
- **Project period:** 2023-05-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841661

## Citation

> US National Institutes of Health, RePORTER application 10841661, Pathophysiological mechanisms of hypoperfusion in mouse models of Alzheimer?s disease and small vessel disease (5R01AG081932-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10841661. Licensed CC0.

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