# Long-Term Tracking of Cerebral Microvascular Structural and Functional Alterations between Normal and Alzheimer's Aging

> **NIH NIH R01** · BROWN UNIVERSITY · 2021 · $368,279

## Abstract

SUMMARY
 Alzheimer’s disease (AD), a progressive neurodegenerative disorder affecting millions of people
worldwide, is currently incurable. As the population ages, AD and related dementia are becoming the biggest
epidemic in medical history: the number of people aged 65 and older with AD is projected to increase between
two- and three-fold by 2050. As shown by imaging and biomarker studies, age is a major risk factor for
developing dementia, and the pathophysiological processes of AD begin more than a decade before the
diagnosis of dementia. However, AD is a heterogeneous and multifactorial disease; thus, it is challenging to
fully understand how the multiple etiologies and age-related prodromal processes contribute to its
pathophysiology. Among other factors, deficits in cerebral microvascular structures and functions may play a
key role in the onset and development of AD. Despite its importance for early diagnosis and as a therapeutic
target, it is still unclear whether they are a causal factor for AD pathogenesis or an early consequence of
multifactorial conditions that lead to AD at a later stage. Especially, two critical knowledge gaps exist: (1)
Temporal relationships between vascular and other key factors during the onset and development of AD are
not clear; (2) Little has been studied about how individual defects in various microvascular structural and
functional properties distinctly correlate with and/or contribute to neuronal degeneration.
 Here, we will develop, optimize, and integrate experimental and computational technologies for the
lifespan tracking and analysis of progressive microvascular alterations in AD versus normal aging in model
mice. First, we will optimize our optical coherence tomography imaging and 3D image processing techniques
to track the time-course of 32 vascular and non-vascular measures longitudinally over the mouse’s lifespan,
including microvascular structure, microcirculation, functional reactivity, Aβ plaque accumulation, neuronal
loss, and cognitive decline (Aim 1). These unprecedentedly comprehensive temporal dynamics data and
advanced statistical/correlation analyses will enable us to determine whether the microvascular deficits
precede neuronal loss or Aβ accumulation, and how those alterations are correlated, directly addressing the
first knowledge gap. In Aim 2, we will improve our computational model of microvascular flow and functional
hyperemia, and then combine the model with the experimental data of Aim 1 to investigate complicated cause-
effect relationships. Our computational model will enable us to essentially “turn on” and “turn off” each
microvascular deficit (e.g., thinner vessels, tortuous capillaries, hypoperfusion, capillary stalling) and test its
effect on oxygen delivery to neurons, which is difficult and sometimes impossible to achieve experimentally.
This combined approach will provide a powerful and unique strategy for testing the role of vascular deficits in
neuronal degeneration, ...

## Key facts

- **NIH application ID:** 10265356
- **Project number:** 5R01AG067228-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Jonghwan Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,279
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265356

## Citation

> US National Institutes of Health, RePORTER application 10265356, Long-Term Tracking of Cerebral Microvascular Structural and Functional Alterations between Normal and Alzheimer's Aging (5R01AG067228-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10265356. Licensed CC0.

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