# Mechanistic role of vascular dysfunction in TBI-mediated cognitive dysfunction

> **NIH VA I01** · PHOENIX VA HEALTH CARE SYSTEM · 2023 · —

## Abstract

Abstract
 Mild traumatic brain injury (mTBI) is a major cause of mortality and morbidity especially among service-
members and veterans. mTBI is linked to long-term development of dementia conditions such as Alzheimer's
disease and related disorders, but the exact pathophysiologic mechanisms remain poorly-defined. Vascular
disease and cardiovascular risk factors are strongly linked with dementia. We propose to test the hypothesis that
long-term mTBI-induced cognitive dysfunction is due to, at least in part, persistent cerebrovascular dysfunction.
We will also test the hypothesis that early onset mTBI and later development of hypertension will have synergistic
effects on cerebrovascular and cognitive dysfunction compared to hypertension or mTBI alone. In Aim 1, we will
measure the temporal changes (subacute and chronic) in cerebrovascular and cognitive function in a rat model
of mTBI while establishing the mechanistic role of cerebrovascular dysfunction in mTBI-induce cognitive
impairment. Following midline fluid percussion injury or sham surgery in Sprague-Dawley rats, we will measure
subacute (8 weeks) and chronic (12 months) cerebrovascular function (in-vivo by brain contrast MRI and ex-vivo
by measuring cerebral artery vasoreactivity) and cognitive function and establish their relationship. We will also
determine if early (starting at 2 weeks post-injury) or late (starting at 10 months post-injury) aerobic exercise
training will improve cerebrovascular function leading to improvement in cognitive function. We will identify
molecular mechanisms by which cerebrovascular function modulates cognitive function in mTBI by investigating
the role of endothelial function in the regulation of brain-derived neurotrophic factor. In Aim 2, we will probe the
interaction between early onset mTBI and later development of hypertension in chronic cerebrovascular and
cognitive dysfunction. Here we will use rats genetically prone to develop hypertension (spontaneously
hypertensive rats) to determine the effects of early onset mTBI in modulating chronic cerebrovascular and
cognitive function. We will also have an exploratory aim to look at effects of mTBI in Sprague-Dawley and
hypertensive rats on cardiac structure and function and coronary artery function. The proposal could provide
critical and novel insights on the mechanisms underlying vascular dysfunction in TBI and their role in the
development of cognitive dysfunction.

## Key facts

- **NIH application ID:** 10610367
- **Project number:** 5I01RX002691-03
- **Recipient organization:** PHOENIX VA HEALTH CARE SYSTEM
- **Principal Investigator:** Jonathan Lifshitz
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10610367

## Citation

> US National Institutes of Health, RePORTER application 10610367, Mechanistic role of vascular dysfunction in TBI-mediated cognitive dysfunction (5I01RX002691-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10610367. Licensed CC0.

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