# Risk factor convergence in the development of lacunar strokes and vascular cognitive impairment and dementia

> **NIH NIH R21** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $411,125

## Abstract

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after
Alzheimer’s Disease (AD). VCID is one of the consequences of cerebral small-vessel disease (SVD). This vascular
disorder produces cerebral perfusion deficits and, ultimately, cortical and/or subcortical lacunar strokes. Lacunar
strokes can be ischemic or microhemorrhagic in nature and can result in long-term physical disabilities and death.
Critical to the current proposal, lacunar strokes are a leading cause of VCID. Hypertension, hyperhomocysteinemia,
diabetes and advanced age are independent, major risk factors for SVD and the resulting lacunar strokes. These
factors are often clustered in individuals with both the highest risk for lacunar strokes and the worst outcomes. The
current proposal is driven by the central hypothesis that combining major human risk factors for SVD in an animal
model produces a synergistic effect that recapitulates the human disease etiology, giving rise to vascular injury that
results in lacunar stokes and ultimately VCID. It is further hypothesized that combining these risk factors facilitates
the coalescence of lacunar strokes and that the resulting augmentation of injury hastens behavioral deficits. In this
study, will use the diet-induced hyperhomocysteinemia model of SVD in aged spontaneously hypertensive rats
(SHR), which also produces an insulin-resistant phenotype. In addition, we will further drive the diabetic phenotype
with 1) a high-fructose diet and 2) promoting a reduction in pancreatic beta cells through the use of the low-dose
streptozocin. The superimposition of diabetes will further test our hypothesis that by combining a greater number of
independent risk factors the progression of SVDlacunar infarcts VCID is accelerated and exacerbated. Our
study will also leverage the use a novel, non-invasive imaging modality, multispectral optoacoustic tomography
(MSOT), to identify and measure regions of perfusion/oxygenation deficits and correlate these with behavioral
outcomes longitudinally and with final histological analysis of structural injury. Successful completion of this proposal
will demonstrate that the combination of these risk factors recapitulates human sequelae of SVDlacunar
infarctsVCID in an animal model. Ultimately, the development of this robust and highly relevant lacunar
stroke/VCID animal model and imaging technique will permit pre-clinical testing of targets and lead compounds for
lacunar stroke and VCID therapeutics. We plan to test our central hypothesis and accomplish our overall objective
by pursuing the following Specific Aims: 1) Aim 1: Determine the synergistic effect of hypertension, diet-induced
hyperhomocysteinemia, and aging on small-vessel disease, lacunar strokes and VCID in rats, and 2) Determine the
impact of insulin-resistance and diabetes on lacunar strokes and VCID in a rat model of hypertension-
hyperhomocysteinemia-aging. The proposed research is innovative because ...

## Key facts

- **NIH application ID:** 10043409
- **Project number:** 1R21NS118380-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** JAVIER CUEVAS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,125
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043409

## Citation

> US National Institutes of Health, RePORTER application 10043409, Risk factor convergence in the development of lacunar strokes and vascular cognitive impairment and dementia (1R21NS118380-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10043409. Licensed CC0.

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