# Metabolic and Hormonal Mechanisms of VCID

> **NIH NIH R01** · ALBANY MEDICAL COLLEGE · 2021 · $355,088

## Abstract

PROJECT SUMMARY/ABSTRACT
Half of all dementia patients have evidence of vascular contributions to cognitive impairment and dementia
(VCID), either as a single pathology or as a mixed dementia. Diabetic women have a 2.3-fold greater risk to
develop VCID than non-diabetic women. However, even though prediabetes causes cognitive deficits and is 3
times more common than diabetes, little is known regarding the effects of prediabetes on VCID. Further, why
metabolic disease is a larger risk factor for VCID in women than in men is unknown. Women are unique in that
they go through menopause. Menopause accelerates mid-life risk factors for dementia, by increasing risk for
cardiovascular and metabolic diseases. Despite the fact that nearly all women with VCID are post-menopausal,
the influence of menopause on VCID is a critical gap in knowledge. The objective of this proposal is to
understand the important interaction between menopause and prediabetes on VCID pathology and identify a
novel therapeutic approach to treat VCID in post-menopausal females. Our preliminary data in a mouse model
of VCID demonstrate that prediabetes reduces blood flow and accelerates cognitive deficits in peri-
menopausal females, the underlying mechanism is unknown but may be related to neuroinflammation or
vascular damage; effects in post-menopausal females have not been assessed. In post-menopausal women,
the major source of estrogen is local synthesis of 17-β estradiol by the enzyme aromatase in a variety of
tissues. Brain aromatase and brain estradiol levels are drastically decreased in women with other forms of
dementia, however, the role of aromatase in VCID has yet to be explored. We have discovered that inhibition
of aromatase severely impairs cerebrovascular function in female mice suggesting that targeting aromatase in
females may be an effective strategy for increasing blood flow to the brain, thereby reducing VCID pathology.
We hypothesize that cerebral hypoperfusion, cognitive deficits, and neuroinflammation induced by prediabetes
will be exacerbated in post-menopausal females and will be reversed by increasing production of brain-derived
estradiol. In Aim 1, using a mouse model of VCID, we will determine if menopause exacerbates cerebral
hypoperfusion, neuroinflammation, and cognitive deficits induced by prediabetes. In Aim 2, we will determine if
loss of endothelial or astrocytic aromatase causes cerebral hypoperfusion and exacerbates cognitive deficits
and neuroinflammation in post-menopausal female mice. In Aim 3, we will determine if increasing estradiol
specifically in the brain improves vascular function and reduces cognitive deficits and neuroinflammation in
prediabetic post-menopausal female mice. We anticipate these studies will provide mechanistic insight that will
facilitate future interventions to decrease the burden of dementia by identifying a novel approach to treat VCID
in post-menopausal females: enhancement of brain estradiol. Without knowledge of t...

## Key facts

- **NIH application ID:** 10120745
- **Project number:** 5R01NS110749-03
- **Recipient organization:** ALBANY MEDICAL COLLEGE
- **Principal Investigator:** Kristen Leanne Zuloaga
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,088
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120745

## Citation

> US National Institutes of Health, RePORTER application 10120745, Metabolic and Hormonal Mechanisms of VCID (5R01NS110749-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120745. Licensed CC0.

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