This is an Administrative Supplement application for 1R01AG049762-01A ?Cardiovascular Consequences of Hypogonadism in Men?. The application is in response to the National Institutes of Health (NIH) NOT-AG-18- 008: Alzheimer?s Disease and its related Dementias (AD/ADRD)-focused Administrative supplements for NIH grants that are not focused on Alzheimer?s disease. The focus of the parent award is to determine the impact of low testosterone (T) on cardiovascular (CV) aging (i.e., large artery stiffening, endothelial dysfunction impaired left ventricular (LV) diastolic function), and mechanisms related to mitochondrial dysfunction and oxidative stress.
Specific aim (SA) 1 of the parent award is examining the chronic effects of low T by assessing CV and biomarkers of mitochondrial function and oxidative stress cross-sectionally in young and older men with normal T (?400 ng/dl), and older men with low T (<300 ng/dl). To better isolate the effects of low T from factors that change with aging and chronic low T, Aim 2 expands on the cross-sectional comparisons by assessing measures of CV function, oxidative stress and mitochondrial function in older men with normal T before and after randomization to short-term (30 d) gonadal suppression (gonadotropin releasing hormone antagonist, GnRHant) + placebo (PL), GnRHant+T alone, or GnRHant+T+aromatase inhibitor (AI). AI will control for the effects of aromatization of T to estradiol (E2), and thereby isolate T effects while suppressing E2. Declines in sex hormones have been associated with cognitive impairment and increased risk of AD/ADRD, but the regulation of cognitive function by these hormones is poorly understood. T and estradiol (E2) are neuroactive steroids with protective effects in the brain. Although the role of E2 on cognition in women has been studied extensively, much less is known about the cognitive effects of sex hormones in men, who experience gradual declines in T and, via conversion by aromatase, E2. The mechanisms by which sex hormones may influence AD/ADRD risk are not known, but may be related to CV aging, which has been linked to AD/ADRD. Given the association between CV aging, cognitive aging and the risk for AD/ADRD, this active award presents an ideal setting in which to explore the effects of low T and biomarkers of CV aging on cognitive function. Under this Supplement, basal cerebral blood flow, cerebrovascular reactivity and cerebral autoregulation measures (transcranial Doppler), neuroimaging (fMRI), and cognitive testing will be performed at baseline in young men and older men with normal T, and before and after short-term gonadal hormone suppression with T, T+ AI, or PL add-back, in older men with normal T. In addition to facilitating the acquisition of new resources and novel preliminary data on the influence of sex hormones on CV contributions to AD/ADRD for future grant applications, this Supplement will also help to support a new focus on AD/ADRD for the PI, advancing progress toward effective treatment and prevention strategies.
The findings from this research should provide new information into whether declines in testosterone causes impairments in blood vessel health in the brain and cognitive function in middle-aged and older men. Understanding the possible causes by which cebrovascular and cognitive health changes in relation to declines in cardiovascular health and testosterone may lead to the development of effective treatment and preventitve strategies to decrease the risk for Alzheimer?s disease and its related Dementias.
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