Project 2 - Bilateral Oophorectomy on Imaging Biomarkers of Alzheimer's and Cerebrovascular Diseases
Funded Grant
Overview
Affiliation
View All
Overview
description
OVERALL: SUMMARY/ABSTRACT Michelle M. Mielke, Ph.D. Aging-associated physical and cognitive decline and Alzheimer's disease (AD) are conditions that affect men and women differently across their lifespan. There are important sex and gender differences for these conditions, including risk factors, manifestations, response to treatments, morbidity, and mortality. The overarching theme of the Mayo Clinic Specialized Center of Research Excellence (SCORE) on Sex Differences is to investigate how abrupt loss of ovarian hormones, caused by bilateral salpingo-oophorectomy (BSO) prior to natural menopause, affects overall aging, physical and cognitive function, and risk for AD pathophysiology. Given the large number of aging women with a history of premenopausal BSO, there is an urgent need to understand the long-term physical and cognitive outcomes. In addition, we need new evidence to empower women considering prophylactic BSO to make more informed decisions in the future. The central hypothesis of our SCORE renewal is that the abrupt endocrine disruption caused by premenopausal BSO will accelerate pathological aging processes that manifest as reductions in physical and cognitive function and in AD pathophysiology. This hypothesis will be tested through three inter-related translational projects, which are supported by three inter-dependent Cores. Our interdisciplinary translational approach using both humans (Projects 1 and 2) and mice (Project 3) provides the foundation to: 1) establish the effects of abrupt endocrine disruption in women, 2) develop a more complete understanding of the biological mechanisms involved, 3) devise a targeted approach to identify and mitigate the adverse outcomes, 4) design future studies to mechanistically test whether targeting senescent cells mitigates the effects of accelerated aging in these women, and 5) empower women considering prophylactic BSO to make more informed decisions. Our rigorous approach is supported by an experienced leadership team through the Leadership Administrative Core, by a Resource Support Core - Clinical that will provide financial and operational efficiency for participant recruitment, and by a Career Enhancement Core that will provide career enrichment, leadership training, and funds to support ancillary studies of the main projects. These resources will stimulate new interest in sex differences and women's health. The Mayo Clinic SCORE will serve as a vital hub for education and dissemination of innovative sex-based translational research methods, results, and best practices. Our integrated approach for research, training, and education is consistent with the goals of the SCORE on Sex Differences RFA, and assures continuing research in areas of women's health and sex differences by training the work force of the future.
PROJECT 2: SUMMARY/ABSTRACT Kejal Kantarci, M.D. The social and economic implications of dementia will be greatest in women because of their longer life expectancy and resulting elevated risk for dementia compared to men. This risk of dementia in women may be, in part, modulated by ovarian hormones and modified by the apolipoprotein E (APOE) ε4 genotype. Women who undergo bilateral salpingo-oophorectomy (BSO) before the onset of menopause have an accelerated accumulation of multimorbidity, with an increased risk of aging-related neurological diseases including dementia. How bilateral salpingo-oophorectomy (BSO) influences the risk of dementia remains unknown, but needs to be addressed, because it is estimated that one in eight U.S. women have their ovaries removed before reaching natural menopause. The most common pathologies that contribute to cognitive impairment and dementia in women are Alzheimer's disease (AD) and cerebrovascular disease (CVD). Determining the effects of BSO before menopause on the risk of dementia would require decades of follow-up; alternatively, non-invasive imaging biomarkers can potentially assess the effects of an abrupt loss of ovarian hormones on the risk of AD and CVD pathologies in a shorter time frame. Our goal in Project 2 is to understand the effects of abrupt disruption of ovarian hormones on AD and CVD pathophysiology in women who underwent BSO before reaching menopause through imaging biomarkers. We will enroll 100 women with BSO and 100 referent women that will be drawn from a well-characterized and established population-based cohort. We hypothesize that imaging biomarkers of AD and CVD pathophysiology will be more abnormal in women who underwent BSO before reaching menopause, compared to an age-matched referent cohort of women who did not undergo premenopausal BSO, and that this difference is modulated by APOE ε4. We will further investigate the relationship of imaging biomarkers with cognitive outcomes as measured in Project 1.The results of the proposed research will address this problem by applying state-of-the art imaging and cognitive testing in a population-based cohort of women. Evaluation of this sample of women, whose midlife history of premenopausal BSO is well-characterized, provides a unique opportunity to clarify the long-term effects of abrupt ovarian hormonal disruption on the risk of cognitive decline and dementia through imaging biomarkers of early pathology. For women considering BSO for cancer prophylaxis, the findings will provide critical insights, guiding their health care decisions.
