With the growing social and economic impact of dementia on the society, emphasis is shifting from eariy diagnosis and treatment to prevention of cognitive impairment and dementia. The neuroprotective effects shown in animal models and cell cultures suggest that estrogen might be used in the prevention or delay of cognitive impairment and dementia in postmenopausal women. However, estrogen used as a menopausal hormone treatment (MHT) in older (i.e., not newly menopausal) women did not prevent dementia, and controversy exists about whether MHT containing estrogen can preserve neurologic function and decrease the risk of dementia when administered eariy in menopause. In this proposal, we will assess the neuroprotective effects of MHT on cognitive performance and surrogate brain imaging markers. This project leverages the existing cohort of women who participated in the Kronos Eariy Estrogen Prevention Study (KEEPS) who were treated with either oral conjugated equine estrogen ortransdremal 17(3 estradiol or with a placebo eariy in menopause, which is considered the critical """"""""window of opportunity"""""""" for estrogen treatment. In addition to cognitive testing (through Core B), we will consider several imaging markers of brain. First is """"""""C-Pittsburgh Compound B (PiB) retention on positron emission tomography;this is a surrogate marker for p-amyloid pathology of Alzheimer's disease (AD). Second is the change in white-matter hyperintensity load on MRI over 7 years after randomization;this is a surrogate marker for ischemic white-matter disease. Third is change in brain volume indices on MRI over 7 years after randomization;this is a surrogate marker for neuronal degeneration. Each imaging marker should provide independent information on the common pathologic features associated with cognitive health in older adults. This project addresses an important and controversial aspect of MHT by determining whether therapy in the immediate postmenopausal years preserves cognition and neuronal integrity. Since participants will also undergo assessment of cerebral microvascular dilatory capacity and characterization of platelet and blood-borne microvesicles in Project III, insight will be gained into mechanisms which might impact progression of AD-related pathology. Collectively, findings from this study have the potential to significantly advance scientific knowledge and clinical practice by providing insight into effects of MHT on cognitive health eariy in menopause. Our findings will help patients and physicians make informed decisions regarding the benefit and risk of such treatments.

Public Health Relevance

This study has the potential to change preventive interventions for dementia in aging women. Identification of neuroprotective effects of estrogen therapy would have a significant influence on women deciding whether to use hormonal treatments during the transition into menopause and in the eariy postmenopausal years.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Boeve, Bradley F; St Louis, Erik K; Kantarci, Kejal (2016) Neuromelanin-sensitive imaging in patients with idiopathic rapid eye movement sleep behaviour disorder. Brain 139:1005-7
Chen, Long; Ding, Mei-Lin; Wu, Fang et al. (2016) Impaired Endothelial Repair Capacity of Early Endothelial Progenitor Cells in Hypertensive Patients With Primary Hyperaldosteronemia: Role of 5,6,7,8-Tetrahydrobiopterin Oxidation and Endothelial Nitric Oxide Synthase Uncoupling. Hypertension 67:430-9
Gilani, Sarwat I; Weissgerber, Tracey L; Garovic, Vesna D et al. (2016) Preeclampsia and Extracellular Vesicles. Curr Hypertens Rep 18:68
Kling, Juliana M; Rose, Steven H; Kransdorf, Lisa N et al. (2016) Evaluation of sex- and gender-based medicine training in post-graduate medical education: a cross-sectional survey study. Biol Sex Differ 7:38
Kantarci, Kejal; Tosakulwong, Nirubol; Lesnick, Timothy G et al. (2016) Effects of hormone therapy on brain structure: A randomized controlled trial. Neurology 87:887-96
Miller, Virginia M; Kararigas, Georgios; Seeland, Ute et al. (2016) Integrating topics of sex and gender into medical curricula-lessons from the international community. Biol Sex Differ 7:44
Walton, Ronald L; Soto-Ortolaza, Alexandra I; Murray, Melissa E et al. (2016) TREM2 p.R47H substitution is not associated with dementia with Lewy bodies. Neurol Genet 2:e85
Miller, Virginia M; Lahr, Brian D; Bailey, Kent R et al. (2016) Longitudinal effects of menopausal hormone treatments on platelet characteristics and cell-derived microvesicles. Platelets 27:32-42
Ranadive, Sushant M; Harvey, Ronee E; Lahr, Brian D et al. (2016) Sympathetic Responsiveness is not Increased in Women with a History of Hypertensive Pregnancy. Am J Physiol Regul Integr Comp Physiol :ajpregu.00379.2016
Graff-Radford, Jonathan; Madhavan, Malini; Vemuri, Prashanthi et al. (2016) Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement 12:391-8

Showing the most recent 10 out of 89 publications