The long-term goal of Project III is to identify non-invasive imaging and blood biomarkers of eariy cerebrovascular dysfunction and cognitive health. Specifically, aims of this project are to define and characterize in participants of Projects I and II: 1) cerebral microvascular dilatory capacity using transcranial Doppler ultrasonography; 2) the cellular origin, content, and thrombotic potential of blood-borne microvesicles using flow cytometry and platelet functions using assays for platelet secretion and activation; and 3) relationships among characteristics of blood-borne microvesicles, platelet functions, and cerebral microvascular dilatory capacity with changes in brain stmeture and cognition, as defined in Projects I and II. Three independent observations from our group provide the basis for this project and potential links among hormonal status, blood-borne elements, vascular function, and cognition. First, numbers of blood-borne prothrombotic microvesicles increase with decreases in estrogen at menopause; second, the dilatory capacity of the cerebral microvasculature decreases in women at menopause; and third, numbers of platelet microaggregates correlate positively with brain white matter hyperintensities and negatively with cognitive performance within 36 months of menopause. Experiments of this proposal will define sources and characteristics of blood elements and microvesicles simultaneously, together with cerebral microvascular dilatory capacity in women at risk for cardiovascular disease and cognitive decline based on either a history of preeclampsia or estrogen deficiency at menopause. Results of this study stand on their own but link results of Projects I and II to the overarching theme oif the SCOR of how female sex-specific conditions of a history preeclampsia or menopausal hormonal status affect cognition through changes in cerebrovascular function. Furthermore, assessment of platelet and microvesicle characteristics provides potential mechanisms by which cerebral microvascular dilatory capacity could be modulated and associate more generally with development of cardiovascular disease in women.
Experiments of this proposal will examine how preeclampsia, menopause, and menopausal hormone treatments affect cognitive health in women at midlife. The overall goal is to examine changes in coagulation of the blood by activation of platelets and membrane vesicles derived from damaged cells and how these affect blood supply to the brain. Reduced blood flow to the brain will cause damage to neurons and declines in cognition. Preeclampsia and menopause are conditions specific to women and may explain, in part, sex differences in risk of stroke and cognitive decline in women as they age. Understanding how platelets and other cells in the blood are activated will provide new targets for therapies to sustain cognitive health in women throughout their life.
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