Project 3. Markers of Cerebrovascular Dysfunction in Women at Risk

Principal investigator: Virginia M. Miller, Ph.D.; co-investigators: Michael J. Joyner, M.D., and Muthuvel Jayachandran, Ph.D.

Cognitive decline is associated with dementia-related pathologies. The most common pathologies associated with dementia in older adults include cerebrovascular disease and Alzheimer's disease. These pathologies typically coexist in older adults with dementia and are thought to contribute independently to the dementia syndrome. We are proposing surrogate imaging markers for these pathologies. The hallmarks of Alzheimer's disease in the brain are neurofibrillary tangles associated with the neuronal degeneration and neuritic plaques associated with the deposition of beta-amyloid.

The long-term goal of this project is to identify noninvasive imaging and blood biomarkers of early cerebrovascular dysfunction and cognitive health. The overall hypothesis is that activation of blood platelets and activated cell membrane-derived microvesicles associated with preeclampsia and hormonal changes at menopause reduce cerebrovascular dilator capacity, which leads to structural changes in the brain and cognitive decline.

This hypothesis is based on previous and preliminary studies. First, numbers of bloodborne prothrombotic microvesicles increase with decreases in estrogen at menopause; second, dilatory capacity of cerebral microvasculature decreases in women at menopause; and third, numbers of platelet microaggregates correlate positively with brain WMH. These in turn correlate negatively with cognitive performance within 36 months of menopause.

Experiments of this proposal will define platelet reactivity, sources and characteristics of blood microvesicles simultaneously in addition to cerebral microvascular dilatory capacity in women at risk of cerebrovascular disease and cognitive decline. Results of this study stand on their own to provide insight into how the blood elements affect cerebral microvascular function. However, when analyzed together with results of Projects 1 and 2, they support the overarching theme of how female sex-specific conditions of a history of preeclampsia or menopausal hormonal status affect cognition.