The vast majority of women who have dementia are also post-menopausal. Following menopause, women become more susceptible to risk factors for VCID (vascular contributions to cognitive impairment and dementia). This effect could be mediated by the plummet in gonadal production of estrogen, a hormone that has been shown to be protective against both VCID risk factors and cerebrovascular dysfunction. The effect of estrogen on cognitive impairment in post-menopausal VCID is unknown. Little is known about the mechanisms through which menopause and diminished ovarian estradiol production produce this altered state of VCID risk, leaving opportunities to preserve cognitive function of post-menopausal women underutilized. A candidate mechanistic link between menopause and cognitive impairment in VCID is the disruption of the blood brain barrier (BBB). The BBB is an endothelial barrier which protects the highly regulated brain environment from exposure to blood proteins and peripheral immune cells. BBB disruption is associated with cognitive impairment in both humans and rodents. The permeability of the BBB is sensitive to the effects of estrogen and therefore could be influenced by menopause and possibly facilitate cognitive decline. In this work, I ask if gonadal estradiol production impacts cognitive impairment in VCID, if these effects could be related to changes in BBB function, and if intraventricular estradiol delivery could have an ameliorative effect on post-menopausal VCID. I will address these questions in two aims. In Aim 1, I will investigate the effects of menopause on VCID in mice by inducing menopause using an ovary-intact method (4-vinylcyclohexene diepoxide). I will use a unilateral carotid artery occlusion surgery to model chronic cerebral hypoperfusion. I will perform behavior testing to assess cognitive deficits and I will compare BBB permeability as a possible contributor to pathological differences between groups. In Aim 2, I will determine if I can protect against the negative effects of our interventions on cognitive function by specifically delivering estradiol to the intraventricular space in the brain. Funding from this grant will allow me the opportunity to investigate these questions, will facilitate my training and development as a scientist, and will potentially contribute to the prevention and treatment of cognitive impairment in post-menopausal women with VCID.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|