The Relationship Between Estradiol, Inflammation, And Brain Connectivity In Females During Midlife

The menopause transition involves hormonal changes relevant to both normal and pathological brain aging. The menopause transition is often accompanied by neurological symptoms such as disruptions in sleep, anxiety and depression, and changes in cognitive performance. Changes in cognitive performance may include subjective complaints of a decline in working memory that are reflective of true cognitive difficulties. However, declines in cognitive performance during the menopause transition are often transient and do not persist into menopause. For a subset of individuals, the menopause transition may be a time of increased vulnerability for risk factors associated with pathological brain aging. It remains unclear what factors contribute to some people experiencing a persistent decline in cognitive processes, while others do not experience cognitive changes around menopause. One potential contributing factor to the individual differences in cognition and risk for pathological aging is the brain’s response to decreased levels of estradiol. Prior to menopause, estradiol is critical for regulating neurological systems. However, during the menopause transition circulating estradiol levels drastically decrease. A growing body of evidence suggests that changing levels of estradiol because of menopause stage may affect brain functional connectivity. Previous work investigating the relationship between menopausal stage and brain functional connectivity found increased bilateral hippocampal connectivity in postmenopausal women compared to premenopausal and perimenopausal women. Findings such as these suggest that the functional connections of brain regions underlying cognition may be altered because of hormone fluctuations and menopause stage. Decreased estradiol in menopause may also play a role in the potential increased presence of inflammation, which in turn may affect risk for pathological aging. Subclinical, chronic low-grade inflammation may be a contributing factor to brain aging. Before menopause, serum levels of C-reactive protein, an acute-phase inflammatory protein, are inversely related to serum estradiol levels. After menopause, the level of inflammatory biomarkers increases. Additionally, the inverse relationship between estradiol and C-reactive protein does not persist in menopause. The nature of the relationship between estradiol and C-reactive protein during the menopause transition is still not well understood, nor is the effect of C-reactive protein on brain connectivity during this time. In this dissertation we investigated the relationship between estradiol and brain connectivity during midlife in females aged 40 and 55 years. We demonstrated that estradiol affected task-modulated effective connectivity during the recall portion of an episodic memory task. Additionally, we investigated the relationship between estradiol and C-reactive protein and found that estradiol and log transformed C-reactive protein were inversely related in the same sample of females. We found that in this sample, serum C-reactive protein level was not related to task-modulated effective connectivity. Lastly, we explored the relationship between menopause stage and brain connectivity at rest. Our results demonstrated differences in resting-state functional connectivity between pre- and postmenopausal individuals in our sample. Our findings demonstrated the influences of both estradiol and menopause stage on brain functioning during midlife.