Abstract
CONTEXT: Changes in verbal memory have been reliably reported across the menopause transition. To understand the role of endogenous estrogens in verbal memory performance, this study assessed the associations of endogenous estradiol and estrone with brain network connectivity during a verbal memory fMRI task. OBJECTIVE: Determine associations of endogenous estrogens with memory systems in the postmenopausal brain and evaluate clinical significance. METHODS: In the MsBrain cohort (n = 199, mean age 59.3 ± 3.9 years, 83.9% White), we examined the cross-sectional association of serum estradiol (E2) and estrone (E1), measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS), during a functional magnetic resonance imaging (fMRI) task of word encoding and recognition. To characterize the clinical significance of those associations, we examined the magnitude of activation in relation to a neuropsychological measures of memory and affect. RESULTS: Endogenous E2 was positively associated with activation in temporal and frontal cortices during encoding and negatively associated with one prefrontal region during recognition (P < .05). Activation in the left inferior frontal gyrus was associated with memory performance (β [SE] = 0.004 [0.002]; P < .05), and anxiety (β [SE] = -0.100 [0.050]; P < .05). The left middle frontal gyrus was associated with memory performance (β [SE] = 0.006 [0.002]; P < .01), depression, and anxiety. The left superior temporal gyrus (STG) was associated with depression (β [SE] = -0.083 [0.036]; P < .05) and anxiety (β [SE] = -0.134 [0.058]; P < .05). E1 was positively associated with activation in a range of brain areas including bilateral STG and right superior frontal gyrus during encoding (P < .05). Activation of the left insula and precentral gyrus were associated with symptoms of depression and anxiety. None related to memory. CONCLUSION: The function of brain areas critical to memory performance varies with estrogen levels in the postmenopause, even though those levels are low. Higher levels of E2 may facilitate memory performance through enhanced function of temporal and frontal cortices during encoding of verbal material.