Distinctive roles of estrone and estradiol in shaping verbal memory circuitry in postmenopausal women: Neuroimaging: Earlier life risk factors and imaging biomarkers.

Background: Declining levels of estrogen have been implicated as a key mechanism contributing to declines in verbal memory that occur with menopause and as a potential factor contributing to risk of AD in women. We examined the association of two estrogens in postmenopausal women ‐ estradiol (E2), secreted by the ovary, and estrone (E1), secreted by peripheral tissues and the dominant estrogen in postmenopause – with functional connectivity during performance of verbal encoding and recognition tasks. We hypothesized that higher estrogen would be associated with greater functional connectivity between the hippocampus and prefrontal cortex (PFC) and between the left and right hippocampus. Method: Participants were enrolled in MsBrain, a cross sectional investigation of postmenopausal women (n=98, mean age 59.2 +/‐ 4.2 years, 78.6% White). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Verbal memory was assessed using the California Verbal Learning Test (CVLT) and a functional MRI verbal memory task using a block design with two phases: encoding and recognition. A generalized psychophysiological interaction (gPPI) analysis estimated task‐based hippocampal‐whole brain functional connectivity using SPM12. Principal time series of the seed region (left or right hippocampus), task conditions (novel words, familiar words), interaction variables (seed times series × task condition), and motion parameters were included in the design matrix. Result: E1 was positively associated with connectivity between the hippocampus and rostral anterior cingulate cortex (ACC), mid cingulate, dorsal ACC, and left insula during verbal encoding. E2 was positively associated with connectivity with rostral ACC/medial PFC and left orbital inferior frontal cortex during encoding and connectivity with rostral ACC, bilateral orbital PFC, bilateral middle temporal cortex, precuneus and posterior cingulate cortex during retrieval. All results survived multiple comparison at corrected p < 0.05. No associations were found between estrogen levels and verbal memory performance. Conclusion: Estrogen levels in postmenopause may play a significant role in functional connections between the hippocampus and key nodes of the salience network via E1 and cognitive control network via E2. Results suggest that estrogens enhance the ability to attend to stimuli and engage neural resources required for encoding and recognizing verbal information. [ABSTRACT FROM AUTHOR]