Women's Brain Health: Midlife Ovarian Removal Affects Associative Memory

Alana Brown, Nicole J Gervais, Jenny Rieck, Anne Almey, Laura Gravelsins, Rebekah Reuben, Laurice Karkaby, M Natasha Rajah, Cheryl Grady, Gillian Einstein, Alana Brown, Nicole J Gervais, Jenny Rieck, Anne Almey, Laura Gravelsins, Rebekah Reuben, Laurice Karkaby, M Natasha Rajah, Cheryl Grady, Gillian Einstein

Abstract

Women with early bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) have greater Alzheimer's disease (AD) risk than women in spontaneous/natural menopause (SM), but early biomarkers of this risk are not well-characterized. Considering associative memory deficits may presage preclinical AD, we wondered if one of the earliest changes might be in associative memory and whether younger women with BSO had changes similar to those observed in SM. Women with BSO (with and without 17β-estradiol replacement therapy (ERT)), their age-matched premenopausal controls (AMC), and older women in SM completed a functional magnetic resonance imaging face-name associative memory task shown to predict early AD. Brain activation during encoding was compared between groups: AMC (n=25), BSO no ERT (BSO; n=15), BSO+ERT (n=16), and SM without hormone therapy (n=16). Region-of-interest analyses revealed AMC did not contribute to functional group differences. BSO+ERT had higher hippocampal activation than BSO and SM. This hippocampal activation correlated positively with urinary metabolite levels of 17β-estradiol. Multivariate partial least squares analyses showed BSO+ERT had a different network-level activation pattern than BSO and SM. Thus, despite being approximately 10 years younger, women with BSO without ERT had similar brain function to those with SM, suggesting early 17β-estradiol loss may lead to an altered functional brain phenotype which could influence late-life AD risk, making face-name encoding a potential biomarker for midlife women with increased AD risk. Despite similarities in activation, BSO and SM groups showed opposite within-hippocampus connectivity, suggesting menopause type is an important consideration when assessing brain function.

Keywords: Associative memory; Estradiol; Functional magnetic resonance imaging; Hippocampus; Menopause; Oophorectomy.

Conflict of interest statement

The authors declare no competing interests.

© 2023. The Author(s).

Figures

Fig. 1
Fig. 1
Locations of spherical regions-of-interest from coordinates from Sperling and colleagues [8] are shown in Montreal Neurological Institute (MNI) space
Fig. 2
Fig. 2
Effect of group on face-name task accuracy (%); age-matched premenopausal control women (AMC) significantly outperformed older spontaneously menopausal (SM) women
Fig. 3
Fig. 3
Effect of group on right posterior lateral hippocampal region-of-interest activity; Women with bilateral salpingo-oophorectomy who were not taking hormone therapy (BSO) and women in spontaneous menopause (SM) showed lower activation (mean parameter estimate: PE) than women with BSO who were taking 17β-estradiol-based hormone therapy (BSO+ERT) during Novel compared to Repeat face-name pair encoding; age-matched premenopausal control women (AMC) did not contribute to significant group differences; error bars represent standard error of the mean; *=p<0.05
Fig. 4
Fig. 4
Relationships between urinary ovarian hormone levels, face-name task accuracy, and hippocampal activation; a) Plot of correlation between estrone-3-glucuronide (E1G) level and face-name task accuracy; b) Plot of correlation between E1G level and right posterior lateral hippocampus activation. Abbreviations: SM spontaneous menopause, BSO bilateral salpingo-oophorectomy, BSO+ERT bilateral salpingo-oophorectomy with 17β-estradiol replacement therapy, with or without other hormone therapy types
Fig. 5
Fig. 5
Latent variable 1 (LV1) from task Partial Least Squares: a) Spatial maps depict highlighted regions for LV1; p=0.008, percent cross-block covariance accounted for 98.25%; b) Bootstrap distribution profile for LV1 with 95% confidence intervals; a pattern of Novel and Repeat face-name pair encoding-related activity was significantly different for BSO+ERT compared to BSO and SM; BSO bilateral salpingo-oophorectomy, BSO+ERT bilateral salpingo-oophorectomy with 17β-estradiol replacement therapy, SM spontaneous menopause
Fig. 6
Fig. 6
LV1 connectivity partial least squares: a) Connectivity between hippocampal regions with significant bootstrap ratios (BSRs) for LV1; p=0.07, percent cross-block covariance accounted for 72.91%; b) Brain score profile for LV1 with 95% confidence intervals; a pattern of Novel and Repeat face-name pair encoding-related connectivity was significantly different for BSO compared to SM; c) Group mean Fisher’s z-transformed correlation coefficients between left and right anterior hippocampal ROIs; d) Group mean Fisher’s z-transformed correlation coefficients between left anterior and posterior hippocampal regions; error bars represent standard error of the mean; BSO bilateral salpingo-oophorectomy, BSO+ERT bilateral salpingo-oophorectomy with 17β-estradiol replacement therapy, SM spontaneous menopause

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