Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition

Lisa Mosconi,Hollie Hristov,Randolph Andrews,Lacey Loughlin,Steven Jett,Mony De Leon,Grace Jang,Roberta Diaz Brinton,Eva Schelbaum,Aneela Rahman,Orli Etingin,Silky Pahlajani,Dawn Matthews,Richard Isaacson,Christine Ganzer,Valentina Berti,Jonathan Dyke

doi:10.1038/s41598-021-90084-y

Abstract

All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer’s disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.

Highlights

IntroductionFor SPM12 analyses, we used two-sample t-tests to compare each MT group to the corresponding age-matched male group, using the same confounders as above
Restricting analysis to HT non-users confirmed results from the entire cohort, with two exceptions: CBF differences between MT groups were more pronounced among non-users, and FA differences between PERI and POST groups did not reach significance
In parallel to the adaptive process, Aβ deposition was more pronounced in PERI and POST women positive for APOE-4 genotype, indicating specificity for AD risk with onset in the peri-menopause

Summary

Introduction

For SPM12 analyses, we used two-sample t-tests to compare each MT group to the corresponding age-matched male group, using the same confounders as above. We used the precuneus cluster described above to test for GMV differences between POST and PERI groups and corresponding age-matched male groups. Comparison to MALEPERI confirmed presence of lower precuneus GMV in the PERI group, while comparison to MALEPOST showed no significant differences in precuneus of the POST group, suggesting POST-specific GMV recovery. As this analysis was restricted to specific clusters, our secondary endpoint was detection of group differences in the entire search volu

Methods

Results

Discussion

Conclusion