Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study.
Pottala James V,Yaffe Kristine,Robinson Jennifer G,Espeland Mark A,Wallace Robert,Harris William S
OBJECTIVE:To test whether red blood cell (RBC) levels of marine omega-3 fatty acids measured in the Women's Health Initiative Memory Study were related to MRI brain volumes measured 8 years later. METHODS:RBC eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and MRI brain volumes were assessed in 1,111 postmenopausal women from the Women's Health Initiative Memory Study. The endpoints were total brain volume and anatomical regions. Linear mixed models included multiple imputations of fatty acids and were adjusted for hormone therapy, time since randomization, demographics, intracranial volume, and cardiovascular disease risk factors. RESULTS:In fully adjusted models, a 1 SD greater RBC EPA + DHA (omega-3 index) level was correlated with 2.1 cm(3) larger brain volume (p = 0.048). DHA was marginally correlated (p = 0.063) with total brain volume while EPA was less so (p = 0.11). There were no correlations between ischemic lesion volumes and EPA, DHA, or EPA + DHA. A 1 SD greater omega-3 index was correlated with greater hippocampal volume (50 mm(3), p = 0.036) in fully adjusted models. Comparing the fourth quartile vs the first quartile of the omega-3 index confirmed greater hippocampal volume (159 mm(3), p = 0.034). CONCLUSION:A higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured 8 years later. While normal aging results in overall brain atrophy, lower omega-3 index may signal increased risk of hippocampal atrophy. Future studies should examine whether maintaining higher RBC EPA + DHA levels slows the rate of hippocampal or overall brain atrophy.
Effects of Hormone Therapy on Brain Volumes Changes of Postmenopausal Women Revealed by Optimally-Discriminative Voxel-Based Morphometry.
Zhang Tianhao,Casanova Ramon,Resnick Susan M,Manson JoAnn E,Baker Laura D,Padual Claudia B,Kuller Lewis H,Bryan R Nick,Espeland Mark A,Davatzikos Christos
BACKGROUNDS:The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an opportunity to evaluate how menopausal hormone therapy (HT) affects the structure of older women's brains. Our earlier work based on region of interest (ROI) analysis demonstrated potential structural changes underlying adverse effects of HT on cognition. However, the ROI-based analysis is limited in statistical power and precision, and cannot provide fine-grained mapping of whole-brain changes. METHODS:We aimed to identify local structural differences between HT and placebo groups from WHIMS-MRI in a whole-brain refined level, by using a novel method, named Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a recently proposed imaging pattern analysis approach for group comparisons utilizing a spatially adaptive analysis scheme to accurately locate areas of group differences, thereby providing superior sensitivity and specificity to detect the structural brain changes over conventional methods. RESULTS:Women assigned to HT treatments had significant Gray Matter (GM) losses compared to the placebo groups in the anterior cingulate and the adjacent medial frontal gyrus, and the orbitofrontal cortex, which persisted after multiple comparison corrections. There were no regions where HT was significantly associated with larger volumes compared to placebo, although a trend of marginal significance was found in the posterior cingulate cortical area. The CEE-Alone and CEE+MPA groups, although compared with different placebo controls, demonstrated similar effects according to the spatial patterns of structural changes. CONCLUSIONS:HT had adverse effects on GM volumes and risk for cognitive impairment and dementia in older women. These findings advanced our understanding of the neurobiological underpinnings of HT effects.
Blood pressure variability and brain morphology in elderly women without cardiovascular disease.
Haring Bernhard,Liu Jingmin,Salmoirago-Blotcher Elena,Hayden Kathleen M,Sarto Gloria,Roussouw Jacques,Kuller Lew H,Rapp Steve R,Wassertheil-Smoller Sylvia
OBJECTIVE:To examine the relationship between blood pressure (BP) variability (BPV), brain volumes, and cognitive functioning in postmenopausal women with few modifiable cardiovascular risk factors. METHODS:Study participants consisted of postmenopausal women enrolled in the Women's Health Initiative Memory MRI study (WHIMS-MRI) without cardiovascular disease, diabetes mellitus, hypertension, or current smoking at baseline (1996-1999). BP readings were taken at baseline and each annual follow-up visit. BPV was defined as the SD associated with a participant's mean BP across visits and the SD associated with the participant's regression line with BP regressed across visits. Brain MRI scans were performed between 2004 and 2006. Cognitive functioning was assessed at baseline and annually thereafter with the Modified Mini-Mental State Examination (3MSE) scoring until 2008. The final sample consisted of 558 women (mean age 69 years, median follow-up time [interquartile range] 8 [0.8] years). RESULTS:In adjusted models including mean systolic BP, women in the highest tertile of systolic BPV had lower hippocampal volumes and higher lesion volumes compared to women in the lowest tertile. No relationship between BPV and 3MSE scoring was detected. CONCLUSIONS:In postmenopausal women with few modifiable cardiovascular risk factors, greater visit-to-visit systolic BPV was associated with reductions in hippocampal volume and increases in lesion volumes at later life. These data add evidence to the emerging importance of BPV as a prognostic indicator even in the absence of documented cardiovascular risk factors.
Trajectories of Relative Performance with 2 Measures of Global Cognitive Function.
Espeland Mark A,Chen Jiu-Chiuan,Weitlauf Julie,Hayden Kathleen M,Rapp Stephen R,Resnick Susan M,Garcia Lorena,Cannell Brad,Baker Laura D,Sachs Bonnie C,Tindle Hilary A,Wallace Robert,Casanova Ramon,
Journal of the American Geriatrics Society
OBJECTIVES:To examine whether trajectories of global cognitive function over time in studies that change assessment protocols may be modeled based on an individual's performance relative to others in the study cohort. DESIGN:Extended follow-up of a cohort originally enrolled in a clinical trial of postmenopausal hormone therapy. SETTING:The Women's Health Initiative Memory Study switched from an in-person interview with the Modified Mini-Mental State Examination to a telephone-based interview with the modified Telephone Interview for Cognitive Status to assess global cognitive function over long-term follow-up. PARTICIPANTS:Women aged 75 to 92 (N=2,561). MEASUREMENTS:Annual cognitive assessments from participants, ranked according to age-, race- and ethnicity-adjusted performance levels, were used to identify distinct trajectories. Participants assigned to the resulting trajectories were compared for selected risk factor profiles. RESULTS:Our approach grouped participants into five trajectories according to relative cognitive performance over time. These groups differed significantly according to 3 known risk factors for cognitive decline-education level, apolipoprotein E-ϵ4 genotype, and type 2 diabetes mellitus-and a biomarker based on brain structure that has been linked to cognitive decline and Alzheimer's disease. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these levels tended to have poorer risk factor profiles. CONCLUSION:Longitudinal measures of an individual's relative performance on different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors.
The Lifespan Human Connectome Project in Aging: An overview.
Bookheimer Susan Y,Salat David H,Terpstra Melissa,Ances Beau M,Barch Deanna M,Buckner Randy L,Burgess Gregory C,Curtiss Sandra W,Diaz-Santos Mirella,Elam Jennifer Stine,Fischl Bruce,Greve Douglas N,Hagy Hannah A,Harms Michael P,Hatch Olivia M,Hedden Trey,Hodge Cynthia,Japardi Kevin C,Kuhn Taylor P,Ly Timothy K,Smith Stephen M,Somerville Leah H,Uğurbil Kâmil,van der Kouwe Andre,Van Essen David,Woods Roger P,Yacoub Essa
The original Human Connectome Project yielded a rich data set on structural and functional connectivity in a large sample of healthy young adults using improved methods of data acquisition, analysis, and sharing. More recent efforts are extending this approach to include infants, children, older adults, and brain disorders. This paper introduces and describes the Human Connectome Project in Aging (HCP-A), which is currently recruiting 1200 + healthy adults aged 36 to 100+, with a subset of 600 + participants returning for longitudinal assessment. Four acquisition sites using matched Siemens Prisma 3T MRI scanners with centralized quality control and data analysis are enrolling participants. Data are acquired across multimodal imaging and behavioral domains with a focus on factors known to be altered in advanced aging. MRI acquisitions include structural (whole brain and high resolution hippocampal) plus multiband resting state functional (rfMRI), task fMRI (tfMRI), diffusion MRI (dMRI), and arterial spin labeling (ASL). Behavioral characterization includes cognitive (such as processing speed and episodic memory), psychiatric, metabolic, and socioeconomic measures as well as assessment of systemic health (with a focus on menopause via hormonal assays). This dataset will provide a unique resource for examining how brain organization and connectivity changes across typical aging, and how these differences relate to key characteristics of aging including alterations in hormonal status and declining memory and general cognition. A primary goal of the HCP-A is to make these data freely available to the scientific community, supported by the Connectome Coordination Facility (CCF) platform for data quality assurance, preprocessing and basic analysis, and shared via the NIMH Data Archive (NDA). Here we provide the rationale for our study design and sufficient details of the resource for scientists to plan future analyses of these data. A companion paper describes the related Human Connectome Project in Development (HCP-D, Somerville et al., 2018), and the image acquisition protocol common to both studies (Harms et al., 2018).
Distinct cognitive effects of estrogen and progesterone in menopausal women.
Berent-Spillson Alison,Briceno Emily,Pinsky Alana,Simmen Angela,Persad Carol C,Zubieta Jon-Kar,Smith Yolanda R
The effects of postmenopausal hormone treatment on cognitive outcomes are inconsistent in the literature. Emerging evidence suggests that cognitive effects are influenced by specific hormone formulations, and that progesterone is more likely to be associated with positive outcomes than synthetic progestin. There are very few studies of unopposed progesterone in postmenopausal women, and none that use functional neuroimaging, a sensitive measure of neurobiological function. In this study of 29 recently postmenopausal women, we used functional MRI and neuropsychological measures to separately assess the effects of estrogen or progesterone treatment on visual and verbal cognitive function. Women were randomized to receive 90 days of either estradiol or progesterone counterbalanced with placebo. After each treatment arm, women were given a battery of verbal and visual cognitive function and working memory tests, and underwent functional MRI including verbal processing and visual working memory tasks. We found that both estradiol and progesterone were associated with changes in activation patterns during verbal processing. Compared to placebo, women receiving estradiol treatment had greater activation in the left prefrontal cortex, a region associated with verbal processing and encoding. Progesterone was associated with changes in regional brain activation patterns during a visual memory task, with greater activation in the left prefrontal cortex and right hippocampus compared to placebo. Both treatments were associated with a statistically non-significant increase in number of words remembered following the verbal task performed during the fMRI scanning session, while only progesterone was associated with improved neuropsychological measures of verbal working memory compared to placebo. These results point to potential cognitive benefits of both estrogen and progesterone.
Association of Estradiol and Visceral Fat With Structural Brain Networks and Memory Performance in Adults.
Zsido Rachel G,Heinrich Matthias,Slavich George M,Beyer Frauke,Kharabian Masouleh Shahrzad,Kratzsch Juergen,Raschpichler Matthias,Mueller Karsten,Scharrer Ulrike,Löffler Markus,Schroeter Matthias L,Stumvoll Michael,Villringer Arno,Witte A Veronica,Sacher Julia
JAMA network open
Importance:Changes in estradiol during aging are associated with increased dementia risk. It remains unclear how estradiol supports cognitive health and whether risk factors, such as midlife obesity, are exacerbated by estrogen loss. Objectives:To assess whether visceral adipose tissue (VAT) moderates the association between age and brain network structure and to investigate whether estradiol moderates the association between VAT and brain network structure. Design, Setting, and Participants:Cross-sectional study of data from 974 cognitively healthy adults in Germany who participated in the Health Study of the Leipzig Research Centre for Civilization Diseases, a previously described population-based cohort study. Two moderation analyses were performed, including VAT as the moderator variable between age and brain network structure and estradiol as the moderator variable between VAT and brain network structure. The study was conducted from August 1, 2011, to November 23, 2014. Analyses were conducted from August 2017 to September 2018. Exposures:Serum estradiol levels from fasting blood and visceral adipose tissue volume from T1-weighted magnetic resonance imaging (MRI). Main Outcomes and Measures:Brain network covariance (individual loading on structural network derived from T1-weighted MRI) and memory performance (composite score from the Consortium to Establish a Registry for Alzheimer Disease [CERAD] verbal episodic memory test on learning [score range, 0-30], recall [score range, 0-10], and recognition [score range, 0-20]). Results:Final analyses included data from 473 women (mean [SD] age, 50.10 [15.63] years) and 501 men (mean [SD] age, 51.24 [15.67] years). Visceral adipose tissue was associated with an exacerbation of the negative association of aging with network covariance for women (interaction term β = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P = .001) and men (interaction term β = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P < .001). Estradiol level was associated with a reduction in the negative association of VAT with network covariance in women (interaction term β = 0.63; 95% bias-corrected bootstrap CI, 0.14-1.12; P = .01), with no significant association in men. In the female midlife subgroup (age range, 35-55 years, when menopause transition occurs), low estradiol levels were associated with lower memory network covariance (Cohen d = 0.61; t80 = 2.76; P = .007) and worse memory performance (Cohen d = 0.63; t76 = 2.76; P = .007). Conclusions and Relevance:This study reports a novel association between VAT, estradiol, and structural brain networks as a potential mechanism underlying cognitive decline in women. These findings appear to highlight the need for sex-specific strategies, including VAT and hormonal screening during midlife, to support healthy cognitive aging.
Impact of sex and reproductive status on memory circuitry structure and function in early midlife using structural covariance analysis.
Seitz Johanna,Kubicki Marek,Jacobs Emily G,Cherkerzian Sara,Weiss Blair K,Papadimitriou George,Mouradian Palig,Buka Stephen,Goldstein Jill M,Makris Nikos
Human brain mapping
Research on age-related memory alterations traditionally targets individuals aged ≥65 years. However, recent studies emphasize the importance of early aging processes. We therefore aimed to characterize variation in brain gray matter structure in early midlife as a function of sex and menopausal status. Subjects included 94 women (33 premenopausal, 29 perimenopausal, and 32 postmenopausal) and 99 demographically comparable men from the New England Family Study. Subjects were scanned with a high-resolution T1 sequence on a 3 T whole body scanner. Sex and reproductive-dependent structural differences were evaluated using Box's M test and analysis of covariances (ANCOVAs) for gray matter volumes. Brain regions of interest included dorsolateral prefrontal cortex (DLPFC), inferior parietal lobule (iPAR), anterior cingulate cortex (ACC), hippocampus (HIPP), and parahippocampus. While we observed expected significant sex differences in volume of hippocampus with women of all groups having higher volumes than men relative to cerebrum size, we also found significant differences in the covariance matrices of perimenopausal women compared with postmenopausal women. Associations between ACC and HIPP/iPAR/DLPFC were higher in postmenopausal women and correlated with better memory performance. Findings in this study underscore the importance of sex and reproductive status in early midlife for understanding memory function with aging.
Impact of BDNF and sex on maintaining intact memory function in early midlife.
Konishi Kyoko,Cherkerzian Sara,Aroner Sarah,Jacobs Emily G,Rentz Dorene M,Remington Anne,Aizley Harlyn,Hornig Mady,Klibanski Anne,Goldstein Jill M
Neurobiology of aging
Sex steroid hormones and neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), play a significant neuroprotective role in memory circuitry aging. Here, we present findings characterizing the neuroprotective effects of BDNF on memory performance, as a function of sex and reproductive status in women. Participants (N = 191; mean age = 50.03 ± 2.10) underwent clinical and cognitive testing, fMRI scanning, and hormonal assessments of menopausal staging. Memory performance was assessed with the 6-Trial Selective Reminding Test and the Face-Name Associative Memory Exam. Participants also performed a working memory (WM) N-back task during fMRI scanning. Results revealed significant interactions between menopausal status and BDNF levels. Only in postmenopausal women, lower plasma BDNF levels were associated with significantly worse memory performance and altered function in the WM circuitry. BDNF had no significant impact on memory performance or WM function in pre/perimenopausal women or men. These results suggest that in postmenopausal women, BDNF is associated with memory performance and memory circuitry function, thus providing evidence of potential sex-dependent factors of risk and resilience for early intervention.
Identifying brain functional alterations in postmenopausal women with cognitive impairment.
Huang Jingjing,Bai Feng,Yang Xiaoqing,Chen Chen,Bao Xueping,Zhang Yuquan
INTRODUCTION:Gender differences and menopause are associated with the cognitive decline and pathogenesis of Alzheimer's disease (AD). Although deficits of subcortical-cortical loops have been implicated in AD, no study has directly examined the resting-state brain functional alterations in postmenopausal women with mild cognitive impairment (MCI). METHODOLOGY:Forty-eight subjects were recruited, including 15 older females with MCI, 13 older females without MCI, 10 older males with MCI and 10 older males without MCI. Full-scale neuropsychological tests were used to evaluate cognitive function. Resting-state fMRI and the amplitude of low-frequency fluctuation (ALFF) approach were used to investigate changes in the brain function in these subjects. A voxel-wise analysis of variance (ANOVA: gender × disease) was performed, and gender-brain-behavior relationships were further examined. RESULTS:First, older females with MCI showed cognitive dysfunction in multiple domains compared to normal controls. Second, the brain function of subcortical-cortical loops was disrupted in older females with MCI. Finally, regional resting-state function of the left precuneus was significantly associated with altered episodic memory in these female patients. CONCLUSIONS:This study revealed the patterns of neural networks in older females with cognitive disorders, and may provide new ideas and evidence regarding the mechanism of cognitive impairment in postmenopausal women.
The effect of estrogen synthesis inhibition on hippocampal memory.
Bayer Janine,Rune Gabriele,Schultz Heidrun,Tobia Michael J,Mebes Imke,Katzler Olaf,Sommer Tobias
17-Beta-estradiol (E2) facilitates long term-potentiation (LTP) and increases spine synapse density in hippocampal neurons of ovariectomized rodents. Consistent with these beneficial effects on the cellular level, E2 improves hippocampus-dependent memory. A prominent approach to study E2 effects in rodents is the inhibition of its synthesis by letrozole, which reduces LTPs and spine synapse density. In the current longitudinal functional magnetic resonance imaging (fMRI) study, we translated this approach to humans and compared the impact of E2 synthesis inhibition on memory performance and hippocampal activity in post-menopausal women taking letrozole (n = 21) to controls (n = 24). In particular, we employed various behavioral memory paradigms that allow the disentanglement of hippocampus-dependent and -independent memory. Consistent with the literature on rodents, E2 synthesis inhibition specifically impaired hippocampus-dependent memory, however, this did not apply to the same degree to all of the employed paradigms. On the neuronal level, E2 depletion tended to decrease hippocampal activity during encoding, whereas it increased activity in the anterior cingulate and the dorsolateral prefrontal cortex. We thus infer that the inhibition of E2 synthesis specifically impairs hippocampal functioning in humans, whereas the increased prefrontal activity presumably reflects a compensatory mechanism, which is already known from studies on cognitive aging and Alzheimer's disease.
Postmenopausal hormone treatment alters neural pathways but does not improve verbal cognitive function.
Berent-Spillson Alison,Kelley Angela S,Persad Carol C,Love Tiffany,Frey Kirk A,Reame Nancy E,Koeppe Robert,Zubieta Jon-Kar,Smith Yolanda R
Menopause (New York, N.Y.)
OBJECTIVE:Cognitive outcomes in trials of postmenopausal hormone treatment have been inconsistent. Differing outcomes may be attributed to hormone formulation, treatment duration and timing, and differential cognitive domain effects. We previously demonstrated treatment benefits on visual cognitive function. In the present study, we describe the effects of hormone treatment on verbal outcomes in the same women, seeking to understand the effects of prior versus current hormone treatment on verbal function. METHODS:This is a cross-sectional evaluation of 57 women (38 hormone users [25 prior long-term users and 13 current users] and 19 never-users). Hormone users took identical formulations of estrogen or estrogen + progestin (0.625 mg/d conjugated equine estrogens with or without medroxyprogesterone acetate) for at least 10 years, beginning within 2 years of menopause. Women were evaluated with tests of verbal function and functional magnetic resonance imaging (fMRI) of a verbal discrimination task. RESULTS:All women scored similarly on assessments of verbal function (Hopkins Verbal Learning Test and a verbal discrimination task performed during the fMRI scanning session); however, women ever treated with hormones had more left inferior frontal (T = 3.72; P < 0.001) and right prefrontal cortex (T = 3.53; P < 0.001) activation during the verbal task. Hormone-treated women performed slightly worse on the verbal discrimination task (mean accuracy 81.72 ± 11.57 ever-treated, 85.30 ± 5.87 never-treated, P = 0.14), took longer to respond (mean reaction time 1.10 ± 0.17 s ever-treated, 1.02 ± 0.11 never-treated, P = 0.03), and remembered fewer previously viewed words (mean accuracy 62.21 ± 8.73 ever-treated, 65.45 ± 7.49 never-treated, P = 0.18). Increased posterior cingulate activity was associated with longer response times (R = 0.323, P = 0.015) and worse delayed verbal recall (R = -0.328, P = 0.048), suggesting that increased activation was associated with less efficient cognitive processing. We did not detect between group differences in activation in the left prefrontal cortex, superior frontal cortex, thalamus, or occipital/parietal junction. CONCLUSIONS:Although current and past hormone treatment was associated with differences in neural pathways used during verbal discrimination, verbal function was not higher than never-users.
Impact of adrenal hormones, reproductive aging, and major depression on memory circuitry decline in early midlife.
Konishi Kyoko,Cherkerzian Sara,Jacobs Emily G,Richards Christine,Remington Anne,Aizley Harlyn,Misra Madhusmita,Lasley Bill L,Goldstein Jill M
Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen that is, in part, aromatized to estradiol. It continues to be produced after menopause and provides estrogenicity after depletion of ovarian hormones. Estradiol depletion contributes to memory circuitry changes over menopause, including changes in hippocampal (HIPP) and dorsolateral- and ventrolateral-prefrontal cortex (DLPFC; VLPFC) function. Further, major depressive disorder (MDD) patients have, in general, lower levels of estradiol and lower DHEAS than healthy controls, thus potentially a higher risk of adverse menopausal outcomes. We investigated whether higher DHEAS levels after menopause is associated with better memory circuitry function, especially in women with MDD. 212 adults (ages 45-55, 50% women) underwent clinical and fMRI testing. Participants performed a working memory (WM) N-back task and an episodic memory verbal encoding (VE) task during fMRI scanning. DHEAS levels were significantly associated with memory circuitry function, specifically in MDD postmenopausal women. On the WM task, lower DHEAS levels were associated with increased HIPP activity. On the VE task, lower DHEAS levels were associated with decreased activity in the HIPP and VLPFC. In contrast, there was no association between DHEAS levels and memory circuitry function in MDD pre/perimenopausal women, men, and non-MDD participants regardless of sex and reproductive status. In fact, MDD postmenopausal women with higher levels of DHEAS were similar to MDD pre/perimenopausal women and men. Thus, memory circuitry deficits associated with MDD and a lower ability of the adrenal gland to produce DHEAS after menopause may contribute to a lower ability to maintain intact memory function with age.
Reorganization of Functional Networks in Verbal Working Memory Circuitry in Early Midlife: The Impact of Sex and Menopausal Status.
Jacobs Emily G,Weiss Blair,Makris Nikos,Whitfield-Gabrieli Sue,Buka Stephen L,Klibanski Anne,Goldstein Jill M
Cerebral cortex (New York, N.Y. : 1991)
Converging preclinical and human evidence indicates that the decline in ovarian estradiol production during the menopausal transition may play a mechanistic role in the neuronal changes that occur early in the aging process. Here, we present findings from a population-based fMRI study characterizing regional and network-level differences in working memory (WM) circuitry in midlife men and women (N = 142; age range 46-53), as a function of sex and reproductive stage. Reproductive histories and hormonal evaluations were used to determine menopausal status. Participants performed a verbal WM task during fMRI scanning. Results revealed robust differences in task-evoked responses in dorsolateral prefrontal cortex and hippocampus as a function of women's reproductive stage, despite minimal variance in chronological age. Sex differences in regional activity and functional connectivity that were pronounced between men and premenopausal women were diminished for postmenopausal women. Critically, analyzing data without regard to sex or reproductive status obscured group differences in the circuit-level neural strategies associated with successful working memory performance. These findings underscore the importance of reproductive age and hormonal status, over and above chronological age, for understanding sex differences in the aging of memory circuitry. Further, these findings suggest that early changes in working memory circuitry are evident decades before the age range typically targeted in cognitive aging studies.
Sex and post-menopause hormone therapy effects on hippocampal volume and verbal memory.
Braden B Blair,Dassel Kara B,Bimonte-Nelson Heather A,O'Rourke Holly P,Connor Donald J,Moorhous Sallie,Sabbagh Marwan N,Caselli Richard J,Baxter Leslie C
Neuropsychology, development, and cognition. Section B, Aging, neuropsychology and cognition
Many studies suggest sex differences in memory and hippocampal size, and that hormone therapy (HT) may positively affect these measures in women; however, the parameters of HT use that most likely confer benefits are debated. We evaluated the impact of sex and postmenopausal HT use on verbal learning and memory and hippocampal size in 94 cognitively intact women and 49 men. Using analysis of covariance that controlled for age and education, women had better total word learning and delayed verbal memory performance than men. HT analyses showed that non-HT users performed similarly to men, while HT users performed better than men in Delayed Memory regardless of whether use was current or in the past. Women had larger hippocampal volumes than men regardless of whether they were HT users. Using univariate linear models, we assessed group differences in the predictive value of hippocampal volumes for verbal learning and memory. Hippocampal size significantly predicted memory performance for men and non-HT users, but not for HT users. This lack of relationship between hippocampal size and verbal learning and memory performance in HT users suggests HT use may impact memory through extra-hippocampal neural systems.
Dopaminergic contributions to working memory-related brain activation in postmenopausal women.
Dumas Julie A,Filippi Christopher G,Newhouse Paul A,Naylor Magdalena R
Menopause (New York, N.Y.)
OBJECTIVE:The current study examined the effects of pharmacologic dopaminergic manipulations on working memory-related brain activation in postmenopausal women to further understand the neurochemistry underlying cognition after menopause. METHODS:Eighteen healthy postmenopausal women, mean age 55.21 years, completed three study days with dopaminergic drug challenges during which they performed a functional magnetic resonance imaging visual verbal N-back test of working memory. Acute stimulation with 1.25 mg oral D2 agonist bromocriptine, acute blockade with 1.5 mg oral haloperidol, and matching placebo were administered randomly and blindly on three study days. RESULTS:We found that dopaminergic stimulation increased activation primarily in the posterior regions of the working memory network compared with dopaminergic blockade using a whole brain cluster-level corrected analysis. The dopaminergic medications did not affect working memory performance. CONCLUSIONS:Patterns of increased blood-oxygen-level dependent signal activation after dopaminergic stimulation were found in this study in posterior brain regions with no effect on working memory performance. Further studies should examine specific dopaminergic contributions to brain functioning in healthy postmenopausal women to determine the effects of the increased brain activation on cognition and behavior.
Neural correlates of depression in women across the reproductive lifespan - An fMRI review.
Stickel Susanne,Wagels Lisa,Wudarczyk Olga,Jaffee Sara,Habel Ute,Schneider Frank,Chechko Natalia
Journal of affective disorders
INTRODUCTION:Depressive disorders in women emerge largely during transitions in their reproductive aging cycle, which can be attributed to internal endocrine possesses that affect emotion-associated brain circuits. A review was performed to outline the neural basis in depression during female puberty, premenstrual dysphoric disorder (PMDD), postpartum depression disorder (PPD) and perimenopausal depression disorder. METHODS:For this review, Web of science, Pubmed and PsychInfo databases were searched for functional brain imaging studies addressing reproductive cycle-related mood disorder. The results are summarized and discussed within a broader theoretical framework of major depression disorder (MDD) to determine how reproductive-sensitive phases contribute to affective symptoms and how they relate to the neurobiology of MDD. RESULTS:Neural activation patterns of all depressive disorders related to female reproductive cycle, except for puberty depression, differ from these observed in MDD. While the PMDD results are widely divergent, the activation patterns in PPD show general hypoactivation in all respects. LIMITATIONS:Systematic comparisons between the diverse depression disorders are impeded by the heterogeneous experimental protocols used on different samples, reproductive aging stages and depression types. CONCLUSION:Given that hormonal fluctuations strongly influence the development of a reproductive cycle-related depression, it is possible that the hormonal and neural patterns are indicative of distinct mood disorder with phase specific biotypes, that only show behavioral similarities to MDD. Understanding the similarities and differences in the neural functioning of female cycle-related mood disorders evaluated against MDD might help elucidate the role of neuroendocrine involvement in development of depression in women, and potentially facilitate the search for prevention and treatment approaches for women' reproductive-related depressions.
Estrogen therapy in postmenopausal women: effects on cognitive function and dementia.
Yaffe K,Sawaya G,Lieberburg I,Grady D
CONTEXT:Several studies have suggested that estrogen replacement therapy in postmenopausal women improves cognition, prevents development of dementia, and improves the severity of dementia, while other studies have not found a benefit of estrogen use. OBJECTIVE:To determine whether postmenopausal estrogen therapy improves cognition, prevents development of dementia, or improves dementia severity. DATA SOURCES:We performed a literature search of studies published from January 1966 through June 1997, using MEDLINE, manually searched bibliographies of articles identified, and consulted experts. STUDY SELECTION:Studies that evaluated biological mechanisms of estrogen's effect on the central nervous system and studies that addressed the effect of estrogen on cognitive function or on dementia. DATA EXTRACTION:We reviewed studies for methods, sources of bias, and outcomes and performed a meta-analysis of the 10 studies of postmenopausal estrogen use and risk of dementia using standard meta-analytic methods. DATA SYNTHESIS:Biochemical and neurophysiologic studies suggest several mechanisms by which estrogen may affect cognition: promotion of cholinergic and serotonergic activity in specific brain regions, maintenance of neural circuitry, favorable lipoprotein alterations, and prevention of cerebral ischemia. Five observational studies and 8 trials have addressed the effect of estrogen on cognitive function in nondemented postmenopausal women. Cognition seems to improve in perimenopausal women, possibly because menopausal symptoms improve, but there is no clear benefit in asymptomatic women. Ten observational studies have measured the effect of postmenopausal estrogen use on risk of developing dementia. Meta-analysis of these studies suggests a 29% decreased risk of developing dementia among estrogen users, but the findings of the studies are heterogeneous. Four trials of estrogen therapy in women with Alzheimer disease have been conducted and have had primarily positive results, but most have been small, of short duration, non-randomized, and uncontrolled. CONCLUSIONS:There are plausible biological mechanisms by which estrogen might lead to improved cognition, reduced risk for dementia, or improvement in the severity of dementia. Studies conducted in women, however, have substantial methodologic problems and have produced conflicting results. Large placebo-controlled trials are required to address estrogen's role in prevention and treatment of Alzheimer disease and other dementias. Given the known risks of estrogen therapy, we do not recommend estrogen for the prevention or treatment of Alzheimer disease or other dementias until adequate trials have been completed.
Depression during the perimenopause: A meta-analysis.
de Kruif M,Spijker A T,Molendijk M L
Journal of affective disorders
BACKGROUND:Women are believed to be more vulnerable to develop a depression or depressive symptoms during the perimenopause. Estimates from individual studies are heterogeneous and hence true risk estimate is unknown. OBJECTIVE:This study investigated the risk on clinical depression and depressive symptoms during the perimenopause when compared to other female hormonal stages. METHODS:We performed a meta-analysis of 11 studies identified in Pubmed, Web of Science and the Cochrane library (up to July 2015). Studies were included when the perimenopause was defined according the criteria of Stages of Reproductive Aging Workshop (STRAW). The outcome measures were Odds Ratio's (OR) on depression diagnosis and depressive symptoms and standardized mean difference (Hedges's g) in depression scores during each menopausal stage. RESULTS:The odds to develop a depression were not significantly higher during the perimenopause than in the premenopause (OR=1.78 95% CI=0.99-3.2; p=0.054). A higher risk was found on depressive symptoms during the perimenopause as compared to the premenopause (OR=2.0, 95% CI=1.48-2.71; p<0.001) but not compared to the postmenopause (OR=1.07, 95% CI=0.737-1.571; p=0.70). There was a higher symptom severity of depression in the perimenopause when compared to the premenopause (Hedges's g=0.44, 95% CI=0.11-0.73, p=0.007). The odds on vasomotor symptoms and depression were 2.25 (95% CI=1.14-3.35; p<0.001) during the perimenopause. LIMITATIONS:Time interval in measuring the depressive symptoms was different in studies. Menopausal symptoms possibly may have confounded our results by increasing the scores on depression questionnaires. Publication bias needs to be considered. CONCLUSION:The perimenopause is a phase in which women are particular vulnerable to develop depressive symptoms and have higher symptom severity compared to the premenopause. There are indications that vasomotor symptoms are positively related to depressive symptoms during menopausal transition.
Long-term hormone therapy for perimenopausal and postmenopausal women.
Marjoribanks Jane,Farquhar Cindy,Roberts Helen,Lethaby Anne,Lee Jasmine
The Cochrane database of systematic reviews
BACKGROUND: Hormone therapy (HT) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005.OBJECTIVES: To assess effects of long-term HT (at least 1 year's duration) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment.SEARCH METHODS: We searched the following databases to September 2016: Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO. We searched the registers of ongoing trials and reference lists provided in previous studies and systematic reviews.SELECTION CRITERIA: We included randomised double-blinded studies of HT versus placebo, taken for at least 1 year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via the oral, transdermal, subcutaneous or intranasal route.DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the quality of the evidence by using GRADE methods.MAIN RESULTS: We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well-conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women.In relatively healthy postmenopausal women (i.e. generally fit, without overt disease), combined continuous HT increased the risk of a coronary event (after 1 year's use: from 2 per 1000 to between 3 and 7 per 1000), venous thromboembolism (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000), stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000), breast cancer (after 5.6 years' use: from 19 per 1000 to between 20 and 30 per 1000), gallbladder disease (after 5.6 years' use: from 27 per 1000 to between 38 and 60 per 1000) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow-up: from 5 per 1000 to between 6 and 13 per 1000).Oestrogen-only HT increased the risk of venous thromboembolism (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000), stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000) and gallbladder disease (after 7 years' use: from 27 per 1000 to between 38 and 60 per 1000) but reduced the risk of breast cancer (after 7 years' use: from 25 per 1000 to between 15 and 25 per 1000) and clinical fracture (after 7 years' use: from 141 per 1000 to between 92 and 113 per 1000) and did not increase the risk of coronary events at any follow-up time.Women over 65 years of age who were relatively healthy and taking continuous combined HT showed an increase in the incidence of dementia (after 4 years' use: from 9 per 1000 to 11 to 30 per 1000). Among women with cardiovascular disease, use of combined continuous HT significantly increased the risk of venous thromboembolism (at 1 year's use: from 3 per 1000 to between 3 and 29 per 1000). Women taking HT had a significantly decreased incidence of fracture with long-term use.Risk of fracture was the only outcome for which strong evidence showed clinical benefit derived from HT (after 5.6 years' use of combined HT: from 111 per 1000 to between 79 and 96 per 1000; after 7.1 years' use of oestrogen-only HT: from 141 per 1000 to between 92 and 113 per 1000). Researchers found no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer.One trial analysed subgroups of 2839 relatively healthy women 50 to 59 years of age who were taking combined continuous HT and 1637 who were taking oestrogen-only HT versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT: Their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded, as this study was not designed to have the power to detect differences between groups of women within 10 years of menopause.For most studies, risk of bias was low in most domains. The overall quality of evidence for the main comparisons was moderate. The main limitation in the quality of evidence was that only about 30% of women were 50 to 59 years old at baseline, which is the age at which women are most likely to consider HT for vasomotor symptoms.AUTHORS' CONCLUSIONS: Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented.HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for prevention of deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable. Data are insufficient for assessment of the risk of long-term HT use in perimenopausal women and in postmenopausal women younger than 50 years of age.
Perimenopausal hormone therapy is associated with regional sparing of the CA1 subfield: a HUNT MRI study.
Pintzka Carl W S,Håberg Asta K
Neurobiology of aging
Observational studies support a neuroprotective role of hormone therapy (HT) in the perimenopause, with hippocampal size being a widely used biomarker. We investigated the effect of HT started before the onset of menopause and lasting for at least 3 years on hippocampal volume and shape in 80 postmenopausal women and 80 controls matched on age and intracranial volume taken from a large community-based sample (Nord-Trøndelag Health Study-magnetic resonance imaging). The main effect of hormone group showed a statistically significant difference in hippocampal volumes (p = 0.028). Both the right (3.2%) and left (2.8%) hippocampal volumes were larger in the HT group but only significant for the right hippocampus (p = 0.023). Shape analysis revealed significant regional sparing of the medial aspect of the right hippocampal head and lateral aspect of the body extending to the tail, corresponding to the cornu ammonis, including part of the subiculum, in the HT group. A similar nonsignificant pattern was observed in the left hippocampus. The present study provides support for the critical window theory demonstrating that HT initiated in the perimenopause has neuroprotective properties.
Changes in the regional homogeneity of resting-state magnetic resonance imaging in perimenopausal women.
Liu Min,Yang Hui,Qin Jian,Yao Qianqian,Yang Guihua,Li Jiang
BMC women's health
BACKGROUND:There is a noticeable lack of systematic researches on evaluating the correlation between serum estrogen levels and changes in brain functional areas of perimenopausal women.The aim of this study is to investigate the regional spontaneous brain activity changes in perimenopausal women. METHODS:Based on the resting-state functional magnetic resonance imaging datasets acquired from 25 perimenopausal women and 20 healthy women of reproductive age, a two-sample t-test was performed on individual normalized regional homogeneity (ReHo) maps. Relationships between abnormal ReHo values and the self-rating anxiety scale (SAS), the self-rating depression scale (SDS) were investigated with Pearson correlation analysis. We also investigated the correlation between abnormal ReHo values and serum estrogen level. RESULTS:In the perimenopausal group, we found increased ReHo in the right posterior cerebellum (region 2), left middle frontal gyrus and left middle cingulate gyrus ([Formula: see text]). Additionally, the ReHo values in left middle frontal gyrus and leftt middle cingulate gyrus showed positively significant correlation with the SAS, SDS scores. On the contrary, there was no significant correlation between the ReHo value in right posterior cerebellum and SDS, SAS scores. In the perimenopausal group, the ReHo values in the left middle frontal gyrus and left middle cingulate gyrus were negatively correlated with the serum estrogen level ([Formula: see text]). CONCLUSION:The results of this preliminary study have suggested that abnormal spontaneous activities of multiple brain regions during resting state was already altered in perimenopausal women. Alterative activities might be related to emotional regulation deficits and cognitive impairment, and might potentially represent the neural mechanism underlying perimenopausal period.
Shift in the brain network of emotional regulation in midlife women: is the menopausal transition the turning point?
Frey Benicio N,Hall Geoffrey B,Attard Stefanie,Yucel Kaan,Skelin Ivan,Steiner Meir,Soares Claudio N
Menopause (New York, N.Y.)
OBJECTIVE:The menopausal transition is marked by hormonal changes and is quite often accompanied by cognitive and emotional complaints. Recent data also suggest a heightened risk for depression. Little is known about the changes in emotional regulation that might contribute to the increased risk of depression in this population. The aim of this study was to examine the brain correlates of emotional regulation in healthy, nondepressed midlife women. METHODS:Functional magnetic resonance imaging was obtained in response to a standardized emotional regulation task. Levels of congruency were set and brain activation was measured during high- and low-conflict-resolution trials. RESULTS:Fourteen women aged 40 to 60 years were enrolled into the study, and 11 were included in the final analyses. Activity associated with resolution of emotional conflict was observed in the dorsolateral prefrontal cortex (P < 0.05). No regions were engaged in the generation/monitoring of emotional conflict. Moreover, there was a significant deactivation of the amygdala in response to fearful faces (P < 0.05). CONCLUSIONS:Unlike similar studies in younger populations, these results suggest a more significant engagement of the dorsolateral prefrontal cortex and less amygdala activation in emotional regulation in midlife women. These findings are, however, consistent with previous studies in older populations. We hypothesize that a shift in emotional regulation circuitry might therefore occur in women during the menopausal transition and possibly contribute to the occurrence of mood and anxiety symptoms in women during/after this period in life.
Perimenopausal use of hormone therapy is associated with enhanced memory and hippocampal function later in life.
Maki Pauline M,Dennerstein Lorraine,Clark Margaret,Guthrie Janet,LaMontagne Pamela,Fornelli Deanne,Little Deborah,Henderson Victor W,Resnick Susan M
Evidence suggests that initiation of some forms of hormone therapy (HT) early in the perimenopausal or postmenopausal stage might confer benefit to verbal memory and the neural systems underlying memory, whereas late-life initiation confers no benefit or harm. This "critical window hypothesis" remains a topic of debate. Using functional magnetic resonance imaging (fMRI), we examined the long-term impact of perimenopausal HT use on brain function during performance of verbal and figural memory tasks. Participants were 34 postmenopausal women (mean age 60 years) from the Melbourne Women's Midlife Health Project and included 17 early (perimenopausal) and continuous users of HT and 17 never users matched on age, education, and verbal knowledge. Continuous HT use from the perimenopausal stage versus no use was validated with prospective daily diary records and study visit data. The primary outcome was patterns of brain activation in an a priori region of interest in the medial temporal lobe during verbal encoding and recognition of words. Results indicated that perimenopausal HT users performed better than nonusers on the imaging verbal memory task (p<.05). During verbal recognition, perimenopausal HT users showed increased activation in the left hippocampus and decreased activation in the parahippocampal gyrus bilaterally compared with never users. Each of these patterns of activation was associated with better memory performance on the imaging memory task. These results suggest that perimenopausal use of HT might confer long-term benefits to verbal memory and the brain systems underlying verbal memory. More generally, the results support the critical window hypothesis.
Hormonal environment affects cognition independent of age during the menopause transition.
Berent-Spillson Alison,Persad Carol C,Love Tiffany,Sowers MaryFran,Randolph John F,Zubieta Jon-Kar,Smith Yolanda R
The Journal of clinical endocrinology and metabolism
CONTEXT:Cognitive decline is prevalent in aging populations, and cognitive complaints are common during menopause. However, the extent of hormonal influence is unclear, particularly when considered independent of the aging process. OBJECTIVE:We sought to determine differences in cognitive function attributable to menopause, hypothesizing that differences would be associated with reproductive rather than chronological age. DESIGN AND SETTING:In this cross-sectional study at a university hospital, we combined neuropsychological measures with functional magnetic resonance imaging to comprehensively assess cognitive function. PARTICIPANTS:Sixty-seven menopausal women, aged 42-61 yr, recruited from a population-based menopause study, grouped into menopause stages based on hormonal and cycle criteria (premenopause, perimenopause, and postmenopause), participated in the study. MAIN OUTCOME MEASURES:Neuropsychological and functional magnetic resonance imaging measures of verbal, visual, and executive cognitive function. RESULTS:We found age-independent menopause effects on verbal function. Menopause groups differed in phonemic verbal fluency (F = 3.58, P < 0.019) and regional brain activation (inferior frontal cortex: corrected P < 0.000 right, P < 0.036 left; left prefrontal cortex: P < 0.012); left temporal pole: P < 0.001). Verbal measures correlated with estradiol and FSH (phonemic fluency: R = 0.249, P < 0.047 estradiol, R = -0.275, P < 0.029 FSH; semantic fluency: R = 0.318, P < 0.011 estradiol, R = -0.321, P < 0.010 FSH; right inferior frontal cortex: R = 0.364, P < 0.008 FSH; left inferior frontal cortex: R = -0.431, P < 0.001 estradiol, left prefrontal cortex: R = 0.279, P < 0.045 FSH; left temporal pole: R = -0.310, P < 0.024 estradiol, R = 0.451, P < 0.001 FSH; left parahippocampal gyrus: R = -0.278, P < 0.044 estradiol; left parietal cortex: R = -0.326, P < 0.017 estradiol). CONCLUSIONS:Results suggest that verbal fluency mechanisms are vulnerable during the menopausal transition. Targeted intervention may preserve function of this critical cognitive domain.
Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women.
Joffe Hadine,Hall Janet E,Gruber Staci,Sarmiento Ingrid A,Cohen Lee S,Yurgelun-Todd Deborah,Martin Kathryn A
Menopause (New York, N.Y.)
OBJECTIVE:Estrogen therapy (ET) seems to differentially effect cognitive processes in younger versus older postmenopausal women, suggesting a window of opportunity when ET is most beneficial. Cognitive improvement in younger postmenopausal women has been attributed to ET's influence on hot flushes and sleep, but empiric examination of the mediating role of menopause symptoms versus direct effects of ET on the brain is limited. DESIGN:In a double-blind trial, 52 women were randomly assigned to estradiol 0.05 mg/day (n = 26) or placebo transdermal patches (n = 26) for 12 weeks. Women completed tests of memory, learning, and executive functioning, and hot flush and sleep assessments at baseline and study end. A subset of women (five ET treated, six placebo treated) also underwent blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. RESULTS:Nondepressed perimenopausal and postmenopausal women were studied. The majority had hot flushes and sleep impairment. Compared with placebo, ET selectively reduced errors of perseveration during verbal recall (P = 0.03), a frontal system-mediated function, but did not influence other cognitive processes. Women with baseline hot flushes had greater cognitive benefit with ET (P < 0.05). Cognitive benefit was not associated with sleep problems or its improvement. Measures of fMRI BOLD activation during tests of verbal and spatial working memory showed significant increases in frontal system activity with ET (P < 0.001). CONCLUSIONS:Estrogen therapy selectively improves executive functioning as demonstrated by reduced perseverative errors and prefrontal cortex activation during verbal recall tasks. Cognitive improvement with ET is associated with hot flushes, but not with sleep, suggesting that ET has a direct central nervous system effect, rather than an indirect effect mediated through improvement of sleep.
Effect of Sex Hormones on Brain Connectivity Related to Sexual Function in Perimenopausal Women: A Resting-State fMRI Functional Connectivity Study.
Lu Weizhao,Guo Wei,Cui Dong,Dong Kejiang,Qiu Jianfeng
The journal of sexual medicine
BACKGROUND:Perimenopause is associated with increased risk of depression, vasomotor symptoms, and sexual dysfunction. AIMS:To explore the effect of sex hormones on the functional connectivity (FC) of different brain regions related to sexual function in perimenopausal women. METHODS:32 premenopausal women (mean age, 47.75 ± 1.55 years) and 25 perimenopausal women (mean age, 51.60 ± 1.63 years) underwent sex hormone level measurements and resting-state fMRI. MAIN OUTCOME MEASURES:Serum levels of sex hormones, including prolactin (PRL), follicle-stimulating hormone (FSH), luteotropic hormone (LH), estradiol (E2), free testosterone (free-T), and progesterone (P), were measured. 10 brain regions related to sexual function were selected according to a meta-analysis, and FCs of the selected regions of interest were calculated as Pearson's correlation coefficient. RESULTS:Compared with premenopausal women, perimenopausal women showed increased FC between the right area 13 (A13_r) and the right medial superior frontal gyrus (mSFG), between the left dorsal granular insula (dIg_L) and the right superior frontal gyrus (SFG) (Gaussian random field-corrected at the voxel level, P < .001, and cluster level, P < .025). Furthermore, the PRL level was negatively correlated with the FC of A13_R with the right mSFG and the FC of dIg_L with the right SFG. CLINICAL TRANSLATION:These findings may be applicable to assessing brain dysfunction with FC changes in women approaching menopause. STRENGTHS & LIMITATIONS:This study is the first to evaluate a direct relationship between sex hormone levels and brain FC changes in women approaching menopause. Sexual function was not assessed, which may weaken the conclusions related to sexual function. CONCLUSIONS:The results show that women approaching menopause suffered from aberrant intrinsic FC in regions related to sexual function, and reveal a direct relationship between serum sex hormone levels and FC changes related to sexual function. Lu W, Guo W, Cui D, et al. Effect of Sex Hormones on Brain Connectivity Related to Sexual Function in Perimenopausal Women: A Resting-State fMRI Functional Connectivity Study. J Sex Med 2019;16:711-720.
Sex and Gender Driven Modifiers of Alzheimer's: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks.
Rahman Aneela,Jackson Hande,Hristov Hollie,Isaacson Richard S,Saif Nabeel,Shetty Teena,Etingin Orli,Henchcliffe Claire,Brinton Roberta Diaz,Mosconi Lisa
Frontiers in aging neuroscience
Research indicates that after advanced age, the major risk factor for late-onset Alzheimer's disease (AD) is female sex. Out of every three AD patients, two are females with postmenopausal women contributing to over 60% of all those affected. Sex- and gender-related differences in AD have been widely researched and several emerging lines of evidence point to different vulnerabilities that contribute to dementia risk. Among those being considered, it is becoming widely accepted that gonadal steroids contribute to the gender disparity in AD, as evidenced by the "estrogen hypothesis." This posits that sex hormones, 17β-estradiol in particular, exert a neuroprotective effect by shielding females' brains from disease development. This theory is further supported by recent findings that the onset of menopause is associated with the emergence of AD-related brain changes in women in contrast to men of the same age. In this review, we discuss genetic, medical, societal, and lifestyle risk factors known to increase AD risk differently between the genders, with a focus on the role of hormonal changes, particularly declines in 17β-estradiol during the menopause transition (MT) as key underlying mechanisms.
Grey matter differences associated with age and sex hormone levels between premenopausal and perimenopausal women: A voxel-based morphometry study.
Lu Weizhao,Guo Wei,Hou Kun,Zhao Huihui,Shi Liting,Dong Kejiang,Qiu Jianfeng
Journal of neuroendocrinology
The present study aimed to explore brain morphological alterations associated with age and sex hormone levels between premenopausal and perimenopausal women using magnetic resonance imaging (MRI) T -weighted structural images. Thirty-two premenopausal women aged (mean ± SD) 47.75 ± 1.55 years and twenty-five recently perimenopausal women aged 51.60 ± 1.63 years were evaluated for sex hormone levels, including prolactin, follicle-stimulating hormone, luteinising hormone, oestradiol, free testosterone and progesterone. A 3.0-Tesla MRI scanner was utilised to acquire T images. Voxel-based morphometry (VBM) was used to evaluate changes in grey matter volume between the two groups. The general linear model was applied with false discovery rate correction for between group voxel-wise statistics. Spearman partial correlation analyses were conducted between age, sex hormone levels and regions of grey matter volume showing significant differences between the two groups. The VBM analysis revealed that age and menopause per se lead to grey matter volume reduction in certain brain structures. These structural changes might be potential causes of sexual dysfunction, nervous system degeneration and depression, which need to be examined in future studies. Our findings might provide evidence and guide future research in understanding the menopausal transition.
Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery.
Mosconi Lisa,Berti Valentina,Quinn Crystal,McHugh Pauline,Petrongolo Gabriella,Osorio Ricardo S,Connaughty Christopher,Pupi Alberto,Vallabhajosula Shankar,Isaacson Richard S,de Leon Mony J,Swerdlow Russell H,Brinton Roberta Diaz
After advanced age, female sex is the major risk factor for Alzheimer's disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40-60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p's<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson's 0.26≤r≤0.32, p≤0.05). These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
The Role of Estrogen in Brain and Cognitive Aging.
Russell Jason K,Jones Carrie K,Newhouse Paul A
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models. Furthermore, E2 interactions have been indicated in a number of neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. In normal brain aging, there are a number of systems that undergo changes and a number of these show interactions with E2, particularly the cholinergic system, the dopaminergic system, and mitochondrial function. E2 treatment has been shown to ameliorate some of the behavioral and morphological changes seen in preclinical models of menopause; however, in clinical populations, the effects of E2 treatment on cognitive changes after menopause are mixed. The future use of sex hormone treatment will likely focus on personalized or precision medicine for the prevention or treatment of cognitive disturbances during aging, with a better understanding of who may benefit from such treatment.
Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.
Mosconi Lisa,Berti Valentina,Quinn Crystal,McHugh Pauline,Petrongolo Gabriella,Varsavsky Isabella,Osorio Ricardo S,Pupi Alberto,Vallabhajosula Shankar,Isaacson Richard S,de Leon Mony J,Brinton Roberta Diaz
OBJECTIVE:This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS:Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology). RESULTS:As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions ( < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women ( < 0.001). Aβ deposition was exacerbated in -positive MENO women relative to the other groups ( < 0.001). CONCLUSIONS:Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory.
Koebele Stephanie V,Bimonte-Nelson Heather A
Female mammals undergo natural fluctuations in sex steroid hormone levels throughout life. These fluctuations span from early development, to cyclic changes associated with the menstrual or estrous cycle and pregnancy, to marked hormone flux during perimenopause, and a final decline at reproductive senescence. While the transition to reproductive senescence is not yet fully understood, the vast majority of mammals experience this spontaneous, natural phenomenon with age, which has broad implications for long-lived species. Indeed, this post-reproductive life stage, and its transition, involves significant and enduring physiological changes, including considerably altered sex steroid hormone and gonadotropin profiles that impact multiple body systems, including the brain. The endocrine-brain-aging triad is especially noteworthy, as many paths meet and interact. Many of the brain regions affected by aging are also sensitive to changes in ovarian hormone levels, and aging and reproductive senescence are both associated with changes in memory performance. This review explores how menopause is related to cognitive aging, and discusses some of the key neural systems and molecular factors altered with age and reproductive hormone level changes, with an emphasis on brain regions important for learning and memory.
Female Sex and Alzheimer's Risk: The Menopause Connection.
Scheyer O,Rahman A,Hristov H,Berkowitz C,Isaacson R S,Diaz Brinton R,Mosconi L
The journal of prevention of Alzheimer's disease
Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer's disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40-60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.
Dopamine-dependent cognitive processes after menopause: the relationship between COMT genotype, estradiol, and working memory.
Dumas Julie A,Makarewicz Jenna A,Bunn Janice,Nickerson Joshua,McGee Elizabeth
Neurobiology of aging
The present study examined how a gene related to functioning of the dopaminergic system, catechol-O-methyltransferase (COMT), and estradiol were related to brain functioning in healthy postmenopausal women. Participants were 118 healthy, cognitively normal postmenopausal women between the ages of 50-60 years. All women provided a blood sample for COMT and estradiol analyses and underwent a magnetic resonance imaging scan. Working memory performance and related brain activation were measured with BOLD functional magnetic resonance imaging during the N-back task. Results were examined across each COMT genotype and a median split was performed on the circulating estradiol levels to create high and low estradiol groups for each genotype. COMT genotype and estradiol level were hypothesized to be proxy measures for brain dopamine levels with the Met/Met and high estradiol group having the most dopamine and Val/Val and low estradiol group having the least dopamine. The functional magnetic resonance imaging results showed that the N-back task activated the expected bilateral frontal and bilateral parietal working memory network. However, no main effects of COMT genotype or estradiol group were found. There was COMT-estradiol interaction found in a small area of decreased activation in the right precentral gyrus (Brodmann Area 6) that was related to the increasing hypothesized dopamine level. Specifically, women with a Met/Met genotype in the high estradiol group had the least activation in this frontal lobe working memory region. Women with a Val/Val genotype in the low estradiol group had greater activation in this region relative to the other groups. Performance on the N-back task did not show any group differences. These data indicate that after menopause COMT genotype and potentially the menopause-related changes to the dopaminergic system are not related to cognition. Future studies should examine how the relationship between COMT, estradiol, and cognition around the menopause transition as there appear to be differences in this relationship for premenopausal and postmenopausal women.
Impact of Sex and Menopausal Status on Episodic Memory Circuitry in Early Midlife.
Jacobs Emily G,Weiss Blair K,Makris Nikos,Whitfield-Gabrieli Sue,Buka Stephen L,Klibanski Anne,Goldstein Jill M
The Journal of neuroscience : the official journal of the Society for Neuroscience
UNLABELLED:Cognitive neuroscience of aging studies traditionally target participants age 65 and older. However, epidemiological surveys show that many women report increased forgetfulness earlier in the aging process, as they transition to menopause. In this population-based fMRI study, we stepped back by over a decade to characterize the changes in memory circuitry that occur in early midlife, as a function of sex and women's reproductive stage. Participants (N = 200; age range, 45-55) performed a verbal encoding task during fMRI scanning. Reproductive histories and serologic evaluations were used to determine menopausal status. Results revealed a pronounced impact of reproductive stage on task-evoked hippocampal responses, despite minimal difference in chronological age. Next, we examined the impact of sex and reproductive stage on functional connectivity across task-related brain regions. Postmenopausal women showed enhanced bilateral hippocampal connectivity relative to premenopausal and perimenopausal women. Across women, lower 17β-estradiol concentrations were related to more pronounced alterations in hippocampal connectivity and poorer performance on a subsequent memory retrieval task, strongly implicating sex steroids in the regulation of this circuitry. Finally, subgroup analyses revealed that high-performing postmenopausal women (relative to low and middle performers) exhibited a pattern of brain activity akin to premenopausal women. Together, these findings underscore the importance of considering reproductive stage, not simply chronological age, to identify neuronal and cognitive changes that unfold in the middle decades of life. In keeping with preclinical studies, these human findings suggest that the decline in ovarian estradiol production during menopause plays a significant role in shaping memory circuitry. SIGNIFICANCE STATEMENT:Maintaining intact memory function with age is one of the greatest public health challenges of our time, and women have an increased risk for memory disorders relative to men later in life. We studied adults early in the aging process, as women transition into menopause, to identify neuronal and cognitive changes that unfold in the middle decades of life. Results demonstrate regional and network-level differences in memory encoding-related activity as a function of women's reproductive stage, independent of chronological age. Analyzing data without regard to sex or menopausal status obscured group differences in circuit-level neural strategies associated with successful memory retrieval. These findings suggest that early changes in memory circuitry are evident decades before the age range traditionally targeted by cognitive neuroscience of aging studies.
Cognition and the menopause transition.
Maki Pauline M,Henderson Victor W
Menopause (New York, N.Y.)
Complaints about forgetfulness, "brain fog," and difficulty concentrating are common in women transitioning through menopause. Women with these cognitive complaints often express concern about whether these problems are normal, related to menopause, or represent a symptom of Alzheimer disease or another serious cognitive disorder. In this Practice Pearl, we provide a brief summary of the scientific literature on the frequency of cognitive complaints in midlife women, the validity of complaints in relation to performance on standardized cognitive tests, and the influence of menopause on cognitive performance. We then offer recommendations for healthcare providers and women to address cognitive concerns.
Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory.
Koebele Stephanie V,Mennenga Sarah E,Hiroi Ryoko,Quihuis Alicia M,Hewitt Lauren T,Poisson Mallori L,George Christina,Mayer Loretta P,Dyer Cheryl A,Aiken Leona S,Demers Laurence M,Carson Catherine,Bimonte-Nelson Heather A
Hormones and behavior
Cognitive changes that occur during mid-life and beyond are linked to both aging and the menopause transition. Studies in women suggest that the age at menopause onset can impact cognitive status later in life; yet, little is known about memory changes that occur during the transitional period to the postmenopausal state. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of perimenopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the trajectory of cognitive change across time with normal aging and aging with transitional menopause via VCD-induced follicular depletion, as well as to evaluate whether age at the onset of follicular depletion plays a role in cognitive outcomes. Animals experiencing the onset of menopause at a younger age exhibited impaired spatial memory early in the transition to a follicle-deplete state. Additionally, at the mid- and post- follicular depletion time points, VCD-induced follicular depletion amplified an age effect on memory. Overall, these findings suggest that age at the onset of menopause is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study illustrates how age at menopause onset might impact cognition in menopausal women, and provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition period. Hormone therapy during this critical juncture might be especially efficacious at attenuating age- and menopause- related cognitive decline, producing healthy brain aging profiles in women who retain their ovaries throughout their lifespan.
Estrogen receptor β deficiency impairs BDNF-5-HT signaling in the hippocampus of female brain: A possible mechanism for menopausal depression.
Chhibber Anindit,Woody Sarah K,Karim Rumi M A,Soares Michael J,Zhao Liqin
Depression currently affects 350 million people worldwide and 19 million Americans each year. Women are 2.5 times more likely to experience major depression than men, with some women appearing to be at a heightened risk during the menopausal transition. Estrogen signaling has been implicated in the pathophysiology of mood disorders including depression; however, the underlying mechanisms are poorly understood. In this study, the role of estrogen receptor (ER) subtypes, ERα and ERβ, in the regulation of brain-derived neurotrophic factor (BDNF) and serotonin (5-HT) signaling was investigated; two pathways that have been hypothesized to be interrelated in the etiology of depression. The analyses in ERα and ERβ mouse models demonstrated that BDNF was significantly downregulated in ERβ but not ERα mice, and the ERβ-mediated effect was brain-region specific. A 40% reduction in BDNF protein expression was found in the hippocampus of ERβ mice; in contrast, the changes in BDNF were at a much smaller magnitude and insignificant in the cortex and hypothalamus. Further analyses in primary hippocampal neurons indicated that ERβ agonism significantly enhanced BDNF/TrkB signaling and the downtream cascades involved in synaptic plasticity. Subsequent study in ERβ mutant rat models demonstrated that disruption of ERβ was associated with a significantly elevated level of 5-HT but not 5-HT in rat hippocampus, indicating ERβ negatively regulates 5-HT. Additional analyses in primary neuronal cultures revealed a significant association between BDNF and 5-HT pathways, and the data showed that TrkB activation downregulated 5-HT whereas activation of 5-HT had no effect on BDNF, suggesting that BDNF/TrkB is an upstream regulator of the 5-HT pathway. Collectively, these findings implicate that the disruption in estrogen homeostasis during menopause leads to dysregulation of BDNF-5-HT signaling and weakened synaptic plasticity, which together predispose the brain to a vulnerable state for depression. Timely intervention with an ERβ-targeted modulator could potentially attenuate this susceptibility and reduce the risk or ameliorate the clinical manifestation of this brain disorder.
Increased Alzheimer's risk during the menopause transition: A 3-year longitudinal brain imaging study.
Mosconi Lisa,Rahman Aneela,Diaz Ivan,Wu Xian,Scheyer Olivia,Hristov Hollie Webb,Vallabhajosula Shankar,Isaacson Richard S,de Leon Mony J,Brinton Roberta Diaz
Two thirds of all persons with late-onset Alzheimer's disease (AD) are women. Identification of sex-based molecular mechanisms underpinning the female-based prevalence of AD would advance development of therapeutic targets during the prodromal AD phase when prevention or delay in progression is most likely to be effective. This 3-year brain imaging study examines the impact of the menopausal transition on Alzheimer's disease (AD) biomarker changes [brain β-amyloid load via 11C-PiB PET, and neurodegeneration via 18F-FDG PET and structural MRI] and cognitive performance in midlife. Fifty-nine 40-60 year-old cognitively normal participants with clinical, neuropsychological, and brain imaging exams at least 2 years apart were examined. These included 41 women [15 premenopausal controls (PRE), 14 perimenopausal (PERI), and 12 postmenopausal women (MENO)] and 18 men. We used targeted minimum loss-based estimation to evaluate AD biomarker and cognitive changes. Older age was associated with baseline Aβ and neurodegeneration markers, but not with rates of change in these biomarkers. APOE4 status influenced change in Aβ load, but not neurodegenerative changes. Longitudinally, MENO and PERI groups showed declines in estrogen-dependent memory tests as compared to men (p < .04). Adjusting for age, APOE4 status, and vascular risk confounds, the MENO and PERI groups exhibited higher rates of CMRglc decline as compared to males (p ≤ .015). The MENO group exhibited the highest rate of hippocampal volume loss (p's ≤ .001), and higher rates of Aβ deposition than males (p < .01). CMRglc decline exceeded Aβ and atrophy changes in all female groups vs. men. These findings indicate emergence and progression of a female-specific hypometabolic AD-endophenotype during the menopausal transition. These findings suggest that the optimal window of opportunity for therapeutic intervention to prevent or delay progression of AD endophenotype in women is early in the endocrine aging process.
Cognition, Mood and Sleep in Menopausal Transition: The Role of Menopause Hormone Therapy.
Gava Giulia,Orsili Isabella,Alvisi Stefania,Mancini Ilaria,Seracchioli Renato,Meriggiola Maria Cristina
Medicina (Kaunas, Lithuania)
During the menopausal transition, which begins four to six years before cessation of menses, middle-aged women experience a progressive change in ovarian activity and a physiologic deterioration of hypothalamic-pituitary-ovarian axis function associated with fluctuating hormone levels. During this transition, women can suffer symptoms related to menopause (such as hot flushes, sleep disturbance, mood changes, memory complaints and vaginal dryness). Neurological symptoms such as sleep disturbance, "brain fog" and mood changes are a major complaint of women transitioning menopause, with a significant impact on their quality of life, productivity and physical health. In this paper, we consider the associations between menopausal stage and/or hormone levels and sleep problems, mood and reduced cognitive performance. The role of estrogen and menopause hormone therapy (MHT) in cognitive function, sleep and mood are also discussed.