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There has been a proliferation of studies demonstrating important sex differences in cognitive aging and dementia, and with this an increased interest in the role of menopause and sex steroid hormones in women's brain health. Foundational longitudinal studies of cognitive changes from the premenopause to perimenopause stage have shown reliable declines in verbal memory, with variable findings in processing speed, attention/working memory and verbal fluency. Continued research is needed to advance understanding of the range of cognitive domains affected, the duration of cognitive changes, the generalizability of these changes across cultures, the factors that account for such changes and the factors that can improve cognition at this time. In this article, we briefly review and draw on findings from large longitudinal studies of cognitive changes across the menopause transition to inform the design of future studies on this topic. We focus on key issues such as objective versus subjective cognitive measures; cognitive domains and tests; staging menopause; study design; mediators of cognitive effects (including hormones and menopause symptoms); and consideration of key covariates. We suggest that a more uniform and evidence-based approach to the investigation of these issues can advance the quality of the science in menopause and cognition.

Objective: Perimenopause is associated with declines in attention, working memory and verbal memory; however, there are significant individual differences. Further, the contributions of hormones and menopausal symptoms to domain-specific cognitive functions remain unknown. This longitudinal study aimed to determine whether there were distinct cognitive profiles in perimenopause and to identify factors associated with each profile., Design: In a sample of 85 women evaluated over 400 bi-annual visits, we administered a comprehensive neuropsychological battery, assessed menopausal symptoms and measured 17β-estradiol and follicle stimulating hormone. Multilevel latent profile analysis was used to identify cognitive profiles. Regressions were conducted to determine differences in hormones and symptoms by profile after adjusting for Stages of Reproductive Aging Workshop + 10 (STRAW + 10) stage and demographic factors., Results: Perimenopausal cognitive profiles consisted of cognitively normal (Profile 1; n  = 162), weaknesses in verbal learning and memory (Profile 2; n  = 94), strengths in verbal learning and memory (Profile 3; n  = 98) and strengths in attention and executive function (Profile 4; n  = 61). Profile 2 was differentiated by less hormonal variability and more sleep disturbance than Profile 1 ( p  < 0.05)., Conclusions: There is significant heterogeneity in cognition during perimenopause. While most women do not develop impairments, a significant minority experience weaknesses in verbal learning and memory. Profile analysis may identify at-risk populations and inform interventions.

BACKGROUNDIdentifying a quantitative biomarker of neuropsychiatric dysfunction in people with HIV (PWH) remains a significant challenge in the neuroHIV field. The strongest evidence to date implicates the role of monocytes in central nervous system (CNS) dysfunction in HIV, yet no study has examined monocyte subsets in blood as a correlate and/or predictor of neuropsychiatric function in virally suppressed PWH.METHODSIn 2 independent cohorts of virologically suppressed women with HIV (vsWWH; n = 25 and n = 18), whole blood samples were obtained either in conjunction with neuropsychiatric assessments (neuropsychological [NP] test battery, self-report depression and stress-related symptom questionnaires) or 1 year prior to assessments. Immune cell subsets were assessed by flow cytometry.RESULTSA higher proportion of intermediate monocytes (CD14+CD16+) was associated with lower global NP function when assessing monocytes concurrently and approximately 1 year before (predictive) NP testing. The same pattern was seen for executive function (mental flexibility) and processing speed. Conversely, there were no associations with monocyte subsets and depression or stress-related symptoms. Additionally, we found that a higher proportion of classical monocytes was associated with better cognition.CONCLUSIONAlthough it is widely accepted that lentiviral infection of the CNS targets cells of monocyte-macrophage-microglial lineage and is associated with an increase in intermediate monocytes in the blood and monocyte migration into the brain, the percentage of intermediate monocytes in blood of vsWWH has not been associated with neuropsychiatric outcomes. Our findings provide evidence for a new, easily measured, blood-based cognitive biomarker in vsWWH.FUNDINGR01-MH113512, R01-MH113512-S, P30-AI094189, R01-MH112391, R01-AI127142, R00-DA044838, U01-AI35004, and P30-MH075673.

BackgroundDespite a female advantage in verbal memory, normative data for verbal memory tests used to diagnose Alzheimer's disease (AD) dementia and amnestic mild cognitive impairment (aMCI) often are not sex-adjusted.ObjectiveTo determine whether sex-adjusted norms improve aMCI diagnostic accuracy when accuracy was evaluated by progression to AD dementia over time.MethodsNon-sex-specific and sex-specific verbal memory test norms were incorporated into Jak/Bondi aMCI criteria and applied to older (age 65-90) non-demented women (N = 1,036) and men (N = 355) from the Rush Memory and Aging Project. Using sex-specific aMCI diagnosis as the "true" condition versus non-sex-specific aMCI diagnosis as the "predicted" condition, we identified True Positives, False Positives, True Negatives, and False Negatives and compared AD dementia risk over 10 years among groups.ResultsRates of aMCI were higher in men versus women (χ2 = 15.39, p < 0.001) when determined based on typical diagnostic criteria, but this difference reversed when using sex-specific diagnostic criteria (χ2 = 8.38, p = 0.004). We identified 8%of women as False Negatives and 12%of men as False Positives. Risk of incident AD dementia in False Positive men was significantly lower than in True Positive men (HR = 0.26, 95%CI = 0.12-0.58, p = 0.001). Risk of incident AD dementia in False Negative women was substantially higher than in True Negative women (HR = 3.11, 95%CI = 2.09-4.63, p < 0.001).ConclusionResults suggest that previous reports of higher aMCI rates in men versus women may be an artifact of non-sex-adjusted norms/cut-scores. Incorporation of sex-specific norms/cut-scores for verbal memory impairment into aMCI diagnostic criteria may improve diagnostic accuracy and avoid diagnostic errors in approximately 20%.

Objective: Studies, conducted largely in North America and Europe, demonstrate that menopausal symptoms and menopausal stage influence cognitive function. Here, we evaluate these associations in a large cohort of sub-Saharan African women, a population where these associations are understudied. We hypothesized that premenopausal women would show better cognitive performance than women later in the transition, and that menopausal symptoms would be inversely related to cognition. Methods: This cross-sectional study included 702 black urban South African women between the ages of 40 and 60 years from the Study of Women Entering and in Endocrine Transition. Participants completed the Symbol Digit Modalities Test, a measure of processing speed and incidental recall. Menopausal stage was ascertained using the Stages of Reproductive Aging Workshop+ 10 criteria and symptoms using the Menopause Rating Scale. Multivariable linear regression analyses were used to examine adjusted associations between menopausal stage and menopausal symptoms on cognitive performance. Results: In adjusted analyses, menopausal stage was not associated with processing speed ( p  = 0.35) or incidental recall ( p  = 0.64). However, more severe symptoms of hot flushes and anxiety were associated with slower processing speed (all p  < 0.05), and more severe mood symptoms were associated with worse incidental recall ( p  = 0.008). Conclusion: Menopausal symptoms, but not menopausal stage, were associated with cognitive function in this cross-sectional study of sub-Saharan African women.

Purpose: To determine if a larger cup-to-disc ratio is associated with poor cognitive function in postmenopausal women without glaucoma or ocular hypertension., Methods: We used data from the Women's Health Initiative (WHI) hormone trial, originally designed to test effects of hormone therapy (HT) on various health outcomes. Large cup-to-disc ratio was defined as greater than 0.6 in either eye based on stereoscopic optic nerve photographs. Global cognitive function was assessed annually by Modified Mini-Mental State Examination (3MSE) in the WHI Memory Study. Exclusions were no information on optic nerve grading; no 3MSE scores at the time of the eye examination, ocular hypertension (intraocular pressure >23 mm Hg, Goldmann applanation tonometry), or glaucoma medication use. A generalized linear model for log-transformed 3MSE scores was used for determining the association between large cup-to-disc ratio and 3MSE scores, adjusting for age, race, diabetes, body mass index, cardiovascular disease, smoking, HT randomization, education, and diabetic retinopathy., Results: Analyses included 1636 women (mean age ± standard deviation, 69.57 ± 3.64 years; 90.39% white). Of those, 122 women had large cup-to-disc ratio. The mean 3MSE scores in women with vs without large cup-to-disc ratio were 95.4 ± 6 vs 96.6 ± 5. In the adjusted model, women with large cup-to-disc ratio had statistically significantly lower 3MSE scores, compared with those without large cup-to-disc ratio, yielding the predicted mean difference in 3MSE scores of 0.75 with a standard error of 0.05 units (P = .04)., Conclusions: Postmenopausal women who had large cup-to-disc ratio without glaucoma or ocular hypertension exhibited lower global cognitive function. Further investigation is warranted. NOTE: Publication of this article is sponsored by the American Ophthalmological Society., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose of Review: Sex differences in cognitive function are well documented yet few studies had adequate numbers of women and men living with HIV (WLWH; MLWH) to identify sex differences in neurocognitive impairment (NCI) and the factors contributing to NCI. Here, we review evidence that WLWH may be at greater risk for NCI., Recent Findings: We conducted a systematic review of recent studies of NCI in WLWH versus MLWH. A power analysis showed that few HIV studies have sufficient power to address male/female differences in NCI but studies with adequate power find evidence of greater NCI in WLWH, particularly in the domains of memory, speed of information processing, and motor function. Sex is an important determinant of NCI in HIV, and may relate to male/female differences in cognitive reserve, comorbidities (mental health and substance use disorders), and biological factors (e.g., inflammation, hormonal, genetic).

Background: Women may be more vulnerable to HIV-related cognitive dysfunction compared with men because of sociodemographic, lifestyle, mental health, and biological factors. However, studies to date have yielded inconsistent findings on the existence, magnitude, and pattern of sex differences. We examined these issues using longitudinal data from 2 large, prospective, multisite, observational studies of US women and men with and without HIV., Setting: The Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS)., Methods: HIV-infected (HIV+) and uninfected (HIV-) participants in the Women's Interagency HIV Study and Multicenter AIDS Cohort Study completed tests of psychomotor speed, executive function, and fine motor skills. Groups were matched on HIV status, sex, age, education, and black race. Generalized linear mixed models were used to examine group differences on continuous and categorical demographically corrected T-scores. Results were adjusted for other confounding factors., Results: The sample (n = 1420) included 710 women (429 HIV+) and 710 men (429 HIV+) (67% non-Hispanic black; 53% high school or less). For continuous T-scores, sex by HIV serostatus interactions were observed on the Trail Making Test parts A & B, Grooved Pegboard, and Symbol Digit Modalities Test. For these tests, HIV+ women scored lower than HIV+ men, with no sex differences in HIV- individuals. In analyses of categorical scores, particularly the Trail Making Test part A and Grooved Pegboard nondominant, HIV+ women also had a higher odds of impairment compared with HIV+ men. Sex differences were constant over time., Conclusions: Although sex differences are generally understudied, HIV+ women vs men show cognitive disadvantages. Elucidating the mechanisms underlying these differences is critical for tailoring cognitive interventions.

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.

Background: In women with schizophrenia, cognition has been shown to be enhanced following administration of hormone therapy or oxytocin. We examined how natural hormonal changes across the menstrual cycle influence cognition in women with schizophrenia. We hypothesized that female patients would perform worse on "female-dominant" tasks (verbal memory/fluency) and better on "male-dominant" tasks (visuospatial) during the early follicular phase (low estradiol and progesterone) compared to midluteal phase (high estradiol and progesterone) in relation to estradiol but not progesterone., Methods: Fifty-four women (23 with schizophrenia) completed cognitive assessments and provided blood for sex steroid assays and oxytocin at early follicular (days 2-4) and midluteal (days 20-22) phases. Men were included to verify the expected pattern of sex differences on cognitive tests., Results: Expected sex differences were observed on "female-dominant" and "male-dominant" tasks (p<0.001), but the magnitude of those differences did not differ between patients and controls (p=0.44). Cognitive performance did not change across the menstrual cycle on "female-dominant" or "male-dominant" tasks in either group. Estradiol and progesterone levels were unrelated to cognitive performance. Oxytocin levels did not change across the menstrual cycle but were positively related to performance on "female-dominant" tasks in female patients only (p<0.05)., Conclusions: Sex differences in cognitive function are preserved in schizophrenia. Oxytocin levels do not change across the cycle, but relate to enhanced performance on female dominant tests in women. Physiological levels of oxytocin may thus have a more powerful benefit in some cognitive domains than estrogens in schizophrenia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: We evaluated the separate and interactive associations of menopausal stage, menopausal symptoms, and human immunodeficiency virus (HIV) infection with cognition. We hypothesized that HIV-infected perimenopausal women would show the greatest cognitive difficulties and that menopausal symptoms would be inversely associated with cognition., Methods: This cross-sectional study included 708 HIV-infected and 278 HIV-uninfected premenopausal, perimenopausal, or postmenopausal women (64% African American; median age, 44 y) from the Women's Interagency HIV Study. Participants completed tests of verbal learning and memory, attention/processing speed, and executive function. We administered a menopausal symptom questionnaire that assessed anxiety, vasomotor, and sleep symptoms and obtained measures of depressive symptoms., Results: In multivariable regression analyses controlling for relevant covariates, HIV infection, but not menopausal stage, was associated with worse performance on all cognitive measures (P's < 0.05). Depressive symptoms were associated with lower cognitive performance on measures of verbal learning and memory, attention, and executive function (P's < 0.05); anxiety symptoms were associated with lower performance on measures of verbal learning and memory (P's < 0.05). Vasomotor symptoms were associated with worse attention (P < 0.05). HIV and anxiety symptoms interacted to influence verbal learning (P's < 0.05); elevated anxiety was associated with worse verbal learning in HIV-infected women only., Conclusions: Vasomotor, depressive, and anxiety symptoms, but not menopausal stage, are associated with worse cognitive performance in both HIV-infected and HIV-uninfected women, although elevated anxiety symptoms are more associated with verbal learning deficits in HIV-infected women. Because cognitive problems can interfere with everyday functioning, including treatment adherence, it may be important to screen and treat anxiety in HIV-infected women.

Objective: It is suggested that declines in estrogen around menopause are associated with declines in cognitive functioning as well as increased risk of depressive symptoms and depressive disorders. Existing studies of objective cognitive function and mood have differed in the criteria used to stage the menopausal transition and in the outcome measures used. The purpose of this review was to synthesize the existing studies of the relationship between menopausal stage and neuropsychological performance and depression., Design: A search of the literature of observational studies was performed using PubMed. Four cross-sectional studies on menopausal transition stage and cognitive function and four longitudinal studies on menopausal transition stage and risk of depression, as measured by symptom inventories and structured clinical interviews, were selected. For the cognitive outcomes, fixed effects models were used to estimate overall standardized effect sizes. For the depression outcomes, the results of group comparisons were summarized using the log odds ratio and its estimated standard error., Results: Postmenopausal women performed significantly worse than pre- and perimenopausal women on delayed verbal memory tasks, and significantly worse than perimenopausal women on phonemic verbal fluency tasks. Peri- and postmenopausal women were at significantly increased risk of depression, as measured by standard symptom inventories and structured clinical interviews, than premenopausal women., Conclusions: The menopausal transition is a time of increased vulnerability to cognitive declines and increased risk of depressive symptoms and depressive disorders. However, these results cannot necessarily be generalized beyond the studies included in this review. This article is part of a Special Issue entitled 'Menopause'., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Memory complaints increase as women transition from the premenopausal stage to the postmenopausal stage. We explored the extent to which subjective memory complaints were associated with objective cognitive test performance, affective symptoms, and menopausal symptoms in midlife women with moderate to severe vasomotor symptoms. We predicted that subjective memory complaints would be related to affective symptoms and lower performance on tests of memory and attention., Methods: Sixty-eight midlife women (mean age, 53 y; 54% African American) with at least 35 hot flashes per week completed the Memory Functioning Questionnaire, a battery of objective cognitive tests, a menopausal symptom inventory, and mood questionnaires. Linear regression analyses were conducted to examine predictors (symptoms and objective cognitive scores) of ratings on each of four Memory Functioning Questionnaire subscales and a validated single-item rating of current memory., Results: Negative affect and delayed verbal memory predicted a single-item rating of current memory. Negative affect and poorer scores on tests of attention and working memory predicted Frequency of Forgetting. Lower positive affect, higher vasomotor symptoms, and increased age predicted lower Retrospective Memory Functioning. Increased age predicted Use of Mnemonics., Conclusions: These findings strengthen the growing body of evidence indicating that women with memory complaints during the menopausal transition have an accurate appraisal of their memory function and that their complaints relate to affect and, to a lesser extent, vasomotor symptoms. Given that cognitive performance is within the reference range, these findings suggest that women can detect subtle changes in memory performance during the menopausal transition.

Objective: The critical window hypothesis of hormone therapy (HT) and cognitive function states that the effects of HT depend on timing of initiation with respect to age, the menopausal transition, or both, and that optimal effects are evident with early initiation. This article reviews clinical studies that bear on this hypothesis., Methods: Recognizing that the typical pattern of HT use is early HT initiation, this review describes findings from observational studies of ever use of HT and observational studies that looked specifically at the timing of HT on Alzheimer's disease (AD) and cognitive test performance. Randomized trials of HT and verbal memory are discussed, and neuroimaging studies bearing on the hypothesis are reviewed., Results: Observational data suggest that HT generally reduces the risk of AD. Three of three observational studies that specifically examined the timing of initiation in relation to AD risk each provide support for the window, whereas three of five observational studies of HT timing and cognitive test performance do. Randomized clinical trials of estrogen therapy in younger women find support for the hypothesis. Conjugated equine estrogens/medroxyprogesterone acetate increases risks regardless of timing. Little is known about the cognitive effects of other combination HT formulations., Conclusions: A definitive trial to test the critical window hypothesis is not feasible. Evidence drawn from other sources provides initial support for the hypothesis. Although these findings are relevant to women who use HT to treat vasomotor symptoms, HT is currently not indicated for the treatment of cognitive complaints or for dementia prevention.

Objective: The aims of this cross-sectional study were to determine if cognitive function differs across stages of reproductive aging and to evaluate whether hormones or menopausal symptoms predict cognition in perimenopause. We hypothesized that women in late menopausal transition and early postmenopause would perform more poorly than those in the late reproductive stage on attention and verbal memory tasks, and that estradiol, depressive symptoms, anxiety symptoms, hot flashes, and sleep disturbance would predict cognitive performance on those tasks., Methods: One hundred seventeen middle-aged women enrolled in the Rochester Investigation of Cognition Across Menopause were categorized into late reproductive stage (n = 34), early menopausal transition stage (n = 28), late menopausal transition stage (n = 41), or early postmenopause stage (n = 14) according to criteria from the Stages of Reproductive Aging Workshop +10. We administered a neuropsychological battery assessing six domains of cognition, assessed menopausal symptoms, and measured serum levels of estradiol and follicle-stimulating hormone. Multivariate regressions were conducted to determine the impact of menopausal stage and symptoms on cognition., Results: Women in the first year of postmenopause performed significantly worse than women in the late reproductive and late menopausal transition stages on measures of verbal learning, verbal memory, and motor function. They also performed significantly worse than women in the late menopausal transition stage on attention/working memory tasks., Conclusions: Cognitive function does not change linearly across perimenopause. Decreases in attention/working memory, verbal learning, verbal memory, and fine motor speed may be most evident in the first year after the final menstrual period.

Evidence from preclinical studies, randomized clinical trials (RCT), and observational studies underscores the importance of distinguishing among the different forms of estrogen and progestogens when evaluating the cognitive effects of hormone therapy (HT) in women. Despite this evidence, there is a lack of direct comparisons of different HT regimens. To provide insights into the effects of different HT formulations on cognition, this minireview focuses on RCT of verbal memory because evidence indicates that HT affects this cognitive domain more than others and because declines in verbal memory predict later development of Alzheimer's disease. Some observational studies indicate that estradiol confers benefits to verbal memory, whereas conjugated equine estrogens (CEE) confer risks. RCT to date show no negative impact of CEE on verbal memory, including the Women's Health Initiative Study of Cognitive Aging. Similarly, the Women's Health Initiative Memory Study showed no negative impact of CEE on dementia. Transdermal estradiol in younger postmenopausal women improved verbal memory in one small RCT but had no effect in another RCT. RCT of oral estradiol in younger and older postmenopausal women had neutral effects on cognitive function. In contrast, RCT show a negative impact of CEE plus medroxyprogesterone acetate on verbal memory in younger and older postmenopausal women. Small RCT show neutral or beneficial effects of other progestins on memory. Overall, RCT indicate that type of progestogen is a more important determinant of the effects of HT on memory than type of estrogen.

Objective: To compare the relative effects of conjugated equine estrogens (CEE), raloxifene, and tamoxifen therapies on cognition among women aged > or =65 years., Methods: Annual Modified Mini-Mental State (3MS) examinations were used to assess global cognitive function in the two randomized placebo-controlled clinical trials of CEE therapies of the Women's Health Initiative Memory Study (WHIMS) and the Cognition in the Study of Tamoxifen and Raloxifene (CoSTAR). Analyses were limited to women who had 3MS testing at baseline and the first 3 years of follow-up and, because of potential ethnic-related differences between studies, to Caucasian women (WHIMS n = 6211, CoSTAR n = 250). Covariate adjustment was used to compare the postrandomization mean 3MS scores among the three active therapies with placebo therapy while controlling for differences between groups with respect to dementia risk factors., Results: At baseline, the average (SD) 3MS scores by group were 95.24 (4.28) for placebo, 95.19 (4.33) for CEE, 94.60 (4.76) for raloxifene, and 95.02 (4.03) for tamoxifen. Compared with placebo, each active therapy was associated with a small mean relative deficit in 3MS scores of < or =0.5 units, which was fairly consistent between women with and without prior hysterectomy. Relative deficits were slightly greater for tamoxifen (p = 0.001) and less marked for raloxifene (p = 0.06) and CEE (p = 0.02) therapies. Relative deficits appeared to be greater among women with lower baseline 3MS scores: p = 0.009 (tamoxifen), p = 0.08 (raloxifene), and p = 0.03 (CEE)., Conclusions: Although unmeasured differences between trials may have confounded analyses, these findings raise the possibility that both tamoxifen and raloxifene adversely affect cognitive function in older women; however, the magnitude of the effect is small, and the long-term consequences are unknown.

Context: Different menopausal hormone therapies may have varied effects on specific cognitive functions. We previously reported that conjugated equine estrogens (CEE) with medroxyprogesterone acetate had a negative impact on verbal memory but tended to impact figural memory positively over time in older postmenopausal women., Objective: The objective of the study was to determine the effects of unopposed CEE on changes in domain-specific cognitive function and affect in older postmenopausal women with prior hysterectomy., Design: This was a randomized, double blind, placebo-controlled clinical trial., Setting: The study was conducted at 14 of 40 Women's Health Initiative (WHI) clinical centers., Participants: Participants were 886 postmenopausal women with prior hysterectomy, aged 65 yr and older (mean 74 yr), free of probable dementia, and enrolled in the WHI and WHI Memory Study (WHIMS) CEE-Alone trial for a mean of 3 yr and followed up for a mean of 2.70 yr., Intervention: Intervention was 0.625 mg of CEE daily or placebo., Main Outcome Measures: Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured., Results: Compared with placebo, unopposed CEE was associated with lower spatial rotational ability (P < 0.01) at initial assessment (after 3 yr of treatment), a difference that diminished over 2.7 yr of continued treatment. CEE did not significantly influence change in other cognitive functions and affect., Conclusions: CEE did not improve cognitive functioning in postmenopausal women with prior hysterectomy. CEE was associated with lower spatial rotational performance after an average of 3 yr of treatment. Overall, CEE does not appear to have enduring effects on rates of domain-specific cognitive change in older postmenopausal women.

Purpose: To compare the effects of two selective estrogen receptor modulators, tamoxifen and raloxifene, on global and domain-specific cognitive function., Patients and Methods: The National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene (STAR) study was a randomized clinical trial of tamoxifen 20 mg/d or raloxifene 60 mg/d in healthy postmenopausal women at increased risk of breast cancer. The 1,498 women who were randomly assigned in STAR were age 65 years and older, were not diagnosed with dementia, and were enrolled onto the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) trial, beginning 18 months after STAR enrollment started. A cognitive test battery modeled after the one used in the Women's Health Initiative Study of Cognitive Aging (WHISCA) was administered. Technicians were centrally trained to administer the battery and recertified every 6 months. Analyses were conducted on all participants and on 273 women who completed the first cognitive battery before they started taking their medications., Results: Overall, there were no significant differences in adjusted mean cognitive scores between the two treatment groups across visits. There were significant time effects across the three visits for some of the cognitive measures. Similar results were obtained for the subset of women with true baseline measures., Conclusion: Tamoxifen and raloxifene are associated with similar patterns of cognitive function in postmenopausal women at increased risk of breast cancer. Future comparisons between these findings and patterns of cognitive function in hormone therapy and placebo groups in WHISCA should provide additional insights into the effects of tamoxifen and raloxifene on cognitive function in older women.

Objective: The aim of this study was to characterize the effects of red clover, black cohosh, and combined hormone therapy on cognitive function in comparison to placebo in women with moderate to severe vasomotor symptoms., Methods: In a phase II randomized, double-blind, placebo-controlled study, 66 midlife women (of 89 from a parent study; mean age, 53 y) with 35 or more weekly hot flashes were randomized to receive red clover (120 mg), black cohosh (128 mg), 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA), or placebo. Participants completed measures of verbal memory (primary outcome) and other cognitive measures (secondary outcomes) before and during the 12th treatment month. A subset of 19 women completed objective, physiological measures of hot flashes using ambulatory skin conductance monitors., Results: Neither of the botanical treatments had an impact on any cognitive measure. Compared with placebo, CEE/MPA led to a greater decline in verbal learning (one of five verbal memory measures). This effect just missed statistical significance (P = 0.057) in unadjusted analyses but reached significance (P = 0.02) after adjusting for vasomotor symptoms. Neither of the botanical treatment groups showed a change in verbal memory that differed from the placebo group (Ps > 0.28), even after controlling for improvements in hot flashes. In secondary outcomes, CEE/MPA led to a decrease in immediate digit recall and an improvement in letter fluency. Only CEE/MPA significantly reduced objective hot flashes., Conclusions: Results indicate that a red clover (phytoestrogen) supplement or black cohosh has no effects on cognitive function. CEE/MPA reduces objective hot flashes but worsens some aspects of verbal memory.

Use of estrogen therapy in the perimenopausal and postmenopausal periods has been shown in several clinical trials to help women maintain a premenopausal level of cognitive function. What is not yet fully understood is how the neurobiological effects of estrogen contribute to these cognitive effects. This review explores data from two related bodies of human literature that provide compelling evidence in support of the biological plausibility that estrogen treatment can benefit cognition. The first half of the literature review focuses on studies from the estrogen neuroimaging literature, and the second half focuses on pharmacologic challenge studies assessing estrogen-neurotransmitter interactions. We integrate these two bodies of literature by focusing on the neurophysiologic underpinnings of estrogen effects on cognition and linking these clinical studies to preclinical studies. The focus on verbal memory is important because it is a cognitive function that has been shown to change with estrogen treatment and predict Alzheimer's disease risk but is not addressed by preclinical studies. Overall, we conclude that estrogen interacts with cholinergic and serotonergic systems to affect hippocampal and frontal cortical brain areas and thereby enhance memory, particularly at the retrieval stage.

Objective: To test the hypothesis that hot flashes specifically relate to verbal memory performance by examining the relationship between objective hot flashes and cognitive test performance in women with moderate to severe vasomotor symptoms., Design: In an observational study, 29 midlife women (mean age, 53 y) with moderate to severe hot flashes provided measures of objective hot flashes with an ambulatory hot flash monitor, subjective hot flashes with a diary and questionnaire, and objective measures of verbal memory and other cognitive functions with standardized neuropsychological tests., Results: The mean number of objective hot flashes was 19.5 per day (range, 6 to 35), including 15.3 (range, 6 to 35) during waking hours and 4.2 (range, 0 to 9) during sleep. The mean sensitivity (ie, subjective detection of objectively measured hot flashes) was 60%. Regression analyses revealed that total number of objective hot flashes, sleep duration, and verbal knowledge were significant predictors of delayed verbal memory. Verbal fluency correlated positively with objective daytime hot flashes. Hot flashes did not predict performance on any of the other secondary cognitive measures (ie, attention, working memory, visual memory), although poor sleep predicted worse performance on several outcome measures., Conclusions: Highly symptomatic women underreport the number of objective hot flashes that they experience by 43%. Verbal memory performance relates significantly to the objective number of hot flashes women experience but not to the number of hot flashes that they report. These findings suggest that physiological factors related to hot flashes, rather than psychological factors, predict poorer verbal memory function.

We extend the investigation of cognitive sex differences in schizophrenia in a novel way by grouping cognitive tests according to the direction of the typical sex difference, an approach used in studies of hormonal effects on behavior in other clinical conditions. Additionally, we explore how performance on these 'male' and 'female' tests changed following antipsychotic treatment. Seventy patients with a first hospitalization for schizophrenia or schizophreniform disorder completed cognitive tests before antipsychotic treatment and approximately 5 weeks after treatment. Thirty-nine healthy comparison subjects completed the tests at similar intervals. Primary outcome variables were composite scores on cognitive tests that in normative studies favor males over females ('male' tests) or favor females over males ('female tests'). Overall, patients performed more poorly than healthy individuals. The expected pattern of sex differences was found on the composite test scores, with an advantage for females on 'female' tests and an advantage for males on 'male' tests. Female patients showed a greater improvement on 'female' tests and a decrease in performance on 'male' tests following treatment. Although male patients did not perform significantly better after treatment on 'female' tests, they did improve on non-motor 'male' tests of visuospatial skills. Future studies of the neurocognitive effects of antipsychotic treatment may need to take potential sex differences in cognitive response into account.

Context: Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions, particularly memory., Objective: The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women., Design: This study was a randomized, double-blind, placebo-controlled clinical trial., Setting: Participants were women from 14 of 40 clinical centers of the Women's Health Initiative (WHI)., Participants: Postmenopausal women (1416) aged 65 yr and older, free of probable dementia, and enrolled in WHI and the WHI Memory Study (WHIMS) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr, were studied., Intervention: Intervention was conjugated equine estrogen (CEE; 0.625 mg) with 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet (CEE + MPA) or placebo., Main Outcome Measures: Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured., Results: CEE + MPA had a negative impact on verbal memory (P

The large majority of women receiving hormone therapy initiate therapy early in life for the treatment of menopausal symptoms. However, the Women's Health Initiative Memory Study, the only randomized clinical trial to date on hormone therapy and dementia, was carried out in women age 65 and older. That trial provided important insights into the detrimental effects of hormone therapy on dementia in women initiating later in life. The generalizability of those findings to the typical hormone therapy user who initiates earlier in life is unknown. To address this important issue, this review focuses on observational trials of hormone therapy and dementia risk, randomized clinical trials of hormone therapy and cognitive function, and basic science studies. These lines of research provide suggestive, but not definitive, evidence that early initiation of hormone therapy may provide cognitive benefits, particularly to verbal memory and other hippocampally mediated functions. Other forms of hormone therapy, other cognitive domains, and cyclic hormone regimens may not conform to this "critical period hypothesis." Further research is needed to test the validity and limits of this hypothesis.

The putative protective effects of hormone therapy (HT) have been cast in doubt by recent findings from the Women's Health Initiative Memory Study showing an increase in dementia and an increased likelihood of impaired cognitive status in women initiating HT after age 65. To explore the external generalizability of those findings to younger postmenopausal women, the medical literature was surveyed for randomized, double-blind, placebo-controlled trials of treatment with either estrogen alone or estrogen plus a progestin on neuropsychological test performance. Findings from trials in younger women (<65 years) are presented separately from those in older women (>or=65 years). This review finds little support for beneficial cognitive effects in older women of estrogen alone or in combination with progestin. However, evidence from younger women suggests potential beneficial effects in select cognitive domains, particularly among symptomatic women and recently menopausal women, and scant evidence of harm. There is a dearth of studies of the cognitive effects of estrogen plus progestin in younger women. Future studies systematically exploring the effect of age and progestin use are needed to better characterize the effects of HT on cognition in younger women. Without firm evidence of benefit to younger women, it is prudent to caution early postmenopausal women about the cognitive risks observed in WHI, recognizing the low likelihood of dementia at that age.

Basic science and clinical studies have investigated the potential neuroprotective effects of estrogen. One apparent area of convergence in these studies is the selective benefits of estrogen on cognitive tasks mediated by the hippocampus and frontal lobes. Findings in non-human primates parallel findings from neuroimaging and behavioral studies in humans and suggest that estrogen might influence memory tasks mediated by the hippocampus as well as working memory tasks mediated by the prefrontal cortex. This evidence provides a framework for the design of future hormone studies, wherein such tasks can serve as primary outcomes. In studies of symptomatic women, hormone therapy can benefit a broader range of cognitive domains, particularly effortful tests that are sensitive to remittance of dysphoria, sleep difficulty, and hot flushes. Serotonin might play a critical role in these potential indirect benefits, and therapies that target these symptoms, even those without estrogenic actions, might have indirect benefits on cognition.

The Women's Health Initiative Study of Cognitive Aging (WHISCA) was a two armed, randomized, placebo controlled, clinical trial designed to assess the efficacy of postmenopausal hormone therapy on age related changes in specific cognitive functions. WHISCA was an ancillary study to the Women's Health Initiative (WHI) and the WHI Memory Study (WHIMS) and enrolled 2302 women aged 66 to 84 years (mean 73.9; standard deviation 3.8) who did not meet criteria for dementia. Women were randomly assigned by the WHI to hormone treatment (unopposed conjugated estrogens (CEE) 0.625 mg/day if they were without a uterus; CEE combined with medroxyprogesterone acetate (MPA) 2.5 mg/day otherwise) or placebo for an average of three years before the first WHISCA assessment. WHISCA investigated the effects of hormone therapy on rates of change over time in memory, other aspects of cognition (language, attention, spatial ability), motor function, and mood. In this paper, we present the study rationale and design, including specific cognitive measures, and the challenges of incorporating WHISCA into an ongoing randomized trial. WHISCA provided a unique opportunity to investigate the potential of hormone therapy to modify age related changes in specific cognitive functions. WHISCA also demonstrated the feasibility of adding a detailed cognitive assessment into an ongoing clinical trial to address an important issue in women's health, despite the challenges of maintaining the integrity of the parent studies, ensuring high retention, and achieving high quality assurance across sites.

Evidence that ovarian steroid hormones such as estrogen and progesterone affect cognition comes from studies of memory in older women receiving estrogen replacement therapy and studies of sexually dimorphic skills in young women across the menstrual cycle. Sixteen women (ages 18-28) completed tests of memory (implicit category exemplar generation, category-cued recall, implicit fragmented object identification) and sexually dimorphic skills (fine motor coordination, verbal fluency, mental rotations) at the early follicular (low estrogen and progesterone) and midluteal (high estrogen and progesterone) phases of the menstrual cycle. Performance on category exemplar generation, a test of conceptual implicit memory, was better at the midluteal than the follicular phase. In contrast, performance on a test of explicit memory, category-cued recall, did not vary across the menstrual cycle. At Session 1, women in the follicular phase performed better on the fragmented object identification task than did those in the midluteal phase. This unexpected finding suggests that high levels of ovarian hormones might inhibit perceptual object priming. Results confirmed previous reports of decreased mental rotations and improved motor skills and fluency in the midluteal phase. Estradiol levels correlated positively with verbal fluency and negatively with mental rotations and perceptual priming, which suggest that estrogen, and not progesterone, was responsible for the observed changes in cognition. Mood did not vary across the cycle phases. Overall, the findings suggest that estrogen may facilitate the automatic activation of verbal representations in memory.

Recent reports suggest that hormone therapy may be associated with a reduced risk for Alzheimer's disease and may offer some protection against age-associated declines in specific cognitive functions. The majority of these reports are based on observational studies, which are confounded by the "healthy user" bias--the tendency for women receiving hormone therapy to be younger, better educated, and have fewer medical problems. In one attempt to address these limitations, we conducted a series of studies examining effects of hormone therapy on cognitive and brain functioning in nondemented postmenopausal women in the Baltimore Longitudinal Study of Aging (BLSA). In this sample, women receiving hormone therapy and women who never received hormone therapy were comparable with respect to educational attainment, general medical health, and performance on a test of verbal knowledge. Despite these similarities, women receiving hormone therapy performed better on tests of verbal and visual memory compared to never-treated women. The two groups also differed in the patterns of regional brain activation evoked during performance of delayed verbal and figural memory tasks. Furthermore, longitudinal comparisons revealed greater relative blood flow increases over two years in women receiving hormone therapy for the hippocampus and other mesial temporal lobe structures that subserve memory. These observational findings from our studies in the BLSA have led to the development of a large-scale randomized clinical trial of hormone therapy and cognitive aging, the ancillary Women's Health Initiative Study of Cognitive Aging (WHISCA), and have important implications for studies of the effects of SERM's on cognitive and brain functioning.

Observational studies suggest that estrogen replacement therapy (ERT) may protect against age-related memory decline and lower the risk of Alzheimer's disease (AD). This study aimed to characterize the neural substrates of those effects by comparing 2-year longitudinal changes in regional cerebral blood flow (rCBF) in 12 ERT users and 16 nonusers. Positron emission tomography (PET) measurements of rCBF were obtained under three conditions: rest, and verbal and figural recognition memory tasks. Groups showed different patterns of change in rCBF over time in a number of brain areas. These group differences, for the most part, reflected regions of increased rCBF over time in users compared to nonusers. The greatest differences between ERT users and nonusers were in the hippocampus, parahippocampal gyrus, and temporal lobe, regions that form a memory circuit and that are sensitive to preclinical AD. Across a battery of standardized neuropsychological tests of memory, users obtained higher scores than did nonusers of comparable intellect. Group differences in longitudinal change in rCBF patterns may reflect one way through which hormones modulate brain activity and contribute to enhanced memory performance among ERT users.