Impact of sex and reproductive status on memory circuitry structure and function in early midlife using structural covariance analysis.

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.

Reorganization of Functional Networks in Verbal Working Memory Circuitry in Early Midlife: The Impact of Sex and Menopausal Status.

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.

Impact of Sex and Menopausal Status on Episodic Memory Circuitry in Early Midlife.

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 17ß-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.

If At First You Don't Succeed Keep Trying: Strategies to Enhance Coalition/School Partnerships to Implement School-Based Prevention Programming.

Community-based coalitions have been advocated as a promising mechanism to reduce youth involvement in violence, delinquency, and substance use, but coalitions have not always been successful in ensuring widespread adoption of evidence-based prevention strategies. This paper describes the strategies used by 12 community coalitions to collaborate with schools to select and implement school-based prevention programs, including the barriers to establishing coalition/school partnerships and methods for overcoming these challenges.In this five-year research project, all communities adopted school-based prevention programs. Coalitions helped achieve this outcome by building relationships with school personnel, fostering champions within the school, creating win/win situations in which schools' needs were addressed, and initiating school-based prevention programs as pilot efforts that were later expanded. While success was achieved in all cases, persistent messaging about the importance of youth problem behaviours was needed to overcome schools' concerns about using academic time to teach prevention messages and replacing current practices with unfamiliar programs.Findings from this study can be used by coalitions and prevention scientists that want to partner with schools to reach a large population of students with effective prevention programming. The results are also of value to researchers and practitioners interested in fostering widespread dissemination of other types of evidence-based programs.

Implementing the Communities That Care Prevention System: Challenges, Solutions, and Opportunities in an Urban Setting.

INTRODUCTION: Communities That Care, refined and tested for more than 25years, offers a step-by-step coalition-based approach to promote well-being and prevent risk behaviors among youth. Communities That Care guides coalitions to identify and prioritize underlying risk and protective factors; set specific, measurable community goals; adopt tested, effective prevention programs to target selected factors; and implement chosen programs with fidelity. Communities That Care has been implemented in a variety of communities, but has only recently begun to be systematically evaluated in diverse, urban communities. METHODS: This paper presents a process evaluation of Communities That Care implementation within a Midwestern ethnically diverse, urban community. In-depth surveys of 25 black male youth aged 8-14years and their caregivers were conducted to determine the degree to which coalition-selected priorities aligned with the experience of black families. Implementation and survey data were collected in 2014-2017 and analyzed in 2017-2018. RESULTS: Roughly 30% of youth reported ever being bullied or bullying someone else on school property; this aligned with the coalition's decision to focus on positive social skills and bullying prevention. Additional data aligned with the coalition's intent to expand its community action plan to encompass other priorities, including family transitions and mobility. For example, roughly one third of caregivers went on welfare and one third of families moved to a new home or apartment in the past year. CONCLUSIONS: In communities whose residents have experienced historical and current inequities, an effective community prevention plan may need to address structural as well as social determinants of well-being among youth and their families. SUPPLEMENT INFORMATION: This article is part of a supplement entitled African American Men's Health: Research, Practice, and Policy Implications, which is sponsored by the National Institutes of Health.

Sex differences in episodic memory in early midlife: impact of reproductive aging.

OBJECTIVE: Few have characterized cognitive changes with age as a function of menopausal stage relative to men, or sex differences in components of memory in early midlife. The study aim was to investigate variation in memory function in early midlife as a function of sex, sex steroid hormones, and reproductive status. METHODS: A total of 212 men and women aged 45 to 55 were selected for this cross-sectional study from a prenatal cohort of pregnancies whose mothers were originally recruited in 1959 to 1966. They underwent clinical and cognitive testing and hormonal assessments of menopause status. Multivariate general linear models for multiple memory outcomes were used to test hypotheses controlling for potential confounders. Episodic memory, executive function, semantic processing, and estimated verbal intelligence were assessed. Associative memory and episodic verbal memory were assessed using Face-Name Associative Memory Exam (FNAME) and Selective Reminding Test (SRT), given increased sensitivity to detecting early cognitive decline. Impacts of sex and reproductive stage on performance were tested. RESULTS: Women outperformed men on all memory measures including FNAME (ß = -0.30, P < 0.0001) and SRT (ß = -0.29, P < 0.0001). Furthermore, premenopausal and perimenopausal women outperformed postmenopausal women on FNAME (initial learning, ß= 0.32, P = 0.01) and SRT (recall, ß= 2.39, P = 0.02). Across all women, higher estradiol was associated with better SRT performance (recall, ß = 1.96, P = 0.01) and marginally associated with FNAME (initial learning, ß = 0.19, P = 0.06). CONCLUSIONS: This study demonstrated that, in early midlife, women outperformed age-matched men across all memory measures, but sex differences were attenuated for postmenopausal women. Initial learning and memory retrieval were particularly vulnerable, whereas memory consolidation and storage were preserved. Findings underscore the significance of the decline in ovarian estradiol production in midlife and its role in shaping memory function.

17ß-estradiol differentially regulates stress circuitry activity in healthy and depressed women.

Many regions within stress neurocircuitry, including the anterior hypothalamus, amygdala, hippocampus, and medial prefrontal cortex, are densely populated with sex steroid receptors. Substantial evidence from animal studies indicates that the gonadal hormone 17ß-estradiol (E2) impacts the structure and function of these regions, but human studies are limited. Characterizing estradiol's role in stress circuitry in vivo in humans may have important clinical implications given the comorbidity between major depressive disorder (MDD), stress circuitry dysfunction and endocrine dysregulation. In this study, we determined estradiol's role in modulating activity within cortical and subcortical stress circuitry regions in healthy and MDD women. Subjects were part of a population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in E2 during the menstrual cycle, we conducted a within-person repeated-measures functional neuroimaging study in which 15 women with recurrent MDD, in remission, and 15 healthy control women underwent hormonal evaluations, behavioral testing, and fMRI scanning on two occasions, under low and high E2 conditions. Subjects completed an fMRI scan while undergoing a mild visual stress challenge that reliably activated stress neural circuitry. Results demonstrate that E2 modulates activity across key stress circuitry regions, including bilateral amygdala, hippocampus, and hypothalamus. In healthy women, robust task-evoked BOLD signal changes observed under low E2 conditions were attenuated under high E2 conditions. This hormonal capacity to regulate activity in stress circuitry was not observed in MDD women, despite their remitted status, suggesting that dysregulation of gonadal hormone function may be a characteristic trait of the disease. These findings serve to deepen our understanding of estradiol's actions in the healthy brain and the neurobiological mechanisms that may underlie the pronounced sex difference in MDD risk.

Measuring risk and protection in communities using the Communities That Care Youth Survey.

The Communities That Care Youth Survey measures risk and protective factors shown in prior studies to predict adolescent problem behaviors such as drug use, delinquency, and violence. This paper describes the development and validation of cut points for the risk and protective factor scales in the Communities That Care Youth Survey that distinguish youths at higher risk for involvement in problem behaviors from those at lower risk. Using these cut points, populations surveyed with this instrument can be described in terms of the proportions of youths experiencing risk and the proportions experiencing protection on each predictor. This facilitates communities' prioritization of specific factors for attention. This paper compares different cut points, and evaluates the discriminant validity of selected cut points. Results indicate that cut points with sufficient sensitivity and selectivity can be established for each of the scales, and that risk and protective factors can be profiled as prevalence rates. Implications of these findings for prevention planning are discussed.