Pauline M. Maki - US grants

The effect of aging on cognitive ability varies from one individual to the next. Recent studies suggest that one of the factors influencing individual differences in cognitive aging is the use of hormone replacement therapy (HRT). For example, recent findings from the Baltimore Longitudinal Study on Aging (BLSA) suggests that the use of estrogen replacement therapy (ERT) protects against age-associated declines in memory and against the development of Alzheimer's disease. One limitation of such studies is that the women who participated in them elected on their own to receive ERT. Research suggests that such women tend to be better educated and to receive better health care than women who do not receive ERT. The bias is termed the "healthy user effect."

sex hormones; neuropsychological tests; neuroanatomy; brain; aging; hormone therapy; memory; testosterone; cognition; estrogens; emotions; clinical research; human subject; human old age (65+);

Estrogen appears to be important for cognitive function and emotional well- being in postmenopausal women. After menopause, estrogen levels drop to approximately 12% of the levels found during fertility. Among surgically menopausal women, those receiving estrogen replacement therapy (ERT) show no decline in cognitive functioning four months post-surgery, whereas those receiving placebo declined significantly on many measures. Similarly, ERT improves attention and self-reported memory functioning and mood. Psychiatrically, postmenopausal women report milder depressive symptoms and decreased anxiety while receiving ERT. Ongoing studies of the effect of estrogen on cognitive performance in young, healthy women suggest that some cognitive abilities improve with increased estrogen while others decline. Women perform slightly better on tests of verbal memory and verbal fluency, as well as tests of psychomotor speed and manual dexterity, during phases of the menstrual cycle when estradiol levels are high. In contrast, they perform slightly better on spatial tests and mental rotations when estradiol is low. These findings suggest that ERT may affect verbal and nonverbal cognitive abilities differentially, though this has not yet been studied systematically. In contrast to the relatively sudden drop in estrogen experienced by aging women, aging men experience a gradual loss of testosterone, with the level at age 80 being approximately 30% of that at age 30. Male rats show improved memory, attention and spatial performance when treated with testosterone. Similar effects have been observed in humans. In a recent study, older men whose testosterone levels were raised to 150% of baseline showed a significant improvement in spatial cognition. A similar finding was observed in hypogonadal men treated with testosterone, though these men also demonstrated a worsening of word recall. Some studies suggest that the relationship between testosterone level and spatial cognition is nonlinear. Men with naturally low testosterone levels perform best on spatial tasks, and men's performance on spatial tasks is best in the spring when testosterone is typically the lowest. The association between high levels of testosterone and poor spatial cognition may be due to the conversion of testosterone into estradiol in the basal forebrain and its binding with estrogen receptors. As discussed above, there is a strong, negative relationship between spatial cognition and estradiol. This study is the first to use double-blind, placebo-controlled, cross-over procedures to investigate the effectiveness of hormone replacement therapy (ERT) in enhancing mood and cognition in both men and women over age 65. It would also improve upon previous studies by including among its outcome measures: 1) tests of spatial and verbal cognitive abilities; 2) measures of negative and positive affect, and 3) an assessment of everyday cognitive "slips". Importantly, unlike previous studies that merely assumed a particular blood hormone level, this study employs redioimmunoassay techniques to measure hormone levels.

[unreadable] DESCRIPTION (provided by applicant): Alternative botanical therapies for menopausal symptoms are becoming more widely used, in part due to recent reports from the Women's Health Initiative (WHI) that combined estrogen and progestin therapy increases risks for breast cancer, stroke, and cardiovascular disease. The National Center for Complementary and Alternative Medicine (NCCAM) Fiscal Year 2003 Research Priorities advocate both clinical studies evaluating the efficacy of botanical therapies for menopausal symptoms and clinical studies elucidating their mechanisms of action, optimally through collaborative randomized clinical trials. This Mentored Scientist Development Award (K01) application focuses on developing the principal investigator's ability to become an independent investigator of the mechanisms by which complementary and alternative therapies affect brain function. There is a pressing need for skilled clinical investigators with advanced training to meet those priorities. This candidate brings to this training effort uncommon expertise and research experience in sex steroid hormones, cognition, and brain function - including co-development of the WHI Study of Cognitive [unreadable] Aging - as well as active collaborations with investigators at the URIC/NIH Center for Botanical Dietary [unreadable] Supplement Research in Women's Health. The active research component of the proposed training program will initially focus on the mechanisms by which black cohosh and red clover affect neurocognitive function and mood. The specific mentored activities of this Award focus on a three-pronged training program to develop the principal investigator's ability to investigate the neural, physiological, and neurochemical mechanisms of action of botanical therapies on the CNS. The first activity focuses on functional magnetic resonance imaging and diffusion tensor imaging to examine the influence of botanicals on the brain systems underlying memory performance. The second activity focuses on the use of ambulatory sternal skin conductance monitors in the measurement of hot flushes to investigate whether botanicals improve cognition by improving menopausal symptoms. The third activity involves implementation of pharmacological challenge methods to examine whether botanical therapies act through serotonin to influence CNS function. The long-term goal of this training experience is to provide the protected time and training for the PI to develop readily generalizable skills for investigating a range of botanical therapies on cognitive function, especially extracts identified by the Center's basic science program as having potential beneficial effects on the CNS. The proposed research program builds on the UIC/NIH Botanical Center's comprehensive program of basic and clinical research and extends its clinical research program in a new and timely direction. The lack of understanding of the effects of botanical therapies on brain function and the basic mechanisms by which alternative therapies can influence cognition both underscore the need to train researchers with the necessary skills to advance clinical research in this area and address pressing needs in women's health research. [unreadable] [unreadable]

oral contraceptives; cognition; emotions; neuroendocrine system; menstrual cycle; hormone regulation /control mechanism; clinical research; female; young adult human (21-34); human subject;

[unreadable] DESCRIPTION (provided by applicant): The broad, long-term objective of this program of research is to better understand the effects of hormone therapy (HT) and alternative botanical supplements on cognition and brain functioning in early postmenopausal women. The specific aims of this research project are to quantify and compare the effects of the botanical menopausal treatments, black cohosh and red clover, and standard HT, Prempro (r) (conjugated equine estrogen plus medroxyprogesterone acetate), on neuropsychological and neuroimaging outcomes. The proposed design is a randomized, double-blind, placebo-controlled clinical trial. The cognitive study is conducted as an ancillary study to the NIH-funded study, A Phase II, Randomized, Double -Blind, Placebo-Controlled Study to Determine the Efficacy of Black Cohosh, Red Clover and Prempro(r) in the Management of Hot Flashes. Participants will include up to 28 women in each study arm - placebo, Prempro(r), black cohosh, and red clover - for a total n of up to 112. The primary outcome measures will be scores on standardized neuropsychological tests and patterns of brain activation during performance of verbal memory [unreadable] tests. Before treatment and at the end of the 12-month treatment period, participants will complete a 1.5- hour battery of neuropsychological tests that have been shown in previous studies to be sensitive to the effects of HT and menopausal symptoms. Half of the participants (n = 60) will also complete neuroimaging assessments using functional magnetic resonance imaging (fMRI) before and after the 12-month treatment period. The tasks performed in the MRI scanner will be verbal and figural memory tasks shown to be sensitive to HT in midlife women. Findings of group differences in the patterns of brain activation (i.e., regional blood flow changes) will point to the brain areas subserving any treatment-related improvements in memory performance. Recent findings of significant health risks associated with Prempro heighten the need for research into the effects of alternative therapies for menopausal symptoms on cognitive outcomes. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Anxiety is a common, but understudied complaint in midlife women, and increases during the menopausal transition. Changes in estrogen are dramatic during the menopausal transition, and indirect data suggest a potential role for estrogen, particularly estrogen receptor beta, in mediating anxiety. Two subtypes of the estrogen receptor, alpha and beta (ER-alpha and ER-beta), appear to be critically involved in the expression of anxiety in females. Compounds that preferentially target ER-beta, including plant-derived estrogens (phytoestrogens), lower both anxiety behaviors and responsivity to discrete stressors, including social stress, in laboratory animals. The primary aim of this application is to carry out the first study to translate these preclinical studies to humans by comparing and contrasting of the effects of phytoestrogens, estradiol, and placebo on daily anxiety and responses to moderate psychosocial stress in the laboratory. Another major focus is emotional and non-emotional cognition. This focus stems from evidence that estrogen can affect the negative impact of glucocorticoids on memory. These aims will be accomplished in a 12-week randomized placebo- controlled, clinical trial comparing three treatments: 1) a widely used phytoestrogen supplement (Novasoy(R) 400, 55 mg tablet twice daily);2) oral estradiol (1 mg/daily);and 3) placebo (identical appearing tablets twice daily) in 120 healthy women in the menopausal transition (40 per group). To measure anxiety, women will complete daily mood diaries at baseline and throughout the treatment period. To measure responsivity to psychosocial stress, parallel forms of the Trier Social Stress Test, a widely used laboratory induction that involves unanticipated public speaking and social evaluative fear, will be used to induce moderate psychosocial stress before and after treatment. At both laboratory sessions, measures of subjective stress, cortisol, and emotional memory performance will be obtained during a control condition and during the psychosocial stress condition. The results from this clinical trial will add critical information about the importance of estrogen changes at midlife as a contributing factor for anxiety and stress symptoms in midlife women. Positive findings would provide a rationale for subsequent investigations of ER-beta agonists in the treatment of anxiety symptoms and disorders in women. PUBLIC HEALTH RELEVANCE: The prevalence of anxiety disorders is higher in women compared to men, and increases significantly in women at midlife (after age 45) but not men. Anxiety traits in non-clinical samples are also more common in women than men and worsen during hormonal transitional states, including the menopausal transition. To further our understanding of treatment options for women with anxiety during the menopausal transition, this study aims to test the effects of two widely used menopausal therapies, estradiol and phytoestrogens, on daily anxiety and stress responsivity, and the cognitive effects of daily and provoked stress.

Anxiety is a common, but understudied complaint in midlife women, and increases during the menopausal transition. Changes in estrogen are dramatic during the menopausal transition, and indirect data suggest a potential role for estrogen, particularly estrogen receptor beta, in mediating anxiety. Two subtypes of the estrogen receptor, alpha and beta (ER-alpha and ER-beta), appear to be critically involved in the expression of anxiety in females. Compounds that preferentially target ER-beta, including plant-derived estrogens (phytoestrogens), lower both anxiety behaviors and responsivity to discrete stressors, including social stress, in laboratory animals. The primary aim of this proposal is to carry out the first study to translate these preclinical studies to humans by comparing and contrasting of the effects of phytoestrogens, estradiol, and placebo on daily anxiety and responses to moderate psychosocial stress in the laboratory. Another major focus is emotional and non-emotional cognition. This focus stems from evidence that estrogen can affect the negative impact of glucocorticoids on memory. These aims will be accomplished in a 12-week randomized placebo- controlled, clinical trial comparing three treatments: 1) a widely used phytoestrogen supplement (Novasoy(R) 400, 55 mg tablet twice daily); 2) oral estradiol (1 mg/daily); and 3) placebo (identical appearing tablets twice daily) in 120 healthy women in the menopausal transition (40 per group). To measure anxiety, women will complete daily mood diaries at baseline and throughout the treatment period. To measure responsivity to psychosocial stress, parallel forms of the Trier Social Stress Test, a widely used laboratory induction that involves unanticipated public speaking and social evaluative fear, will be used to induce moderate psychosocial stress before and after treatment. At both laboratory sessions, measures of subjective stress, cortisol, and emotional memory performance will be obtained during a control condition and during the psychosocial stress condition. The results from this clinical trial will add critical information about the importance of estrogen changes at midlife as a contributing factor for anxiety and stress symptoms in midlife women. Positive findings would provide a rationale for subsequent investigations of ER-beta agonists in the treatment of anxiety symptoms and disorders in women.

DESCRIPTION (provided by applicant): More than 80% of women experience vasomotor symptoms (VMS; hot flashes and night sweats) during the menopausal transition. The use of hormone therapy, the standard treatment for VMS, decreased by 75% after publication of the findings from the Women's Health Initiative. The only FDA-approved nonhormonal treatment for VMS is paroxetine, a low-dose antidepressant that showed significant but modest efficacy in randomized trials. In the past decade, our understanding of the efficacy of nonhormonal therapies on VMS has increased considerably based on findings from randomized clinical trials. Unfortunately, the results from these trials show no-to-minimal efficacy, and two nonhormonal VMS medications recently failed to win FDA approval. Women therefore have very few nonhormonal treatment options for VMS. To address the continuing need for development of new nonhormonal therapies for VMS, we propose a multidisciplinary, 2-day conference, The Science of Thermoregulation and Vasomotor Symptoms: Possible New Targets for Treatment. The conference will convene a diverse group of 20 to 25 basic and clinical researchers as well as clinicians to discuss normal and aberrant thermoregulation, the neurophysiology of VMS, and new potential treatment targets. The aim of the conference is to facilitate synthesis and exchange of new data by promoting scientific exchange among experts who do not typically interact scientifically but whose work informs the others. In recent years, scientific understanding of the mechanisms involved in VMS has evolved considerably based on findings from basic science, physiology, neuroimaging, and studies of skin dynamics. The specific aims are to 1) describe current understanding of the physiology and neuropharmacology of thermoregulation and VMS; 2) describe current understanding of nonhormonal treatments for VMS; 3) review existing evidence from studies linking VMS to adverse health outcomes in women, including quality of life, cardiovascular outcomes, and cognitive function; 4) integrate new and emerging data from multiple areas of inquiry into an initial conceptual framework to better understand the causal pathway of VMS and potential avenues for new drug development. The Day 1 public symposium, open to 80 participants, will feature oral and poster presentations of recent scientific advances in thermoregulation and VMS and discussion of the implications of this new evidence for the development of nonhormonal VMS treatments. On Day 2, facilitated working groups will discuss and respond to targeted questions regarding research priorities. We offer four travel awards for new investigators. The meeting will be sponsored by The North American Menopause Society (NAMS) and will take place October 14-15, 2014, just before the 25th NAMS Annual Meeting in Washington, DC. The symposium recommendations will be presented in a special session at the NAMS meeting. A Program Planning Committee will prepare a conference summary for oral presentation at the NAMS Annual Meeting, an executive summary of the recommendations for publication in the official NAMS journal, Menopause, and a lay version to be published on the NAMS website.

Identifying risk factors for cognitive change early in the natural history of Alzheimer's disease (AD) is critical, as there is yet no cure for the disease. The lifetime risk of AD is higher in women than men, yet few studies have identified female-related risk factors for the disease. The menopause is a universal event in women and affects cognitive and brain health. In addition to hormonal changes, the menopause is accompanied by vasomotor symptoms (VMS) and sleep problems. Over 70% of midlife women report VMS, and for a third of women, VMS are persistent for over a decade, well into the 60s. Further, half of women report poor sleep at menopause. Few studies have examined the effect of VMS on brain health, particularly during sleep (sleep VMS). Informed by our novel pilot work showing links of sleep VMS to brain health and the growing understanding of the negative effect of poor sleep on brain health and AD pathology, the MsBrain I study focused on VMS and sleep disturbance, persistent symptoms tied to risk factors for AD including cardiovascular disease (CVD). Our initial MsBrain I findings indicate that objectively-assessed sleep VMS (measured with state-of-the-art ambulatory monitors) as well as poor sleep (measured with actigraphy) are associated with worse cognitive function and adverse indicators of brain structure and function. Sex steroid hormones do not explain these associations. In MsBrain II, we propose to test VMS and poor sleep as risk factors for adverse changes in brain and cognitive health among 160 MsBrain I participants (current mean age=60 years). Our primary aim is to leverage a longitudinal design to test whether a greater burden of objectively-assessed menopausal symptoms (sleep VMS, poor sleep) assessed up to three times over ten years is associated with declines brain and cognitive health over time. We will test the role of estrogens and CVD risk in the relationships of sleep VMS and sleep to brain and cognitive health. This aim recognizes the complex interplay among risk factors for cognitive impairment, with a focus on factors that change with menopause. Further, a wealth of basic science shows menopause-induced changes in mitochondrial function that contribute to adverse brain changes. Our pilot data finds VMS and sleep related to altered mitochondrial function. Our third aim tests the relations of mitochondrial function to brain health and the role of mitochondrial function in links between VMS, sleep, and brain health. To achieve these aims, we will invite 160 MsBrain I participants back to repeat objective assessments of VMS and sleep, as well as CVD risk factor assessment, carotid ultrasound imaging, sex hormone measurement, blood- based measures of mitochondrial function, and neuropsychological testing. To advance this science, we will extend our brain imaging work to leverage state-of-the-art 7 Tesla (7T) magnetic resonance imaging to assess brain structure and function. Findings from this study will determine whether VMS and poor sleep can be identified as markers for midlife women at risk of cognitive decline. The ultimate goal of this work is to assist in early intervention efforts to improve cognition, enhance brain reserve, and reduce AD risk in aging women.

Project Summary/Abstract Depression is the most common complication of pregnancy and affects 10-20% of women. Up to 75% of women with perinatal depression do not receive mental health care. In lower income African American and Hispanic women, the prevalence of perinatal depression (PND) is particularly high and the treatment rates are lower. Cognitive behavioral therapy (CBT) is an effective treatment but practical barriers such as time commitment, insurance coverage, and transportation, as well as stigma, limit uptake of CBT particularly for minority women. Similarly, concern about the adverse effects of antidepressant treatment on maternal and infant outcomes limits uptake of pharmacological treatments. A novel avenue for the development of safe therapeutics for depression focuses on the brain-gut axis and is supported by initial demonstrations that probiotics can improve mood symptoms. Our long-term goal is to assist in the discovery of potential microbes that are correlated with PND, and could be novel biomarkers for the diagnosis and treatment of this disorder, particularly in minority women. As a first step, we propose a multi-PI feasibility study involving the implementation and optimization of processes for participant recruitment and stool sample collection, as well as the initial assessments of longitudinal differences in gut microbiota between pregnant women with and without major depressive disorder (MDD). To meet these goals, we will leverage an established research infrastructure to conduct a prospective, nested case-control study. We will prospectively collect depression diagnoses and gut microbiome samples on 300 women at four points during pregnancy and after delivery to yield a total of 58 women, 29 cases with MDD and 29 controls without MDD. The two groups will be matched on key covariates (e.g., age, race, socio- economic status, gestational age, health). At their scheduled usual care, prenatal appointment, consented participants will complete mental health, demographics, microbiome-related, and dietary and physical habits questionnaires and provide a fecal sample either at that time of their appointment or at home. To achieve our first aim - to determine the feasibility of a larger similarly designed study - we will estimate the total number of potential participants, the number assessed and not assessed for eligibility (and reasons), the number excluded and reasons for exclusion, the number lost to follow-up, and the data available for analysis at each of the 4 visits. To achieve our second aim - to determine whether the gut microbiome dynamically differs in pregnant women with and without MDD - we will employ a suite of systems level approaches, including multivariate statistical techniques, network modeling and machine learning techniques. This R03 will allow us to optimize our research processes for the prospective collection of stool samples and mental health data in preparation for larger nested case-control studies, and ultimately clinical trials of probiotic therapies for PND.

PROJECT SUMMARY/ABSTRACT Despite the availability of effective antiretroviral therapies, cognitive deficits persist in HIV-infected (HIV+) individuals. For example, in the Women's Interagency HIV Study (WIHS), HIV+ virally suppressed (HIV+VS) women showed neurocognitive impairment (NCI) in verbal learning and memory as well as working memory, attention and executive function. These domains of cognitive performance relate to the declarative memory and cognitive control subdomains of the NIMH Research Domain Criteria (RDoC), a framework that has not yet been leveraged to advance understanding of the mechanisms contributing to patterns of NCI in HIV. There is a strong scientific premise that HIV-associated brain injury stems from immunological processes, particularly neuroinflammation, mediated by cells of the monocyte/macrophage lineage. In support of this view, studies by our team and others demonstrate that NCI in HIV is associated with microglial activation and monocyte activation. In this proposal, our multidisciplinary team will provide innovation to this line of inquiry by conducting a longitudinal neuroimaging study that not only uses the RDoC framework but also assesses neuroinflammation. Building on our cross-sectional neuroimaging studies, we will first use task-based functional magnetic resonance imaging (fMRI) and resting state fMRI in HIV+VS individuals and HIV-uninfected individuals to identify the neural circuitry contributing to deficits in declarative memory and cognitive control. Second, we will use positron emission tomography (PET) to assess HIV-related alterations in chronic neuroinflammation in relation to NCI. Third, we will computationally integrate the multimodal imaging data in relation to changes in cognitive performance over time. To achieve our goal, we propose a single-site, longitudinal study in phenotypically well- characterized HIV+VS (N=100) and HIV- controls (N=50) from the WIHS and Multicenter AIDS Cohort Study (MACS). Participants will complete neuroimaging assessments (resting state and task-based fMRI, structural MRI, diffusion-weighted MRI) annually for three years and cognitive assessments every six months over that same time. The longitudinal design allows an assessment of the reproducibility of key findings over time and the sensitivity of these neuroimaging measures to changes in cognitive performance. To examine HIV-related alterations in chronic neuroinflammation, a subset of individuals (total n =42; 24 HIV+VS) will also complete PET assessments using [11C]DPA-713 (DPA). In keeping with NIH research priorities, after 5 years of potential funding, the impact of this R01 on the field will be to inform our understanding of the mechanisms linked to neurological comorbidity and to provide novel, more sensitive neuroimaging biomarkers to guide testing of new cognitive therapies for HIV+ individuals.

The overall goal of the UIC BIRCWH Program is to align with the 2019-23 Trans-NIH Strategic Plan for Women?s Health Research to ?promote training and careers to develop a well-trained, diverse, and robust workforce to advance science for the health of women? (NIH ORWH, 2019). Our long-term objective is to promote training and career development of a new generation of researchers equipped with the knowledge and career skills necessary to advance science for the health of women in the next decade and beyond. We are based in the UIC College of Medicine, but draw on the interdisciplinary strengths of UIC?s seven health colleges. Our past success directing a BIRCWH from 2007-2017 fostered the academic careers of 18 Scholars (33% under-represented minorities; URM). Their success is evident in 24 NIH grants as Principal Investigator and 32 as Co-Investigator, as well as numerous non-NIH grants (55 as PI and 50 as Co-I). We also have a record of success mentoring in the UIC-funded Women?s Health Research (WHR) Associates Program which supported 8 Scholars (38% URM) and the UIC-funded Bridge Program which currently supports 3 Scholars. All three programs have received strong institutional support from UIC leadership. We seek BIRCWH funding over the next 5 years to train 6 junior faculty researchers in women?s or sex/gender-based health research: 3 MDs for 3 years and 3 PhDs for 2 years. We will build upon our demonstrated success by capitalizing on 4 program strengths: (1) our success in launching the careers of 29 junior faculty in women?s health research; (2) alignment with the Trans-NIH Strategic Plan for Women?s Health; (3) the highly interdisciplinary nature of the program and integration across UIC and regional BIRCWH Programs; and (4) the use of evidence-based mentoring practices to prepare scholars to conduct team science and address barriers facing new female and URM investigators. Our short-term objectives build upon these strengths through ongoing program activities and several new initiatives. Ongoing activities include: a) supplementing team mentoring programs with new training and tools, b) optimizing existing and new UIC partnerships, and c) augmenting our strong didactic curriculum in women?s health research. We also have 4 novel initiatives. First, the Diversification of the Sciences Initiative identifies institutional and other barriers to optimal academic quality of life among new investigators, and pursues policy changes and program activities to improve recruitment, retention, and advancement of women and URMs. Second, we will engage in the Midwest BIRCWH Program, an initiative to increase collaboration across Midwestern BIRCWH Programs. Third, we will incorporate new curriculum content on reproducibility, transparency, and rigor. Lastly, we will provide training on fundamental research approaches, hands-on bioinformatics training, and experimental design for personalized medicine. BIRCWH activities at UIC related to sex and gender influences in health and disease will advance the ORWH goal to accelerate the translation of knowledge into improved health care for women.