Rebecca Thurston, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The purpose of this proposed Mentored Patient-Oriented Research Career Development (K23) Award is to support the Candidate's long term career goal of conducting interdisciplinary research to characterize the biological, psychological, and social determinants of women's health during menopause. The specific objective of this award is to understand disparities in menopausal hot flashes. Hot flashes are a pressing public health issue among aging women. They are experienced by the majority of midlife women, are a leading determinant of quality of life, and are in need of safe and effective treatments. Like many health issues in the United States, hot flashes are overrepresented among key racial/ethnic minority groups. The training aims of this award are to build upon the Candidate's training in clinical health psychology and social epidemiology to address the primary training areas obesity/body composition and physiologic aspects of hot flashes and secondary training areas racial/ethnic disparities in health and longitudinal data analysis. Because the understanding of hot flashes has been limited by the incomplete understanding of hot flash physiology, proposed research will focus on one important biological factor relevant to racial/ethnic disparities in hot flashes: body size and composition. The Candidate will conduct an ancillary investigation to the Study of Women's Health Across the Nation applying physiologic and self-report measures of hot flashes to examine associations between body size/composition and hot flashes among African American and Caucasian midlife women. Secondary aims include examining aims include examining the role of reproductive hormones in this association and comparing the subjective reporting of physiologically measured hot flashes by body size/composition. Achieving these training and research objectives has the potential to clarify key mechanisms involved in hot flashes and to inform interventions for hot flashes to improve the lives of diverse women as they age. The skills, training, and data obtained from this award will support the Candidate's development as an independent investigator and an interdisciplinary women's midlife health expert, with particular expertise in hot flashes. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Two major health issues facing women as they age are cardiovascular disease (CVD) and menopausal hot flashes. CVD is the leading cause of death among women. Hot flashes are experienced by many midlife women, and for 30% of women, they are frequent or severe. Although hot flashes are traditionally regarded as a benign midlife symptom, recent research has linked a high burden of hot flashes to CVD risk. Several large trials have indicated that the greatest risk of cardiovascular events with hormone use appears concentrated among women reporting moderate to severe hot flashes. Our research shows elevated subclinical CVD among women reporting frequent hot flashes. Important mechanisms linking a high burden of hot flashes to CVD risk may be changes in endothelial function, inflammation/coagulation and cardiac vagal control. However, findings linking hot flashes to cardiovascular risk are just emerging. None of these studies was designed to examine associations between hot flashes and cardiovascular risk. Most have notable limitations, including the reliance upon crude, self-report measures of hot flashes vulnerable to multiple biases. The aim of this investigation is to examine whether women with daily hot flashes have adverse indicators of cardiovascular risk, including poorer endothelial function, higher carotid intima media thickness, lower cardiac vagal control, and an adverse inflammatory and hemostatic profile, relative to women without hot flashes. It is hypothesized that these differences will be independent of traditional CVD risk factors. Secondary aims include testing acute changes in cardiac vagal control during hot flashes and examining key pathways involved in these associations. The proposed sample includes 300 perimenopausal and postmenopausal women aged 40-60, half with daily hot flashes and half without hot flashes. Participants will be nonsmokers, free of heart disease and treated diabetes or hypertension, and free of medications impacting hot flashes. All women will undergo 3 days of physiologic hot flash monitoring, 24 hours of which will include ambulatory electrocardiography for measurement of cardiac vagal control (high frequency heart rate variability), a brachial artery ultrasound for measurement of endothelial function (flow mediated dilation), a carotid artery ultrasound for measurement of intima media thickness, and a blood sample for assessment of inflammatory/hemostatic markers and estradiol concentrations. Relations between hot flashes and cardiovascular risk indicators will be examined using linear regression and linear mixed models. This study represents the first study specifically designed to examine relations between hot flashes and CVD risk, and is an important first step in better understanding links between hot flashes and CVD risk. Addressing these aims may inform a better understanding of the physiology of hot flashes and support the development of a novel marker of cardiovascular risk among midlife women. This work has the potential to challenge the way that this presumably benign menopausal symptom is understood by researchers, clinicians, and women.

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death among women. Complex diseases such as CVD are multifactorial in origin, with their causes and sequelae spanning multiple scientific and medical disciplines. Researchers and clinicians that can work across disciplinary boundaries are needed to effectively understand and reduce the burden of CVD in women. This application for an NHLBI Mid-Career Investigator Award in Patient-Oriented Research seeks support for Dr. Rebecca Thurston, a mid-career investigator with a strong track record in interdisciplinary mentoring, training, and research in midlife women's cardiovascular health. The specific aims of this Project are to provide Dr. Thurston with the training, resources, and protected time to strengthen and amplify the public health impact of her NIH-supported research program by: (1) providing outstanding mentorship and support for young investigators from the fields of behavioral medicine, psychology, epidemiology, and medicine to address issues of importance to women's cardiovascular health; (2) supporting training for Dr. Thurston in interdisciplinary mentoring, sleep research methods, and advanced time-series methods; and (3) support extension of the aims of an ongoing NHLBI R01-supported research project testing the relation between menopausal hot flashes and cardiovascular risk to: a) investigate the role of sleep in these associations and to b) utilize th multiple streams of ambulatory time series data collected in this protocol to more innovatively model the dynamics of human physiology and behavior. The mentoring and career development activities are highly integrated, with the mutually reinforcing goals of advancing trainee careers and enhancing Dr. Thurston's growing program of research in women's cardiovascular health.

Alzheimer's disease (AD) is the leading cause of dementia in the United States. Women are particularly affected by AD. Compared to men, women have a higher prevalence of AD, higher risk of AD with the apolipoprotein (APOE)-?4 allele, and a more rapid decline in cognition following diagnosis of mild cognitive impairment or AD. The neuropathological hallmarks of AD are laid down beginning at midlife, and increasing evidence supports the need to better understand midlife risk factors for cognitive change early in the natural history of AD. However, few studies have examined sex-specific midlife risk factors. The menopause is a critical midlife transition affecting multiple aspects of women's health, including brain and cardiovascular outcomes. Clinical studies show small but significant decrements in subjective memory complaints, performance on standardized memory tests, and brain function as women transition through the menopause. Accelerated accumulation of atherosclerosis and worsening of key cardiovascular disease (CVD) risk factors are also common during this time. These brain and cardiovascular changes are not due to aging alone. Further, over 70% of midlife women report menopausal vasomotor symptoms (VMS); for a third of women they are frequent or persistent for over a decade. VMS have long been believed to be solely a quality of life issue, but recent findings have called this assumption into question. Emerging evidence with state-of-the-art physiologic measures of VMS suggests that VMS may be associated with poorer cognitive function and adverse changes in brain structure and function. A parallel line of research links VMS to an adverse CVD risk factor profile and greater subclinical CVD. In the proposed research we will test whether more frequent or persistent VMS are associated with adverse structural and functional brain outcomes and poorer cognitive function. We will test the role of CVD risk factors and subclinical CVD in these associations, while additionally considering the role of sleep, negative mood, and estradiol concentrations. Finally, we will test APOE status as a moderator of VMS-cognition and brain relations. We will address these questions in a sample of 230 women recruited from an established cohort of midlife women free of CVD and dementia who have undergone detailed physiologic characterization of their VMS as well as of their hormonal, sleep, and CVD risk profiles. We will invite the cohort back to repeat ambulatory physiologic measurement of VMS; ultrasound measures of subclinical CVD (carotid intima media thickness); actigraphic assessment of sleep; and blood markers of CVD risk factors and estradiol. We will also expand the battery to include cognitive testing; APOE genotyping; and functional and structural brain imaging. Findings from this study have the potential to identify VMS as a female- specific marker that can identify midlife women at risk of cognitive decline. This work may ultimately assist in early intervention efforts to improve cognition, enhance brain reserve, and reduce risk for AD among women.

This is a resubmission application for the Cardiovascular Behavioral Medicine Research Training grant (HL07560), continuously funded since 1983. The purposes of our program are to provide advanced training in cardiovascular behavioral medicine research methods and knowledge to postdoctoral and predoctoral fellows. Specifically, our training program for the postdoctoral and predoctoral trainees is designed to foster proficiency in four distinct areas: ? Principles of behavior and behavior change, through which the theoretical underpinnings of behavioral risk factors are understood and interventions designed. ? Research methods and statistics, whereby the skills necessary for designing and conducting research and for drawing valid inferences from empirical data are developed, with exposure to analytic approaches to complex longitudinal data. ? Cardiovascular physiology and psychophysiology, through which an understanding is established of the cardiovascular and metabolic functioning in the healthy human. ? Cardiovascular diseases, including disparities among populations and principles of pathophysiology as related to disorders of the heart and vasculature and state of the art approaches to assessing biomarkers of risk and imaging subclinical and clinical cardiovascular diseases. Based on these foundations, our program facilitates the development of independent clinical research scientists who take a multidisciplinary approach within the following three primary areas of concentration: mechanistic pathways, determinants and consequences of health behaviors; and behavioral interventions to reduce cardiovascular risk. These areas and program goals align themselves closely with the NHLBI special programmatic emphases for training and the NHLBI Strategic vision for research in the next 5 to 10 years, and fill an important niche in the NHLBI T32 portfolio. Our training program benefits from the participation of enthusiastic and committed faculty who mentor our trainees from the Departments of Psychiatry, Psychology, Medicine, Health and Physical Activity, and Epidemiology and newly appointed training faculty who are physician scientists. The diverse faculty provide collaborative and innovative research training in the above three primary areas. Our program also benefits from the availability of appropriate course offerings; the history of multidisciplinary research and training efforts by the above departments; and training resources at the University of Pittsburgh?s School of Medicine, including the Clinical and Translational Science Research Institute, and Dietrich School of Arts and Sciences. Support is requested to continue the program at the level of 4 postdoctoral and 4 predoctoral trainees.

The overall goal of this U19 application, SWAN-Aging, is to determine the impact of midlife health and the menopause transition (MT) on health and function in women in early old age (66-75 years), a pivotal period when declines in cardiac health and physical and mild cognitive impairment begin to accumulate. SWAN-Aging capitalizes on the rich resources of the Study of Women?s Health Across the Nation (SWAN), a multi-ethnic longitudinal cohort study that provided seminal information on the MT. By extending follow up of the SWAN cohort, SWAN-Aging can fill critical knowledge gaps by linking prospectively-assessed features of the MT to health and function as women enter early old age. Cardiovascular disease (CVD) is the leading cause of death and a major risk factor for physical impairment, Alzheimer?s disease, and vascular dementia in women. CVD has unique features in women, including a role of the MT that is poorly understood. Project 2 will test how the MT relates to CVD events and cardiac health in women in early old age and test how cardiac health relates to early markers of physical impairment, Alzheimer?s disease, and vascular dementia risk at a critical period in the lifespan. Early work indicates that multiple aspects of the MT are critical to CVD risk, yet few studies have the extended follow up from midlife to older ages required to test whether the MT relates to CVD. Further, a major form of CVD, heart failure, is an emerging epidemic. It is the leading cause of hospitalization and may increase risk of physical impairment, Alzheimer?s disease, and vascular dementia in women. Its female-predominant phenotype, heart failure with preserved ejection faction, is poorly understood. Whether the MT is linked to later heart failure risk, and the role that cardiac function plays in risk for disability, cognitive decline, and cognitive impairment is not known. Understanding the role of cardiac health as a remediable risk factor for Alzheimer?s disease and vascular dementia early in the natural history of dementia is critical. Leveraging the strengths of the SWAN-Aging cohort, Cores, and Projects, Project 2 will test the relations of the MT to CVD events in early old age, adding a focus on markers of cardiac dysfunction (echocardiographic indices of cardiac function, serial measures of N-terminal pro-brain natriuretic peptide, NTproBNP) and its links to indices of physical and cognitive impairment. Project 2 aims are to: 1) Test whether the MT predicts cardiac dysfunction, higher NTproBNP across the MT, CVD events, and mortality; 2) Test whether cardiac dysfunction and NTproBNP relate to early markers of physical disability and mild cognitive impairment in women, placing women at risk for disability and dementia; 3) Test racial/ethnic differences in preclinical cardiac dysfunction and its links to early markers of disability and cognitive impairment; 4) Translate findings to women and providers to improve CVD, disability, Alzheimer?s disease, and vascular dementia prevention. Findings can inform midlife risk stratification and interventions to reduce CVD, disability, and dementia in women. CVD is the leading cause of death in women and is linked to functional impairment, Alzheimer?s disease, and vascular dementia as women age.

PROJECT SUMMARY This U19 application, referred to as SWAN-Aging, is designed to determine the extent to which midlife health, and specifically the menopause transition (MT), affects successful aging in women. This proposal capitalizes on the rich resources of the Study of Women's Health Across the Nation (SWAN), a longitudinal cohort study initiated in 1994 to characterize the physiological and psychosocial changes that occur during the MT. A total of 3302 Black, Chinese, Japanese, Hispanic and White women were enrolled at seven sites, with 74% of still- living women completing up to 16 visits spanning the pre-menopause to post-menopause. SWAN has described the natural history of the MT -- its timing, patterns of hormonal changes, and symptoms ? and their relation to midlife health indicators. In SWAN-Aging, we will extend follow-up of the SWAN cohort into early old age (66-75 years) and will prospectively link comprehensive longitudinal characterization of both the MT and midlife health indicators to functioning and health across multiple domains in early old age, a pivotal time of transition into old age when adverse changes in health and functioning begin to accumulate. The global specific aims of this U19 application are to: 1) determine the impact of MT characteristics and trajectories of midlife health indicators on the preservation of cognitive, physical, genitourinary, sexual, and psychosocial function and sleep in early old age; 2) determine the impact of MT characteristics and trajectories of midlife health indicators on risk of adverse health outcomes, including falls, osteoporosis and fractures, poor cardiometabolic function, cardiovascular events and early mortality; 3) determine if racial/ethnic disparities in health and functioning in early old age are attributable to midlife racial/ethnic differences in MT characteristics and midlife health indicators; and 4) translate the SWAN and SWAN-Aging findings for women and their health care providers. These aims will be achieved through three integrated scientific Projects that are organized around key health domains (functioning, cardiometabolic health and musculoskeletal health) and linked by a common focus on MT characteristics and midlife changes in health indicators as key exposures. The three Projects will be supported by three Cores which will a) provide the necessary organizational infrastructure to conduct this study and to disseminate results to the research and medical communities; b) conduct accurate, high volume assays, adopting new methods as needed to provide state-of-the-art laboratory data, and c) oversee the design and conduct of the core clinic visit, data collection and data management, and the creation of the analytic datasets. SWAN-Aging will include one clinic visit and a National Death Index search to ensure complete mortality ascertainment for the cohort. SWAN-Aging is uniquely positioned to fill important scientific gaps in understanding of the impact of the MT and midlife indicators on women's health and functioning in early old age and to facilitate the application of new knowledge to clinical practice. This study will provide valuable insights into modifiable factors relevant to the design of future prevention and treatment programs.