Yolanda R. Smith - US grants

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award proposal contains didactic coursework, mentored instruction, and a clinical research project designed to apply the principles learned. The investigators' clinical research interest is in the integration of reproductive endocrinology with cognition, aging, and brain function and neurochemistry. The proposed clinical training and research studies in this application are designed to increase her skills in study design, biostatistics, cognitive neurosciences and neuroimaging techniques, with the ultimate goal of developing into an independent clinical investigator. The curriculum of the K30 Training Grant in Clinical Research, leading to a Master of Science in Clinical Research Design and Statistical Analysis at the UM, is included in the coursework. The goal of the research proposal is to study the neurobiological effects of long-term hormone therapy in healthy postmenopausal women. Sixty postmenopausal women, 60 years or older, will be recruited for this cross-sectional study (20 will never have used hormones, 20 will have used estrogen only for at least 10 years, and 20 will have used estrogen and progestin for at least 10 years). All women will undergo an extensive neuropsychological testing battery, a single photon emission computed tomography (SPECT) scan with a marker of cholinergic synaptic terminal density, an anatomic magnetic resonance image (MRI), and measures of estradiol and estrone. Ten women from each group will also undergo a functional MRI (fMRI) during a cognitive task designed to activate brain areas affected by estrogen and altered in Alzheimer's Disease. Comparison between groups will offer a greater understanding of the effect of hormone therapies on brain neurochemistry and cognition.

human therapy evaluation; neurobiology; estrogens; hormone therapy; postmenopause; aging; patient oriented research; clinical research; human subject; magnetic resonance imaging; female; women's health;

[unreadable] DESCRIPTION (provided by applicant): The menopausal transition is an important life process, significantly impacting the cognitive and psychological health of women. Postmenopausal neuroimaging studies of hormone therapy indicate that estrogen levels have significant effects on brain neural circuitry. However, mechanistic studies of the neurobiology of the menopausal transition are lacking. This proposal combines the rich historical data from and access to a uniquely well-characterized population of women, transitioning the menopause, with neuropsychological testing and state-of-the-art neuroimaging techniques, to characterize the neurobiology of the menopausal transition. To test hypotheses concerning mechanisms of menopausal cognitive and affective changes, we will recruit from a well-characterized population of women at the mid-life who have been participants in a bone health and metabolism study involving extensive hormone and cycle monitoring since 1992. Recruits will be women aged 40-55 years, stratified into panels representing premenopause, early perimenopause, late perimenopause and natural postmenopause defined by follicle-stimulating hormone levels and menstrual bleeding patterns. This collaboration will involve extensive neuropsychological testing combined with a validated functional magnetic resonance (fMRI) imaging paradigm to determine brain activation patterns during cognitive and emotional tasks among women of each panel. The Specific Aims include: 1. Identify if specific stages or characteristics of the menopausal transition are associated with alterations in brain functioning as manifested either by fMRI-BOLD activation during cognitive and emotional tasks or by neuropsychological testing. 2. Delineate the relative contribution of ovarian aging vs. chronological aging in brain functioning as manifested either by fMRI-BOLD activation during cognitive and emotional tasks or by neuropsychological testing. 3. Demonstrate whether cognitive processing changes noted on fMRI-BOLD precede, occur concurrent, or follow observable changes in neuropsychological testing. These studies will determine the contributions of hormones and aging to changes in cognitive and emotional processing. A better understanding of the areas and sequence of brain processing changes will allow the health community to plan interventions which most effectively preserve cognitive and emotional health for women. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Menopause is an important life stage with implications for cognitive health of women. Ovarian hormones are known to regulate neuronal function beyond the neuroendocrine reproductive axis, influencing brain regions critical to cognition. However, the specific cognitive effects of gonadal steroids in woman have been difficult to define and are potentially confounded by brain health at initiation of hormone therapy (HT), as well as mood, sleep and vasomotor changes. This collaborative application combines extensive neuropsychological assessment and validated state-of-the-art neuroimaging techniques, to pilot test mechanistic hypotheses concerning the neurobiological effects of HT in healthy early postmenopausal women. To test hypotheses concerning mechanisms of gonadal steroid effects on menopausal cognitive changes, we will recruit early postmenopausal women in the age group of 45-55 years, within 12 to 24 months since their last menstrual period. Using a randomized double placebo-controlled cross-over design, 36 women will be randomized to both the treatment group (18 estradiol only, 18 progesterone only) and the order they receive 3 months of hormones and placebo. Brain functional measures will be evaluated at the end of each treatment period, in addition to hot flash and sleep monitoring and menopausal symptom assessments. The functional measures will include the performance of the volunteers on a comprehensive neuropsychological testing battery, and the brain functional responses to episodic verbal and non-verbal memory challenges, as determined with fMRI. The Specific Aims include: 1. To examine the effect of estradiol alone on brain functioning in early post- menopausal women as manifested by fMRI-BOLD activation during verbal and non-verbal cognitive tasks and 2. To determine the effects of progesterone alone on brain functioning in early postmenopausal women as manifested by fMRI-BOLD activation during verbal and non-verbal cognitive tasks. PUBLIC HEALTH RELEVANCE: These studies will determine the differential contributions of estrogen and progesterone to cognitive processing in early postmenopausal women. A better understanding of the specific contributions of gonadal sex hormones to brain processing changes will allow for preparation of an R01 to comprehensively study the neurobiology of hormone use in early menopause and will ultimately allow the health community to plan interventions which may most effectively preserve cognitive health for women.

DESCRIPTION (provided by applicant): This competitive renewal proposal describes the accomplishments of the University of Michigan Reproductive Medicine Network (RMN) site and the qualifications and experience of the research team comprised of collaborative faculty from Reproductive Endocrinology, Urology, Medical Endocrinology, and Biostatistics. The University of Michigan Center for Reproductive Medicine includes 6 Board Certified clinicians in Obstetrics and Gynecology, Reproductive Endocrinology or Urology. Collaborating within the Center is a biostatistician with over 20 years of clinical trials experience and 2 Medical Endocrinology faculties who provide expertise on obesity and metabolism and unique metabolomics research resources. We have partnered with Michigan State University to serve as an Ancillary Site for enrollment into clinical trials extending the subject catchment areas to Western and Northern Michigan and surrounding states. In the previous funding period, the University of Michigan site participated actively in the inception, selection, design, and review of four clinical protocols, te establishment of the RMN tissue and DNA repositories and birth outcomes database. The University also provided leadership in the evaluation and treatment of male infertility, recruited and mentored a Clinical Research/Reproductive Scientist Training (CREST) scholar to develop a successful ancillary recruitment site, and contributed to numerous RMN manuscripts and committees. We bring to the RMN the valuable resources of the NIH supported Michigan Clinical Research Unit, Michigan Nutrition Obesity Research Center, and Michigan Regional Comprehensive Metabolomics Resource Core, as well as the full support of the Departments of Obstetrics and Gynecology, Department of Urology, and Division of Metabolism, Endocrinology and Diabetes at the University of Michigan and the Women's Program at the Ann Arbor VA Medical Center. In addition, Michigan State University brings full support of its statewide Department of Ob/Gyn, numerous University Research cores, and experience in conducting clinical trials in women's health. The concept protocol addresses treatment of infertility associated with obesity-related ovulatory dysfunction. It investigates the impact of intensive preconceptual weight loss on reproductive outcomes and response to clomiphene citrate, and assesses if pretreatment or treatment-induced alteration in clinical or metabolomics profiles predicts reproductive outcomes. In summary, the research investigators at the University of Michigan Center for Reproductive Medicine and associated Centers and Departments provide an unparalleled environment to perform multicenter clinical trials. The University has been an effective site in the current RMN, and is fully prepared to recruit, participate, and lead in the fll breath of RMN activities in the next stage of this important program.

DESCRIPTION (provided by applicant): The long-term objective of this application is to foster the development of clinician- investigators in neuroscience. The goal of the research education program proposed here is to allow selected Emory neuroclinical trainees (in Neurology, Neurosurgery, Neuropathology, Neuroradiology and Emergency Medicine), during residency and fellowship training, to acquire the necessary research skills and background to enable them to be competitive for mentored career development awards and thus catalyze the continuity of the neuroclinician-investigator species. To this end, the specific aim of this application is to provide an outstanding research education experience to one or more residents each year from Neurology, Neurosurgery, Neuropathology, Neuroradiology or Emergency Medicine, to be complemented by a continuation of the participants' research education during subsequent fellowship training. A key component of the research education will be mentored laboratory or clinical research under the supervision of an experienced mentor. The participants in the present program will also have the benefit of a mentor team comprising 1-2 members in addition to the primary mentor, and their development will be closely monitored by the PIs. The participants in the present program will also be able to take advantage of additional educational resources, including courses in research design and analysis, grant-writing and research ethics.