2008 — 2010 |
Sundermann, Erin Elizabeth |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Genetic Predictors of Cognition in Hiv+ Women @ University of Illinois At Chicago
[unreadable] DESCRIPTION (provided by applicant): This application proposes a predoctoral training program aimed at identifying genetic predictors of cognitive performance and brain dysfunction in Human Immunodeficiency Virus (HIV). The training program involves mentored, didactic, and experiential research training in three primary areas: 1) HIV, 2) functional magnetic resonance imaging (fMRI) and 3) psychogenetics. The candidate aims to build on previous training in fMRI and genetics and to conduct a dissertation project that unites the two methods in a novel direction. The project would be an important step in achieving the applicant's career goal to independently research cognition and mental health in relation to genetic markers. Within this broader goal, the general aim of the proposed research training program is to characterize the effect of a common polymorphism of the catechol- O-methyl transferase (COMT) gene, Val158Met, on cognition and brain function in midlife women with HIV. The motivation for examining this particular genotype in this particular disease comes from the large overlap in the specific cognitive and neural mechanisms shown to be affected by COMT in healthy adults and to be impaired in individuals with HIV. The hypothesis is that this polymorphism compounds the cognitive vulnerabilities that characterize this disease. Data suggests that the Val158Met polymorphism impairs prefrontal-mediated cognition and physiological response. The Val allele has been associated with abnormal activation and decreased processing efficiency of the prefrontal cortex during working memory tasks. The proposed project aims to examine the effect of the Val158Met polymorphism on executive function and prefrontal cortex dysfunction in midlife women with HIV. Data will be included from participants of the Chicago site of the Women's Interagency HIV Study (WIHS). Behavioral data will include performance on the N-back and will be collected in approximately 240 women during their routine WIHS study visits. We predict worse cognitive performance with the Val/Val genotype compared with Val/Met and Met/Met genotypes, and that the negative effect of Val/Val genotype would be more pronounced in HIV+ women compared to HIV- controls. To investigate the neural substrates of this genetic vulnerability, 18 HIV+ women will undergo fMRI assessments during performance of an N-back test. It is predicted that Val allele carriers will show increased prefrontal cortex activity during the N-back compared to women without the allele. This study will be the first to evaluate relationships between the COMT Val 158Met polymorphism and cognition in an HIV population. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: The findings will provide insight into genetic predictors of cognitive function in HIV+ women and will help identify a risk factor that may compound executive function deficits in the disease. [unreadable] [unreadable] [unreadable]
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0.958 |
2021 |
Sundermann, Erin Elizabeth |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex Differences in the Clinical Expression of Alzheimer's Disease Neuropathology and Their Underlying Biological Mechanisms @ University of California, San Diego
PROJECT SUMMARY/ABSTRACT Sex differences in the risk of Alzheimer?s disease (AD) and AD pathology burden have been extensively studied; however, little is known about how AD pathology burden relates to clinical symptoms in women versus men. Evidence of a cognitive advantage in the preclinical stage of AD, yet a two-times steeper cognitive decline thereafter indicate that the question of sex differences in the clinical manifestation of AD pathology is an important one. These sex differences have clinical implications in that our established thresholds for AD clinical and biological markers used to diagnose and track disease were typically generated without consideration for sex disparities. If women are better able to maintain what our current cognitive thresholds consider ?normal? cognition until a more advanced pathology state than men, then diagnosis of MCI could be delayed, thus limiting the opportunity for early intervention. We hypothesize that sex differences in the clinical translation of AD pathology results from a sex-specific balance of brain-related resilience/risk factors that change with disease stage. Our proposal is particularly innovative in that we will first characterize sex differences in how AD pathology relates to clinical symptoms by disease stage and then examine its neurobiological underpinnings and clinical implications. We will leverage both in-vivo, longitudinal biomarker data from the Alzheimer?s Disease Neuroimaging Initiative (ADNI) and prospective neuropathological data in brain tissue from multiple Alzheimer?s Disease Research Centers (ADRCs). Given their strong ties to AD pathology and the sex differences that our earlier data show, we will examine the brain resilience/risk mechanisms of (1) PET-measured brain glucose metabolism, (2) NMDAR density, a marker of glutamate neurotransmission, and (3) translocator protein 18kDA (TSPO) levels, a marker of microglial activation. Specifically, Aim 1 will utilize ADNI data to examine sex differences in trajectories of cognitive function and their relationship to longitudinal variation in AD pathology (A? and Tau) and brain metabolism by AD stage. In Aim 2, we will conduct in vitro autoradiography in hippocampal and cortical brain tissue of 60 normal control, 60 mild cognitive impairment and 60 AD dementia autopsy cases to determine sex differences in plaque, tangle, NMDAR and TSPO density and how they relate to each other and to antemortem cognitive function in each of the three diagnostic groups. In Aim 3, we will take action on these sex differences by generating sex-specific cut-scores for cognitive tests commonly used in MCI/AD diagnostic criteria with the optimal balance of sensitivity/specificity in detecting the presence of clinically-significant levels of AD biomarkers/pathology. The public health benefits of our project would be significant in that by understanding and accounting for sex disparities in our clinical and biomarker approaches to AD diagnosis, we will improve clinical and biomarker approaches to disease diagnosis and tracking in both sexes and possibly identify sex-specific therapeutic targets.
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0.902 |