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.
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.
|Rubin, Leah H; Meyer, Vanessa J; J Conant, Rhoda et al. (2016) Prefrontal cortical volume loss is associated with stress-related deficits in verbal learning and memory in HIV-infected women. Neurobiol Dis 92:166-74|
|Rubin, Leah H; Wu, Minjie; Sundermann, Erin E et al. (2016) Elevated stress is associated with prefrontal cortex dysfunction during a verbal memory task in women with HIV. J Neurovirol 22:840-851|
|Sundermann, Erin E; Bishop, Jeffrey R; Rubin, Leah H et al. (2015) Genetic predictor of working memory and prefrontal function in women with HIV. J Neurovirol 21:81-91|
|Meyer, Vanessa J; Little, Deborah M; Fitzgerald, Daniel A et al. (2014) Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection. J Neurovirol 20:352-61|
|Sundermann, Erin E; Bishop, Jeffrey R; Rubin, Leah H et al. (2013) HIV serostatus differs by catechol-O-methyltransferase Val158Met genotype. AIDS 27:1779-82|
|Sundermann, Erin E; Maki, Pauline M; Bishop, Jeffrey R (2010) A review of estrogen receptor alpha gene (ESR1) polymorphisms, mood, and cognition. Menopause 17:874-86|