Genetic Predictors of Cognition and Prefrontal Function in Women with HIV
thesisposted on 10.12.2012, 00:00 by Erin E. Sundermann
The HIV virus enters the central nervous system (CNS) leading to neurological and cognitive complications. Mild neurocognitive impairment persists in approximately 45% of HIV-infected individuals particularly in the domains of executive function, learning and memory. The Val158Met (rs4680) single nucleotide polymorphism (SNP) of the catechol-O-methyltransferase gene (COMT) impacts executive function and prefrontal function through its effect on dopamine metabolism. Both HIV and the Val allele of the Val158Met SNP have been associated with compromised executive function and inefficient brain processing. Therefore, this study involved both behavioral and imaging substudies to determine the independent and interactive effects of HIV serostatus and COMT genotype on working memory in women and the neural systems underlying this effect. For the behavioral study, participants included 54 HIV-infected women (33 Met allele carriers, 21 Val/Val) and 33 HIV-uninfected women (12 Met allele carriers, 21 Val/Val). Participants completed the 0-, 1- and 2-back conditions of the N-back, a working memory test. Results showed that HIV-infected women demonstrated significantly worse N-back performance compared to HIV-uninfected women (p < 0.05). A significant serostatus by genotype interaction (p < 0.01) revealed that, among Val/Val, but not Met allele carriers, HIV-infected women performed significantly worse than HIV-uninfected controls across N-back conditions (p < 0.01). For the imaging study, 33 women (20 HIV-infected, 13 HIV-uninfected women) underwent fMRI assessments while completing the N-back task. Similar to behavioral findings, the imaging analysis showed that serostatus and genotype interacted to impact brain activation (p < 0.01). HIV-infected, Val/Val carriers showed significantly greater brain activation in the anterior cingulate and prefrontal regions compared to HIV-uninfected, Val/Val carriers. Conversely, HIV-uninfected, Met allele carriers demonstrated significantly greater brain activation in the anterior cingulate and a prefrontal region compared to HIV-infected, Met allele carriers. Perhaps the association between HIV infection and working memory deficits and inefficient brain processing is driven by individuals with suboptimal, prefrontal dopamine levels (Val/Val). Findings highlight dopamine dysfunction as a neural mechanism underlying HIV-neurocognitive disorders and suggest that the decrease in dopamine signaling that results from the combination of HIV and the Val/Val genotype contributes to a vulnerability to working memory impairment.