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Discussion In this cross-sectional study, we investigated the relationship between the COMT ValMet polymorphism and age on regional cortical thickness in healthy adults across the lifespan. The mesocortical pathway was of primary interest because of its projections from the ventral tegmental area to the prefrontal Tyrphostin 9 and throughout the neocortex (Li et al., 2010). We found that several target cortical regions of the mesocortical system were thinner in individuals who were predisposed to lower dopamine via carrying the COMT Val allele(s). Specifically, beyond the effects of age, we found thinner cortex in COMT Val carriers than in Met carriers in the frontal, parietal, and cingulate regions, most predominantly in frontal regions, which are highly populated with dopamine D1 receptors (Lidow et al., 1991, Matsumoto et al., 2003). Given the known role of COMT in the regulation of dopamine in the prefrontal cortex (Hong et al., 1998), these results suggest that genotypic differences influencing dopamine regulation also play a role in mesocortical target thickness differences among genetic variants. Further, in this lifespan sample, these differences were not modulated by age, suggesting that COMT-related effects are apparent throughout the adult lifespan and not only as a magnification of older age. Finally, we sought to examine whether these COMT-related reductions in cortical thickness were related to cognitive performance. Past research provides evidence that COMT plays an influential role in cognition (e.g., Barnett et al., 2007, Caldú et al., 2007, Egan et al., 2001, Joober et al., 2002, Malhotra et al., 2002, Raz et al., 2009, Rosa et al., 2004), and we sought to evaluate whether thickness measures in dopamine-rich cortex mediated the association between COMT and executive function. Results indicated that, indeed, COMT Val carriers performed more poorly on executive function tasks, but also that mesocortical thickness completely mediated this COMT-EF association.
Acknowledgements This study was supported in part by the National Institutes of Health (Grants AG-036818, AG-036848, AG-056535) and BvB Dallas and AWARE foundation grants. The authors thank Marci Horn, Elizabeth Reese, and Asha Unni for assistance with neuropsychological testing, and Elizabeth Reese for help with FreeSurfer processing and manual edits.
Introduction There appear to be large individual difference factors contributing to how the hormone change at menopause is related to brain functioning. Evidence for cognitive changes after menopause is equivocal with some studies showing declines in cognition after menopause (e.g., Fuh et al., 2003, Greendale et al., 2009, Halbreich et al., 1995), whereas other studies showed no changes from premenopausal levels of performance (e.g., Henderson et al., 2003, Kok et al., 2006, Luetters et al., 2007). What is clear from the prior literature on menopause and cognition is that there are large individual differences in whether or not women experience cognitive changes. In an effort to begin to disentangle the individual differences in cognition after menopause, the present study examined how a gene that influenced the functioning of the dopaminergic system was related to brain functioning in healthy postmenopausal women. The dopaminergic system may be important for cognition after menopause because age-related changes in the dopaminergic system have been implicated in normal cognitive aging (Braver and Barch, 2002). Perhaps understanding the role of dopaminergic functioning on cognition will elucidate mechanisms involved in individual differences in cognition after menopause. Studies have shown that the dopaminergic system modulates working memory performance through the striatal-frontal pathway (e.g., Cools et al., 2007) and age changes in frontal lobe dopamine systems are responsible for cognitive aging (Braver and Barch, 2002). One mechanism by which this age-related decline in dopaminergic function may occur is through age-related changes in dopaminergic receptor availability that have been shown using positron emission tomography (e.g., Volkow et al., 1998, Wong et al., 1984). These studies estimated a decline of 12% D2 receptor availability per decade, primarily in the frontal cortex. The age-related changes in D2 receptor availability in the frontal cortex imply that age changes in dopaminergic functioning may be related to age changes in cognition that rely on the frontal cortex such as working memory (Backman et al., 2006). In addition to age-related changes in dopaminergic systems, there are also sex differences in D2 receptor binding particularly in the frontal cortex (Wong et al., 1984). These data implicate a potential role for gonadal steroid modulation of dopaminergic functioning.