Cortical Thickness and Age-associated Executive Function: Influence of Dopamine and Health & Lifestyle Factors



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Throughout history, many individuals have pondered what it means to age and what we can do to improve not only our lifespan but also our healthspan. How we age is strongly linked to our genetic makeup and is very sensitive to our environmental conditions. Regardless of our age trajectory, what we observe is an overall decline of a multitude of cognitive processes along with structural changes to the brain. Dopamine (DA) signaling is critical for optimal cognitive performance as we age, especially in prefrontal-parietal networks and in fronto-striatal networks. COMT Val 158Met (rs4680), a common polymorphism that affects DA D1 receptor dopamine availability, influences enzymatic breakdown of DA, with COMT Val carriers having a 3- to 4- fold reduction in synaptic DA compared to COMT Met carriers. Dopamine receptors and postsynaptic availability are drastically reduced with aging, coupled with a loss of striatal and extrastriatal D2 binding potential. The reduction in dopamine modulation with age negatively influences various aspects of cognition, as performance ostensibly relies on DA pathways. DRD2 C957T (rs6277) impacts DA D2 receptor density and availability, with C homozygotes linked to lower striatal DA availability and reduced executive functioning, but also high extrastriatal binding potential. In a healthy lifespan sample of adults, the current studies aimed to showcase the impact of DA on cortical thickness and executive function, coupled with demonstrating how various physical, mental, and vascular health factors modify this association. Study 1 sought to evaluate the cognitive consequences of longitudinal aging of brain structure, while addressing the role of dopamine on these associations. We also investigated whether tests of executive function demonstrated four-year longitudinal change, with the goal of assessing the role of dopamine and cortical thinning on cognitive decline. Study 2 sought to investigate the complex associations among mental and physical health variables as potential modifiers of cognitive and structural brain aging in a cross-sectional sample, while also assessing how health and lifestyle factors modify the links among dopamine, executive function, and cortical thickness. We identified novel evidence that dopamine-dependent cortical thinning predicts performance on tasks of executive function, helping to further elucidate mesocortical thickness as one mechanism underlying the link between the genetically influenced propensity for D1 and D2 availability and cognitive performance across adulthood. Additionally, we demonstrated that dopamine and age impact executive function through mesocortical thickness, while also demonstrating that arterial stiffness, sleep quality, lifetime stress and trauma, and physical activity, are all salient factors that modify both brain structure and cognitive performance. This dissertation highlights the critical role of dopamine and health and lifestyle factors on both structural and cognitive outcomes. Here, we show that aging of the brain and cognition is a surprisingly heterogeneous process and is, in part, a product of our mental and physical health.



Psychology, Cognitive