Abstract
Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system’s cortical targets, and reductions in the density of dopamine receptors. Through a combination of positron emission tomography (PET) imaging of the dopamine system, (f)MRI scanning, behavioral tasks, and genetic polymorphism analyses, this dissertation investigates the role of the dopamine system in cognition and brain function in healthy older adults.Study 1 examines dopamine synthesis capacity as a putative mechanism of resilience against age-related neurodegeneration. Countering declines in dopamine receptors and transporters, dopamine synthesis appears to be stable or elevated in older age. I tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss. To address this hypothesis, I investigated relationships among striatal dopamine synthesis capacity ([18F]Fluoro-l-m-tyrosine PET) and longitudinal reductions in cortical thickness and working memory. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.
In Study 2, I investigate the impact of individual differences in baseline dopamine function on the effects of a dopamine-enhancing drug on reward memory and hippocampal post-encoding processes. Converging evidence implicates dopamine in post-encoding hippocampal mechanisms inferred to support long-term memory, though there is a lack of direct evidence in humans. Using a motivated reward encoding task on and off oral methylphenidate, I tested whether individual differences in baseline dopamine ([11C]raclopride PET D2/3 receptor density) relate to drug-induced changes in hippocampal post-encoding processes. We found methylphenidate administration was associated with improved memory performance relative to placebo for both high and low reward conditions. Older adults with high receptor density showed greater persistence of hippocampal multivoxel patterns into post-encoding rest and stronger hippocampus-midbrain resting state connectivity following encoding while on methylphenidate. These findings support the view that enhanced dopaminergic tone, verified through PET, directly modulates hippocampal post-encoding dynamics in humans.
In Study 3, I test whether non-optimal dopamine function is associated with risk for developing Alzheimer’s-related pathology. Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer’s disease pathology. I investigated effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal -amyloid (A) and tau pathology (measured with PET), hippocampal volume, and cognition. The sample consisted of cognitively normal older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). DAT1 and BDNF interacted to predict A-PET, tau-PET, and hippocampal atrophy. Carriers of both “non-optimal” DAT1 C and BDNF Met alleles demonstrated greater pathology and atrophy. Our findings provide novel links between dopamine and neurotrophic factor genes and AD pathology, consistent with previous research implicating these variants in greater risk for developing AD.