The long-range goal of the proposed research is to develop effective, evidenced-based interventions for remediating cognitive decline associated with normal aging. Cognitive flexibility, a component of executive function that allows dynamic switching between tasks, is differentially impaired in older adults. The brain's dopamine system has been linked to cognitive flexibility, and function of this system declines with age. The curren proposal aims to define a possible mechanism by which altered dopamine function influences cognitive flexibility: disrupted communication between prefrontal cortex and striatum. I will employ a within-subjects multimodal imaging approach in young and older adults that will include endogenous measures of dopamine function in striatum (using positron emission tomography (PET) radiotracer 6-[18F]fluoro-L-m-tyrosine (FMT)), structural measures of atrophy within striatum (using structural magnetic resonance imaging (MRI)), and functional network measures between prefrontal cortex and striatum (using functional MRI connectivity analyses at rest and during task-switching). Our preliminary research indicates FMT measures of synthesis capacity increase with age. Increased dopamine synthesis in older adults may reflect compensation to counteract atrophy and other functional declines in the system (e.g. dopamine receptor and transporter downregulation). However, increased synthesis capacity is associated with disrupted cognition, suggesting compensation is either not sufficient or indicates detrimental overcompensation. The current experiments are a necessary first step in prescribing future therapeutic interventions, as they will define the functional significance of age-related increases in dopamine synthesis. My proposed research will test the following hypotheses: (1) Greater cognitive flexibility will be related to greater striatal volume, but this effect will be mediated by dopamine function as measured by FMT-PET, (2) Older adults will have decreased prefrontal cortex-striatal functional connectivity strength measured at rest, but that dopamine function will account for these age differences, and (3) Older adults will show less prefrontal cortex-striatal functional connectivity during task switching relative to young adults, and that connectivity differences mediate the effect of dopamine on cognitive flexibility. Together, the proposed experiments will contribute to a model establishing how age-related structural atrophy leads to dopaminergic dysregulation, which, in turn, disrupts functional network activity to cause cognitive deficits. This research area holds great promise for impacting public health, through eventual clinical applications for age-related cognitive decline as well as disorders associated with dopaminergic dysfunction such as schizophrenia. My proposed research will provide me with training integral to my development as a translationally-focused, multidisciplinary researcher. I will gain valuable experience in PET imaging and in cognitive aging research during my training with Dr. William Jagust, and will take advantage of the rich academic resources available through Lawrence Berkeley National Laboratory and UC Berkeley.
Cognitive function declines with age and cognitive flexibility, the ability to dynamically respond to new task demands, is particularly impacted. Clinically effective interventions that improve cognition in older adults have the potential to make a profound impact on public health, but basic research is needed to characterize the mechanisms that influence age-related cognitive decline and to identify conditions that must be met in order to achieve optimal performance. A better understanding of how age-related declines in cognitive flexibility are mediated by changes in the dopamine system and decreased network activity strength will guide the subsequent development of effective, evidence-based treatment approaches targeting the dopamine system.