Elevated Dopamine Synthesis as a Mechanism of Cognitive Resilience in Aging

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. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using [18F]Fluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13 years earlier. 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.

Keywords: PET; atrophy; compensation; older adults; working memory.

Figure 1

Schematic showing time in years between PET scans, MR scans, and Listening Span sessions for each participant.

Figure 2

Age group differences in [¹⁸F]FMT Ki. Older adults showed significantly higher [¹⁸F]FMT Ki in the striatum (A) and the DCA (B) compared with young adults. ^*P < 0.001.

Figure 3

Cortical regions showing a relationship between change in thickness, striatal [¹⁸F]FMT Ki, and Listening Span. (A) Higher [¹⁸F]FMT Ki was significantly related to reductions in cortical thickness. Cool colors represent regions for which participants with higher [¹⁸F]FMT Ki values in whole striatum had higher rates of cortical thinning. (B) Reductions in Listening Span performance was associated with reductions in cortical thickness. Warm colors represent regions for which participants with declines in working memory function had declines in cortical thickness. (C) Regions of overlap between [¹⁸F]FMT Ki analyses (blue) and Listening Span analyses (red) are displayed in purple. Each analysis adjusted for age, sex, and years of education and underwent Monte Carlo correction for multiple comparisons (P = 0.05). Color bars display significance using -log(10) P value.

Figure 4

Associations among [¹⁸F]FMT Ki, Listening Span, and change in cortical thickness. Negative numbers on the x-axis indicate reductions in thickness over time (atrophy). (A) Striatal [¹⁸F]FMT Ki was negatively related to change in Listening Span (P = 0.04). (B) There was a positive relationship between change in thickness and change in Listening Span (P < 0.0001). (C) There was a significant interaction between [¹⁸F]FMT Ki and change in thickness (P = 0.009) such that the impact of change in thickness on Listening Span was reduced for participants with the highest levels of striatal [¹⁸F]FMT Ki.