The Role of Dopamine Decline, Astrocyte Reactivity, and Cerebral Small-Vessel Disease in Cognitive Aging

Several aging-related brain changes have been associated with unsuccessful cognitive aging, including dopamine decline, increased astrocyte reactivity, and cerebral small-vessel disease (SVD). We hypothesized that dopamine decline is exacerbated in older adults with higher measures of astrocyte reactivity and cerebral SVD, and that reduced dopamine integrity would be the strongest predictor of lower cognitive performance. Healthy adults (n = 55, ages: 60-79 years) underwent positron emission tomography with ligands 18F-FE-PE2I to estimate levels of dopamine transporters (DAT) and 11C-L-deprenyl-D2 to estimate levels of monoamine oxidase B (MAO-B)-a protein expressed to some degree by neurons but mainly by astrocytes. Cerebral SVD was assessed by white matter lesion volumes from magnetic resonance images. General cognition was evaluated via tests of episodic memory, working memory, and perceptual speed. Contrary to expectations, increased MAO-B levels (indicative of astrocyte reactivity) were associated with higher DAT availability (r = 0.53, p < 0.001) and reduced white matter lesion volumes (r = -0.33, p = 0.021). Reduced DAT availability was more strongly related to reduced MAO-B (r = 0.47, p < 0.001) than white matter lesion volumes (r = -0.22, p > 0.05), and only DAT was a significant predictor of cognition (r = 0.36, p = 0.032). These findings underscore the critical role of dopamine for cognition and indicate reduced glial function to underlie dopaminergic losses.