Importance: The neurobiologic basis of late-life depressive symptoms is not well understood.
Objective: To test the hypothesis that neurodegeneration and neuronal density in brainstem aminergic nuclei are related to late-life depressive symptoms. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE: Longitudinal clinicopathological cohort study at residences of participants in the Chicago, Illinois, metropolitan area. Participants included 124 older persons without dementia in the Rush Memory and Aging Project who had annual evaluations for a mean (SD) of 5.7 (2.8) years, died, and underwent a postmortem neuropathological examination that provided estimates of the densities of Lewy bodies, neurofibrillary tangles, and aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area.
Main outcomes and measures: The number of depressive symptoms (mean [SD], 1.61 [1.48]; range, 0-6; skewness, 0.94) on the Center for Epidemiological Studies Depression Scale averaged across annual evaluations.
Results: Brainstem Lewy bodies were associated with depressive symptoms, and the association was attenuated in those taking antidepressant medication. Brainstem tangles were associated with more depressive symptoms in those without cognitive impairment but with fewer symptoms in those with mild cognitive impairment. Lower density of tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area was robustly associated with a higher level of depressive symptoms (mean [SE] estimate, -0.014 [0.003]; P < .001; 16.3% increase in adjusted R2). The association was not modified by medication use or cognitive impairment. Neither tyrosine hydroxlyase-immunoreactive neurons in the locus ceruleus nor tryptophan hydroxlyase-immunoreactive neurons in the dorsal raphe nucleus were related to depressive symptoms.
Conclusions and relevance: The results suggest that the mesolimbic dopamine system, especially the ventral tegmental area, has an important role in late-life depressive symptoms.