Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer's disease with and without depression

Objective: Few studies have examined pathological changes in serotonergic neurons in depression, particularly in elderly patients and in elderly patients in which depression occurs in dementia. The authors hypothesized that greater neurofibrillary pathology and fewer serotonergic neurons would be found in the dorsal raphe nuclei in depressed elderly subjects, compared with nondepressed elderly subjects, and in Alzheimer's disease patients with depression, compared to Alzheimer's disease patients without depression. Method: In a postmortem study, immunocytochemistry and two-dimensional image analysis were used to measure neuronal density and neuritic pathology in serotonergic neurons in the dorsal raphe nuclei of elderly subjects with primary major depression (N=14), elderly Alzheimer's disease patients with (N=8) and without (N=7) comorbid depression, and nondepressed elderly comparison subjects (N=10). Results: No differences in neuritic pathology or neuronal density were found between the subjects with primary major depression and the nondepressed comparison subjects. The Alzheimer's disease subjects showed markedly fewer serotonergic neurons and associated higher levels of neuritic pathology, compared with the subjects with primary depression and the nondepressed comparison subjects, but the Alzheimer's disease subjects with comorbid major depression did not differ from the Alzheimer's disease subjects without depression on these measures. Conclusions: The study found no evidence of a loss of serotonergic neurons or of neuritic pathology in the dorsal raphe nuclei in older people with depression, with or without comorbid Alzheimer's disease. These findings suggest that if serotonergic dysfunction occurs in older depressed subjects, it is not due to neuronal loss in the brainstem. Pathophysiological changes may lie elsewhere, such as in the frontal-subcortical circuits.