Original Investigation |

Brainstem Aminergic Nuclei and Late-Life Depressive Symptoms

Robert S. Wilson, PhD1,2,3; Sukriti Nag, MD, PhD1,4; Patricia A. Boyle, PhD1,3; Loren P. Hizel, BA1; Lei Yu, PhD1,2; Aron S. Buchman, MD1,2; Raj C. Shah, MD1; Julia A. Schneider, MD1,2,4; Steven E. Arnold, MD5; David A. Bennett, MD1,2
[+] Author Affiliations
1Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
3Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois
4Department of Pathology and Family Medicine, Rush University Medical Center, Chicago, Illinois
5Departments of Psychiatry and Neurology, University of Pennsylvania, Philadelphia
JAMA Psychiatry. 2013;70(12):1320-1328. doi:10.1001/jamapsychiatry.2013.2224.
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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.

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Figure 1.
Consecutive Transverse Blocks of Fixed Tissue Obtained to Examine the Nuclei of Interest

A, Low-power view of a hemisection of the midbrain at the level of the red nucleus (R Nuc) immunostained with tyrosine hydroxylase antibody. The substantia nigra (SN) is present laterally, and the paranigral nucleus of the ventral tegmental area (arrowhead) is present medially and is traversed by the exiting third nerve fibers. B and C, The paranigral nucleus with high density (B) and low density (C) of neurons is shown. Scale bar, 125 µm.

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Figure 2.
Neuropathological Examination

Tyrosine hydroxylase immunostaining demonstrates high density (A and C) and low density (B and D) of neurons in a quadrant of the substantia nigra and in the locus ceruleus, while tryptophan hydroxylase immunostaining demonstrates high density (E) and low density (F) of neurons in the dorsal raphe nucleus. The medial longitudinal fasciculus is present in the lower borders. Scale bar, 125 μm.

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Figure 3.
Association of Density of Tyrosine Hydroxylase–Immunoreactive Neurons in the Ventral Tegmental Area With Depressive Symptoms

Adjusted for sex, age at death, and education.

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