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Original Investigation |

Brainstem Aminergic Nuclei and Late-Life Depressive Symptoms FREE

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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Published online

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.

Figures in this Article

Late-life depressive symptoms are common1 and are associated with increased risk of disability,2 dementia,3 and death.4 Because brainstem aminergic nuclei have an important role in the pathogenesis of depression5 and are early sites of age-related neurodegeneration,6,7 it has long been hypothesized that late-life depressive symptoms are partly due to neurodegenerative changes in these nuclei.811 Support for the hypothesis has been inconsistent, likely because of several factors. Few studies have had more than 50 participants8,10,12 or used continuous measures of depressive symptoms,9,10 limiting statistical power. Also, much research has been conducted among individuals with dementia.6,810,1315 However, the presence of dementia introduces substantial error into the measurement of depressive symptoms,16,17 in addition to extensive pathological conditions elsewhere in the brain, and the neurodegenerative changes associated with dementia are robustly related to cognitive,18 sensory,19 and motor20 symptoms years before dementia onset, suggesting that associations with depressive symptoms might be easier to identify during this period.11 Finally, despite evidence that brainstem dopamine neurons have an important role in regulating depression-related behavior,2123 previous investigations have primarily focused on the locus ceruleus and dorsal raphe nucleus.

The present study examines the association of neurodegenerative lesions and aminergic neurons in 4 brainstem nuclei with the level of depressive symptoms in late life. At annual intervals for a mean of 5.7 years, older persons without dementia had structured evaluations that included a standard self-report measure of depressive symptoms. At death, a uniform neuropathological examination was performed that yielded 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. We tested the hypothesis that higher pathological burden and lower neuronal density are associated with more depressive symptoms.

Participants

The Rush Memory and Aging Project is an ongoing clinicopathological study that began September 1, 1997, and includes annual clinical evaluations and brain autopsy at death.24 Persons were recruited from social service agencies, subsidized housing facilities, retirement communities, and churches in the Chicago, Illinois, metropolitan region. After a presentation on the project, interested individuals met for further discussions with staff, who obtained written informed consent. The project was approved by the institutional review board of Rush University Medical Center, Chicago, Illinois.

There had been 550 deaths (among 1533 participants) at the time of these analyses. A brain autopsy had been performed in 439 (79.8%), and a uniform neuropathological examination had been completed in the first consecutive 417 individuals. From these, 170 individuals were selected to provide a wide range of cognitive, motor, and affective functioning proximate to death for a clinicopathological substudy of brainstem aminergic nuclei as described elsewhere.25,26 We excluded 45 individuals with a diagnosis of dementia (see the Clinical Evaluation subsection), and 1 person was missing data about depressive symptoms. Analyses are based on the remaining 124 individuals, who had a mean (SD) age at death of 87.7 (5.7) years. They had completed a mean (SD) of 14.3 (2.5) years of education, 69.4% were women, and 43.5% had mild cognitive impairment.

Assessment of Depressive Symptoms

A 10-item version27 of the Center for Epidemiological Studies Depression Scale28 was used to assess depressive symptoms at each annual clinical evaluation. For each item, the interviewer read a brief statement (eg, “I felt depressed”), and the participant indicated whether or not he or she had felt that way much of the past week. The score is the number of symptoms reported (range, 0-10). This 10-item scale is less burdensome than the original 20-item scale but has similar psychometric properties,27 and its measures have been associated with adverse health outcomes, including dementia29 and death.4 Supported by prior factor analyses,27,30 subscores were created for negative affect (3 items, including “I felt depressed,” “I felt lonely,” and “I felt sad”), positive affect (2 items, including “I was happy” and “I enjoyed life”), somatic symptoms (3 items, including “I felt like everything I did was an effort,” “My sleep was restless,” and “I could not get going”), and interpersonal problems (2 items, including “People were unfriendly” and “I felt that people disliked me”), as previously described.31

Clinical Evaluation

The annual evaluations included a structured medical history, neuropsychological testing, and neurological examination.24 Prescription and over-the-counter medications were inspected, identified, and coded using the Medi-Span Master Drug Database system.32 The neurological examination included a modified version33 of the motor portion of the Unified Parkinson’s Disease Rating Scale,34 as previously described.35 After each evaluation, an experienced clinician diagnosed dementia and mild cognitive impairment. Classification of dementia was based on the criteria of the joint working group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association, which require a history of cognitive decline and impairment in at least 2 cognitive domains.36 The diagnosis of mild cognitive impairment required impairment in 1 or more cognitive domains in the absence of dementia.37 Upon death, all clinical data were reviewed by a board-certified neurologist blinded to all pathological data, and final diagnoses of mild cognitive impairment and dementia were made.

Neuropathological Examination

The brain was removed a median of 6.0 hours (interquartile range, 4.8-8.6 hours) after death, which occurred a median of 9.3 months (interquartile range, 5.5-12.9 months) after the last complete clinical evaluation. Examiners blinded to all clinical data followed a standard protocol for tissue preservation, tissue sectioning, and quantification of pathological findings.20

To examine the nuclei of interest, consecutive transverse blocks of fixed tissue were obtained at 4 brainstem levels, as previously described.25,26 The first block included the substantia nigra and paranigral nucleus of the ventral tegmental area (Figure 1A); the second block included the rostral level of the dorsal raphe nucleus, the trochlear nucleus, and the decussation of the superior cerebellar peduncles; the third block included the caudal level of the dorsal raphe nucleus, rostral levels of the locus ceruleus nuclei, and the mesencephalic nucleus of the trigeminal nerve; and the fourth block included the main body of the locus ceruleus. Following routine processing, blocks were embedded in paraffin, and 6-μm sections stained with hematoxylin-eosin were used to survey the regions of interest. Blocks without anatomically matching levels of the regions of interest were excluded. Immunohistochemistry was performed using an indirect immunoenzyme horseradish peroxidase method with 3,3′diaminobenzidine as the chromogen in an autostainer (Leica Bond Max; Leica Microsystems) using a kit (Bond Polymer Refine Detection Kit; Leica Microsystems). Tyrosine hydroxylase–positive and tyrosine hydroxylase–negative neurons in the substantia nigra, ventral tegmental area, and locus ceruleus were identified using a monoclonal anti–tyrosine hydroxylase antibody (1:750; ImmunoStar). Nickel chloride (5%) added to the 3,3′diaminobenzidine substrate (Vector Laboratories) enhanced the signal of the tyrosine hydroxylase–positive neurons and their processes to a brown-black color. The count of ventral tegmental area neurons was based on the paranigral nucleus. The figures show examples of high and low densities of tyrosine hydroxylase–positive neurons in the paranigral nucleus of the ventral tegmental area (Figure 1B and C), substantia nigra (Figure 2A and B), and locus ceruleus (Figure 2C and D). Serotonergic neurons in the dorsal raphe nucleus were identified using an anti–tryptophan hydroxylase monoclonal antibody (1:1000; Sigma Chemical Company). Examples of high and low densities of tryptophan hydroxylase–positive neurons are shown in Figure 2E and Figure 2F, respectively.

Place holder to copy figure label and caption
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.

Graphic Jump Location
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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.

Graphic Jump Location

Neuronal density, neurofibrillary tangles, and Lewy bodies were quantitated at 1 level of the substantia nigra and the ventral tegmental area, at 2 levels of the dorsal raphe nucleus, and at 2 levels of the right and left locus ceruleus. The immunohistochemical preparations were used to outline the regions of interest using software (Stereo Investigator Program; MBF Biosciences) attached to a microscope (BX60; Olympus) with a motorized stage. These outlines were superimposed on slides used to determine the neuron, neurofibrillary tangle, and Lewy body counts in the locus ceruleus, dorsal raphe nucleus, and ventral tegmental area. The counting frame and motorized stage facilitated counting in contiguous fields in the outlined regions. In these fields, unstained and immunostained neurons with nuclei were manually selected at a magnification of ×400. Densities of neurons, tangles, and Lewy bodies in the 4 quadrants of the substantia nigra were determined, as described previously.25

Analyses were based on the density per millimeter squared of immunostained neurons. The interrater reliability of these neuronal density measures, estimated among a subset of 12 participants, was high for the locus ceruleus (r = 0.97), dorsal raphe nucleus (r = 0.96), substantia nigra (r = 0.97), and ventral tegmental area (r = 0.99) (P < .001 for all). Their discriminant validity is supported by previous research linking neuronal density in the substantia nigra to subclinical parkinsonism25 and linking neuronal density in the locus ceruleus to cognitive decline.26

Neurofibrillary tangles were identified using a monoclonal anti–paired helical filament tau phosphorylated antibody (clone AT8, 1:2000; Thermo Scientific), and Lewy bodies were identified using a monoclonal phosphorylated antibody to α-synuclein (1:20 000; Wako Chemical USA Inc).20 The total numbers of neurofibrillary tangles and Lewy bodies in each brainstem nucleus within the outlined area referred to above were counted manually in the regions of interest, and results were expressed as density per millimeter squared.

To assess pH, 250 to 300 mg of frozen cerebellum was homogenized (Polytron PT10-35GT; Kinematica) in 5 volumes of nuclease-free water adjusted to pH 7.2. The pH of each homogenate was measured twice at room temperature (sympHony SB70 pH meter; VWR). Analyses are based on the mean of the 2 readings, which were highly correlated (r = 0.998, P < .001).

Statistical Analysis

All analyses included terms to adjust for the effects of sex, age at death, and education. A mixed-effects model was used to determine whether depressive symptoms changed over time. The mean depressive symptom score was regressed on postmortem variables in a series of linear regression models. The initial model had a term for the composite measure of brainstem Lewy bodies. The model was repeated using the following variables: controlling for parkinsonism; with depression subscores as outcomes; separately analyzing Lewy bodies within each nucleus; with an indicator for antidepressant use and its interaction with Lewy bodies; with an indicator for mild cognitive impairment and its interaction with Lewy bodies; and controlling for pH, postmortem interval, and time from the last clinical evaluation to death. Similar analyses were conducted with the measures of brainstem tangle density. The 4 neuronal density scores were modeled separately, ventral tegmental area neurons and nigral neurons were modeled together, and ventral tegmental area neurons were modeled controlling for pH, postmortem interval, and time from the last clinical evaluation to death. We also assessed whether ventral tegmental area neurons were related to depression subscores, accounted for the association of Lewy bodies with depressive symptoms, or interacted with antidepressant medication use or mild cognitive impairment.

At the initial evaluation, depressive symptom scores ranged from 0 to 5 (mean [SD], 1.48 [1.66]; skewness, 1.04). During a mean (SD) of 5.7 (2.8) annual follow-up years, depressive symptoms did not seem to change (eFigure 1 in the Supplement). In a mixed-effects model adjusted for age, sex, and education, there was no evidence that the number of depressive symptoms changed over time (mean [SD] estimate for time, 0.005 [0.03]; P = .85) or that residual variation not captured by the model was related to the brainstem postmortem variables. Therefore, we averaged scores across evaluations to create a composite index of late-life depressive symptoms (mean [SD], 1.61 [1.48]; range, 0-6; skewness, 0.94), as done in previous clinicopathological research.38,39 The composite score was not related to sex (t122 = 1.42, P = .16), age at death (r = −0.00, P = .97), education (r = −0.09, P = .30), pH (r = −0.12, P = .19), postmortem interval (r = 0.11, P = .22), or time from the last clinical evaluation to death (r = 0.17, P = .05).

Because the measures of tangles and Lewy bodies in the nuclei clustered in a factor analysis (Table), we used composite measures of tangle density (n = 124; mean [SD], 1.66 [1.51]; range, 0-5.44; skewness, 1.80) and Lewy body density (n = 124; mean [SD], 0.09 [ 0.29]; range, 0-0.88; skewness, 3.52) based on all 4 nuclei in primary analyses. The composite measures were not correlated (r = 0.13, P = .16). Higher density of tangles (r = 0.24, P = .006) but not Lewy bodies (r = 0.03, P = .75) was related to older age at death; neither was related to sex, education, pH, postmortem interval, or time from the last clinical evaluation to death.

Table Graphic Jump LocationTable.  Information on the Density of Tangles and Lewy Bodies in Brainstem Aminergic Nuclei
Lewy Bodies and Depressive Symptoms

In a linear regression model adjusted for sex, age at death, and education, higher density of brainstem Lewy bodies was associated with a higher level of depressive symptoms (mean [SE] estimate, 1.133 [0.443]; P = .01; 4.0% increase in adjusted R2). Results were similar after controlling for pH, postmortem interval, and time from the last clinical evaluation to death (mean [SE] estimate, 1.159 [0.437]; P = .009) or parkinsonism proximate to death (mean [SE] estimate, 1.168 [0.450]; P = .01). The association was observed in 3 of 4 nuclei, with mean (SE) estimates of 0.363 (0.175) for locus ceruleus (P = .04), 5.302 (2.000) for dorsal raphe nucleus (P = .009), 1.301 (0.609) for substantia nigra (P = .04), and 0.420 (0.368) for ventral tegmental area (P = .26). In analyses of subscores, higher Lewy body density was marginally related to negative affect (mean [SE] estimate, 0.495 [0.237]; P = .04), robustly related to somatic symptoms (mean [SE] estimate, 0.634 [0.204]; P = .002), and unrelated to positive affect (mean [SE] estimate, 0.007 [0.107]; P = .95) or interpersonal problems (mean [SE] estimate, −0.005 [0.033]; P = .88).

We conducted additional analyses to determine whether antidepressant medication use (32.3% during at least part of the observation period) (eTable 1 in the Supplement) or mild cognitive impairment (43.5%) was obscuring the association of Lewy bodies with depressive symptoms. There was no interaction with mild cognitive impairment (mean [SE] estimate, 0.859 [0.991]; P = .39), but an interaction was observed with medication use (mean [SE] estimate, −2.476 [0.913]; P = .008): the association of Lewy bodies with depressive symptoms was attenuated in those taking antidepressant medication compared with those not taking antidepressant medication.

Tangles and Depressive Symptoms

The composite measure of brainstem tangle density was not related to depressive symptoms (mean [SE] estimate, −0.038 [0.090]; P = .68); adjustment for pH, postmortem interval, and time from the last clinical evaluation to death yielded comparable results (mean [SE] estimate, 0.087 [0.093]; P = .35), and the results of a subsequent analysis with a quadratic term for tangles (mean [SE] estimate, −0.061 [0.039]; P = .12) did not suggest a nonlinear association. No association with tangles was present in the individual nuclei, with mean (SE) estimates of 0.031 (0.071) for locus ceruleus (P = .66), −0.007 (0.045) for dorsal raphe nucleus (P = .88), 0.482 (0.332) for substantia nigra (P = .15), and −0.105 (0.087) for ventral tegmental area (P = .23). There was no interaction with antidepressant medication use (mean [SE] estimate, 0.027 [0.217]; P = .90), but an interaction was observed with mild cognitive impairment (mean [SE] estimate, −0.491 [0.190]; P = .01): higher tangle density was associated with higher level of depressive symptoms in those without cognitive impairment but with lower level of depressive symptoms in those with mild cognitive impairment (eFigure 2 in the Supplement).

Aminergic Neuronal Density and Depressive Symptoms

Because of missing or insufficient tissue, 6 to 13 participants per nucleus had missing neuronal data. eFigure 3 in the Supplement shows the distributions of aminergic neuronal density in the locus ceruleus (n = 118; mean [SD], 44.1 [17.8]; skewness, 0.39), dorsal raphe nucleus (n = 117; mean [SD], 105.4 [28.3]; skewness, 0.54), substantia nigra (n = 113; mean [SD], 31.1 [11.9]; skewness, 0.01), and ventral tegmental area (n = 111; mean [SD], 82.8 [47.9]; skewness, 0.33). None of the density measures were related to sex, age at death, or education; their crude correlations with pH, postmortem interval, time from the last clinical evaluation to death, and brainstem pathological conditions are summarized in eTable 2 in the Supplement.

We constructed a series of linear regression models adjusted for sex, age at death, and education to assess the hypothesized association between brainstem aminergic neurons and depressive symptoms. Lower density of tyrosine hydroxylase–immunoreactive neurons in the ventral tegmental area was related to higher level of depressive symptoms in the ventral tegmental area (Figure 3) (mean [SE] estimate, −0.014 [0.003]; P < .001; 16.3% increase in adjusted R2) and substantia nigra (mean [SE], estimate, −0.025 [0.012]; P = .03; 1.5% increase in adjusted R2) but not the locus ceruleus (mean [SE] estimate, −0.011 [0.008]; P = .18). There was no association for tryptophan hydroxylase–immunoreactive neurons in the dorsal raphe nucleus (mean [SE] estimate, 0.000 [0.005]; P > .99). When the ventral tegmental area and substantia nigra were included in the same model, only neurons in the ventral tegmental area were related to depressive symptoms (mean [SE] estimate, −0.012 [0.003]; P < .001). Adjustment for pH, postmortem interval, and time from the last clinical evaluation to death did not affect the association of ventral tegmental area neurons with depressive symptoms (mean [SE] estimate, −0.013 [0.003]; P < .001). The use of antidepressant medication was not related to the density of ventral tegmental area neurons (t109 = −1.21, P = .23). Neither antidepressant use (mean [SE] estimate, 0.006 [0.005]; P = .26) nor the presence of mild cognitive impairment (mean [SE] estimate, 0.001 [0.006]; P = .88) modified the association of ventral tegmental area neurons with depressive symptoms.

Place holder to copy figure label and caption
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.

Graphic Jump Location

Because lower density of ventral tegmental area neurons was associated with higher density of brainstem Lewy bodies (r = −0.19, P = .046), we modeled them together. In this analysis, the association of Lewy bodies with depressive symptoms was attenuated (mean [SE] estimate, 0.615 [0.434]; P = .16), but the association of neurons with symptoms persisted (mean [SE] estimate, −0.013 [0.003]; P < .001), suggesting that the association of brainstem Lewy bodies with depressive symptoms was in part due to the density of ventral tegmental area neurons.

To further investigate how ventral tegmental area neurons were related to depressive symptoms, we analyzed different symptom domains. Lower density of tyrosine hydroxylase–immunoreactive neurons in the ventral tegmental area was associated with negative affect (mean [SE] estimate, −0.007 [0.002]; P < .001), lack of positive affect (mean [SE] estimate, −0.002 [0.001]; P = .003), and somatic symptoms (mean [SE] estimate, −0.004 [0.001]; P = .007) but not with interpersonal problems (mean [SE] estimate, −0.0003 [0.0001]; P = .17).

During a mean of approximately 5 years of observation, depressive symptoms were assessed annually in 124 older persons who subsequently died and had a postmortem neuropathological examination. Lower density of tyrosine hydroxylase–immunoreactive neurons in the ventral tegmental area was associated with higher level of depressive symptoms, with 16.3% of the variability in symptoms explained by individual differences in density. The results suggest that the mesolimbic dopamine system has an important role in late-life depressive symptoms.

Animal models2123 and human neuroimaging studies40,41 have highlighted the potential importance of mesolimbic dopaminergic mechanisms in depression, particularly for aspects of apathy and anhedonia. However, we are unaware of previous clinicopathological studies of ventral tegmental area neuronal density and depressive symptoms. Higher neuronal ratings in the substantia nigra were associated with lower likelihood of depressive symptoms in a study14 of older persons without dementia. The association in the present study between the density of nigral dopaminergic neurons and depressive symptoms is consistent with this finding and extends it by more precisely quantifying nigral neurons and by showing that the association is largely confounded by the density of dopaminergic neurons in the ventral tegmental area. We did not find the density of noradrenergic neurons in the locus ceruleus or serotonergic neurons in the dorsal raphe nucleus to be related to depressive symptoms. These null results agree with some studies42,43 but not another study44 of the locus ceruleus and are consistent with the weight of the evidence from studies of dorsal raphe nucleus neurons in depression, which have reported levels to be lower,11,45 no different,12,46 and higher47 than controls.

The factors responsible for the observed individual differences in the density of dopaminergic neurons in the ventral tegmental area are unknown, and because the present study did not include persons who died before old age, it is uncertain whether the association between dopaminergic neurons in the ventral tegmental area and depressive symptoms is specific to late life. That the association was observed after excluding individuals with dementia and controlling for postmortem markers linked to dementia suggests that some of the variability in dopamine neuron density was long-standing. Therefore, it is possible that a less populated ventral tegmental area due to neurodevelopmental or other causes occurring earlier in adulthood somehow increases vulnerability to depressive symptoms. However, a substantial subgroup had few dopamine neurons in the ventral tegmental area (eFigure 3 in the Supplement), and older age had an almost significant correlation with lower neuronal density (eTable 2 in the Supplement), suggesting that age-related pathological processes are also involved. Because Parkinson disease also involves a loss of brainstem dopaminergic neurons for uncertain reasons, it provides a useful point of comparison. Depressive symptoms are common in the disease48 and are reduced by pramipexole hydrochloride use,49,50 a dopamine agonist, suggesting that late-life depressive symptoms in some persons without Parkinson disease might also be alleviated by pharmacologic enhancement of dopamine transmission with agonists or with reuptake inhibitors such as bupropion hydrochloride51 or nomifensine maleate.52

Neurodegenerative lesions in brainstem aminergic nuclei were related to depressive symptoms, but the associations were weak and conditional on other factors. Therefore, the presence of Lewy bodies in brainstem aminergic nuclei was related to depressive symptoms, consistent with a previous clinicopathological study12 and the prominent place of depressive symptoms in synucleinopathies, such as Parkinson disease and Lewy body disease. However, the association was only seen in those not taking antidepressants, and controlling for ventral tegmental area neuronal density eliminated it.

There was no overall association between brainstem tangles and depressive symptoms, consistent with previous research in persons without dementia12,44 and with some studies9,44 but not another study13 of persons with dementia. In contrast with previous research, the present study included clinical classification of mild cognitive impairment, and higher brainstem tangle density was associated with a higher level of depressive symptoms in persons without cognitive impairment but with a lower level of depressive symptoms in those with mild cognitive impairment. This suggests that tangles make a modest contribution to depressive symptoms before the onset of cognitive impairment but that, as cognitive problems develop, depressive symptoms may be less consistently reported, possibly because they are harder to remember or acknowledge.16,17 In addition, incipient cognitive decline may disrupt the continuity of mood states and their ability to regulate behavior. These observations agree with longitudinal data that suggest little increase in depressive symptoms during the development of mild cognitive impairment and dementia.31,53,54

Study strengths and limitations should be noted. There was a high rate of participation in the annual clinical evaluations and brain autopsy, minimizing bias due to selective attrition. Uniform annual evaluations and the application of widely used diagnostic criteria allowed us to reliably classify mild cognitive impairment and dementia. The measure of depressive symptoms was based on a standard scale administered at regular intervals for several years, which probably enhanced assessment of the enduring tendency to be depressed while reducing measurement error and the influence of episodic fluctuations in mood. An important limitation is that the cohort was selected, so replication of these results will be important. In addition, the findings for the ventral tegmental area are based on the paranigral nucleus, and it is uncertain whether they will generalize to other subpopulations of ventral tegmental area dopaminergic neurons.55

Submitted for Publication: November 13, 2012; final revision received February 18, 2013; accepted March 29, 2013.

Corresponding Author: Robert S. Wilson, PhD, Rush Alzheimer’s Disease Center, Rush University Medical Center, 600 S Paulina St, Ste 1038, Chicago, IL 60612 (rwilson@rush.edu).

Published Online: October 16, 2013. doi:10.1001/jamapsychiatry.2013.2224.

Author Contributions: Dr Wilson had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wilson, Nag, Boyle, Arnold, Bennett.

Acquisition of data: Nag, Hizel, Schneider, Bennett.

Analysis and interpretation of data: Wilson, Nag, Boyle, Yu, Buchman, Shah, Schneider, Arnold, Bennett.

Drafting of the manuscript: Wilson, Nag, Hizel, Schneider, Arnold.

Critical revision of the manuscript for important intellectual content: Wilson, Nag, Boyle, Yu, Buchman, Shah, Schneider, Arnold, Bennett.

Statistical analysis: Yu.

Obtained funding: Wilson, Buchman, Bennett.

Administrative, technical, and material support: Nag, Boyle, Hizel, Schneider, Arnold, Bennett.

Study supervision: Schneider, Bennett.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was supported by grants R01AG17917, R01AG15819, R01AG24871, R01AG34374, R01AG33678, R01AG43379, and R01NS78009 from the National Institutes of Health and by the Illinois Department of Public Health.

Role of the Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Traci Colvin, MPH, and Karen Skish, MS, assisted with study coordination; John Gibbons, MS, and Greg Klein, MS, contributed to data management; and Wenqing Fan, MS, provided statistical programming. We thank the neuropathologic laboratory of the Rush Memory and Aging Project and the many Illinois residents for participating in the project.

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PubMed   |  Link to Article
Zweig  RM, Ross  CA, Hedreen  JC,  et al.  The neuropathology of aminergic nuclei in Alzheimer’s disease. Ann Neurol. 1988;24(2):233-242.
PubMed   |  Link to Article
Braak  H, Del Tredici  K, Rüb  U, de Vos  RA, Jansen Steur  EN, Braak  E.  Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211.
PubMed   |  Link to Article
Förstl  H, Burns  A, Luthert  P, Cairns  N, Lantos  P, Levy  R.  Clinical and neuropathological correlates of depression in Alzheimer’s disease. Psychol Med. 1992;22(4):877-884.
PubMed   |  Link to Article
Chen  CPLH, Eastwood  SL, Hope  T, McDonald  B, Francis  PT, Esiri  MM.  Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer’s disease prospectively assessed for behavioural changes. Neuropathol Appl Neurobiol. 2000;26(4):347-355.
PubMed   |  Link to Article
Matthews  KL, Chen  CP, Esiri  MM, Keene  J, Minger  SL, Francis  PT.  Noradrenergic changes, aggressive behavior, and cognition in patients with dementia. Biol Psychiatry. 2002;51(5):407-416.
PubMed   |  Link to Article
Syed  A, Chatfield  M, Matthews  F, Harrison  P, Brayne  C, Esiri  MM.  Depression in the elderly: pathological study of raphe and locus ceruleus. Neuropathol Appl Neurobiol. 2005;31(4):405-413.
PubMed   |  Link to Article
Tsopelas  C, Stewart  R, Savva  GM,  et al; Medical Research Council Cognitive Function and Ageing Study.  Neuropathological correlates of late-life depression in older people. Br J Psychiatry. 2011;198(2):109-114.
PubMed   |  Link to Article
Zubenko  GS, Moossy  J.  Major depression in primary dementia: clinical and neuropathologic correlates. Arch Neurol. 1988;45(11):1182-1186.
PubMed   |  Link to Article
Chan-Palay  V, Asan  E.  Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson’s disease with and without dementia and depression. J Comp Neurol. 1989;287(3):373-392.
PubMed   |  Link to Article
Hoogendijk  WJ, Sommer  IE, Pool  CW,  et al.  Lack of association between depression and loss of neurons in the locus coeruleus in Alzheimer disease. Arch Gen Psychiatry. 1999;56(1):45-51.
PubMed   |  Link to Article
Gilley  DW, Wilson  RS.  Criterion-related validity of the Geriatric Depression Scale in Alzheimer’s disease. J Clin Exp Neuropsychol. 1997;19(4):489-499.
PubMed   |  Link to Article
Gilley  DW, Wilson  RS, Fleischman  DA, Harrison  DW, Goetz  CG, Tanner  CM.  Impact of Alzheimer’s-type dementia and information source on the assessment of depression. Psychol Assess. 1995;7:42-48.
Link to Article
Wilson  RS, Leurgans  SE, Boyle  PA, Schneider  JA, Bennett  DA.  Neurodegenerative basis of age-related cognitive decline. Neurology. 2010;75(12):1070-1078.
PubMed   |  Link to Article
Wilson  RS, Arnold  SE, Schneider  JA, Tang  Y, Bennett  DA.  The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry. 2007;78(1):30-35.
PubMed   |  Link to Article
Schneider  JA, Li  JL, Li  Y, Wilson  RS, Kordower  JH, Bennett  DA.  Substantia nigra tangles are related to gait impairment in older persons. Ann Neurol. 2006;59:166-173.
PubMed   |  Link to Article
Lammel  S, Lim  BK, Ran  C,  et al.  Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491(7423):212-217.
PubMed   |  Link to Article
Chaudhury  D, Walsh  JJ, Friedman  AK,  et al.  Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493(7433):532-536.
PubMed   |  Link to Article
Tye  KM, Mirzabekov  JJ, Warden  MR,  et al.  Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2013;493(7433):537-541.
PubMed   |  Link to Article
Bennett  DA, Schneider  JA, Buchman  AS, Barnes  LL, Boyle  PA, Wilson  RS.  Overview and findings from the Rush Memory and Aging Project. Curr Alzheimer Res. 2012;9(6):646-663.
PubMed   |  Link to Article
Buchman  AS, Nag  S, Shulman  JM,  et al.  Locus coeruleus neuron density and parkinsonism in older adults without Parkinson’s disease. Mov Disord. 2012;27(13):1625-1631.
PubMed   |  Link to Article
Wilson  RS, Nag  S, Boyle  PA,  et al.  Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology. 2013;80(13):1202-1208.
Link to Article
Kohout  FJ, Berkman  LF, Evans  DA, Cornoni-Huntley  J.  Two shorter forms of the CES-D (Center for Epidemiological Studies Depression) depression symptoms index. J Aging Health. 1993;5(2):79-193.
PubMed
Radloff  LS.  The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385-401.
Link to Article
Wilson  RS, Barnes  LL, Mendes de Leon  CF,  et al.  Depressive symptoms, cognitive decline, and risk of AD in older persons. Neurology. 2002;59(3):364-370.
PubMed   |  Link to Article
Shafer  AB.  Meta-analysis of the factor structures of four depression questionnaires: Beck, CES-D, Hamilton, and Zung. J Clin Psychol. 2006;62(1):123-146.
PubMed   |  Link to Article
Wilson  RS, Hoganson  GM, Rajan  KB, Barnes  LL, Mendes de Leon  CF, Evans  DA.  Temporal course of depressive symptoms during the development of Alzheimer disease. Neurology. 2010;75(1):21-26.
PubMed   |  Link to Article
Medi-Span, Inc.Master Drug Database Documentation Manual. Indianapolis, IN: Medi-span Inc; 1995.
Bennett  DA, Shannon  KM, Beckett  LA, Goetz  CG, Wilson  RS.  Metric properties of nurses’ ratings of parkinsonian signs with a modified Unified Parkinson’s Disease Rating Scale. Neurology. 1997;49(6):1580-1587.
PubMed   |  Link to Article
Fahn  S, Elton  R. Unified Parkinson’s Disease Rating Scale. In: Fahn  S, Marsden  C, Goldstein  M, Caine  D, eds. Recent Developments in Parkinson’s Disease.Vol 12. Florham Park, NJ: MacMillan Healthcare Information; 1987:153-163.
Wilson  RS, Schneider  JA, Bienias  JL, Evans  DA, Bennett  DA.  Parkinsonianlike signs and risk of incident Alzheimer disease in older persons. Arch Neurol. 2003;60(4):539-544.
PubMed   |  Link to Article
McKhann  G, Drachman  D, Folstein  M, Katzman  R, Price  D, Stadlan  EM.  Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939-944.
PubMed   |  Link to Article
Bennett  DA, Wilson  RS, Schneider  JA,  et al.  Natural history of mild cognitive impairment in older persons. Neurology. 2002;59(2):198-205.
PubMed   |  Link to Article
Wilson  RS, Schneider  JA, Bienias  JL, Arnold  SE, Evans  DA, Bennett  DA.  Depressive symptoms, clinical AD, and cortical plaques and tangles in older persons. Neurology. 2003;61(8):1102-1107.
PubMed   |  Link to Article
Bennett  DA, Wilson  RS, Schneider  JA, Bienias  JL, Arnold  SE.  Cerebral infarctions and the relationship of depression symptoms to level of cognitive functioning in older persons. Am J Geriatr Psychiatry. 2004;12(2):211-219.
PubMed
Schott  BH, Minuzzi  L, Krebs  RM,  et al.  Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci. 2008;28(52):14311-14319.
PubMed   |  Link to Article
Tremblay  LK, Naranjo  CA, Graham  SJ,  et al.  Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry. 2005;62(11):1228-1236.
PubMed   |  Link to Article
Zhu  MY, Klimek  V, Dilley  GE,  et al.  Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry. 1999;46(9):1275-1286.
PubMed   |  Link to Article
Gos  T, Krell  D, Bielau  H,  et al.  Tyrosine hydroxylase immunoreactivity in the locus coeruleus is elevated in violent suicidal depressive patients. Eur Arch Psychiatry Clin Neurosci. 2008;258(8):513-520.
PubMed   |  Link to Article
Baumann  B, Danos  P, Diekmann  S,  et al.  Tyrosine hydroxylase immunoreactivity in the locus coeruleus is reduced in depressed non-suicidal patients but normal in depressed suicide patients. Eur Arch Psychiatry Clin Neurosci. 1999;249(4):212-219.
PubMed   |  Link to Article
Hendricksen  M, Thomas  AJ, Ferrier  IN, Ince  P, O’Brien  JT.  Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer’s disease with and without depression. Am J Psychiatry. 2004;161(6):1096-1102.
PubMed   |  Link to Article
Baumann  B, Bielau  H, Krell  D,  et al.  Circumscribed numerical deficit of dorsal raphe neurons in mood disorders. Psychol Med. 2002;32(1):93-103.
PubMed
Underwood  MD, Khaibulina  AA, Ellis  SP,  et al.  Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims. Biol Psychiatry. 1999;46(4):473-483.
PubMed   |  Link to Article
Aarsland  D, Påhlhagen  S, Ballard  CG, Ehrt  U, Svenningsson  P.  Depression in Parkinson disease: epidemiology, mechanisms and management. Nat Rev Neurol. 2012;8(1):35-47.
PubMed   |  Link to Article
Barone  P, Poewe  W, Albrecht  S,  et al.  Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(6):573-580.
PubMed   |  Link to Article
Seppi  K, Weintraub  D, Coelho  M,  et al.  The Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord. 2011;26(suppl 3):S42-S80.
PubMed   |  Link to Article
Rush  AJ, Trivedi  MH, Wisniewski  SR,  et al; STAR*D Study Team.  Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.
PubMed   |  Link to Article
Feighner  JP, Merideth  CH, Claghorn  JL.  Multicenter placebo-controlled evaluation of nomifensine treatment in depressed outpatients. J Clin Psychiatry. 1984;45(4, pt 2):47-51.
PubMed
Amieva  H, Le Goff  M, Millet  X,  et al.  Prodromal Alzheimer’s disease: successive emergence of the clinical symptoms. Ann Neurol. 2008;64(5):492-498.
PubMed   |  Link to Article
Wilson  RS, Arnold  SE, Beck  TL, Bienias  JL, Bennett  DA.  Change in depressive symptoms during the prodromal phase of Alzheimer disease. Arch Gen Psychiatry. 2008;65(4):439-445.
PubMed   |  Link to Article
Ikemoto  S.  Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev. 2007;56(1):27-78.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Information on the Density of Tangles and Lewy Bodies in Brainstem Aminergic Nuclei

References

Beekman  ATF, Copeland  JRM, Prince  MJ.  Review of community prevalence of depression in later life. Br J Psychiatry. 1999;174:307-311.
PubMed   |  Link to Article
Bruce  ML, Seeman  TE, Merrill  SS, Blazer  DG.  The impact of depressive symptomatology on physical disability: MacArthur Studies of Successful Aging. Am J Public Health. 1994;84(11):1796-1799.
PubMed   |  Link to Article
Devanand  DP, Sano  MP, Tang  MX,  et al.  Depressed mood and the incidence of Alzheimer’s disease in the elderly living in the community. Arch Gen Psychiatry. 1996;53(2):175-182.
PubMed   |  Link to Article
Wilson  RS, Bienias  JL, Mendes de Leon  CF, Evans  DA, Bennett  DA.  Negative affect and mortality in older persons. Am J Epidemiol. 2003;158(9):827-835.
PubMed   |  Link to Article
Manji  HK, Drevets  WC, Charney  DS.  The cellular neurobiology of depression. Nat Med. 2001;7(5):541-547.
PubMed   |  Link to Article
Zweig  RM, Ross  CA, Hedreen  JC,  et al.  The neuropathology of aminergic nuclei in Alzheimer’s disease. Ann Neurol. 1988;24(2):233-242.
PubMed   |  Link to Article
Braak  H, Del Tredici  K, Rüb  U, de Vos  RA, Jansen Steur  EN, Braak  E.  Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211.
PubMed   |  Link to Article
Förstl  H, Burns  A, Luthert  P, Cairns  N, Lantos  P, Levy  R.  Clinical and neuropathological correlates of depression in Alzheimer’s disease. Psychol Med. 1992;22(4):877-884.
PubMed   |  Link to Article
Chen  CPLH, Eastwood  SL, Hope  T, McDonald  B, Francis  PT, Esiri  MM.  Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer’s disease prospectively assessed for behavioural changes. Neuropathol Appl Neurobiol. 2000;26(4):347-355.
PubMed   |  Link to Article
Matthews  KL, Chen  CP, Esiri  MM, Keene  J, Minger  SL, Francis  PT.  Noradrenergic changes, aggressive behavior, and cognition in patients with dementia. Biol Psychiatry. 2002;51(5):407-416.
PubMed   |  Link to Article
Syed  A, Chatfield  M, Matthews  F, Harrison  P, Brayne  C, Esiri  MM.  Depression in the elderly: pathological study of raphe and locus ceruleus. Neuropathol Appl Neurobiol. 2005;31(4):405-413.
PubMed   |  Link to Article
Tsopelas  C, Stewart  R, Savva  GM,  et al; Medical Research Council Cognitive Function and Ageing Study.  Neuropathological correlates of late-life depression in older people. Br J Psychiatry. 2011;198(2):109-114.
PubMed   |  Link to Article
Zubenko  GS, Moossy  J.  Major depression in primary dementia: clinical and neuropathologic correlates. Arch Neurol. 1988;45(11):1182-1186.
PubMed   |  Link to Article
Chan-Palay  V, Asan  E.  Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson’s disease with and without dementia and depression. J Comp Neurol. 1989;287(3):373-392.
PubMed   |  Link to Article
Hoogendijk  WJ, Sommer  IE, Pool  CW,  et al.  Lack of association between depression and loss of neurons in the locus coeruleus in Alzheimer disease. Arch Gen Psychiatry. 1999;56(1):45-51.
PubMed   |  Link to Article
Gilley  DW, Wilson  RS.  Criterion-related validity of the Geriatric Depression Scale in Alzheimer’s disease. J Clin Exp Neuropsychol. 1997;19(4):489-499.
PubMed   |  Link to Article
Gilley  DW, Wilson  RS, Fleischman  DA, Harrison  DW, Goetz  CG, Tanner  CM.  Impact of Alzheimer’s-type dementia and information source on the assessment of depression. Psychol Assess. 1995;7:42-48.
Link to Article
Wilson  RS, Leurgans  SE, Boyle  PA, Schneider  JA, Bennett  DA.  Neurodegenerative basis of age-related cognitive decline. Neurology. 2010;75(12):1070-1078.
PubMed   |  Link to Article
Wilson  RS, Arnold  SE, Schneider  JA, Tang  Y, Bennett  DA.  The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry. 2007;78(1):30-35.
PubMed   |  Link to Article
Schneider  JA, Li  JL, Li  Y, Wilson  RS, Kordower  JH, Bennett  DA.  Substantia nigra tangles are related to gait impairment in older persons. Ann Neurol. 2006;59:166-173.
PubMed   |  Link to Article
Lammel  S, Lim  BK, Ran  C,  et al.  Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491(7423):212-217.
PubMed   |  Link to Article
Chaudhury  D, Walsh  JJ, Friedman  AK,  et al.  Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493(7433):532-536.
PubMed   |  Link to Article
Tye  KM, Mirzabekov  JJ, Warden  MR,  et al.  Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2013;493(7433):537-541.
PubMed   |  Link to Article
Bennett  DA, Schneider  JA, Buchman  AS, Barnes  LL, Boyle  PA, Wilson  RS.  Overview and findings from the Rush Memory and Aging Project. Curr Alzheimer Res. 2012;9(6):646-663.
PubMed   |  Link to Article
Buchman  AS, Nag  S, Shulman  JM,  et al.  Locus coeruleus neuron density and parkinsonism in older adults without Parkinson’s disease. Mov Disord. 2012;27(13):1625-1631.
PubMed   |  Link to Article
Wilson  RS, Nag  S, Boyle  PA,  et al.  Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology. 2013;80(13):1202-1208.
Link to Article
Kohout  FJ, Berkman  LF, Evans  DA, Cornoni-Huntley  J.  Two shorter forms of the CES-D (Center for Epidemiological Studies Depression) depression symptoms index. J Aging Health. 1993;5(2):79-193.
PubMed
Radloff  LS.  The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385-401.
Link to Article
Wilson  RS, Barnes  LL, Mendes de Leon  CF,  et al.  Depressive symptoms, cognitive decline, and risk of AD in older persons. Neurology. 2002;59(3):364-370.
PubMed   |  Link to Article
Shafer  AB.  Meta-analysis of the factor structures of four depression questionnaires: Beck, CES-D, Hamilton, and Zung. J Clin Psychol. 2006;62(1):123-146.
PubMed   |  Link to Article
Wilson  RS, Hoganson  GM, Rajan  KB, Barnes  LL, Mendes de Leon  CF, Evans  DA.  Temporal course of depressive symptoms during the development of Alzheimer disease. Neurology. 2010;75(1):21-26.
PubMed   |  Link to Article
Medi-Span, Inc.Master Drug Database Documentation Manual. Indianapolis, IN: Medi-span Inc; 1995.
Bennett  DA, Shannon  KM, Beckett  LA, Goetz  CG, Wilson  RS.  Metric properties of nurses’ ratings of parkinsonian signs with a modified Unified Parkinson’s Disease Rating Scale. Neurology. 1997;49(6):1580-1587.
PubMed   |  Link to Article
Fahn  S, Elton  R. Unified Parkinson’s Disease Rating Scale. In: Fahn  S, Marsden  C, Goldstein  M, Caine  D, eds. Recent Developments in Parkinson’s Disease.Vol 12. Florham Park, NJ: MacMillan Healthcare Information; 1987:153-163.
Wilson  RS, Schneider  JA, Bienias  JL, Evans  DA, Bennett  DA.  Parkinsonianlike signs and risk of incident Alzheimer disease in older persons. Arch Neurol. 2003;60(4):539-544.
PubMed   |  Link to Article
McKhann  G, Drachman  D, Folstein  M, Katzman  R, Price  D, Stadlan  EM.  Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939-944.
PubMed   |  Link to Article
Bennett  DA, Wilson  RS, Schneider  JA,  et al.  Natural history of mild cognitive impairment in older persons. Neurology. 2002;59(2):198-205.
PubMed   |  Link to Article
Wilson  RS, Schneider  JA, Bienias  JL, Arnold  SE, Evans  DA, Bennett  DA.  Depressive symptoms, clinical AD, and cortical plaques and tangles in older persons. Neurology. 2003;61(8):1102-1107.
PubMed   |  Link to Article
Bennett  DA, Wilson  RS, Schneider  JA, Bienias  JL, Arnold  SE.  Cerebral infarctions and the relationship of depression symptoms to level of cognitive functioning in older persons. Am J Geriatr Psychiatry. 2004;12(2):211-219.
PubMed
Schott  BH, Minuzzi  L, Krebs  RM,  et al.  Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci. 2008;28(52):14311-14319.
PubMed   |  Link to Article
Tremblay  LK, Naranjo  CA, Graham  SJ,  et al.  Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry. 2005;62(11):1228-1236.
PubMed   |  Link to Article
Zhu  MY, Klimek  V, Dilley  GE,  et al.  Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry. 1999;46(9):1275-1286.
PubMed   |  Link to Article
Gos  T, Krell  D, Bielau  H,  et al.  Tyrosine hydroxylase immunoreactivity in the locus coeruleus is elevated in violent suicidal depressive patients. Eur Arch Psychiatry Clin Neurosci. 2008;258(8):513-520.
PubMed   |  Link to Article
Baumann  B, Danos  P, Diekmann  S,  et al.  Tyrosine hydroxylase immunoreactivity in the locus coeruleus is reduced in depressed non-suicidal patients but normal in depressed suicide patients. Eur Arch Psychiatry Clin Neurosci. 1999;249(4):212-219.
PubMed   |  Link to Article
Hendricksen  M, Thomas  AJ, Ferrier  IN, Ince  P, O’Brien  JT.  Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer’s disease with and without depression. Am J Psychiatry. 2004;161(6):1096-1102.
PubMed   |  Link to Article
Baumann  B, Bielau  H, Krell  D,  et al.  Circumscribed numerical deficit of dorsal raphe neurons in mood disorders. Psychol Med. 2002;32(1):93-103.
PubMed
Underwood  MD, Khaibulina  AA, Ellis  SP,  et al.  Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims. Biol Psychiatry. 1999;46(4):473-483.
PubMed   |  Link to Article
Aarsland  D, Påhlhagen  S, Ballard  CG, Ehrt  U, Svenningsson  P.  Depression in Parkinson disease: epidemiology, mechanisms and management. Nat Rev Neurol. 2012;8(1):35-47.
PubMed   |  Link to Article
Barone  P, Poewe  W, Albrecht  S,  et al.  Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(6):573-580.
PubMed   |  Link to Article
Seppi  K, Weintraub  D, Coelho  M,  et al.  The Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord. 2011;26(suppl 3):S42-S80.
PubMed   |  Link to Article
Rush  AJ, Trivedi  MH, Wisniewski  SR,  et al; STAR*D Study Team.  Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.
PubMed   |  Link to Article
Feighner  JP, Merideth  CH, Claghorn  JL.  Multicenter placebo-controlled evaluation of nomifensine treatment in depressed outpatients. J Clin Psychiatry. 1984;45(4, pt 2):47-51.
PubMed
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Supplement.

eTable 1. Antidepressant Medication Use in 40 Participantsa

eTable 2. Relation of Demographic and Postmortem Variables to Density of Aminergic Neurons in Brainstem Nuclei*

eFigure 1. Change in Number of Depressive Symptoms on the Center for Epidemiological Studies Depression Scale

eFigure 2. Relation of Brainstem Tangle Density to Depressive Symptoms in Persons With No (Green) and Mild (Orange) Cognitive Impairment, Adjusted for Sex, Age at Death, and Education

eFigure 3. Distributions of Aminergic Neuronal Density in Brainstem Nuclei

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