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. Author manuscript; available in PMC: 2009 Oct 5.
Published in final edited form as: Int J Geriatr Psychiatry. 2009 Aug;24(8):856–864. doi: 10.1002/gps.2281

Reductions in neuronal density in elderly depressed are region specific

Eric Van Otterloo 1, Gillian O’Dwyer 1, Craig A Stockmeier 1, David C Steffens 2, Ranga R Krishnan 2, Grazyna Rajkowska 1,*
PMCID: PMC2756775  NIHMSID: NIHMS134449  PMID: 19405038

SUMMARY

Objective

Frontal regions, including the orbitofrontal cortex (ORB) and dorsolateral prefrontal cortex (dlPFC) have been implicated in the neuropathology of geriatric depression. Prominent reductions in pyramidal neuron density have been recently reported in the ORB of older depressed subjects. However, the cellular pathology of the dlPFC has not yet been examined in these subjects.

Methods

Postmortem tissue from the dlPFC (Brodmann’s area 9, BA9) was collected from 10 older (>60 years old) subjects diagnosed with major depression and 10 age-matched non-psychiatric controls (CTRL). The majority of the subjects were the same as those used for our previous study on neuronal reductions in the ORB in older depressed. Overall (all six layers combined), and laminar density of pyramidal (presumably glutamatergic), and non-pyramidal (GABAergic) neurons as well as cortical and laminar width were measured using linear optical disector of Stereoinvestigator software.

Results

Neither the overall nor laminar density of pyramidal or non-pyramidal neurons was significantly different between groups. The cortical and laminar widths were also not affected.

Conclusions

These results suggest that neuronal prefrontal pathology in elderly depressed is region specific. No significant changes were detected in the density of any type of neurons in the dlPFC of elderly depressed subjects (present study) whereas, prominent reductions in the density of pyramidal glutamatergic neurons were observed previously in the ORB.

Keywords: prefrontal cortex, postmortem, glutamatergic neurons, major depressive disorder, aging

INTRODUCTION

Clinical evidence increasingly suggests a different etiology and pathology of depression in elderly patients as compared with younger depressed patients (Krishnan et al., 2004; Alexopoulos, 2006). Cerebro-vascular disease is suggested to be one of the factors contributing to the unique etiology and pathology of geriatric depression (Krishnan, 1993; Alexopoulos et al., 1997; Steffens and Krishnan, 1998; Steffens et al., 1999; Thomas et al., 2001). Moreover, neuroimaging studies demonstrate that older depressed patients have more frontal white matter hyperintensities than age-matched non-depressed controls (Coffey et al., 1990; Zubenko et al., 1990; Rabins et al., 1991; Steffens and Krishnan, 1998; MacFall et al., 2001; Taylor et al., 2001; O’Brien et al., 2006). These hyperintensities correspond to ischemic lesions as defined by gross neuropathological studies (Thomas et al., 2002; Thomas et al., 2003) and are found to be most prevalent in the orbitofrontal cortex (ORB) and periventricular gray matter (Greenwald et al., 1998; Lee et al., 2003). It is presumed that white matter hyperintensities disrupt prefrontal subcortical white matter tracts involved in emotional processing leading to risk for depression (Meyer et al., 1992; Krishnan, 1993; Alexopoulos et al., 1997; Steffens and Krishnan, 1998; Rajkowska et al., 2005). Hyperintensities are also associated with reduced response to antidepressant treatments (Hickie et al., 1995; O’Brien et al., 1998; Simpson et al., 1998; Steffens and Krishnan, 1998).

Cognitive impairment, most specifically executive dysfunction, is associated with depression in the elderly (Lesser et al., 1996; Lockwood et al., 2002; Lee et al., 2003; Baudic et al., 2004; Sair et al., 2006; Steffens and Potter, 2008; Wang et al., 2008). Lesions located in the left frontal lobe have been linked to both depression and executive dysfunction in the elderly depressed patients (Starkstein et al., 1988; Morris et al., 1996; Lyketsos et al., 1998; Taylor et al., 2003a; Vataja et al., 2005). Executive dysfunction in elderly depressed has also been associated with a diminished response to certain antidepressants (Simpson et al., 1998; Kalayam and Alexopoulos, 1999; Dunkin et al., 2000; Alexopoulos et al., 2004; Potter et al., 2004; Alexopoulos et al., 2008). Executive functions are regulated by the dorsolateral prefrontal cortex (dlPFC) and corticostriatal projections (D’Esposito et al., 1995; Smith and Jonides, 1999). Thus, the dlPFC, similar to the ORB, may be a site of cellular pathology in geriatric depression.

Along with the above clinical observations recent postmortem studies have shown unique cellular (Rajkowska et al., 1999; Cotter et al., 2002; Cotter et al., 2005; Rajkowska et al., 2005) and vascular (Thomas et al., 2002; Thomas et al., 2003) pathology in the ORB and dlPFC of subjects diagnosed with major depressive disorder (MDD). Prominent reductions (20–60%) in the overall and laminar density of pyramidal, projection glutamatergic, neurons were observed in the ORB of elderly depressed subjects as compared with age-matched non-depressed controls and younger MDD subjects (Rajkowska et al., 2005). These reductions were most prominent in cortical layers connecting the ORB with striatum, amygdala, hypothalamus, ventral thalamus, and associational cortical regions. In two other studies, subtle reductions in the soma size and size-dependant density of neuronal somatas have also been reported in the dlPFC of younger depressed subjects (average age 48 years) (Rajkowska et al., 1999; Cotter et al., 2002). However, a quantitative analysis of cell pathology in the dlPFC of a more homogeneously defined age group of older depressed subjects has yet to be examined.

The goal of this study was to estimate the packing density of pyramidal and non-pyramidal neurons as well as cortical and laminar width in the dlPFC of elderly subjects with and without depression. Most of these subjects (14 out of 20) were also analyzed in our previous study on the ORB region (Rajkowska et al. 2005). Comparison of these parameters between the two prefrontal regions will establish whether reductions in the overall density and pyramidal projection neuron density are specific to the ORB or if this pathology is also evident in the dlPFC region.

METHODS

Subjects

Postmortem brain tissue was collected from 10 elderly subjects (>60 years old) diagnosed with MDD and 10 age-matched non-psychiatric controls (CTRL). Tissue was collected at the time of autopsy at the Cuyahoga County coroner’s office in Cleveland, Ohio. For all subjects, written consent was obtained from the legal next-of-kin following the guidelines established by the institutional review boards of the University of Mississippi Medical Center and University Hospitals of Cleveland, OH. Retrospective psychiatric assessment was performed on all subjects by interviewing subjects’ knowledgeable next-of-kin as described previously (Rajkowska et al., 1999). Diagnosis of MDD was based on DSM IV criteria (American Psychiatric Association, 1994). Postmortem neuropathology and prior medical records were used for exclusion criteria which included head trauma, neurological disorders including Alzheimer’s disease, Parkinsons disease, infarcts, demyelinating diseases, atrophy or heterotopia or a clinical history of these disorders (testing included H&E staining, a monoclonal antibody which recognizes amyloid deposits of Alzheimer type, Tau immunostaining for neurofibrillary tangles, and an antibody to glial fibrillary acid protein (GFAP) which identifies reactive astroglial cells), or a diagnosis of psychoactive substance use disorder within the last year of life. Most CTRL and MDD subjects had some form of cardiovascular disease, as previously defined (Rajkowska et al., 2005), at the time of death. Subjects were matched with respect to age (MDD: 74.50 ± 6.65; CTRL: 74.30 ± 6.11), postmortem interval (h; MDD: 21.85 ± 5.68; CTRL: 23.58 ± 6.11), time tissue was stored in formalin(months; MDD: 34.29 ± 20.80; CTRL: 38.62 ± 22.97), and tissue pH (MDD: 6.64 ± 0.13; CTRL: 6.65 ± 0.28) (see Table 1). Groups were also matched with regard to sex (six males and four females per group). Of the 20 subjects analyzed in this study, 14 (7 MDD and 7 CTRL) were the same as in our previous paper on neuronal pathology in the ORB (Rajkowska et al., 2005).

Table 1.

Demographic characteristics of subjects

Parameter Controls (n = 10) Major depressive disorder (n = 10)
Age (mean ± SD) 74 ± 6 years 75 ± 7 years
Age range 66–86 years 65–87 years
PMI (mean ± SD) 23.6 ± 6.1 h 21.9 ± 5.7 h
PMI range 12.5–32 h 10–29 h
pH (mean ± SD) 6.65 ± 0.28 6.64 ± 0.13
pH range 5.98–6.96 6.51–6.94
Time in formalin (mean ± SD) 38.6 ± 23.0 months 34.3 ± 20.8 months
Time in formalin range 4.97–68.8 months 9–72.76 months
Gender (Female/Male) 4/6 4/6
Toxicology:
Clean n = 8 n = 4
Antidepressant drugs none n = 3 (sertraline n = 1, nortriptyline n = 1, sertraline and bupropion n = 1)
Other n = 1 (morphine) n = 4 (ethanol n = 1, diazepam and acetaminophen n = 1, diazepam n = 1, diphenyhydramine n = 1)
n = 1 (diltiazem)
Cause of death Cardiovascular disease n = 10 Cardiovascular disease n = 5 Suicide n = 5 (hanging n = 2, single gun shot wound head n = 1, single gun shot wound chest n = 1, jumper n = 1)
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n = number; PMI = postmortem interval, defined as the time between death and the beginning of formalin fixation; SD = standard deviation.

TISSUE

Blocks of tissue from the dorsal half of the left prefrontal cortex (Figure 1A) were embedded in 12% celloidin, sectioned at 40 μm, and stained with the basic Nissl (cresyl violet) method (final section thickness after processing was 35–38 μm). Due to limitations in the amount of tissue available, the blocks did not span the entire rostro-caudal length of the dlPFC and contained only the central portion of Brodmann’s area 9, (BA9). In each subject, BA9 was distinguished from the surrounding Brodmann’s areas 10, 46, 32, and 8, based on anatomical and cytoarchitectonic criteria (see Figure 1B) (Rajkowska and Goldman-Rakic, 1995a; Rajkowska and Goldman-Rakic, 1995b). Three evenly spaced coronal sections (400 μm apart, spanning at total length of 1200 μm) were then chosen from among all of the sections containing BA9, for each subject, and used for measurement of cell density and laminar and cortical width. Neuronal density was estimated within individual cortical layers using 3-D cell counting boxes (100 μm × 120 μm × 25 μm; 5 μm ‘guard zone’ on top and 5–8 μm ‘guard zone’ on the bottom) established by the ‘linear optical disector’ probe of StereoInvestigator (6.00) software (MicroBrightField, Inc., Colchester, VT). Layer boundaries were obeyed by using a separate probe for each layer (see Figure 1C). Both pyramidal and non-pyramidal neuronal density was assessed individually using morphological criteria established previously (Selemon et al., 1995; Rajkowska et al., 2005). Pyramidal were distinguished from non-pyramidal neurons by the presence of a triangular cell body, a thick apical dendrite, and thinner basal dendrites. In most instances pyramidal cell bodies and nuclei were larger than those of non-pyramidal neurons. Glial cells were distinguished from small non-pyramidal neurons by the lack of visible cytoplasm around their nuclei, thicker nuclear membrane, and more heterogeneous chromatin. Cortical width, including the absolute and relative (% of any given layer width when compared to the total width of the cortex at the site of measurement) width, were also calculated.

Figure 1.

Figure 1

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Figure 1. (A) Lateral view of the left hemisphere. A shaded box indicates a midsection of area 9, which was dissected from the dorsolateral prefrontal cortex (dlPFC) for cell counting. (B) Coronal section with delineation of area 9. White lines indicate borders between area 9 and adjacent areas established by microscopic cytoarchitecture. A white rectangle indicates the position of the counting probe. (C) Nissl-stained section from area 9 displaying details of the application of a linear disector probe. Separate contours were drawn for each cortical layer and sublayer to delineate their borders. A vertical line spanning the width of each layer was inserted. The software randomly positioned 3-D counting boxes along each vertical line and automatically estimated the combined volume of boxes located along the vertical line within each contour (for example, a volume of 1.5 counting boxes in layer I).

Statistical analysis

Individual means, from three sections per subject, of total neuronal density and cortical width were compared between groups using analysis of covariance (ANCOVA) (p <0.05) with age, postmortem interval, time in formalin, and brain pH, as covariates. Laminar neuronal density as well as relative width of individual layers was compared between groups using multivariate repeated-measures ANCOVA (p = 0.006 [0.05/8 layers]). Pearson correlation matrices were used to test correlations between neuronal densities and laminar width and confounding variables.

RESULTS

The overall density of Nissl-stained neurons in the dlPFC (layers I–IV combined) was not significantly different between the elderly depressed and age-matched control groups (ANCOVA: F(1,14) = 1.908, p = 0.189). Similarly, the overall density of pyramidal neurons (ANCOVA: F(1,14) = 2.150, p = 0.165), (Figure 2A) and non-pyramidal neurons (ANCOVA: F(1,14) = 0.848, p = 0.373) showed no significant differences between the groups.

Figure 2.

Figure 2

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Comparison of the neuronal density between the dorsolateral prefrontal cortex (dlPFC) (BA9) (A, B) (present study) and orbitofrontal cortex (BA47) (C, D) (Rajkowska et al. 2005). Graphs represent the overall (A) (shown as individual values with group mean) and laminar (B) mean density (±SD) of pyramidal neurons in the dlPFC and the overall (C) and laminar density (D) in the orbitofrontal cortex in elderly subjects with major depressive disorder (MDD) as compared to elderly controls (CTRL). Note the significant reductions, *p <0.05 and **p <0.006 (Bonferroni adjusted) in the orbitofrontal cortex and lack of significant reductions in the dlPFC.

Laminar density of all neurons (pyramidal + non-pyramidal) (ANCOVA: F(1,14) = 1.612, p = 0.225) or pyramidal neurons (ANCOVA: F(1,14) = 2.370, p = 0.146) (Figure 2B), and non-pyramidal neurons (ANCOVA: F(1,14) = 0.495, p = 0.493) analyzed in individual cortical layers were also not different between elderly depressed and control subjects.

Consistent with the above findings, the overall density or laminar densities of Nissl-stained neurons in the dlPFC displayed no significant differences between depressed males (n = 6) and depressed females (n = 4). Similarly, no significant differences were noted in overall or laminar densities of pyramidal or non-pyramidal neurons between depressed males and depressed females. There were also no differences in the overall or laminar densities of any type of neuron between depressed subjects dying by suicide as compared to depressed subjects dying by natural causes. Finally, no differences were found in the overall or laminar densities of any type of neuron between depressed subjects with antidepressants present in their postmortem toxicology (n = 3) as compared to depressed subjects without antidepressants (n = 7).

The overall cortical width of the dlPFC gray matter was almost identical between the groups (MDD: 2.02 ± 0.251 mm; CTRL: 2.02 ± 0.245 mm; ANCOVA: F(1,14) = 0.023, p = 0.881) (Figure 3). Similarly, no significant difference in the relative thickness of any of the six dlPFC layers was observed between elderly depressed and control groups (ANCOVA: F(1,14) = 0.948 p = 0.347), Figure 4.

Figure 3.

Figure 3

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Graph representing the overall cortical thickness (measured in millimeters) of the dorsolateral prefrontal cortex (BA9). No significant differences were observed between the elderly group with major depressive disorder (MDD, n = 10) as compared with age-matched non-psychiatric control patients (CTRL, n = 10). Individual values shown along with group mean.

Figure 4.

Figure 4

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Graph representing a relative width (mean ± SD) of individual cortical layers (i.e., the percentage each cortical layer contributes to the overall cortical width at the site of measurement) at BA9 of the dorsolateral prefrontal cortex (dlPFC). No significant differences were observed between the elderly group with major depressive disorder (MDD, n = 10) as compared with age-matched non-psychiatric control subjects (CTRL, n = 10) in all cortical layers

No significant correlations between any of the confounding variables (age, postmortem interval, time in formalin, brain pH) and neuronal densities or cortical and laminar width were observed in any group of subjects.

DISCUSSION

This study provides evidence that the overall (all layers combined) and laminar packing density of the general population of neurons in the dlPFC is not significantly different between older depressed patients compared with age and gender-matched non-psychiatric controls. There were also no differences in neuronal density between depressed males and females, or between depressed subjects dying by suicide as compared to those dying by natural causes (cardiovascular disease). The effect of medication also appears to be of no influence to the packing density of neurons as there were no differences between depressed subjects with a clean postmortem toxicology (n = 7) as compared to depressed subjects with antidepressants present in their postmortem toxicology screening (n = 3). Similar to the density of the general population of neurons, no obvious differences between groups were observed in the overall or laminar packing density of pyramidal or non-pyramidal neurons. This is in sharp contrast (compare Figures 2A, B with 2C, D) with our recent observations of prominent and significant reductions of 20–60% in the overall and laminar density of pyramidal (glutamatergic) neurons in the ORB from elderly depressed as compared to age matched controls (Rajkowska et al., 2005). These observations are in line with a recent neuroimaging study showing reduced N-acetylaspartate (NAA) levels (a marker of neuronal integrity and function) in the medial prefrontal cortex, including ORB, of living elderly depressed patients as compared with controls (Venkatraman et al., 2009).

In the present study, no differences in the thickness of cortical gray matter or width of any of the six cortical layers were observed in the dlPFC between elderly depressed and non-depressed subjects. This observation in elderly depressed subjects agrees with our earlier postmortem study of a younger cohort of depressed and control subjects (average subject age 48 years) also showing unchanged thickness of gray matter in the dlPFC (Rajkowska et al., 1999). In contrast, in the ORB a 12% reduction in the thickness of cortical ribbon was observed in the same depressed subjects as compared to age-matched controls (Rajkowska et al., 1999). This region specific cortical thinning is further supported by neuroimaging observations of a reduced volume in the ORB (Bremner et al., 2002; Lee et al., 2003; Taylor et al., 2003b) of elderly depressed patients as compared to age-matched non-depressed control subjects.

The above postmortem and neuroimaging studies suggest more pronounced neuroanatomical susceptibility of the ORB, and more resilient nature of the dlPFC to the insults and etiologies of geriatric depression. Further, dysfunction of the dlPFC observed in geriatric depression (e.g., executive impairment) may result from the neuronal pathology of dlPFC areas other than BA9, which was the only dlPFC area analyzed in this study. For example, in a recent study on geriatric depressed patients alterations in neuronal responses to executive challenges were specifically observed in the middle frontal gyrus (Wang et al., 2008) which corresponds to cytoarchitectonic Brodmann area 46 (Rajkowska and Goldman-Rakic, 1995a; Rajkowska and Goldman-Rakic, 1995b).

Another possible explanation for the more resilient nature of the dlPFC as compared to ORB consistent with our, and other findings, is that executive impairment observed in geriatric depression may result from disruption of white matter tracts as opposed to pathological change in neuronal cell bodies residing in the dlPFC gray matter. In fact, recent diffusion tensor imaging studies showed a lower fractional anisotrophy of the dlPFC white matter in elderly depressed (Bae et al., 2006; Alexopoulos et al., 2008). In the aging adult brain, the white matter of the prefrontal lobe appears to be the most notably affected by age-related shrinkage (Bartzokis et al., 2003), suggesting its relative susceptibility as compared with gray matter. This regional decline in frontal white matter volume is also associated with a reduction in cognitive processes seen in geriatric depression (Guttmann et al., 1998; Resnick et al., 2003; Brickman et al., 2006; Wang et al., 2008). Further morphometric studies of the frontal white matter at the microscopic level will establish whether white matter of the dlPFC is more affected in elderly depressed than its gray matter.

There are potential limitations to our study. Firstly, we were only able to estimate neuronal density on selected sections from BA9 rather than assess the total number of neurons within the entire extent of BA9. In order to estimate the total cell number in a particular brain region it is necessary to define the entire volume of this region by delineating its boundaries. Unfortunately, due to limitations of the availability of the postmortem tissue, the entire BA9 was not available for the estimation of total cell number. On the other hand, neuronal density (and not total number of neurons) was also analyzed in our previous study on the ORB cortex in the same subjects and large differences were found between the control and depressed subjects (Rajkowska et al., 2005). Although reductions in neuronal density do not necessarily translate to a loss of neurons, this study provides evidence for a region-specific neuronal pathology in elderly depressed, with ORB cortex being more affected than dlPFC.

Another potential limitation of this, as well as other studies of postmortem tissue, is a small sample size. In the present study, the small number of subjects analyzed is likely a consequence of the strict inclusion and exclusion criteria employed in the selection of our subjects, most notably a lack of comorbid drug or alcohol abuse, exclusion of subjects with evidence of neurological (including Alzheimer disease) or psychiatric disorders other than major depression and relatively short (<32 h) postmortem interval. We feel the homogeneity from these criteria is a major strength of this study that mitigates against possible concerns regarding sample size.

KEY POINTS

  • Neuronal density in the dorsolateral prefrontal cortex did not differ between older depressed patients and age-matched controls.

  • This lack of between-group difference in neuronal density in the dlPFC appears to be region-specific within the prefrontal cortex and stands in contrast to our finding of prominent reductions in neuronal density in the orbitofrontal cortex.

  • There were no between-group differences in the overall density of pyramidal neurons and non-pyramidal neurons.

  • Neither the overall cortical width of the dlPFC gray matter nor the thickness of any of the six dlPFC layers was different between the depressed and non-depressed groups.

Acknowledgments

The authors gratefully acknowledge the work of James C. Overholser, Ph.D., George Jurjus, M.D., and Lisa Konick in the establishment of retrospective psychiatric diagnoses. The excellent assistance of the Cuyahoga County Coroner’s Office, Cleveland, OH, is greatly appreciated, as is the cooperation and support of the next-of-kin of the deceased. This study was supported by grants from the National Institute of Mental Health: MH60451, MH54846, MH67996, and RR17701.

Footnotes

CONFLICT OF INTEREST

KRRK, M.B., Ch.B. is a consultant at Amgen, Bristol-Myer Squibb, CeNeRx, Corcept, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Merck, Organon, Pfizer, Sepracor, and Wyeth. GR, Ph.D. is a consultant at Eli Lilly. EVO, GO’D, CAS, Ph.D., and DCS M.D. have no conflict of interest.

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