You are on page 1of 11

This article was downloaded by: [University of Chicago]

On: 06 June 2012, At: 14:20


Publisher: Routledge
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK

Aging & Mental Health


Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/camh20

Depression, hippocampal volume changes, and


cognitive decline in a clinical sample of older
depressed outpatients and non-depressed controls
a a a b
Kathryn Sawyer , Elizabeth Corsentino , Natalie Sachs-Ericsson & David C. Steffens
a
Department of Psychology, Florida State University, Tallahassee, FL, USA
b
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center,
Durham, NC, USA

Available online: 01 May 2012

To cite this article: Kathryn Sawyer, Elizabeth Corsentino, Natalie Sachs-Ericsson & David C. Steffens (2012): Depression,
hippocampal volume changes, and cognitive decline in a clinical sample of older depressed outpatients and non-depressed
controls, Aging & Mental Health, DOI:10.1080/13607863.2012.678478

To link to this article: http://dx.doi.org/10.1080/13607863.2012.678478

PLEASE SCROLL DOWN FOR ARTICLE

Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions

This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.

The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss, actions,
claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.
Aging & Mental Health
2012, 1–10, iFirst

Depression, hippocampal volume changes, and cognitive decline in a clinical sample of


older depressed outpatients and non-depressed controls
Kathryn Sawyera, Elizabeth Corsentinoa*, Natalie Sachs-Ericssona and David C. Steffensb
a
Department of Psychology, Florida State University, Tallahassee, FL, USA; bDepartment of
Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
(Received 24 October 2011; final version received 15 March 2012)

Objective: The aim of this study was to develop and test a model of depression, hippocampal changes, and
cognitive decline.
Method: Participants were 248 community-dwelling, depressed patients and 147 healthy, non-depressed
individuals 60 years and older. Participants received a structured interview assessing current depressive
symptoms and past depressive episodes, completed cognitive testing with the Mini Mental State Examination
(MMSE), and underwent structural Magnetic Resonance Imaging (MRI) of the brain. For up to 10 years,
assessment of depressive symptoms and MMSE administration was repeated at least annually, and MRI was
repeated every two years.
Downloaded by [University of Chicago] at 14:20 06 June 2012

Results: Regression analyses demonstrated that depression diagnosis at baseline predicted decrease in right (but not
left) hippocampal volume over a four-year period. Analyses using structural equation modeling demonstrated that
a decrease in left and right hippocampal volumes predicted decrease in MMSE score over four years.
Conclusion: Results provide some evidence for relationships between depression and decrease in right
hippocampal volume, and between hippocampal volume and MMSE score. This would be consistent with
depression as a causal factor in subsequent cognitive decline. Plausible biological mechanisms include a
glucocorticoid cascade or a facilitating effect of depression on amyloid-beta plaque formation. Future studies
should examine the relationship between hippocampal volume and specialized memory measures, as well as
between depression diagnosis and volume of other brain structures.
Keywords: major depressive disorder; glucocorticoid cascade hypothesis; neuroimaging; structural equation
modeling

Introduction thereby enhancing Alzheimer’s disease (AD) pathology


Many studies demonstrate a relationship between (for review, see Dong & Csernansky, 2009). It is
depression and cognitive decline, but researchers are important to note that these explanations are not
still working to understand the cause and direction of necessarily mutually exclusive.
this relationship. Jorm (2001) reviewed three of the Findings that depression may occur in the absence
most prominent explanations for the relationship of cognitive impairment and predicts subsequent
between depression and cognitive decline. One expla- cognitive decline provide some evidence that depres-
nation is that depressive symptoms may represent an sion may be a contributor to dementia. Sachs-Ericsson,
early prodrome or warning sign of dementia, rather Joiner, Plant, and Blazer (2005) reported that depres-
than true depression (i.e., the prodrome hypothesis). sive symptoms at baseline predicted subsequent cogni-
Another explanation is that depression may be a tive decline over a three-year period, even among
response to early cognitive losses. That is, an individual individuals with no cognitive impairment at baseline.
may recognize that he or she is having memory In a series of studies, Kessing et al. found that the risk
difficulties, become concerned about the possibility of of developing dementia increased significantly with
dementia and loss of independence, and therefore each additional lifetime episode of depression; having a
become depressed. A third explanation, however, is more severe course with shorter amount of time
that depression may have an etiological role in between episodes also increased the risk of developing
cognitive decline. For instance, the glucocorticoid dementia (Kessing & Andersen, 2004; Kessing,
cascade hypothesis contends that depression initiates Mortensen, & Bolwig, 1998; Kessing & Nilsson,
neurological changes that in turn lead to prolonged 2003). Thus, the influence of depression on dementia
activation of the hypothalamic-pituitary-adrenal axis may be dose-dependent, with greater severity and more
(HPA), and ultimately to hippocampal damage and episodes of depression increasing the risk of subse-
neuronal death, which in turn places depressed indi- quently developing dementia.
viduals at greater risk for developing dementia Not all studies, however, have found this relation-
(Sapolsky, 1996). Alternatively, prolonged HPA acti- ship between depression and subsequent cognitive
vation may promote amyloid-beta plaque deposition, decline (Chen, Ganguli, Mulsant, & DeKosky, 1999;

*Corresponding author. Email: corsentino@psy.fsu.edu

ISSN 1360–7863 print/ISSN 1364–6915 online


ß 2012 Taylor & Francis
http://dx.doi.org/10.1080/13607863.2012.678478
http://www.tandfonline.com
2 K. Sawyer et al.

Dufouil, Fuhrer, Dartigues, & Alpérovitch, 1996; not respond to treatment had decreased right hippo-
Henderson, Korten, & Jacomb, 1997). Some have campal volumes. This speaks to one important factor
argued that depression only represents a prodromal in the relationship of depression and Alzheimer’s
phase of Alzheimer’s disease or dementia, as it tends to disease – severity of the depression. In general, studies
have its onset within one–two years of development of that have used community samples of adults may have
dementia (Berger, Fratiglioni, Forsell, Winblad, & included an insufficient number of severely depressed
Bäckman, 1999; Cannon-Spoor et al., 2005; Cervilla, individuals to capture the relationship between depres-
Prince, Joels, & Mann, 2000; Ganguli, Du, Dodge, sion and hippocampal volume.
Ratcliff, & Chang, 2006; Schweitzer, Tuckwell, Although the literature supports relationships
O’Brien, & Ames, 2002; Sun et al., 2008). between severe, chronic depression, and dementia;
Discrepancies appear to be explained, in part, by the between depression and smaller hippocampal
age of onset of the depression. Green et al. (2003) volumes; and between smaller hippocampal volumes
found retrospectively that depression occurring within and dementia; only one study to date has explicitly
one year prior to AD diagnosis robustly predicted AD. examined the mediating role of hippocampal volumes
Importantly, depression occurring up to 25 years prior in the depression–dementia relationship (Geerlings,
to the diagnosis still conveyed modest risk for AD. den Heijer, Koudstaal, Hofman, & Breteler, 2008).
Thus, the study provided evidence that depressive Unfortunately, this study used a community sample
symptoms may be a prodrome of dementia (when of older adults with minimal levels of depressive
occurring close to dementia diagnosis) and that symptomatology; given that more severe levels of
Downloaded by [University of Chicago] at 14:20 06 June 2012

depression may also be a risk factor for dementia depression may be necessary to impact the hippo-
(when occurring many years before dementia onset). campus or increase risk of dementia, the low level of
Emerging evidence suggests that depression may depressive symptoms in Geerlings and colleagues’
have a biological, etiological role in increasing risk of study must be considered a limitation.
dementia. One important mechanism through which The current study is uniquely able to address
depression may increase risk of dementia is the limitations of the extant research. We prospectively
glucocorticoid cascade hypothesis. That is, many
examined the relationship between depression, hippo-
depressed individuals have high-circulating levels of
campal volume change, and cognitive change in a
glucocorticoids, which can lead to neuronal death and
population of older adults with major depressive
inhibit neurogenesis in the hippocampus (Sapolsky,
disorder (MDD). We used a prospective longitudinal
1996). In addition, some research using animal models
design in which all participants were evaluated and
of Alzheimer’s disease suggests that increased levels of
found to be nondemented at baseline; and depressive
glucocorticoids can contribute to amyloid-beta depo-
symptoms, cognitive functioning, and hippocampal
sition (Dong & Csernansky, 2009), thus also contrib-
volume were objectively measured on three occasions
uting to Alzheimer’s disease pathology and
throughout the study. This allowed for examination of
to hippocampal atrophy. As decreased hippocampal
change over time among depressed individuals and
volumes are associated with cognitive decline in studies
of humans and rodents (Laakso et al., 1998; Lupien controls, using more sophisticated modeling techniques
et al., 1998), depression could increase risk of dementia (i.e., structural equation modeling).
by contributing to amyloid-beta deposition and to In a recent study, our group reported greater left
hippocampal atrophy. hippocampal volume reduction in depression versus
In fact, imaging studies do suggest that a history of controls and that among older depressives, there was
major depression and longer lifetime duration of an association between change in hippocampal
depression is associated with smaller hippocampal volume from baseline to two years and subsequent
volumes (Sheline, Sanghavi, Mintun, & Gado, 1999; decline in Mini Mental State Examination (MMSE)
Sheline, Wang, Gado, Csernansky, & Vannier, 1996). score from two to 2.5 years (Steffens, McQuoid,
In particular, research with older adults has demon- Payne & Potter, 2011). Our analyses extend this
strated reduced right hippocampal volumes in older study in several ways. First, our study extended
adults with depression (Bell-McGinty et al., 2002). across 4 years of data, allowing us to examine
Not all studies have detected a clear relationship change over time across a longer timeframe. Second,
between depression and hippocampal volume (Ashtari as we used structural equation modeling, a sophis-
et al., 1999; Rusch, Abercrombie, Oakes, Schaefer, & ticated statistical technique that allowed us to model
Davidson, 2001). Vakili et al. (2000) found no differ- relations among all of our variables. It also allowed
ence between the hippocampal size of depressed us to address missing data using the full information
participants and controls, who were between 18 and maximum likelihood (FIML) method. Lastly, we
60 years old. However, they did find that among the planned to test for mediation, if appropriate. We
male participants, Hamilton Depression Rating Scale hypothesisized that (1) depression would predict
score predicted hippocampal volume, with higher hippocampal volume reduction, (2) depression
scores (indicating more severe depression) predicting would predict cognitive decline, and (3) hippocampal
reduced hippocampal volumes. Likewise, among volume would mediate the relationship between
female participants, depressed participants who did depression and cognitive decline, such that smaller
Aging & Mental Health 3

hippocampal volume would be associated with Baseline cognitive screening


greater cognitive decline. At baseline, a geriatric psychiatrist examined each
participant, reviewed the participant’s medical records,
and consulted the participant’s referring physician to
Methods determine whether the participant had dementia.
This study used previously collected data from the Additionally, all participants were administered the
Neurocognitive Outcomes of Depression in the Elderly MMSE. Participants (depressed or control) with
study, an NIMH-supported study that has enrolled MMSE scores of 25 or higher, and no indications of
older depressed and non-depressed adult participants dementia, were enrolled. Some severely depressed
since 1994. Participants were evaluated at least annu- patients had MMSE scores below 25. These patients
ally for depression and cognitive functioning, and were followed during an eight-week course of treat-
received MRI of the brain approximately every two ment; if their MMSE score improved during this time,
years. Whereas the study has been conducted over a they were enrolled, and if it did not improve they were
10-year period, there was considerable attrition of excluded. In addition, any participants who experi-
participants with time. To capitalize on greater sample enced a decline in MMSE score of four or more points
size, we examined data for the initial four-year period. over the initial one-year follow-up period were elimi-
nated from the analysis as likely to have been
demented at baseline (Tangalos et al., 1996). This
resulted in elimination of 11 participants.
Downloaded by [University of Chicago] at 14:20 06 June 2012

Participants
Non-demented adults age 60 and older who presented at
the Psychiatry Services unit of Duke University Medical Treatment
Center or at the Duke General Internal Medicine Clinic, Treatment history prior to baseline was assessed using
and met Diagnostic and Statistical Manual of Mental the DDES. All participants diagnosed with MDD were
Disorders - Third Edition, Revised (DSM-III-R) crite- referred for treatment at baseline. Treatment options
ria for a current episode of major depression, were included antidepressant medications, electroconvulsive
recruited into the study. Participants were excluded if therapy, and individual and group cognitive behavioral
they met criteria for another major psychiatric illness therapy. The dataset includes a record of medication
(schizophrenia, schizoaffective disorder, bipolar disor- prescribed to study participants.
der, lifetime alcohol or substance dependence, and
dementia). Likewise, participants were excluded if they
had neurological illnesses that could lead to structural Measures
change visible by MRI, including Parkinson’s disease, Demographic information
multiple sclerosis, and seizure disorder. This study Participants reported demographic information during
included data from 248 depressed participants. administration of the DDES, including age, sex, race/
Adults over age 60 were recruited from the Duke ethnicity, and years of education.
University Center for Aging Subject Registry. They
underwent a nonfocal neurological examination to rule
out neurological disorder and were excluded if they Mini Mental State Examination
had a lifetime history of depression. Four additional The MMSE assesses cognitive functioning in five areas:
control participants were eliminated from the study orientation, registration, attention and calculation,
during the follow-up period because they experienced a recall, and language; and provides an objective mea-
first major depressive episode. This study included data sure of global cognitive functioning (M.F. Folstein,
from 147 (non-depressed) control participants. S.E. Folstein, & McHugh, 1975). Scores ranging from
0 to 30, with higher scores indicative of better cognitive
functioning, and a score below 25 generally indicative
Baseline depression assessment of cognitive impairment. Participants were adminis-
Trained interviewers administered the Duke Depression tered the MMSE at least yearly. The MMSE has been
Evaluation Schedule (DDES) to all participants to used extensively in epidemiologic research of older
assess demographic information and DSM-III-R or -IV adults. In the current study, reliability is acceptable
current and lifetime major depression using the (baseline ¼ 0.7, two-year follow-up ¼ 0.6, and four-
National Institute of Mental Health Diagnostic year follow-up ¼ 0.7).
Interview Schedule depression assessment (Robins,
Helzer, Croughan, & Ratcliff, 1981). Included in the Center for Epidemiologic Studies Depression scale
DDES are indices of depression severity, including The Center for Epidemiologic Studies Depression
(if applicable) questions about number of lifetime (CESD) scale is a 20-item self-report instrument that
episodes of depression, the number of DSM symptoms assesses symptoms of depression experienced in the
at baseline, and the number of DSM symptoms at worst previous week (Radloff, 1977). Items are scored from
episode. 0 to 4, with a maximum possible score of 60. CESD
4 K. Sawyer et al.

scores for the current study have good reliability, as patient or non-depressed control) at baseline would
represented by the inter-item correlation ( ¼ 0.8). predict subsequent decrease in (a) left and (b) right
hippocampal volume over a four-year follow-up
Neuroimaging period. Hippocampal volume at baseline, cerebrum
All participants underwent structural MRI of the brain (head) size, and age were controlled in each analysis.
at two-year intervals. The methodology of hippocam- A third multiple regression model (c) tested whether
pal measurement has been reported previously by depression status predicted change in MMSE score
Steffens et al. (2002). Briefly, participants were imaged over a four-year period. Baseline MMSE score, age,
using a 1.5-tesla whole-body MRI system (Signa, GE minority status, and years of education were controlled
Medical Systems, Milwaukee, WI, USA). Two sets of in the analyses.
dual-echo fast spin-echo (FSE) acquisitions were
obtained, one in the axial plane for morphometry of
most cerebral structures, and a second in a coronal Analysis 2
oblique plane for segmentation of the hippocampus. We predicted that indices of baseline depression
The pulse sequence parameters were repetition time - severity among both depressed participants and con-
4000 ms, and echo time ¼ 30, 135 ms, with 32 kHz (16 trol participants would predict change in MMSE score
kHz) full imaging bandwidth; echo train length ¼ 16, a over a four-year follow-up period, and that this
256  256 matrix, 3 mm section thickness, 1 Nex, and a relationship would be mediated by left and right
20 cm field of view. The images were acquired in two hippocampal volume four years after baseline.
Downloaded by [University of Chicago] at 14:20 06 June 2012

separate acquisitions, with a 3 mm gap between Specifically, we predicted that smaller hippocampal
sections for each acquisition. The second acquisition volume would be associated with greater decrease in
was offset by 3 mm from the first, so that the resulting MMSE score.
data set consisted of contiguous sections. For the near This hypothesis was tested using MPLUS version 5
coronal acquisition, the localizer scan was used to (L.K. Muthén & B.O. Muthén, 2007) to evaluate two
identify the anterior commissure–posterior commissure structural equation models using maximum likelihood
line. Oblique, near-coronal images were prescribed estimation. A latent variable was created representing
perpendicular to this line, covering the entire brain lifetime depression severity. The variable had five
from just anterior of the temporal lobe to a plane indicators: CESD score at baseline, lifetime number of
posterior to the lateral ventricles. Images were archived depressive episodes, symptom count for the worst
as normal procedure on magneto-optical disks in the episode of major depression, symptom count for the
MR Imaging Center. The MR images were then current episode of major depression, and number of
transferred to the Neuropsychiatric Imaging Research days to remission from the depression. Remission was
Laboratory (NIRL), located at Duke University defined as a Montgomery Asberg Depression Scale
Medical Center, for processing on SUN workstations, score below 10 (Hawley, Gale, & Sivakumaran, 2002).
and secondary archive. Thin-slice, dual-echo FSE The latent severity of depression variable was specified
images, consisting of proton-density and T2-weighted as predicting reduction in right hippocampal volume
images, were used for all processing. Hippocampal over the four-year follow-up period and change in
measurements used an oblique/coronal series of slices, MMSE score over this four-year follow-up period. We
and all other measures were done with axial images. planned to use bootstrapping to test for mediation, if
Two computer programs were used to make volume appropriate (Preacher & Hayes, 2004). Additionally,
measurements. Hippocampal volumes were determined the analysis considered age, gender, race, years of
with the GRID Program, which was developed at education, cerebrum size, baseline left or right hippo-
NIRL. Technicians computing hippocampal volume campal volume, and baseline MMSE score as control
using the GRID program demonstrated acceptable variables. We created two identical structural equation
interrater reliability (left hippocampus intraclass cor- modeling (SEM) models with the first including right
relation coefficient ¼ 0.8, right hippocampus intraclass hippocampal volume (Figure 1) and the second model
correlation coefficient ¼ 0.7). replacing this variable with left hippocampal volume
(Figure 2). We addressed missing data by using a
FIML algorithm (Allison, 2003).
Analytic model
Descriptive analyses
Descriptive analyses were performed to examine the Results
distribution of the study variables and check for
Descriptive statistics
outliers, skewness, and kurtosis. Transformations
were conducted to correct outliers, skew, or kurtosis. At baseline, participants were on average 70 years old
(SD ¼ 7.04). The sample was 69% female, and the
distribution of participants’ ethnicities was as follows:
Analysis 1 85.3% Caucasian, 10.9% African-American, 2.0%
We used multiple regression analyses to test our Mixed Race, 0.8% Asian, 0.3% Native American,
hypothesis that major depression diagnosis (depressed and 0.7% Other (see Table 1). Mean MMSE score at
Aging & Mental Health 5

Number of
Symptom Symptom
Days to baseline, excluding scores of the 11 participants iden-
count current count worst CESD score
episodes episode episode remission tified as likely demented at baseline, was 28.49
(SD ¼ 1.89), and participants had an average of 14
0.97* 0.94* 0.84* 0.87*
0.28* years of education (SD ¼ 2.78).
The 11 participants eliminated because they were
Depression Severity identified as likely demented at baseline, were on
average more likely to be depressed (90.9% vs. 9.1%,
2(n ¼ 395) ¼ 3.83, p 5 0.05), more likely to be a
–0.05 –0.03 minority (36.4% vs. 11.5%, 2(n ¼ 395) ¼ 6.21,
p 5 0.05), and had fewer years of education (10.73 vs.
14.33 F(1, 394) ¼ 18.73, p 5 0.01).
Right Alternatively, the depressed participants did not
MMSE at 4-year 0.18*Hippocampus at
follow-up 4-year follow-up significantly differ from the control participants by
age, sex, or minority status but did have fewer years of
0.58* 0.39* –0.32* education (13.55 vs. 15.38 years, F(1, 383) ¼ 44.42,
Baseline
p 5 0.01) and a marginally lower baseline MMSE
Baseline
MMSE Age score (28.31 vs. 28.92 points, F(1, 383) ¼ 14.17,
HIppocampus
p 5 0.01).
Figure 1. Note the significant relationship between change in A considerable portion of participants either
Downloaded by [University of Chicago] at 14:20 06 June 2012

right hippocampal volume and change in MMSE score over dropped out between the baseline and four-year
the four-year follow-up period. *Significant at the 0.05 level. follow-up assessments or had missing data on some
of the variables. Specifically, 123 participants were
missing baseline imaging data, 184 participants were
Symptom Symptom missing imaging data at four-year follow-up, and 47
Number of count current count worst Days to
episodes episode episode
CESD score
remission participants were missing MMSE score at four-year
follow-up. No participants had missing data for
0.28*
0.97* 0.94* 0.84* 0.87* baseline MMSE score, demographic variables (age,
sex, ethnicity, and years of education), or depression
Depression Severity diagnosis and severity variables (diagnosis, CESD
score, symptom counts, and number of past depressive
episodes), but 39 participants were missing data for
–0.04 –0.06 days to remission.
A total of 114 participants with complete neuro-
imaging data were included in the first regression
Left analysis examining the relationship of depression
MMSE at 4-year 0.2* Hippocampus at
follow-up diagnosis and change in hippocampal volume.
4-year follow-up
Participants with missing data differed from partici-
0.57* 0.5* -0.27* pants who remained in the study in that they were
more likely to be minorities (13.6% vs. 6.2%,
Baseline
MMSE
Baseline
HIppocampus
Age 2(n ¼ 384) ¼ 4.23, p 5 0.05), had marginally lower
baseline MMSE scores (28.38 vs. 28.96 points,
Figure 2. Note the significant relationship between change in F(1, 383) ¼ 26.72, p 5 0.05), and had fewer years of
left hippocampal volume and change in MMSE score over education (14.44 vs. 15.19 years, F(1, 383) ¼ 44.19,
the four-year follow-up period. p 5 0.05). Importantly, participants with missing imag-
ing data were no more likely to be depressed.

Table 1. Demographic and cognitive differences between depressed participants and controls.

Depressed mean (SD) Control mean (SD)


Variable n ¼ 238 n ¼ 146 For 2 p-value

Age 70.03 (7.5) 70.43 (6.26) 0.281 p ¼ 0.59


Gender 67.7% 70.7% 0.389 p ¼ 0.31
Female (%)
White (%) 89.1% 85.7% 0.99 p ¼ 0.20
MMSE score (baseline) 28.31 (1.7) 28.92 (1.3) 14.17 p 5 0.01
Years of education 14.2 (2.03) 15.41 (1.76) 35.72 p 5 0.01
Left hippocampal volume (baseline) 2.93 mL (0.41) 2.95 mL (0.42) 0.131 p ¼ 0.72
Right hippocampal volume (baseline) 3.07 mL (0.42) 3.11 mL (0.43) 0.505 p ¼ 0.48
Cerebrum volume (baseline) 1149.91 mL (130) 1141.19 mL (122.22) 0.42 p ¼ 0.52

Note: Significant differences are italicized.


6 K. Sawyer et al.

Table 2. Depression diagnosis predicts change in right hippocampal volume over four years controlling for baseline
hippocampal volume, cerebrum (head) size, and age.

Unstandardized coefficients

Variable df Beta Standard error F p-value

Constant 2.255 0.652 3.456 0.001


Baseline right hippocampal volume 1, 113 0.275 0.114 2.414 0.017
Cerebrum volume 1, 113 0.001 0.00 3.29 0.001
Age 1, 113 0.019 0.007 2.696 0.008
Depressed? 0 ¼ No, 1 ¼ Yes 1, 113 0.172 0.079 2.168 0.032

Table 3. Depression diagnosis does not predict change in left hippocampal volume over four years controlling for baseline
hippocampal volume, cerebrum (head) size, and age.

Unstandardized coefficients

Variable df Beta Standard error F p-value


Downloaded by [University of Chicago] at 14:20 06 June 2012

Constant 2.495 0.583 4.282 0.00


Baseline left hippocampal volume 1, 113 0.411 0.100 4.103 50.001
Cerebrum volume 1, 113 0.001 0 1.814 0.072
Age 1, 113 0.019 0.006 3.165 0.002
Depressed? 0 ¼ No, 1 ¼ Yes 1, 113 0.104 0.070 1.50 0.136

Table 4. Depression diagnosis does not predict change in MMSE score over the four-year follow-up period, controlling for age,
years of education, and minority group membership.

Unstandardized coefficients

Variable df Beta Standard error F p-value

Constant 20.73 1.877 11.044 50.001


MMSE baseline 1, 335 0.360 0.053 6.76 50.001
Age 1, 335 0.059 0.011 5.499 50.001
Years of education 1, 335 0.115 0.037 3.075 0.002
Minority status (0 ¼ Caucasion, 1 ¼ not Caucasian) 1, 335 0.870 0.237 3.667 50.001
Depressed? 0 ¼ No, 1 ¼ Yes 1, 335 0.032 0.152 0.212 0.832

For the second regression analysis, examining the Analyses were repeated for left hippocampal
relationship of depression diagnosis and change in volume. Depression diagnosis at baseline had no
MMSE score, complete data were available for 336 relationship to change in left hippocampal volume
participants. Participants with missing data had mar- over the four-year follow-up period (F(1, 113) ¼ 0.10,
ginally lower baseline MMSE scores (27.81 vs. 28.65 p ¼ 0.136); age did significantly predict change in left
points, F(1, 383) ¼ 28.99, p 5 0.05) and had fewer years hippocampal volume (Table 3).
of education (14 vs. 14.75 years, F(1, 383) ¼ 23.25, For the third regression analysis, depression diag-
p 5 0.05). Importantly, participants with missing nosis at baseline had no relationship to change in
MMSE data were no more likely to be depressed. MMSE score over the four-year period (F(1, 335) ¼
0.32, p ¼ 0.832); however, consistent with the literature,
age, years of education, and minority group mem-
bership all significantly predicted change in MMSE
Analysis 1
score (Table 4).
Regression analyses demonstrated a significant rela-
tionship between baseline depression diagnosis and
change in right hippocampal volume over the four-year
follow-up period (F(1, 113) ¼ 0.17, p 5 0.05); baseline Analysis 2
cerebrum volume and age also significantly predicted Overall model fit was good for the model examining
change in right hippocampal volume (Table 2). right hippocampal volume. The Chi-square test of
Aging & Mental Health 7

Table 5. Correlation matrix for the first SEM model.

Number Current Worst Right Right


of symptom symptom CESD Days to MMSE hippo-campus Age at MMSE hippo-campus
episodes count count score remission 3 3 baseline 1 1

Number of episodes 1
Current symptom count 0.27 1
Worst symptom count 0.27 0.93 1
CESD score 0.23 0.81 0.79 1
Days to remission 0.26 0.85 0.81 0.79 1
MMSE 3 0.09 0.14 0.12 0.11 0.17 1
Right hippo-campus 3 0.13 0.02 0.04 0.02 0.01 0.27 1
Age at baseline 0.09 0.1 0.09 0.05 0.06 0.23 0.41 1
MMSE1 0.04 0.16 0.13 0.17 0.16 0.63 0.13 0.26 1
Right hippo-campus 1 0.02 0.04 0.06 0.03 0.03 0.16 0.46 0.21 0.25 1

model fit was statistically significant, indicating a period. Subsequent analyses using structural equation
poorly fitting model (2(df ¼ 28) ¼ 43.75, p ¼ 0.03). modeling demonstrated a significant relationship
The Tucker–Lewis index (TLI ¼ 0.99), comparative between change in hippocampal volume and change
Downloaded by [University of Chicago] at 14:20 06 June 2012

fit index (CFI ¼ 0.99), root mean square error of in MMSE score over the four-year follow-up period,
approximation (RMSEA ¼ 0.03), and standardized such that decrease in both right and left hippocampal
root mean square residual (SRMR ¼ 0.03) all indicated volume was associated with decrease in MMSE score.
a good fitting model. The correlation matrix for the Other studies have also demonstrated smaller
model is presented in (Table 5). hippocampal volumes in individuals with current
In this model (Figure 1), the path between depres- major depression (e.g., Bell-McGinty et al., 2002;
sion severity and right hippocampal volume at four- McKinnon, Yucel, Nazarov, & MacQueen, 2009;
year follow-up was not significant. The path between Sheline et al., 1996). Our findings extend the literature,
depression severity and MMSE score at four-year demonstrating that depression diagnosis predicts
follow-up was also non-significant. However, change decrease in right hippocampal volume over time
in right hippocampal volume over the four-year among older adults. An additional important finding
follow-up period significantly predicted change in is that this decrease in hippocampal volume predicts
MMSE score over the four-year follow-up period. decreased scores on the MMSE over a four-year follow-
Overall model fit for the second SEM model up period.
including left hippocampal volume (Figure 2) was This latter finding is consistent with recent pub-
good. The Chi-square test of model fit was statistically lished findings examining the same dataset across a
significant, indicating a poorly-fitting model two-year timeframe (Steffens et al., 2011). In that
(2(df ¼ 28) ¼ 43.44, p ¼ 0.03). However, the TLI study, investigators used regression to examine con-
(0.99), CFI (0.99), RMSEA (0.04), and SRMR (0.03) current change in normalized hippocampal volumes
all indicated a good-fitting model. and in MMSE score over the initial 2.5-year period of
The path between depression severity and left the study. They found that hippocampal volume
hippocampal volume at four-year follow-up was not decrease from baseline to year two of the study
significant. The path between depression severity and predicted MMSE score decrease from year two to 2.5
MMSE score at four-year follow-up was also non- of the study. The current analyses examined this
significant; however, change in hippocampal volume phenomenon over a four-year timeframe. In addition,
over the four-year follow-up period significantly pre- our methodology (structural equation modeling)
dicted change in MMSE score over the four-year allowed for inclusion of additional subjects that were
follow-up period. excluded from the regression analyses of the 2011
study. The current analyses robustly demonstrate a
continued effect of hippocampal volume decrease on
Discussion decline in MMSE score in years two–four of the study.
The current study prospectively examined the relation- The finding that depressed participants experienced
ship between depression, hippocampal volume change, greater atrophy of the right hippocampus than non-
and cognitive change in a population of older adults depressed control participants over a four-year period
with MDD who presented for depression treatment provides some support for an etiological role of
and a population of healthy age-matched control depression in cognitive decline. While our study does
participants. not directly measure the biological mechanism of
Regression analyses revealed that depression diag- action, our findings are consistent with the glucocor-
nosis at baseline predicted decrease in right (but not ticoid hypothesis, as well as with findings that stress
left) hippocampal volume over a four-year follow-up can accelerate Alzheimer’s disease pathology.
8 K. Sawyer et al.

One interesting finding is the asymmetry of our effect of severity in the population, as we hoped to do
results. That is, we found a significant relationship in the SEM model.
between depression and change in right hippocampal It should also be noticed that in this population of
volume, but not between depression and change in left older adults with depression, many had experienced
hippocampal volume. This may have occurred because prior depressive episodes. Thus, they likely had previ-
the hippocampus is a reliably asymmetrical structure in ous experience of elevated cortisol. This historical
normal adults, with adults tending to have larger right experience of hypercortisolemia may have maximally
hippocampal volumes (Pedraza, Bowers, & Gilmore, reduced hippocampal volumes in this group prior to
2004). In our sample, right hippocampus was in fact enrollment in the study, limiting the extent to which
larger than the left hippocampus at baseline. As the further hippocampal atrophy could be sustained.
right hippocampus is a larger structure, this may have Finally, it is important to note that all depressed
allowed for greater decrease in volume over time. This participants in the study received treatment with
is an important area of future research. antidepressant medication, including regular monitor-
Decrease in both left and right hippocampal ing of symptoms by a geriatric psychiatrist and
volume predicted decrease in MMSE score. Again, medication adjustment as necessary. In fact, among
this provides support for an etiological role of depres- the depressed participants, there is no significant
sion in dementia, in so far as hippocampal volume relationship between depressive symptoms at baseline
decrease has cognitive implications and may lead to and depressive symptoms at two–four-year follow-up,
cognitive impairment. Moreover, this is consistent with most likely indicating that this treatment was highly
Downloaded by [University of Chicago] at 14:20 06 June 2012

the literature, which has shown significant relation- effective in treating participants’ symptoms. If their
ships between hippocampal volume and MMSE score symptoms were treated effectively, it could be that the
cross-sectionally (Apostolova et al., 2006; Du et al., glucocorticoid cascade was interrupted or prevented,
2001). Our study extends the extant literature, demon- thus minimizing further hippocampal damage.
strating a longitudinal relationship between change in While the restriction of range in depressive symp-
hippocampal volume and change in MMSE score. toms, previous experiences of hypercortisolemia, or the
However, it should be noted that, while there were treatment provided to depressed participants, may
significant relationships between depression and right have acted to obscure the effect of depression on
hippocampal volume change over time and between hippocampal volume, it is also possible that our lack of
hippocampal volume decrease and decreased MMSE significant findings is due to a true lack of relationship
score over time, neither depression diagnosis nor between depression and hippocampal volume over
depression severity predicted change in MMSE score time. Importantly, most studies that have demon-
over time. It is highly surprising that we found no strated a relationship between depression and hippo-
relationship between depression diagnosis and change campal volume have been cross-sectional. While we
in MMSE score over time. Consequently, we were originally argued that one strength of this study is the
unable to test for mediation. ability to track change in hippocampal volume over
This is particularly surprising, as a previous study time, it may be the case that decrease in hippocampal
using this data set showed increased risk for dementia volume occur during episodes of depression but are not
among depressed participants relative to controls maintained, or do not cascade, over time.
(Steffens et al., 2004). Importantly, among the study This study has many strengths: a sample of older,
participants, 31 individuals developed dementia over clinically depressed adults, and an age-matched sample
the course of their participation in the study. In the of controls; regular monitoring of depressive symp-
current study, we eliminated 11 individuals, 10 of toms, regular cognitive testing, and regular MRI of the
whom were in the depressed group, because their brain; and a prospective longitudinal design enabling
MMSE score decreased by four points or more in the us to examine change over time. However, some
first year of the study, and we considered them as likely limitations must be acknowledged.
to have prodromal dementia at baseline. By eliminat- First, the sample is mostly Caucasian and college-
ing these individuals from the study, we removed those educated, with high-MMSE scores at baseline. Such a
with greatest cognitive decline, which may have sample is not representative of the general population of
obscured the effect of depression on cognitive decline older adults. Moreover, some studies have shown that
over time. Our lack of a finding here may also be due individuals with greater educational attainment are
to our use of the MMSE as the measure of cognition. more likely than individuals with few years of education
Limitations regarding this instrument are discussed to experience cognitive decline after becoming
below. depressed. Thus, it may be the case that these results
Additionally, there was limited variability in are not typical of the general population of older adults.
depression severity across the participants, with all Moreover, older adults who are minorities, have
depressed participants tending to have moderate to smaller household incomes, and have fewer years of
severe depression and multiple past depressive education are more likely to experience cognitive
episodes. Therefore, it may be the case that there was decline. While the population of participants used in
insufficient variability in depression severity (i.e., a this study may have been more likely to demonstrate
restriction of range) to enable us to detect a significant cognitive decline after becoming depressed due to their
Aging & Mental Health 9

higher educational attainment, overall they are not References


typical of the older adults most at risk for cognitive
decline. Again, therefore, caution should be exercised Allison, P.D. (2003). Missing data techniques for structural
in applying these results to the general population of equation modeling. Journal of Abnormal Psychology, 112,
545–557.
elders.
Apostolova, L.G., Dinov, I.D., Dutton, R.A., Hayashi,
Additionally, in this study we used the MMSE as K.M., Toga, A.W., Cummings, J.L., & Thompson, P.M.
our measure of cognitive functioning. The MMSE is a (2006). 3D comparison of hippocampal atrophy in
broad, global measure of cognition. Only two ques- amnestic mild cognitive impairment and Alzheimer’s
tions directly assess memory; the remaining questions disease. Brain, 129, 2867–2873.
assess orientation, registration, attention, and lan- Ashtari, M., Greenwald, B.S., Kramer-Ginsberg, E., Hu, J.,
guage. Yet, the hippocampus is primarily associated Wu, H., Patel, M., . . . Pollack, S. (1999). Hippocampal/
with episodic and spatial memory, with the right amygdala volumes in geriatric depression. Psychological
hippocampus being implicated in the memory of visual Medicine, 29, 629–638.
Bell-McGinty, S., Butters, M.A., Meltzer, C.C., Greer, P.J.,
stimuli and the left hippocampus implicated in the
Reynolds, C.F., & Becker, J.T. (2002). Brain morphomet-
verbal memory. Thus, the MMSE may not be the best
ric abnormalities in geriatric depression: Long-term
or most sensitive measure of cognitive impairment neurobiological effects of illness duration. American
resulting from hippocampal atrophy or damage. Journal of Psychiatry, 159, 1424–1427.
Future studies might examine the relationship between Berger, A.-K., Fratiglioni, L., Forsell, Y., Winblad, B., &
depression, hippocampal volume change, and change Bäkman, L. (1999). The occurrence of depressive symp-
Downloaded by [University of Chicago] at 14:20 06 June 2012

in performance on these measures. toms in the preclinical phase of AD: A population based
Finally, it should be noted that there was signifi- study. Neurology, 53, 1998–2002.
cant attrition over time in our study. Participants’ Cannon-Spoor, E., Levy, J., Zubenko, G., Zubenko, W.,
reasons for dropping out of the study (e.g., death, Cohen, R., Mirza, N., . . . Sunderland, T. (2005). Effects of
previous major depressive illness on cognition in
unable to travel to the study site) are not recorded.
Alzheimer disease patients. American Journal of Geriatric
However, participants who dropped out of the study Psychiatry, 13, 312–318.
tended to have lower baseline MMSE scores, fewer Cervilla, J.A., Prince, M., Joels, S., & Mann, A. (2002). Does
years of education, and were more likely to be depression predict cognitive outcome 9 to 12 years later?
minorities. These individuals would be at greater risk Psychological Medicine, 30, 1017–1023.
for cognitive decline, and their loss from the study may Chen, P., Ganguli, M., Mulsant, B., & DeKosky, S. (1999).
have served to mask the effects of depression on The temporal relationship between depressive symptoms
hippocampal volume loss and cognitive decline. and dementia: A community based prospective study.
In conclusion, depression is thought to initiate a Archives of General Psychiatry, 56, 261–266.
glucocorticoid cascade that damages the hippocam- Dong, H., & Csernansky, J.G. (2009). Effects of stress and
stress hormones on amyloid-beta protein and plaque
pus, a brain structure key to formation of new
deposition. Journal of Alzheimer’s Disease, 18, 459–469.
memories, and thus places depressed individuals at Du, A.T., Schuff, N., Amend, D., Laakso, M.P., Hsu, Y.Y.,
increased risk for cognitive decline. In this study, we Jagust, W.J., . . . Weiner, M.W. (2001). Magnetic resonance
used regression and structural equation modeling to imaging of the entorhinal cortex and hippocampus in mild
prospectively examine relationships between depres- cognitive impairment and Alzheimer’s disease. Journal of
sion diagnosis and symptoms, hippocampal volume, Neurology, Neurosurgery, & Psychiatry, 71, 441–447.
and MMSE score over time in a sample of older Dufouil, C., Fuhrer, R., Dartigues, J., & Alpérovitch, A.
adults. Results indicated support for the glucocor- (1996). Longitudinal analysis of the association between
ticoid cascade hypothesis, with depression diagnosis depressive symptomatology and cognitive deterioration.
American Journal of Epidemiology, 144, 634–641.
predicting decrease in right, but not left, hippocam-
Folstein, M.F., Folstein, S.E., & McHugh, P.R. (1975).
pal volume, and hippocampal volume decrease ‘Mini-Mental State’: A practical method for grading the
predicting decrease in MMSE score. Future research cognitive state of patients for the clinician. Journal of
may consider use of neuroendocrine markers such as Psychiatric Research, 12, 189–198.
measures of cortisol to test the glucocorticoid Ganguli, M., Du, Y., Dodge, H., Ratcliff, G., & Chang, C.
cascade hypothesis. Lastly, specialized measures of (2006). Depressive symptoms and cognitive decline in late
memory, as well as examination of other brain areas life. Archives of General Psychiatry, 63, 153–160.
affected by depression, may shed additional light on Geerlings, M.I., den Heijer, T., Koudstaal, M.D.,
the relationship between depression and cognitive Hofman, A., & Breteler, M. (2008). History of
depression, depressive symptoms, and medial temporal
decline or dementia.
lobe atrophy and the risk of Alzheimer disease.
Neurology, 70, 1258–1264.
Green, R.C., Cupples, L.A., Kurz, A., Auerbach, S., Go, R.,
Sadornick, D., . . . Farrer, L. (2003). Depression as a risk
Acknowledgments factor for Alzheimer disease: The MIRAGE study.
This research was supported by NIMH Grant Nos. K01 Archives of Neurology, 60, 753–759.
MH066380, K24 MH70027, R01 MH54846, and P50 MH Hawley, C.J., Galea, T.M., & Sivakumarana, T. (2002).
60451. Defining remission by cut off score on the MADRS:
10 K. Sawyer et al.

Selecting the optimal value. Journal of Affective Disorders, Rusch, B.D., Abercrombie, H.C., Oakes, T.R., Schaefer,
72, 177–184. S.M., & Davidson, R.J. (2001). Hippocampal morphometry
Henderson, A., Korten, A., & Jacomb, P. (1997). The in depressed patients and control subjects: Relations to
course of depression in the elderly: A longitudinal anxiety symptoms. Biological Psychiatry, 50, 960–964.
community-based study in Australia. Psychological Sachs-Ericsson, N., Joiner, T., Plant, A., & Blazer, D.G.
Medicine, 27, 119–129. (2005). The influence of depression on cognitive decline in
Jorm, A.F. (2001). History of depression as a risk factor for community-dwelling elderly persons. American Journal of
dementia: An updated review. Australia and New Zealand Geriatric Psychiatry, 13, 402–408.
Journal of Psychiatry, 35, 776–781. Sapolsky, R. (1996). Why stress is bad for your brain.
Kessing, L.V., & Andersen, P.K. (2004). Does the risk of Science, 273, 749–750.
developing dementia increase with the number of episodes Schweitzer, I., Tuckwell, V., O’Brien, J., & Ames, D. (2002).
in patients with depressive disorder and in patients with Is late onset depression a prodrome to dementia?
bipolar disorder? Journal of Neurosurgery and International Journal of Geriatric Psychiatry, 17, 997–1005.
Neuropsychiatry, 75, 1662–1666. Sheline, Y.I., Sanghavi, M., Mintun, M.A., & Gado, M.H.
Kessing, L.V., Mortensen, P.B., & Bolwig, T.G. (1998). (1999). Depression duration but not age predicts hippo-
Clinical consequences of sensitization in affective disorder. campal volume loss in medically healthy women with
Journal of Affective Disorders, 47, 41–47. recurrent major depression. The Journal of Neuroscience,
Kessing, L.V., & Nilsson, F.M. (2003). Increased risk of 19, 5034–5043.
developing dementia in patients with major affective dis- Sheline, Y., Wang, P., Gado, M.H., Csernansky, J., &
orders compared to patients with other medical illnesses. Vannier, M. (1996). Hippocampal atrophy in recurrent
Journal of Affective Disorders, 73, 261–269. major depression. Proceedings of the National Academy of
Downloaded by [University of Chicago] at 14:20 06 June 2012

Laakso, M.P., Soininen, H., Partanen, K., Lehtovirta, M., Sciences Medical Sciences, 93, 3908–3913.
Hallikainen, M., Hanninen, T., . . . Riekkinen Sr, P.J. Steffens, D.C., McQuoid, D.R., Payne, M.E., & Potter, G.G.
(1998). MRI of the hippocampus in Alzheimer’s disease: (2011). Change in hippocampal volume of magnetic
Sensitivity, specificity, and analysis of the incorrectly resonance imaging and cognitive decline among older
classified subjects. Neurobiology of Aging, 19, 23–31. depressed and nondepressed subjects in the
Lupien, S., de Leon, M., De Santi, S., Convit, A., Tarshish, Neurocognitive Outcomes of Depression in the Elderly
C., Nair, N., . . . Meaney, M. (1998). Cortisol levels during Study. American Journal of Geriatric Psychiatry, 19, 4–12.
human aging predict hippocampal atrophy and memory Steffens, D.C., Payne, M.E., Greenberg, D.L., Byrum, C.E.,
deficits. Nature Neuroscience, 1, 69–73. Welsh-Bohmer, K.A., Wagner, H.R., & MacFall, J.R.
McKinnon, M.C., Yucel, K., Nazarov, A., & MacQueen, (2002). Hippocampal volume and incident dementia in
G.M. (2009). A meta-analysis examining clinical predictors geriatric depression. American Journal of Geriatric
of hippocampal volume in patients with major depressive Psychiatry, 10, 62–71.
disorder. Journal of Psychiatry and Neuroscience, 34, Steffens, D.C., Welsh-Bohmer, K.A., Burke, J.R., Plassman,
41–54. B.L., Beyer, J.L., Gersing, K.R., & Potter, G.G. (2004).
Muthén, L.K., & Muthén, B.O. (2007). Mplus user’s guide Methodology and preliminary results from the neurocog-
(5th ed.). Los Angeles, CA: Muthén & Muthén. nitive outcomes of depression in the elderly study. Journal
Pedraza, O., Bowers, D., & Gilmore, R. (2004). Asymmetry of Geriatric Psychiatry and Neurology, 17, 202–211.
of the hippocampus and amygdala in MRI volumetric Sun, X., Steffens, D., Au, R., Folstein, M., Summergrad, P.,
measurements of normal adults. Journal of the Yee, J., . . . Qiu, W. (2008). Amyloid-associated depression:
International Neuropsychological Society, 10, 664–678. A prodromal phase of Alzheimer’s disease. Archives of
Preacher, K.J., & Hayes, A.F. (2004). SPSS and SAS General Psychiatry, 65, 542–550.
procedures for estimating indirect effects in simple media- Tangalos, E.G., Smith, G.E., Ivnik, R.J., Petersen, R.C.,
tion models. Behavior Research Methods, Instruments, & Kokmen, E., Kurland, L.T., . . . Parisi, J.E. (1996). The
Computers, 36, 717–731. Mini-Mental State Examination in general medical
Radloff, L.S. (1977). The CES-D scale: A self-report practice: Clinical utility and acceptance. Mayo Clinic
depression scale for research in the general population. Proceedings, 71, 829–837.
Applied Psychological Measurement, 1, 385–401. Vakili, K., Pillay, S.S., Lafer, B., Fava, M., Renshaw, P.F.,
Robins, L.N., Helzer, J.E., Croughan, J., & Ratcliff, K.S. Bonello-Cintron, C.M., & Yurgelun-Todd, D.A. (2000).
(1981). The NIMH Diagnostic Interview Schedule: Its Hippocampal volume in primary unipolar major depres-
history, characteristics and validity. Archives of General sion: A magnetic resonance imaging study. Biological
Psychiatry, 38, 381–389. Psychiatry, 47, 1087–1090.

You might also like