Brain & Mind Research Institute, University of Sydney
School of Psychiatry, University of New South Wales
Brain & Mind Research Institute, University of Sydney
School of Psychiatry, University of New South Wales, NSW, Australia
Correspondence: Professor Ian Hickie, Brain & Mind Research Institute, PO Box M160, Missenden Road, NSW Australia. Tel: +612 9351 0799, Fax: +612 9351 0652; E-mail: ianh{at}med.usyd.edu.au
Declaration of interest Supported by National Health and Medical Research Council Program Grant No.953208.
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ABSTRACT |
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Aims To evaluate the interrelationships between hippocampal volumes, memory and key clinical, vascular and genetic risk factors.
Method Totals of 66 people with depression and 20 control participants underwent magnetic resonance imaging and clinical assessment. Measures of depression severity, psychomotor retardation, verbal and visual memory and vascular and specific genetic risk factors were collected.
Results Reduced hippocampal volumes occurred in older people with depression, those with both early-onset and late-onset disorders and those with the melancholic subtype. Reduced hippocampal volumes were associated with deficits in visual and verbal memory performance.
Conclusions Although reduced hippocampal volumes are most pronounced in late-onset depression, older people with early-onset disorders also display volume changes and memory loss. No clear vascular or genetic risk factors explain these findings. Hippocampal volume changes may explain how depression emerges as a risk factor to dementia.
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INTRODUCTION |
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METHOD |
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Potential participants were excluded if there was any indication of neurodegenerative disorder, history of stroke, head injury, substance misuse or medical contraindications to magnetic resonance imaging (MRI) scanning. Individuals who had received electroconvulsive therapy within the preceding 3 months also were excluded. All participants gave written informed consent prior to participation.
Clinical assessment
Psychiatrists performed structured clinical assessments
(Hickie et al, 2001) generating DSM-IV (American Psychiatric
Association, 1994) diagnoses. Additionally, severity of
psychomotor change was evaluated using the CORE scale
(Parker et al, 1994)
and depression severity was rated using the 21-item Hamilton Rating Scale for
Depression (HRSD; Hamilton,
1960). Duration of current episode (maximum= 104 weeks) was
recorded, and duration since onset of illness (total years since onset) was
calculated by subtracting age of depression onset from current age.
Participants with depression were subclassified into DSM-IV
(American Psychiatric Association,
1994) non-melancholic (n=19, 29%) or melancholic
(n=47, 71%; including 13 individuals with psychotic features)
subtypes. Those who had their first episode of depression prior to age 50
years were classified as having early-onset depression
(n=49, 74%) whereas those who first experienced depression at age 50
years or later were classified as having late-onset depression
(n=17, 26%). Fourteen participants had a bipolar disorder, all of
early onset (2=6.2, P=0.013). Fifteen (88%) of those
with late-onset depression also had a diagnosis of melancholia in comparison
with 32 (65%) of those with early-onset depression (
2=3.2,
NS). The total years since onset of illness ranged from 0 to 60, with an
average duration of 15 years (s.d.=15.8). Participants with early- and
late-onset depression had mean lifetime illness duration of 19.3 (s.d.=16.4)
and 3.5 (s.d.=2.8) years, respectively. Those with late-onset depression were
significantly older (mean age=63.7 years, s.d.=10.4) than those with
early-onset depression (mean age=50.1 years, s.d.=12.7; F=15.6,
P<0.001).
Neuropsychological assessment
All participants were administered the Mini-Mental State Examination (MMSE;
Folstein et al, 1975).
As part of a wider neuropsychological assessment
(Naismith et al,
2003), a subset of control participants (n=19) and
participants with depression (n=46) were administered the Rey
Auditory Verbal Learning Test (RAVLT; delayed recall percentage retention
scores, maximum score=100; Lezak,
1983) and the Benton Visual Retention Test (BVRT; Form D,
administration A, maximum score=10; Benton,
1967) to assess verbal and visual memory, respectively.
Magnetic resonance imaging
Participants underwent high-resolution MRI scanning (124x1.5 mm
coronal slices; time to repetition=24 ms, time to echo=5 ms, field of view=26
cm, matrix 256x256) using a 1.5 T GE Signa machine. Data were
transferred to a Silicon Graphics workstation and analysed using the BRAINS
software package (Andreasen et al,
1993). Images were re-sampled digitally in the anterior
commissure-posterior commissure plane to standardise anatomical orientation.
Whole-brain volumes were traced using methods described previously
(Levitan et al,
1999). All slices of the left and right hippocampi were traced
manually by a rater masked to diagnosis. Although all traces were made in the
coronal plane, additional traces were made on sagittal and axial views, and
points from these were telegraphed to orthogonal planes, to be used as
guidelines to tracing. Volumes (cm3) of each structure were summed
across coronal slices to give total left and right hippocampal volumes.
Definitions of anatomical boundaries and landmarks were derived from the
literature (Cook et al,
1992; Watson et al,
1992), by consultation with a neuroanatomist and by use of a brain
atlas (Duvernoy, 1991).
Vascular risk factors
Based on a combination of self-report and close informant questionnaires
and medical review by a psychiatrist, the following vascular risks were
recorded as present (1) or absent (0): diabetes; treated or untreated
hypertension; smoking; cardiovascular disease; elevated cholesterol; and
family history of at least two vascular disorders (including stroke and
transient ischaemic attack). These six vascular risk factors were summed for
each participant to give a total risk rating (range: 0-6;
Hickie et al, 2001; Naismith et al,
2003).
Apolipoprotein E and methylenetetrahydrofolate reductase genotyping
As described in our previous studies
(Hickie et al, 2001;
Naismith et al, 2002,
2003), genotypes of ApoE and
MTHFR were determined by polymerase chain reaction-based methods. Heterozygous
(n=31) and homozygous (n=9) groups for the C677T MTHFR
mutant allele were pooled to form a group at risk
(n=40). Similarly, participants with at least one ApoE 2
(ApoE2) or
4 (ApoE4) allele were coded as either positive (n=9
and n=23, respectively) or negative (n=71 and n=57,
respectively) for the allele.
Statistical analysis
Data were analysed using the Statistical Package for the Social Sciences
(version 11.5 for PC). An level of 0.05 was employed for all tests
except those employing Bonferroni corrections.
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RESULTS |
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Importantly, there was no association between cumulative vascular risk factors and hippocampal volumes or whole-brain volumes for participants with or without depression (Table 2). Hippocampal volumes were not significantly associated with depression severity, clinician-rated psychomotor change, duration of depressive episode, total number of years since depression onset (Table 2) or bipolar disorder (Table 3).
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Neuropsychological performance
There was no association between visual and verbal memory performance and
hippocampal volumes in control participants
(Table 2). However, for those
with depression there were significant associations between smaller left and
total hippocampal volumes and poorer general cognition (i.e. as measured by
the MMSE) and memory.
Analysis of covariance indicated a significant difference in memory scores between control participants and those with early and late-onset depression, even after controlling for age (BVRT: F2, 63=8.4, P=0.001; RAVLT: F2, 61=4.2, P=0.021). After Bonferroni correction, visual memory scores were poorer for both depression groups relative to controls (P=0.002 and P=0.004 for early and late-onset depression, respectively). However, within this lower subsample, verbal memory scores were significantly lower for those with early-onset (n=36, P=0.017) but not late-onset (n=10, NS) depression relative to control participants.
Hippocampal volumes
For participants with depression, there were significant relationships
between current age, age of depression onset and hippocampal volumes (Tables
2 and
3). After controlling for age
and whole-brain volume, there was a significant effect of age of onset group
(i.e. control and early- and late-onset depression groups) on total
(F2,80=4.5, P=0.015), left
(F2,80=5.3, P=0.007) and right
(F2,80=3.2, P=0.045) hippocampal volumes. As
shown in Fig. 1, people with
early-onset depression had smaller total hippocampal volumes than controls but
larger volumes than those with late-onset depression. For the left
hippocampus, age, whole-brain volume and Bonferroni-corrected analyses
revealed that participants with both early- and late-onset depression had
smaller (P=0.021 and P=0.013, respectively) left hippocampal
volumes than control participants, although they did not differ from each
other. For the right and total hippocampal volumes only the participants with
late-onset depression differed significantly from controls (P=0.045
and P=0.013, respectively), whereas those with early-onset depression
did not differ from either control participants or those with late-onset
depression.
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DSMIV subtype
After controlling for age and whole-brain volume, there was a significant
difference between participants with melancholia and non-melancholic
depression and controls in left (F2,80=5.2,
P=0.008) and total (F2,80=3.8, P=0.025)
but not right (F2,80=2.2, NS) hippocampal volumes.
Bonferroni analyses revealed that only participants with melancholia differed
significantly from controls (left: P=0.006; total: P=0.021),
whereas those with non-melancholic depression did not differ significantly
from controls or those with melancholia.
Apolipoprotein E and MTHFR
There was no difference in age between those positive and negative for the
ApoE4 allele. As shown in Table
3, there was no significant difference in hippocampal volumes for
those with depression who were positive and negative for the ApoE2 allele,
whereas those with the ApoE4 allele had larger (i.e. not smaller)
volumes. Participants with depression and the MTHFR gene mutation did not have
smaller hippocampal volumes than those without the mutation.
Multivariate predictors of hippocampal volumes
In order to identify the best predictors of total hippocampal volumes,
significant univariate predictors were entered into a stepwise regression
model after controlling for whole-brain volume (forced entry). Hence, the
entered variables were age of onset group (i.e. control and early- and
late-onset depression), DSM-IV subtype group (i.e. control, non-melancholic
and melancholic), ApoE4 and age. The resulting model, accounting for 53% of
the variance in hippocampal volumes (F4,74=20.8,
P<0.001), included whole-brain volume (t=6.3,
P<0.001), age of onset group (t=-2.8, P=0.007),
age (t=-2.6, P=0.010) and presence of the ApoE4 allele
(t=2.3, P=0.024). These predictors uniquely
contributed to 25%, 4.8%, 4.4% and 3.3% of the variance, respectively, with an
additional 15.5% being shared predictor variance.
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DISCUSSION |
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Functional significance of reduced hippocampal volume
The reductions in hippocampal volumes in people with depression are of
considerable functional significance because of their relationship with visual
and verbal memory decrements. Although it is well established that people with
depression have impaired memory, such functional deficits are often attributed
to poor encoding of information, poor effort
(Elliot, 1998) or difficulties
with executive functioning. This study, however, supports previous research in
people with chronic depression (Shah
et al, 1998) and in those with subjective memory problems
(von Gunten et al,
2000) in suggesting that impaired memory may be a direct
consequence of structural change within the hippocampus.
Depression has been recognised increasingly as a risk factor for later dementia (Steffens et al, 2002), and a variety of explanatory models have been proposed (Jorm, 2001). Importantly, in our study, hippocampal volumes were also reduced in persons with early-onset disorders, making it less likely that the onset of depression simply reflects an early phase of another dementing illness such as Alzheimers disease or vascular dementia. Consistent with this interpretation, hippocampal volume reductions were not predicted by the ApoE4 allele or at-risk isoforms of the MTHFR gene or clinical risk factors to vascular disease.
Potential preventive strategies
Because hippocampal atrophy was most pronounced in people with depression
who were older at assessment or had late-onset disorders, potential risk
factors that increase with age (e.g. neurodegeneration, vascular disease)
still remain our primary targets for potential preventative strategies
(Hickie et al, 2003).
Previously we have reported strong associations between both white matter and
subcortical nuclei (i.e. caudate nucleus volume) structural brain changes and
neurocognitive impairment, vascular risk factors, age, age of depression onset
and poor response to treatment (Hickie et al,
1995,
1997b;
Naismith et al,
2002). Additionally we have noted associations between at-risk
isoforms of the MTHFR gene (which underpin raised homocysteine levels) and
depression of later onset (Hickie et
al, 2001), and reduced psychomotor speed in patients with
depression (Naismith et al,
2002). Such studies do imply common pathophysiologies underpinning
the epidemiological association between at least late-onset depressions and
dementia.
Is depression associated with neurodegenerative changes?
Importantly, it now also appears likely that hippocampal atrophy occurs
directly as a consequence of early-onset depression (or other risk factors to
that condition). Consistent with this view, lifetime duration of untreated
depressive illness has emerged as a predictor of such hippocampal changes
(Sheline et al, 1999,
2003;
MacQueen et al,
2003). Although we did not find a direct correlation with years
since onset of the illness, we were not able to differentiate the importance
of treated v. untreated periods of illness. In our study,
participants with melancholic disorders demonstrated more hippocampal atrophy.
Such people are more likely to experience hypercortisolaemia, which is a
possible mechanism for hippocampal atrophy
(Sapolsky, 2000). An
accumulation of evidence is also emerging suggesting that brain-derived
neurotrophic factor (important for the development, maintenance and survival
of neurons) is decreased in patients with depression and is enhanced by
anti-depressant treatment (Duman et
al, 1997; Dwivedi et
al, 2003). This suggests another important mechanism whereby
untreated depression may be detrimental to key brain structures such as the
hippocampus, which in turn is likely to have prognostic significance
(Steffens et al,
2002).
Important challenges arise from this research. First, we need to determine whether hippocampal atrophy is a risk factor to or a consequence of depressive disorders or to key subtypes (e.g. late-onset depression, melancholia). Second, we need to make greater use of population-based cohorts or other informative samples (e.g. twins, discordant sib-pairs). Third, more research needs to focus on longitudinal examination of at-risk groups and follow, in particular, the brain changes that may accompany either the transition to illness or the longer-term effects of its untreated or treated course.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication December 22, 2003. Accepted for publication August 26, 2004.
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