Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue2.2001:
Cognitive Impairment in Depression Is Not Associated
with Neuropathologic Evidence of Increased Vascular
or Alzheimer-Type Pathology
John O’Brien, Alan Thomas, Clive Ballard, Andrew Brown, Nicol Ferrier,
Evelyn Jaros, and Robert Perry
Background: Cognitive impairment is common in depression, but underlying mechanisms remain unknown. We
examined whether increases in Alzheimer-type or vascular
pathology are associated with cognitive impairments in
elderly depressed subjects.
Methods: Eleven subjects who had died during a welldocumented episode of DSM-IV major depression were
included. Neuropathologic assessments, blind to group
membership, included standardized assessment of neuritic
plaques, neurofibrillary tangles, and Lewy Bodies in
frontal, temporal, parietal, and occipital cortices. Braak
staging of Alzheimer pathology was also performed. Cerebral microvascular disease was scored according to a
previously validated scale, and a score for cerebral and
systemic atheroma of large and medium sized arteries was
obtained.
Results: No subject had Lewy bodies. Plaque and tangle
counts for all subjects were well within published norms
for age-matched control subjects. There were no significant differences in plaque or tangle counts between
subjects who were cognitively impaired (n 5 5) and those
who were nonimpaired (n 5 6) during their depressive
illness. Similarly, neither total microvascular pathology
nor deep frontal microvascular pathology differed between the two groups.
Conclusions: Our results indicate that the liability for
some patients to develop cognitive impairment during a
depressive episode is not related to an increase in Alzheimer-type or vascular neuropathologic change. This indicates that other mechanisms must underlie both the
cognitive impairment associated with depression and the
observation that depression is a risk factor for dementia.
Biol Psychiatry 2001;49:130 –136 © 2001 Society of Biological Psychiatry
From the Institute for the Health of the Elderly (JO, AT, CB, AB, EJ, RP) and the
Department of Psychiatry (NF), University of Newcastle upon Tyne, Newcastle
upon Tyne, United Kingdom.
Address reprint requests to John O’Brien, D.M., Newcastle General Hospital,
Wolfson Research Centre, Institute for the Health of the Elderly, Westgate
Road, Newcastle upon Tyne NE4 6BE, United Kingdom.
Received January 3, 2000; revised May 19, 2000; accepted May 26, 2000.
© 2001 Society of Biological Psychiatry
Key Words: Depression, affective disorder, neuropathology, cognitive impairment, postmortem, elderly
Introduction
I
t is well known that depression, particularly in elderly
subjects, is associated with a number of deficits in
cognitive function (Abas et al 1990; Austin et al 1999;
Beats et al 1996). These deficits, when severe, can
resemble those seen in an organic dementia such as
Alzheimer’s disease, giving rise to the clinical syndrome
of “pseudo dementia” and the emphasis placed on trying to
obtain an accurate diagnosis in such patients (Bulbena and
Berrios 1986; McAllister 1985). It is now clear that the
relationship between cognitive impairments occurring as
part of a depressive disorder and those seen in organic
conditions is complex. Cognitive impairments occurring
during depression do not always remit on recovery from
illness. For example, Abas et al (1990) found that whereas
70% of depressed subjects were impaired on a learning
task during illness, 30% remained impaired despite clinical recovery. The cause of such enduring cognitive deficits
is unknown, though they may carry an adverse prognosis
with regard to long-term outcome. Kral and Emery (1989)
followed up 44 elderly patients who had previously
suffered from what was thought to be “depressive
pseudodementia” on the grounds that cognitive function
reverted to premorbid levels following treatment. After an
average follow-up of 8 years, 89% were felt to have
developed Alzheimer’s disease. Epidemiologic studies
have shown that depression is an independent risk factor
for dementia (Jorm et al 1991). These lines of evidence
suggest that cognitive impairment occurring during a
depressive illness may indicate an increased liability to
subsequently develop dementia and, in particular, Alzheimer’s disease. If so, neuropathologic study of such cases
might be expected to show a greater burden of Alzheimer
type pathology in those depressed subjects who develop
significant cognitive dysfunction compared to those who
do not.
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Neuropathology of Cognitive Impairment
There are, however, other reasons why elderly depressed patients may develop cognitive impairments. It is
now clear that neuropsychological deficits affect most
domains tested and include problems with attention, learning and memory, frontal and executive tasks, as well as
motivation (Abas et al 1990; Austin et al 1999; Beats et al
1996; Elliot 1998; Salloway et al 1996). It has also been
suggested that some impairments, particularly those in
learning and memory, may be associated with hippocampal damage due to the raised levels of corticosteroids
known to be associated with depressive illness, particularly in the elderly (O’Brien 1997). The recent demonstration of reduced hippocampal volume in depressed subjects
that correlated with lifetime duration of depression (and
therefore presumably exposure to corticosteroids) supports
this view (Sheline et al 1999).
Another possible explanation for depressed subjects
developing cognitive impairment is the presence of cerebrovascular pathology. One of the most consistently observed abnormalities in elderly depressed subjects is of an
increased frequency of hyperintensities in the white matter
and subcortical grey matter visualized on magnetic resonance imaging (Coffey et al 1990; Figiel et al 1991;
Greenwald et al 1996, 1998; O’Brien et al 1996). These
lesions are more common in depressed subjects with onset
in late life (Figiel et al 1991; O’Brien et al 1996; Salloway
et al 1996) and have been associated with cognitive
impairments both during the depressive episode (Salloway
et al 1996) and at follow-up (Hickie et al 1997). Partly on
the basis of these lesions and the link between depression
and cardiovascular disorder, the notion of “vascular depression” has been proposed (Alexopoulos et al 1997;
Hickie and Scott 1998; Krishnan and McDonald 1995).
Because microvascular change is a cause of white matter
hyperintensities on magnetic resonance imaging (MRI)
(Chimowitz et al 1992) and such lesions are associated
with cognitive impairments in depression, it is possible
that cognitive impairments occurring during depressive
episode may be related to an increase in microvascular
pathology.
There have been no previous studies of the neuropathologic basis of the cognitive impairments that occur during
depression. We wished to test the hypothesis that such
impairments would be associated with an increased burden
of Alzheimer-type and/or microvascular pathology in
cortical areas.
Methods and Materials
Subjects
Cases were obtained from records of the Neuropathology Department and the Newcastle Brain Tissue Bank. All depressed
cases were from referrals to a secondary care unit, the Brighton
BIOL PSYCHIATRY
2001;49:130 –136
131
Clinic. All were inpatients except one who was attending the day
hospital. Full ethical approval has been granted for this postmortem study and consent for postmortem examination obtained
from the next of kin.
Clinical Assessment
Subjects were included if they were 60 years or over at death and
had died during a well-documented episode of DSM-IV Major
Depression (American Psychiatric Association 1994). They had
all undergone extensive assessments including a full history,
mental state examination, physical examination, screening blood
tests and, in some cases, computed tomography (CT) or MRI
scans. Subjects were excluded if they had committed suicide by
violent means or had ever met DSM-IV criteria for dementia,
schizophrenia, or other psychotic disorders, manic or hypomanic
episode or a mood disorder due to a general medical condition.
Subjects were divided into a cognitively impaired group who
were significantly impaired when depressed, and a nonimpaired
group who showed no evidence of impairment even when
depressed.
Neuropathologic Assessment
All subjects received a full postmortem examination (except one
whose body was taken by the undertakers after the brain was
removed) and the delay to postmortem was recorded. The right
hemisphere was fixed in 10% formalin and the brains were
dissected in a standard manner (Perry et al 1990a). Blocks were
taken from the frontal, temporal, parietal, and occipital cortices,
the hippocampus, the cingulate, the basal ganglia, the cerebellum, the upper and lower midbrain, the pons and the medulla.
Five mm or 20 mm sections were cut, and sections were prepared
on glass slides. These were stained with haematoxylin and eosin
(H&E), luxol fast blue (LFB) and/or Loyez (myelin), cresyl fast
violet (CFV) or Nissl, methanamine silver and/or von Braunmuhl
(plaques), Palmgren and/or tau-2 (tangles) and ubiquitin (Lewy
bodies). These were then examined by experienced neuropathologists (RP and EJ) Subjects were excluded if they met
neuropathologic criteria for any neurodegenerative disease such
as Alzheimer’s disease or dementia with Lewy bodies.
Assessment of Alzheimer and Lewy Body Pathology
Histopathologic analysis was carried out to quantify the number
of neuritic plaques and neurofibrillary tangles in the four neocortical lobes (Perry et al 1990a, 1996). Both neuritic and diffuse
plaques were counted in five fields (including gyral crests and
sulcal depths and including all cortical layers) from each neocortical lobe (frontal, temporal, parietal, occipital). A mean score
was obtained and converted to numbers per mm2. Neocortical
tangles were also counted in a similar manner, except the count
used was the mean of the fields across all the cortical layers.
Alzheimer-type pathology was staged according to the procedure
of Braak and Braak (1991), assessing neurofibrillary tangles and
neuropil threads in different parts of the hippocampus (stages
1– 4) and neocortex (stages 5 and 6). Reliability was assessed by
the single operator responsible for the study rating 10 subjects
132
BIOL PSYCHIATRY
2001;49:130 –136
selected at random on 5 occasions for plaque and tangle counts.
Co-efficients of variation (SD/mean) were 0% for tangle counts
and 5.3% for plaque counts.
Assessment of Large and Medium-Sized Arteries
The extent of atheromatous degeneration in the coronary arteries,
cerebral carotid and vertebrobasilar systems, and aorta was rated
on a semiquantitative 0 –3 scale (RP and AT). 0 5 none; 1 5
mild: atheroma only mild and patchy; 2 5 moderate: more
extensive atheroma with less than 50% luminal stenosis; 3 5
severe: atheroma widespread with greater than 50% luminal
stenosis in at least one vessel. An overall atheroma score was
obtained for each subject by adding together the scores from each
site.
Assessment of Small Arteries and Arterioles
For assessing microvascular disease the sections stained with
H&E, LFB, and/or Loyez and Nissl from the frontal, temporal,
parietal, and occipital cortices were used. In addition, large
full-face coronal blocks were taken from the frontal and occipital
cortices to include all the deep white matter in these two areas,
coronal levels 4/5 and 27 (Perry 1993). Ten-mm or 20-mm
sections were prepared on large (30 3 20) slides and stained with
H&E, LFB, and/or Loyez (myelin) and Nissl. Microvascular
disease was then scored blind to diagnosis by two raters (RP and
AT) in each neocortical area in accordance with a scale previously used in vascular dementia (Esiri et al 1997). Briefly, this is
a 0 –3 scale in which 0 5 normal; 1 5 dilatation of perivascular
spaces or hyaline thickening or a few perivascular macrophages;
2 5 dilatation of perivascular spaces or hyaline thickening plus
mild to moderate perivascular pallor of myelin staining or
loosening of the nerve fibres or nerve cells with gliosis; 3 5
Binswanger’s disease (2 plus more widespread myelin pallor,
nerve fibre or nerve cell disruption and gliosis). An overall
microvascular score was calculated for each subject by adding
together the scores for each neocortical area. A separate score
was obtained by assessment of the frontal deep white matter.
Statistical Analysis
The two groups were compared statistically using standard
software. Minitab (version 12; Minitab, State College, PA) was
used to carry out Mann–Whitney tests for the quantitative data
(age, post-mortem interval, plaques, tangles, Lewy bodies) and
StatXact (version 4, Cytel Software, Cambridge, MA) was used
to carry out Fisher–Freeman–Halton test (more appropriate than
x2 because of the low cell frequency) for the categorical data
(sex, Braak, atheroma, and microvascular scores).
Results
Eleven subjects were studied. Eight suffered from recurrent unipolar depression, and all but one were depressed at
death. All except one had received past treatment with
J. O’Brien et al
electroconvulsive therapy. Five subjects were cognitively
impaired when depressed. Of these, two had such marked
psychomotor retardation that meaningful standardized
cognitive testing was not possible, though both were
clearly clinically very impaired, as for a time genuine
doubt existed as to whether or not they had an organic
dementia or a “depressive pseudodementia.” Testing of the
other three showed scores in the impaired range on either
the Mini-Mental State Examination (MMSE, maximum
score 30; Folstein et al 1975) or the Mental Test Score
(MTS, maximum score 37; Blessed et al 1968). One
subject had an MMSE score of 22; the others had MTS
scores of 22 and 25. Six subjects showed no clinical
evidence of cognitive impairment. Two were recorded in
casenotes as having undergone cognitive testing and being
completely oriented, with normal concentration and memory, although neither the MMSE nor MTS was completed.
Tests on the other four revealed MMSE scores of 28 and
29 and MTS scores of 36 and 37. Cause of death for the
cognitively impaired patients was carcinoma (n 5 2) and
bronchopneumonia (n 5 3). Cause of death for the
nonimpaired patients was cardiac arrest (n 5 3), suicide
(n 5 1), pulmonary embolus (n 5 1) and congestive
cardiac failure (n 5 1). Four of the five cognitively
impaired patients had failed to respond to adequate
courses of two different antidepressants. Of unimpaired
subjects, two had failed to respond to adequate courses of
two different antidepressants, two had shown some response but were still depressed, and two died without
apparent response to an antidepressant.
Subject characteristics and results are shown in Table 1,
whereas Table 2 contains a detailed breakdown of neuropathologic scores for each subject. For comparison, scores
are also presented in Table 2 from published data on
control and demented subjects of very similar age obtained
using the same methodology (Perry et al 1996). There
were no significant differences in age (t 5 36, p 5 .31)
or postmortem delay (t 5 22, p 5 .31), but there was
a trend toward a difference in gender (Fisher statistic 4.8,
p 5 .06), because all five cognitively impaired depressed
subjects were female. No statistical differences were found
between the groups on Alzheimer-type pathology (p .
.41) or Lewy body pathology (p 5 1.00, no Lewy
bodies were seen in any case). The total atheroma and total
microvascular scores were very similar (Fisher statistic 5
1.42, p 5 .70 and Fisher statistic 5 4.31, p 5 .51,
respectively) and, although the frontal microvascular
scores were slightly higher in the nonimpaired group, this
did not approach significance statistically (Fisher statistic 5 6.9, sig. 5 0.23). As seen in Table 2, levels of
Alzheimer type pathology is comparable to that of similarly aged normal control subjects and much less than
found in Alzheimer’s disease.
Neuropathology of Cognitive Impairment
BIOL PSYCHIATRY
2001;49:130 –136
133
Table 1. Comparison of Cognitively Impaired and Nonimpaired Groups
Impaired
a
Age (years)
Gender (male/female)b
Postmortem delay (hours)a
Total atheroma scoreb
Total microvascular scoreb
Deep white matter frontal
microvascularb
Neocortical plaques (per mm2)a
Neocortical tangles (per mm2)a
Braak stageb
Lewy bodies (per cm2)a
a
b
Nonimpaired
79.0 (4.69)
0/5
47.5 (28.62)
3
3
0
73.0 (8.81)
4/2
27.8 (6.34)
3
5
2
1.4 (1.27)
0.2 (0.39)
1
0 (0)
0.98 (1.41)
0 (0)
1
0 (0)
Test statistic
Significance
36
4.8
22
1.42
4.31
0.55
.31
.06
.31
1.00
.84
1.00
34
,34
2.59
Not applicable
.52
..41
.65
1.00
Values are mean (SD) and comparisons are made using the Mann–Whitney test.
Values are medians and comparisons are made using the Fisher–Freeman–Halton test.
original study of Blessed et al (1968) which found a
correlation, now replicated by several groups, between
plaque count and cognitive test score in dementia included
some cases with functional illness, seven of whom were
depressed; however, our more detailed study (which does
not include any of the same cases used by Blessed et al)
shows that this well-recognized relationship in dementia
does not apply to cognitive impairment in depression.
Minimal Alzheimer-type pathology was seen in the
depressed cases, of the same order as would be expected in
age-matched control subjects (Perry et al 1990b). Microvascular pathology was also not extensive using currently
available methods of assessment (Esiri et al 1997). Although the link between vascular disease and late life
depression is well recognised (Hickie and Scott 1998),
such pathology did not explain the occurrence of signifi-
Discussion
This is the first study to investigate neuropathologic
changes in depressed subjects with and without cognitive
impairment. We found no evidence of increased neuropathologic abnormalities in the form of Alzheimer-type
pathology or microvascular change in depressed subjects
who developed cognitive impairment during depression
compared to those who did not. A relationship with
Alzheimer pathology might have been expected because
of the similarity of some aspects of cognitive dysfunction
in depression to those seen in Alzheimer’s disease (Abas
et al 1990), the high proportion of cognitively impaired
depressed patients who subsequently develop the disorder
(Kral and Emery 1989), and the fact that depression is a
risk factor for Alzheimer’s disease (Jorm et al 1991). The
Table 2. Neuropathologic Scores in Two Depressed Groups
Cognitive
impairment
Impaired
Impaired
Impaired
Impaired
Impaired
Nonimpaired
Nonimpaired
Nonimpaired
Nonimpaired
Nonimpaired
Nonimpaired
Control subjects
(n 5 138) a
Alzheimer’s disease
(n 5 113) a
Senile dementia of
Lewy body type
(n 5 61) a
Total
Total
Deep frontal
atheroma microvascular microvascular
4
3
0
1
3
0
NA
3
3
4
NA
4
3
2
8
2
3
4
6
8
1
8
2
1
0
2
1
1
0
2
2
0
1
Plaques
per mm2
0.9
0.9
0.4
3.6
1.1
1.0
1.0
0.2
3.7
0.0
0.0
2.0 (3.3)
Tangles
per mm2
Braak
stage
0.1
1
0.0
2
0.0
0
0.0
0
0.9
2
0.0
1
0.0
1
0.0
0
0.0
3
0.0
2
0.0
1
0.07 (0.58) 2.6 (1.1)
Lewy
bodies
0
0
0
0
0
0
0
0
0
0
0
19.6 (13.4) 23.3 (17.3)
NA, not available.
a
Data taken for comparison from Perry et al (1990b, 1996) using the same criteria. Values are mean (SD).
110 (134)
134
BIOL PSYCHIATRY
2001;49:130 –136
cant cognitive dysfunction in our patients during their
depression. Consistent with this, we found no difference
between impaired and nonimpaired groups for atheromatous degeneration score that reflected cerebral and systemic large and medium vessel pathology.
Although many studies have examined neurotransmitter
and receptor changes during depression, there has been
only very limited focus on neuropathologic changes. This
is partly because affective illness has been viewed as a
state-dependent, reversible condition. This is, particularly
in the elderly, now known to be flawed, as elderly
depressed subjects have both enduring cognitive impairments (Abas et al 1990) and demonstrable neurobiological
changes, which suggest structural abnormalities. For example, depressed subjects have increased cortical atrophy
and ventricular enlargement when compared to control
subjects (Elkis et al 1995; Jacoby and Levy 1980; Rabins
et al 1991). In an MRI study, Rabins et al (1991) was
unable to differentiate those with depression and Alzheimer’s disease on the basis of either cortical atrophy or the
presence of white matter change. Our findings show that
the causes of cognitive impairment and structural brain
changes in depression lie outside those of degenerative or
microvascular pathology. Results are consistent with the
notion that deficits in some areas, particularly in learning
and memory, may be related to excess cortisol secretion as
a result of hypothalmic–pituitary–adrenal axis activation
during the illness (O’Brien 1997). Several lines of evidence support this view. First, in animal models prolonged
raised corticosteroid secretion is associated with deficits in
learning and memory and hippocampal cell loss (Sapolsky
and Plotsky 1990; Sapolsky et al 1986). Second, the
hippocampus is a major site of glucocorticoid receptors,
and at a cellular level excess glucocorticoids increase
calcium dependent influx, which is known to be neurotoxic (Landfield and Eldridge 1994). Third, following
exogenous steroid administration or raised endogenous
levels as a result of stress, cognitive deficits can be
demonstrated in healthy subjects (Kirschbaum et al 1996).
Fourth, in Cushing’s syndrome excess cortisol production
is associated with cognitive impairments and hippocampal
change (Starkman et al 1992). Finally, depression has been
shown to be associated with mild hippocampal atrophy
(Sheline et al 1999), which correlates with the total
duration of depression. To determine whether hippocampal cell loss is a cause of cognitive decline associated with
depression, further neuropathologic study of cell morphometry in the hippocampus would need to be
performed.
Cognitive impairments during depression have also
been associated with abnormalities in other brain areas,
particularly the medial prefrontal cortex (Dolan et al
1992). Changes in similar brain areas have also been
J. O’Brien et al
described on MRI (Drevets et al 1997), and a preliminary
neuropathologic report suggests glial loss in the absence of
neuronal loss in one part of the prefrontal cortex, at least
in younger patients with depression (Drevets et al 1998).
Changes in these or related areas may also underlie some
of the neuropsychological impairments that occur during
depression. Salloway et al (1996) found white matter
lesions to be associated with impairments in attentional
function. Although such lesions may be an important
correlate of impairment, we could find no evidence that
this was accompanied by microvascular change, at least in
the cortical areas that we examined (which did include
frontal cortex). The tests of cognition used in this study,
however, the MMSE and the MTS, are global measures of
cognitive function not particularly sensitive to executive
function, processing speed and other tasks subserved by
frontal–subcortical areas. Because these are the regions
most affected in imaging studies (Coffey et al 1993;
Greenwald et al 1998), it may be that there would be
correlations between microvascular pathology in these
regions and more specific frontal tests.
Some other limitations of our study should be considered. Our cases were not prospectively assessed, and so
information regarding their depressive illness and cognitive function came from case notes; however, case notes
within the service were of a very high quality, with
detailed typed summaries. All cases had detailed comment
about cognitive performance, and the majority had received a standardized assessment of cognitive function.
Numbers of depressed subjects were small and, although
the cognitive impairment documented during the depressive illness was felt to be secondary to depression, we
were not able to document reversibility on recovery from
the depression and so cannot be certain that this impairment was not due to another cause. Although this may
have been a possible confounding explanation if we had
found an increase in microvascular or Alzheimer type
pathology in the group with cognitive impairment, we do
not feel this can explain our negative results. Although our
subjects were impaired on clinical measures of cognition,
scores were in the moderate range and it may be that by
studying a group with more pronounced cognitive impairments during depression correlations with neurodegenerative pathology may exist.
In summary, we found no evidence of neuropathologic
differences between cognitively impaired and nonimpaired depressed subjects. This supports the view that
cognitive dysfunction in depression is mediated by mechanisms that are different from those related to Alzheimer’s
disease or vascular dementia. Hypercortisolaemia is one
possible explanation. There also needs to be further study
of the possible neurochemical basis of cognitive impairments in depression, as previous reports have suggested
Neuropathology of Cognitive Impairment
cholinergic loss may be important (Perry et al 1978). To
investigate this further, in vivo study of subjects who have
undergone detailed neuropsychological testing, assessment of endocrine function, and brain imaging should be
combined with clinico-pathological study that includes
detailed assessment of hippocampal cell morphometry,
investigation of glucocorticoid receptor changes, and detailed neurochemical analysis.
The authors thank the Medical Research Council and the Stanley
Foundation for financial support.
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with Neuropathologic Evidence of Increased Vascular
or Alzheimer-Type Pathology
John O’Brien, Alan Thomas, Clive Ballard, Andrew Brown, Nicol Ferrier,
Evelyn Jaros, and Robert Perry
Background: Cognitive impairment is common in depression, but underlying mechanisms remain unknown. We
examined whether increases in Alzheimer-type or vascular
pathology are associated with cognitive impairments in
elderly depressed subjects.
Methods: Eleven subjects who had died during a welldocumented episode of DSM-IV major depression were
included. Neuropathologic assessments, blind to group
membership, included standardized assessment of neuritic
plaques, neurofibrillary tangles, and Lewy Bodies in
frontal, temporal, parietal, and occipital cortices. Braak
staging of Alzheimer pathology was also performed. Cerebral microvascular disease was scored according to a
previously validated scale, and a score for cerebral and
systemic atheroma of large and medium sized arteries was
obtained.
Results: No subject had Lewy bodies. Plaque and tangle
counts for all subjects were well within published norms
for age-matched control subjects. There were no significant differences in plaque or tangle counts between
subjects who were cognitively impaired (n 5 5) and those
who were nonimpaired (n 5 6) during their depressive
illness. Similarly, neither total microvascular pathology
nor deep frontal microvascular pathology differed between the two groups.
Conclusions: Our results indicate that the liability for
some patients to develop cognitive impairment during a
depressive episode is not related to an increase in Alzheimer-type or vascular neuropathologic change. This indicates that other mechanisms must underlie both the
cognitive impairment associated with depression and the
observation that depression is a risk factor for dementia.
Biol Psychiatry 2001;49:130 –136 © 2001 Society of Biological Psychiatry
From the Institute for the Health of the Elderly (JO, AT, CB, AB, EJ, RP) and the
Department of Psychiatry (NF), University of Newcastle upon Tyne, Newcastle
upon Tyne, United Kingdom.
Address reprint requests to John O’Brien, D.M., Newcastle General Hospital,
Wolfson Research Centre, Institute for the Health of the Elderly, Westgate
Road, Newcastle upon Tyne NE4 6BE, United Kingdom.
Received January 3, 2000; revised May 19, 2000; accepted May 26, 2000.
© 2001 Society of Biological Psychiatry
Key Words: Depression, affective disorder, neuropathology, cognitive impairment, postmortem, elderly
Introduction
I
t is well known that depression, particularly in elderly
subjects, is associated with a number of deficits in
cognitive function (Abas et al 1990; Austin et al 1999;
Beats et al 1996). These deficits, when severe, can
resemble those seen in an organic dementia such as
Alzheimer’s disease, giving rise to the clinical syndrome
of “pseudo dementia” and the emphasis placed on trying to
obtain an accurate diagnosis in such patients (Bulbena and
Berrios 1986; McAllister 1985). It is now clear that the
relationship between cognitive impairments occurring as
part of a depressive disorder and those seen in organic
conditions is complex. Cognitive impairments occurring
during depression do not always remit on recovery from
illness. For example, Abas et al (1990) found that whereas
70% of depressed subjects were impaired on a learning
task during illness, 30% remained impaired despite clinical recovery. The cause of such enduring cognitive deficits
is unknown, though they may carry an adverse prognosis
with regard to long-term outcome. Kral and Emery (1989)
followed up 44 elderly patients who had previously
suffered from what was thought to be “depressive
pseudodementia” on the grounds that cognitive function
reverted to premorbid levels following treatment. After an
average follow-up of 8 years, 89% were felt to have
developed Alzheimer’s disease. Epidemiologic studies
have shown that depression is an independent risk factor
for dementia (Jorm et al 1991). These lines of evidence
suggest that cognitive impairment occurring during a
depressive illness may indicate an increased liability to
subsequently develop dementia and, in particular, Alzheimer’s disease. If so, neuropathologic study of such cases
might be expected to show a greater burden of Alzheimer
type pathology in those depressed subjects who develop
significant cognitive dysfunction compared to those who
do not.
0006-3223/01/$20.00
PII S0006-3223(00)00944-6
Neuropathology of Cognitive Impairment
There are, however, other reasons why elderly depressed patients may develop cognitive impairments. It is
now clear that neuropsychological deficits affect most
domains tested and include problems with attention, learning and memory, frontal and executive tasks, as well as
motivation (Abas et al 1990; Austin et al 1999; Beats et al
1996; Elliot 1998; Salloway et al 1996). It has also been
suggested that some impairments, particularly those in
learning and memory, may be associated with hippocampal damage due to the raised levels of corticosteroids
known to be associated with depressive illness, particularly in the elderly (O’Brien 1997). The recent demonstration of reduced hippocampal volume in depressed subjects
that correlated with lifetime duration of depression (and
therefore presumably exposure to corticosteroids) supports
this view (Sheline et al 1999).
Another possible explanation for depressed subjects
developing cognitive impairment is the presence of cerebrovascular pathology. One of the most consistently observed abnormalities in elderly depressed subjects is of an
increased frequency of hyperintensities in the white matter
and subcortical grey matter visualized on magnetic resonance imaging (Coffey et al 1990; Figiel et al 1991;
Greenwald et al 1996, 1998; O’Brien et al 1996). These
lesions are more common in depressed subjects with onset
in late life (Figiel et al 1991; O’Brien et al 1996; Salloway
et al 1996) and have been associated with cognitive
impairments both during the depressive episode (Salloway
et al 1996) and at follow-up (Hickie et al 1997). Partly on
the basis of these lesions and the link between depression
and cardiovascular disorder, the notion of “vascular depression” has been proposed (Alexopoulos et al 1997;
Hickie and Scott 1998; Krishnan and McDonald 1995).
Because microvascular change is a cause of white matter
hyperintensities on magnetic resonance imaging (MRI)
(Chimowitz et al 1992) and such lesions are associated
with cognitive impairments in depression, it is possible
that cognitive impairments occurring during depressive
episode may be related to an increase in microvascular
pathology.
There have been no previous studies of the neuropathologic basis of the cognitive impairments that occur during
depression. We wished to test the hypothesis that such
impairments would be associated with an increased burden
of Alzheimer-type and/or microvascular pathology in
cortical areas.
Methods and Materials
Subjects
Cases were obtained from records of the Neuropathology Department and the Newcastle Brain Tissue Bank. All depressed
cases were from referrals to a secondary care unit, the Brighton
BIOL PSYCHIATRY
2001;49:130 –136
131
Clinic. All were inpatients except one who was attending the day
hospital. Full ethical approval has been granted for this postmortem study and consent for postmortem examination obtained
from the next of kin.
Clinical Assessment
Subjects were included if they were 60 years or over at death and
had died during a well-documented episode of DSM-IV Major
Depression (American Psychiatric Association 1994). They had
all undergone extensive assessments including a full history,
mental state examination, physical examination, screening blood
tests and, in some cases, computed tomography (CT) or MRI
scans. Subjects were excluded if they had committed suicide by
violent means or had ever met DSM-IV criteria for dementia,
schizophrenia, or other psychotic disorders, manic or hypomanic
episode or a mood disorder due to a general medical condition.
Subjects were divided into a cognitively impaired group who
were significantly impaired when depressed, and a nonimpaired
group who showed no evidence of impairment even when
depressed.
Neuropathologic Assessment
All subjects received a full postmortem examination (except one
whose body was taken by the undertakers after the brain was
removed) and the delay to postmortem was recorded. The right
hemisphere was fixed in 10% formalin and the brains were
dissected in a standard manner (Perry et al 1990a). Blocks were
taken from the frontal, temporal, parietal, and occipital cortices,
the hippocampus, the cingulate, the basal ganglia, the cerebellum, the upper and lower midbrain, the pons and the medulla.
Five mm or 20 mm sections were cut, and sections were prepared
on glass slides. These were stained with haematoxylin and eosin
(H&E), luxol fast blue (LFB) and/or Loyez (myelin), cresyl fast
violet (CFV) or Nissl, methanamine silver and/or von Braunmuhl
(plaques), Palmgren and/or tau-2 (tangles) and ubiquitin (Lewy
bodies). These were then examined by experienced neuropathologists (RP and EJ) Subjects were excluded if they met
neuropathologic criteria for any neurodegenerative disease such
as Alzheimer’s disease or dementia with Lewy bodies.
Assessment of Alzheimer and Lewy Body Pathology
Histopathologic analysis was carried out to quantify the number
of neuritic plaques and neurofibrillary tangles in the four neocortical lobes (Perry et al 1990a, 1996). Both neuritic and diffuse
plaques were counted in five fields (including gyral crests and
sulcal depths and including all cortical layers) from each neocortical lobe (frontal, temporal, parietal, occipital). A mean score
was obtained and converted to numbers per mm2. Neocortical
tangles were also counted in a similar manner, except the count
used was the mean of the fields across all the cortical layers.
Alzheimer-type pathology was staged according to the procedure
of Braak and Braak (1991), assessing neurofibrillary tangles and
neuropil threads in different parts of the hippocampus (stages
1– 4) and neocortex (stages 5 and 6). Reliability was assessed by
the single operator responsible for the study rating 10 subjects
132
BIOL PSYCHIATRY
2001;49:130 –136
selected at random on 5 occasions for plaque and tangle counts.
Co-efficients of variation (SD/mean) were 0% for tangle counts
and 5.3% for plaque counts.
Assessment of Large and Medium-Sized Arteries
The extent of atheromatous degeneration in the coronary arteries,
cerebral carotid and vertebrobasilar systems, and aorta was rated
on a semiquantitative 0 –3 scale (RP and AT). 0 5 none; 1 5
mild: atheroma only mild and patchy; 2 5 moderate: more
extensive atheroma with less than 50% luminal stenosis; 3 5
severe: atheroma widespread with greater than 50% luminal
stenosis in at least one vessel. An overall atheroma score was
obtained for each subject by adding together the scores from each
site.
Assessment of Small Arteries and Arterioles
For assessing microvascular disease the sections stained with
H&E, LFB, and/or Loyez and Nissl from the frontal, temporal,
parietal, and occipital cortices were used. In addition, large
full-face coronal blocks were taken from the frontal and occipital
cortices to include all the deep white matter in these two areas,
coronal levels 4/5 and 27 (Perry 1993). Ten-mm or 20-mm
sections were prepared on large (30 3 20) slides and stained with
H&E, LFB, and/or Loyez (myelin) and Nissl. Microvascular
disease was then scored blind to diagnosis by two raters (RP and
AT) in each neocortical area in accordance with a scale previously used in vascular dementia (Esiri et al 1997). Briefly, this is
a 0 –3 scale in which 0 5 normal; 1 5 dilatation of perivascular
spaces or hyaline thickening or a few perivascular macrophages;
2 5 dilatation of perivascular spaces or hyaline thickening plus
mild to moderate perivascular pallor of myelin staining or
loosening of the nerve fibres or nerve cells with gliosis; 3 5
Binswanger’s disease (2 plus more widespread myelin pallor,
nerve fibre or nerve cell disruption and gliosis). An overall
microvascular score was calculated for each subject by adding
together the scores for each neocortical area. A separate score
was obtained by assessment of the frontal deep white matter.
Statistical Analysis
The two groups were compared statistically using standard
software. Minitab (version 12; Minitab, State College, PA) was
used to carry out Mann–Whitney tests for the quantitative data
(age, post-mortem interval, plaques, tangles, Lewy bodies) and
StatXact (version 4, Cytel Software, Cambridge, MA) was used
to carry out Fisher–Freeman–Halton test (more appropriate than
x2 because of the low cell frequency) for the categorical data
(sex, Braak, atheroma, and microvascular scores).
Results
Eleven subjects were studied. Eight suffered from recurrent unipolar depression, and all but one were depressed at
death. All except one had received past treatment with
J. O’Brien et al
electroconvulsive therapy. Five subjects were cognitively
impaired when depressed. Of these, two had such marked
psychomotor retardation that meaningful standardized
cognitive testing was not possible, though both were
clearly clinically very impaired, as for a time genuine
doubt existed as to whether or not they had an organic
dementia or a “depressive pseudodementia.” Testing of the
other three showed scores in the impaired range on either
the Mini-Mental State Examination (MMSE, maximum
score 30; Folstein et al 1975) or the Mental Test Score
(MTS, maximum score 37; Blessed et al 1968). One
subject had an MMSE score of 22; the others had MTS
scores of 22 and 25. Six subjects showed no clinical
evidence of cognitive impairment. Two were recorded in
casenotes as having undergone cognitive testing and being
completely oriented, with normal concentration and memory, although neither the MMSE nor MTS was completed.
Tests on the other four revealed MMSE scores of 28 and
29 and MTS scores of 36 and 37. Cause of death for the
cognitively impaired patients was carcinoma (n 5 2) and
bronchopneumonia (n 5 3). Cause of death for the
nonimpaired patients was cardiac arrest (n 5 3), suicide
(n 5 1), pulmonary embolus (n 5 1) and congestive
cardiac failure (n 5 1). Four of the five cognitively
impaired patients had failed to respond to adequate
courses of two different antidepressants. Of unimpaired
subjects, two had failed to respond to adequate courses of
two different antidepressants, two had shown some response but were still depressed, and two died without
apparent response to an antidepressant.
Subject characteristics and results are shown in Table 1,
whereas Table 2 contains a detailed breakdown of neuropathologic scores for each subject. For comparison, scores
are also presented in Table 2 from published data on
control and demented subjects of very similar age obtained
using the same methodology (Perry et al 1996). There
were no significant differences in age (t 5 36, p 5 .31)
or postmortem delay (t 5 22, p 5 .31), but there was
a trend toward a difference in gender (Fisher statistic 4.8,
p 5 .06), because all five cognitively impaired depressed
subjects were female. No statistical differences were found
between the groups on Alzheimer-type pathology (p .
.41) or Lewy body pathology (p 5 1.00, no Lewy
bodies were seen in any case). The total atheroma and total
microvascular scores were very similar (Fisher statistic 5
1.42, p 5 .70 and Fisher statistic 5 4.31, p 5 .51,
respectively) and, although the frontal microvascular
scores were slightly higher in the nonimpaired group, this
did not approach significance statistically (Fisher statistic 5 6.9, sig. 5 0.23). As seen in Table 2, levels of
Alzheimer type pathology is comparable to that of similarly aged normal control subjects and much less than
found in Alzheimer’s disease.
Neuropathology of Cognitive Impairment
BIOL PSYCHIATRY
2001;49:130 –136
133
Table 1. Comparison of Cognitively Impaired and Nonimpaired Groups
Impaired
a
Age (years)
Gender (male/female)b
Postmortem delay (hours)a
Total atheroma scoreb
Total microvascular scoreb
Deep white matter frontal
microvascularb
Neocortical plaques (per mm2)a
Neocortical tangles (per mm2)a
Braak stageb
Lewy bodies (per cm2)a
a
b
Nonimpaired
79.0 (4.69)
0/5
47.5 (28.62)
3
3
0
73.0 (8.81)
4/2
27.8 (6.34)
3
5
2
1.4 (1.27)
0.2 (0.39)
1
0 (0)
0.98 (1.41)
0 (0)
1
0 (0)
Test statistic
Significance
36
4.8
22
1.42
4.31
0.55
.31
.06
.31
1.00
.84
1.00
34
,34
2.59
Not applicable
.52
..41
.65
1.00
Values are mean (SD) and comparisons are made using the Mann–Whitney test.
Values are medians and comparisons are made using the Fisher–Freeman–Halton test.
original study of Blessed et al (1968) which found a
correlation, now replicated by several groups, between
plaque count and cognitive test score in dementia included
some cases with functional illness, seven of whom were
depressed; however, our more detailed study (which does
not include any of the same cases used by Blessed et al)
shows that this well-recognized relationship in dementia
does not apply to cognitive impairment in depression.
Minimal Alzheimer-type pathology was seen in the
depressed cases, of the same order as would be expected in
age-matched control subjects (Perry et al 1990b). Microvascular pathology was also not extensive using currently
available methods of assessment (Esiri et al 1997). Although the link between vascular disease and late life
depression is well recognised (Hickie and Scott 1998),
such pathology did not explain the occurrence of signifi-
Discussion
This is the first study to investigate neuropathologic
changes in depressed subjects with and without cognitive
impairment. We found no evidence of increased neuropathologic abnormalities in the form of Alzheimer-type
pathology or microvascular change in depressed subjects
who developed cognitive impairment during depression
compared to those who did not. A relationship with
Alzheimer pathology might have been expected because
of the similarity of some aspects of cognitive dysfunction
in depression to those seen in Alzheimer’s disease (Abas
et al 1990), the high proportion of cognitively impaired
depressed patients who subsequently develop the disorder
(Kral and Emery 1989), and the fact that depression is a
risk factor for Alzheimer’s disease (Jorm et al 1991). The
Table 2. Neuropathologic Scores in Two Depressed Groups
Cognitive
impairment
Impaired
Impaired
Impaired
Impaired
Impaired
Nonimpaired
Nonimpaired
Nonimpaired
Nonimpaired
Nonimpaired
Nonimpaired
Control subjects
(n 5 138) a
Alzheimer’s disease
(n 5 113) a
Senile dementia of
Lewy body type
(n 5 61) a
Total
Total
Deep frontal
atheroma microvascular microvascular
4
3
0
1
3
0
NA
3
3
4
NA
4
3
2
8
2
3
4
6
8
1
8
2
1
0
2
1
1
0
2
2
0
1
Plaques
per mm2
0.9
0.9
0.4
3.6
1.1
1.0
1.0
0.2
3.7
0.0
0.0
2.0 (3.3)
Tangles
per mm2
Braak
stage
0.1
1
0.0
2
0.0
0
0.0
0
0.9
2
0.0
1
0.0
1
0.0
0
0.0
3
0.0
2
0.0
1
0.07 (0.58) 2.6 (1.1)
Lewy
bodies
0
0
0
0
0
0
0
0
0
0
0
19.6 (13.4) 23.3 (17.3)
NA, not available.
a
Data taken for comparison from Perry et al (1990b, 1996) using the same criteria. Values are mean (SD).
110 (134)
134
BIOL PSYCHIATRY
2001;49:130 –136
cant cognitive dysfunction in our patients during their
depression. Consistent with this, we found no difference
between impaired and nonimpaired groups for atheromatous degeneration score that reflected cerebral and systemic large and medium vessel pathology.
Although many studies have examined neurotransmitter
and receptor changes during depression, there has been
only very limited focus on neuropathologic changes. This
is partly because affective illness has been viewed as a
state-dependent, reversible condition. This is, particularly
in the elderly, now known to be flawed, as elderly
depressed subjects have both enduring cognitive impairments (Abas et al 1990) and demonstrable neurobiological
changes, which suggest structural abnormalities. For example, depressed subjects have increased cortical atrophy
and ventricular enlargement when compared to control
subjects (Elkis et al 1995; Jacoby and Levy 1980; Rabins
et al 1991). In an MRI study, Rabins et al (1991) was
unable to differentiate those with depression and Alzheimer’s disease on the basis of either cortical atrophy or the
presence of white matter change. Our findings show that
the causes of cognitive impairment and structural brain
changes in depression lie outside those of degenerative or
microvascular pathology. Results are consistent with the
notion that deficits in some areas, particularly in learning
and memory, may be related to excess cortisol secretion as
a result of hypothalmic–pituitary–adrenal axis activation
during the illness (O’Brien 1997). Several lines of evidence support this view. First, in animal models prolonged
raised corticosteroid secretion is associated with deficits in
learning and memory and hippocampal cell loss (Sapolsky
and Plotsky 1990; Sapolsky et al 1986). Second, the
hippocampus is a major site of glucocorticoid receptors,
and at a cellular level excess glucocorticoids increase
calcium dependent influx, which is known to be neurotoxic (Landfield and Eldridge 1994). Third, following
exogenous steroid administration or raised endogenous
levels as a result of stress, cognitive deficits can be
demonstrated in healthy subjects (Kirschbaum et al 1996).
Fourth, in Cushing’s syndrome excess cortisol production
is associated with cognitive impairments and hippocampal
change (Starkman et al 1992). Finally, depression has been
shown to be associated with mild hippocampal atrophy
(Sheline et al 1999), which correlates with the total
duration of depression. To determine whether hippocampal cell loss is a cause of cognitive decline associated with
depression, further neuropathologic study of cell morphometry in the hippocampus would need to be
performed.
Cognitive impairments during depression have also
been associated with abnormalities in other brain areas,
particularly the medial prefrontal cortex (Dolan et al
1992). Changes in similar brain areas have also been
J. O’Brien et al
described on MRI (Drevets et al 1997), and a preliminary
neuropathologic report suggests glial loss in the absence of
neuronal loss in one part of the prefrontal cortex, at least
in younger patients with depression (Drevets et al 1998).
Changes in these or related areas may also underlie some
of the neuropsychological impairments that occur during
depression. Salloway et al (1996) found white matter
lesions to be associated with impairments in attentional
function. Although such lesions may be an important
correlate of impairment, we could find no evidence that
this was accompanied by microvascular change, at least in
the cortical areas that we examined (which did include
frontal cortex). The tests of cognition used in this study,
however, the MMSE and the MTS, are global measures of
cognitive function not particularly sensitive to executive
function, processing speed and other tasks subserved by
frontal–subcortical areas. Because these are the regions
most affected in imaging studies (Coffey et al 1993;
Greenwald et al 1998), it may be that there would be
correlations between microvascular pathology in these
regions and more specific frontal tests.
Some other limitations of our study should be considered. Our cases were not prospectively assessed, and so
information regarding their depressive illness and cognitive function came from case notes; however, case notes
within the service were of a very high quality, with
detailed typed summaries. All cases had detailed comment
about cognitive performance, and the majority had received a standardized assessment of cognitive function.
Numbers of depressed subjects were small and, although
the cognitive impairment documented during the depressive illness was felt to be secondary to depression, we
were not able to document reversibility on recovery from
the depression and so cannot be certain that this impairment was not due to another cause. Although this may
have been a possible confounding explanation if we had
found an increase in microvascular or Alzheimer type
pathology in the group with cognitive impairment, we do
not feel this can explain our negative results. Although our
subjects were impaired on clinical measures of cognition,
scores were in the moderate range and it may be that by
studying a group with more pronounced cognitive impairments during depression correlations with neurodegenerative pathology may exist.
In summary, we found no evidence of neuropathologic
differences between cognitively impaired and nonimpaired depressed subjects. This supports the view that
cognitive dysfunction in depression is mediated by mechanisms that are different from those related to Alzheimer’s
disease or vascular dementia. Hypercortisolaemia is one
possible explanation. There also needs to be further study
of the possible neurochemical basis of cognitive impairments in depression, as previous reports have suggested
Neuropathology of Cognitive Impairment
cholinergic loss may be important (Perry et al 1978). To
investigate this further, in vivo study of subjects who have
undergone detailed neuropsychological testing, assessment of endocrine function, and brain imaging should be
combined with clinico-pathological study that includes
detailed assessment of hippocampal cell morphometry,
investigation of glucocorticoid receptor changes, and detailed neurochemical analysis.
The authors thank the Medical Research Council and the Stanley
Foundation for financial support.
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