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Ischemic Basis for Deep White Matter Hyperintensities in Major Depression
A Neuropathological Study
Alan J. Thomas, MRCPsych;
John T. O'Brien, DM;
Sue Davis, PhD;
Clive Ballard, MD;
Robert Barber, MD;
Rajesh N. Kalaria, FRCPath;
Robert H. Perry, FRCPath
Arch Gen Psychiatry. 2002;59:785-792.
ABSTRACT
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Background White matter hyperintensities on magnetic resonance imaging are increased
in major depression in the deep white matter, especially in frontal areas.
These lesions have been hypothesized to be ischemic in origin, but there have
been no previous neuropathological studies in depression. We investigated
the neuropathological basis of these lesions in depression, hypothesizing
that they would be more frequently ischemic in origin in depressed subjects.
Methods We carried out in vitro magnetic resonance imaging on 3 slices of brain
tissue (2 frontal, 1 occipital) from 20 elderly subjects who had a history
of major depression and 20 elderly controls. The films were blindly rated,
and sections were prepared for neuropathological analysis from the same slices
and stained conventionally and by means of immunohistochemistry for microglia,
macrophages, and astroglia. Lesions on the films were identified in the tissue,
blindly described neuropathologically, and subsequently divided into ischemic
and nonischemic lesions.
Results All the deep white matter hyperintensities in the depressed group were
found to be ischemic, compared with less than a third of those in the control
group, a highly significant difference (P<.001).
This difference was due to smaller punctate lesions (<3 mm), which were
predominantly ischemic in depressed subjects but not in control subjects.
Larger lesions were usually ischemic in both groups. Compared with control
subjects, ischemic lesions were significantly more likely to be in the dorsolateral
prefrontal cortex compared with the anterior cingulate cortex (P = .003) and the occipital cortex (P = .01)
in the depressed subjects.
Conclusions Deep white matter hyperintensities are more frequently due to cerebral
ischemia, and such ischemic lesions are more frequently located at the level
of dorsolateral prefrontal cortex in depressed subjects. Our findings strongly
support the "vascular depression" hypothesis of late-life depression.
INTRODUCTION
MAGNETIC resonance (MR) imaging studies examining elderly patients with
depression have identified an increase in hyperintensities in the subcortical
white and deep gray matter.1-2
White matter hyperintensities (WMHs) have been divided into 2 types: those
adjacent to the ventricular system (periventricular hyperintensities [PVHs])
and those separate from the ventricles in the deep white matter (deep white
matter hyperintensities [DWMHs]). In depression, the frequency of PVHs appears
to be comparable with that in age-matched control subjects, but DWMHs are
increased.1-2 Such lesions appear
most strongly linked to depression when they involve frontal-subcortical circuits
that reciprocally link prefrontal areas (the dorsolateral prefrontal cortex
[DLPFC] and the anterior cingulate cortex [ACC]) to the basal ganglia.3
White matter hyperintensities have clinical importance, as they predict
a poor response to treatment and increased relapse rate,4
but their cause in depression remains unclear. Studies have shown WMHs to
be associated with increasing age,5-6
vascular risk factors, and cerebrovascular disease.5-6
The few published neuropathological studies of WMH, eg, those by Awad et al,7 Chimowitz et al,8 and
Fazekas et al,9 have included only a small
number of subjects, with a variety of diseases, and none included any subjects
with depression. These found that DWMHs reflect a mixture of pathologic conditions,
with smaller punctate lesions often corresponding to dilated perivascular
spaces and larger lesions to patches of ischemic damage, but other causes
have been reported, eg, congenital cysts and demyelination.7, 9
We have carried out a neuroimaging-neuropathological correlative study
to examine the neuropathological basis of WMHs in depression. On the basis
of the above findings, and wider evidence of cerebrovascular disease contributing
to depression in the elderly,10-11
we tested 2 hypotheses: first, that ischemic DWMHs would occur more frequently
in the depressed group than in the control group, and second, that ischemic
DWMHs would be more frequent in the prefrontal white matter in depressed subjects
than in control subjects.
SUBJECTS AND METHODS
SUBJECTS
Brain tissue from 40 elderly subjects (20 depressed and 20 control)
was obtained from our Neuropathology Department Brain Tissue Bank. Postmortem
permission for research had been given and ethical approval granted for the
study. Depressed subjects had suffered at least 1 well-documented episode
of DSM-IV major depression and had never fulfilled
criteria for other DSM-IV psychiatric disorders.12 They had been treated by experienced psychiatrists
who had made the diagnosis of unipolar depression, and 19 of the 20 had been
inpatients in Newcastle upon Tyne, England. All had received standard antidepressant
treatment, with selective serotonin reuptake inhibitors or tricyclic antidepressants
singly or often in combination with other agents, and 11 had received electroconvulsive
therapy. Eleven had had their first depression before age 65 years, and the
mean age at onset for the group was 64 years. Control subjects had also been
hospital inpatients in Newcastle upon Tyne and were known to be capable of
living an independent existence, and a review of their medical records showed
no evidence that they had ever suffered any psychiatric disorder.
The case notes of all subjects were searched for information about vascular
risk factors, and the cause of death and details have been published previously13; there were no group differences on any vascular
risk factor, and the groups were very similar in their cause of death. All
subjects received a full postmortem examination (except one whose body was
taken by the undertakers after brain removal), and the cause of death and
delay to postmortem examination were recorded. Brains were dissected in a
standard manner, a full neuropathological examination was carried out and
subjects excluded if they met neuropathological criteria for any known causes
of dementia (eg, Alzheimer disease) or other neurological disease, or had
evidence they died of hypoxia.
MR IMAGING AND RATING OF WMH
To locate WMHs for pathological analysis, we carried out postmortem
MR imaging. To facilitate translation from WMHs seen on MR imaging to the
corresponding lesions in the tissue, we carried out in vitro imaging on coronal
slices (7 mm thick) of formalin-fixed brain tissue. Previous studies have
used in vitro scanning of such brain tissue and found the method to be valid.7 We designed a special apparatus made up of a number
of plastic trays slotting on top of each other and shaped to fit into the
knee coil of the scanner and piloted this with coronal slices to obtain the
optimal imaging sequences.14 One of the depressed
subjects with a large number of WMHs had had in vivo imaging about a year
before he died and, comparing the in vitro images with this earlier image,
we found all WMHs were clearly visualized on the slice images.14
Three coronal slices (right hemisphere) were scanned from each subject.
We chose 2 slices from the frontal areas (DLPFC and ACC) that have been demonstrated
to be abnormal in functional imaging studies15-16
and that include the frontal-subcortical circuits,3
and one from the occipital lobe as a control area to allow comparison with
the prefrontal levels. Slices were removed from formalin, placed in sealed
bags, laid out on trays, and taken immediately to the MR imager before any
tissue degradation could occur. The MR imaging was performed on a 1.0-T imager
(Siemens Magnetom Impact Expert; Siemens AG, Erlangen, Germany), and coronal
3-mm slices were acquired through each postmortem slice. Proton density and
T2-weighted images were obtained with a dual spin-echo sequence (repetition
time, 2500 milliseconds; echo time, 16/98 milliseconds), and a T1-weighted
sequence was also obtained (repetition time, 6838 milliseconds; echo time,
60 milliseconds). The resulting films were coded so that rating was blind
to diagnosis. Two experienced raters (J.T.O'B. and R.B.) used the rating scale
of Scheltens et al17 to score the WMHs in all
120 slices.
NEUROPATHOLOGICAL ASSESSMENT OF WMH
After scanning, the tissue was embedded in paraffin and 10-µm
and 20-µm sections were prepared on large slides (7.6 x 5.1 cm)
that were coded to enable the analysis to be carried out blind to diagnosis.
Sections were stained with hematoxylin-eosin, Luxol fast blue, and cresyl
fast violet. The hematoxylin-eosin enabled assessment of the integrity of
the parenchyma and the microvasculature, Luxol fast blue indicated areas of
myelin pallor, and cresyl fast violet was used to assess adjacent cortical
tissue for evidence of microinfarcts or other abnormalities.
We also carried out immunocytochemistry for specific antibody markers
of microglia (HLA-DR; 1:500; Dako Ltd, Cambridgeshire, England), macrophages
(CD-68; 1:50; Dako Ltd), and astrocytes (glial fibrillary acid protein [GFAP];
1:4000; Dako Ltd). HLA-DR is a major histocompatibility complex class II marker
of microglia that is constitutively expressed but markedly increased when
microglia are activated.18 Microglia are recognized
to be exquisitely sensitive to perturbation of the central nervous system
microenvironment,19 and ischemia is a potent
stimulator of microglia.20 CD-68 is an intracytoplasmic
protein of macrophages, as well as microglia, and its expression is markedly
increased by cellular activation, such as that following ischemia.18, 21 Glial fibrillary acid protein is
a marker of astrocytes, which are activated by ischemia but more slowly than
microglia. They are central to the gliotic response to neuronal damage, and
the extent of GFAP increase correlates well with the extent of neuronal damage.20, 22
Sections were processed for immunocytochemistry in a standard manner
with the use of microwave antigen retrieval for HLA-DR and GFAP and protease
retrieval for CD-68. After incubation with the primary antibody, appropriate
secondary antibodies were applied, followed by avidin-biotinylated horseradish
peroxidase complex (Vector Laboratories Ltd, Peterborough, England) and diaminobenzidine
as a chromagen. The sections were repeatedly washed in Tris-buffered saline
(pH, 7.6) between each stage in this process and finally lightly counterstained
with hematoxylin.
Neuropathological assessment of the WMHs was carried out blind to diagnosis
and patient identity by 2 experienced raters (A.J.T. and R.H.P), who located
the WMHs seen on the MR image in the corresponding sections from the tissue.
This involved identifying the WMHs on the images, holding the slides beside
the image on the light box, and marking the corresponding lesions on the slides
(Figure 1). The raters then examined
each lesion in turn by using each of the above 6 stains, described its neuropathological
features, and paid careful attention to the presence or absence of evidence
of ischemic tissue damage. A lesion was rated as ischemic if both raters agreed
there was clear evidence of increased macrophage or microglial activity in
the lesion and/or if there was evidence from GFAP of astrogliosis. In such
lesions, inspection of the tissue by means of hematoxylin-eosin and Luxol
fast blue stains showed loss of myelin, thinning, and loss of fibers and cells.
In a couple of cases where immediate agreement was not obtained, the slides
were reviewed and discussed; the raters agreed that, since ischemia was not
clearly present, such lesions should be classified as nonischemic. The histologic
features of the white and gray matter tissue surrounding each lesion that
had normal signal on MR imaging were also carefully examined to compare them
with those of the tissue in the lesion.
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Figure 1. Deep white matter hyperintensities
on in vitro magnetic resonance images and myelin-stained tissue. A, Arrows
indicate 2 large deep white matter hyperintensities on a T2 sequence from
the anterior cingulate cortex (there is also a periventricular hyperintensity
not indicated by arrow). B, Same lesions in a Luxol fast blue–stained
section from the same tissue. C, Arrow indicates a punctate deep white matter
hyperintensity on a T2 sequence from the dorsolateral prefrontal cortex. D,
Same lesion in the Luxol fast blue–stained section.
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To test the hypotheses, the planned analyses were to compare ischemic
and nonischemic lesions in each group as a proportion of lesions examined
pathologically by means of Fisher exact test to compare the lesions and their
location in the two groups (SPSS version 10 software; SPSS Inc, Chicago, Ill).
In addition, on the basis of previous findings,7, 9
we also divided DWMHs according to their Scheltens et al rating17
into punctate lesions (score of 1 or 2, <3 mm) and larger lesions (score
of 3-6, >3 mm), and unpaired t tests were used to
compare groups on age and postmortem interval.
RESULTS
There were 7 men and 13 women in each group, and there were no significant
differences in age (mean [SD], 75.0 [7.37] years in the depressed group and
74.2 [7.46] years in the control group; t38 = 0.30, P = .77) or postmortem delay (mean
[SD], 34.5 [22.7] hours in the depressed group and 28.0 [16.2] hours in the
control group; t38 = 1.05, P = .30) between the groups. On the MR images, 38 DWMHs (19 in DLPFC,
17 in ACC, and 2 in occipital cortex) were rated in 13 subjects in the depressed
group and 36 (17 in DLPFC, 16 in ACC, and 3 in occipital cortex) in 13 subjects
in the control group; neither the total numbers nor the distributions were
significantly different. In addition, 4 infarcts (2 in depressed subjects
and 2 in controls) were identified and confirmed at pathological analysis.
Thirty DWMHs seen on the images (22 in depressed subjects and 8 in control
subjects) could not be identified on the slides taken from the slices. Most
(26) of these were punctate lesions. On retrospective analysis, these missed
lesions did not appear any different on the MR images from the lesions we
were able to examine microscopically, nor did ischemic lesions appear different
from nonischemic lesions on the images. This left 44 DWMHs (16 in 7 depressed
subjects and 28 in 11 control subjects) that were examined microscopically
and on which group comparisons are based.
These 44 DWMHs consisted of 30 punctate lesions and 14 larger DWMHs. Figure 1 shows examples of punctate and larger
DWMHs from the in vitro MR images and the corresponding lesions in the tissue,
and Table 1 shows the ischemic
and nonischemic basis of all 44 DWMHs. There was a highly significant increase
in the proportion of ischemic DWMHs in the depressed group (Fisher exact test, P<.001). Table 2
shows the number of subjects in each group who had any ischemic DWMHs compared
with those who had none. There was also a significant increase in the proportion
of depressed subjects with ischemic DWMHs (Fisher exact test, P = .01). To investigate whether these group differences were due to
a disproportionately large number of ischemic DWMHs in 1 or 2 subjects, which
might have confounded the results, we compared the frequency of lesions per
subject in the 2 groups. The 16 ischemic DWMHs in the depressed group were
found in 7 subjects (mean per subject, 2.29; range, 1-4), while the 8 ischemic
DWMHs in the control group were found in 4 subjects (mean, 2.00; range, 1-4).
There was no statistically significant difference in the frequency of ischemic
DWMHs per subject between the 2 groups (Mann-Whitney test, U = 11.5; P = .62).
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Table 1. Frequency of Ischemic and Nonischemic Deep White Matter Hyperintensities
in 7 Depressed and 11 Control Subjects*
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Table 2. Numbers of Subjects With Ischemic and Nonischemic Deep White
Matter Hyperintensities in Depressed and Control Subjects*
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PUNCTATE DWMH
Table 1 shows the basis
of the punctate DWMHs in each group and compares the proportions of ischemic
and nonischemic lesions. Of the 30 punctate lesions analyzed microscopically,
21 were in control subjects. Thirteen were found to be dilated perivascular
spaces with no evidence of any ischemia in the surrounding tissue (Figure 2A and B); 4 lesions corresponded
to small foci of demyelination with no evidence of ischemia (Figure 3C and D); 3 lesions were dilated perivascular spaces with
evidence of ischemic tissue damage in adjacent tissue (Figure 2C and D); and the other lesion corresponded to an abnormal
conglomeration of small vessels. In the depressed subjects, 8 of the 9 punctate
lesions were caused by dilation of the perivascular spaces with evidence of
associated ischemic tissue damage (Figure
2C and D), and the other lesion was a small focus of demyelination
that showed clear evidence of ischemic tissue damage (Figure 3E and F). Thus, all 9 punctate lesions in depressed subjects
were associated with ischemia, while only 3 of the 21 punctate lesions in
the control subjects showed evidence of ischemia. This difference was highly
significant (Fisher exact test, P<.001). Table 2 compares the groups by the number
of subjects who had any ischemic punctate DWMHs compared with those who had
none, and there was a significant increase in the proportion of depressed
subjects with ischemic punctate DWMHs (Fisher exact test, P = .03).
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Figure 2. Dilated perivascular spaces with
and without ischemia seen as punctate deep white matter hyperintensities on
magnetic resonance images. A and B, Dilated perivascular space. There is no
evidence of ischemia. C and D, Some pallor of the myelin (D) associated with
microglial activity (C) indicating perivascular ischemia (HLA-DR with hematoxylin
counterstain [A and C] and Luxol fast blue [B and D]; bars indicate 100 µm).
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Figure 3. Deep white matter hyperintensities
due to ischemic and nonischemic demyelination. A and B, Normal tissue for
comparison. C, Normal HLA-DR staining. D, Myelin pallor. E and F, Phagocytic
microglial infiltration indicating ischemic tissue damage (E) associated with
marked pallor (F) (HLA-DR with hematoxylin counterstain [A, C, and E] and
Luxol fast blue [B, D, and F]; bars indicate 100 µm).
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LARGER DWMH
Table 1 shows the findings
for larger DWMHs and compares the proportions of ischemic and nonischemic
lesions. Of the 14 larger lesions, 12 corresponded to areas of demyelination
associated with evidence of ischemia. These lesions showed oligodendrocyte
loss and evidence of macrophage or microglial infiltration and/or the GFAP
showed astrocytosis (as in Figure 3E
and F, but these were larger lesions). CD-68 was found to be a more reliable
marker for microglia than HLA-DR. Seven of these were in depressed subjects
(5 with a Scheltens et al score of 3 [4-10 mm]; 2 with a score of 5 [>11 mm])
and 5 were in controls (4 with a score of 3; 1 with a score of 6 [confluent]).
The 2 other larger DWMHs in the control subjects were lesions with scores
of 5 and 6 that corresponded to areas of demyelination with some evidence
of tissue thinning but no clear evidence of ischemia (no macrophage infiltration
or astrocytosis; like Figure 3C
and D, but larger lesions). Thus, for these larger lesions, all 7 in depressed
subjects were due to ischemic tissue damage, while 5 of the 7 control subjects
showed evidence of ischemia (Fisher exact test, P
= .46).
DISTRIBUTION OF DWMH
Table 3 shows the distribution
of the DWMHs. All 16 ischemic DWMHs in the depressed subjects were frontal
(12 DLPFC and 4 ACC), while in the control subjects, only 6 ischemic DWMHs
were frontal (all ACC) and the other 2 ischemic lesions were in the occipital
lobe. Comparisons with control subjects showed a highly statistically significant
elevation of ischemic DWMHs in the depressed group in the DLPFC compared with
both the ACC (Fisher exact test, P = .003) and the
occipital cortex (Fisher exact test, P = .01), but
no significant difference in the ACC compared with the occipital cortex (Fisher
exact test, P = .42).
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Table 3. Anatomic Distribution of the 44 Ischemic and Nonischemic Deep
White Matter Hyperintensities*
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COMMENT
This is the first study, to our knowledge, to examine the pathological
basis of WMHs in depression. We found that all DWMHs examined in our depressed
subjects showed evidence of ischemic damage compared with less than a third
of these lesions in control subjects, a highly significant difference. While
most larger lesions in both groups were ischemic, smaller punctate lesions
were ischemic in depressed subjects but usually not in control subjects. It
is important to note that ischemic DWMHs showed a marked specificity for the
white matter at the level of the DLPFC in depressed subjects. Our findings
strongly support the "vascular depression" hypothesis, which proposes that
vascular disease predisposes to, precipitates, or perpetuates depression.
The high frequency of ischemic lesions in depressed subjects contrasted
with their surprisingly low frequency in control subjects. This was not due
to an excess of vascular disease in the control subjects, as, paradoxically,
they had more clinical vascular disease.13
Perhaps the most likely explanation is that DWMHs progress from nonischemic
lesions to ischemic lesions when a certain threshold for ischemic damage is
crossed. Thus, with normal aging, a mild loss of perfusion or age-related
degenerative changes might induce loss of myelin without producing sufficient
cell damage to activate microglia and macrophages. If there is a further reduction
in perfusion, then immune cells and glia would be activated as ischemic damage
develops and the DWMHs progress to ischemic lesions. It may be that such a
threshold for progressing from nonischemic to ischemic lesions is lower in
depressed subjects, making them more vulnerable to ischemia. Alternatively,
depressed subjects may have a generally poorer perfusion of cerebral, especially
prefrontal, tissue through some combination of large vessel, small vessel,
and hypotensive disease processes. This alternative would harmonize with clinical
studies, which have shown that depression is more common after myocardial
infarction, stroke, and hypertension3 and that
depression is also an independent risk factor for each of these conditions.23-25 The large difference
between the groups in ischemic DWMHs was due to group differences in the frequency
of punctate DWMHs. Cerebral ischemia associated with these lesions would appear
to be important, and, although some have questioned the significance of punctate
lesions26 in general, Lenze and colleagues27 found punctate lesions to be increased in late-life
depression after controlling for vascular disease and Simpson and colleagues28 found punctate DWMHs to be the most robust predictor
of poor clinical outcome in depression in the elderly. Our finding that punctate
lesions are usually ischemic in depression therefore appears to be of clinical
importance. The difference in the frequency of ischemic DWMHs between the
groups was not due to 1 or 2 depressed subjects having a large number of ischemic
lesions, because there were no differences in the frequency of ischemic DWMHs
per subject between the groups and, more important, the difference therefore
remained even when groups were compared by subjects rather than by lesions.
There was a striking difference in the distribution of ischemic DWMHs
in the 2 groups. All the ischemic DWMHs were located frontally in the depressed
group, and this was especially the case for the DLPFC, which had significantly
more ischemic DWMHs than either of the other 2 areas. These findings imply
that the burden of ischemia due to DWMHs is underestimated by MR imaging comparisons
of depressed and control subjects, even though these comparisons show that
DWMHs are more common in the frontal lobes.29
Such lesions may contribute to the pattern of depression in the elderly and
have clinical importance, because previous studies have demonstrated that
executive dysfunction in depression in the elderly, associated with the DLPFC,
predicts poor response to antidepressant treatment30
and a higher frequency of relapses and recurrences.31
It is difficult to compare our findings with previous work, as no other
study has examined WMHs in depression and the few published of WMHs in other
conditions have not used specific markers for macrophages and microglia. However,
the findings in the few published studies7-9
appear similar to ours in that punctate lesions were usually caused by dilated
perivascular spaces, often with evidence of associated perivascular myelin
pallor or gliosis, and larger DWMHs showed myelin pallor with or without gliosis.
Earlier studies, eg, that of Awad and colleagues,7
also missed some lesions in the tissue, and this raises the question as to
whether the missed lesions might be different from those examined microscopically.
Review of the films after pathological analysis did not show the missed lesions
to be any different, and, although it is likely that some DWMHs in depressed
subjects are nonischemic, it is difficult to think of a reason why the DWMHs
we examined should be systematically different pathologically from those we
missed.
Our findings apply to severe depression, and the extent to which they
can be generalized to late-life depression in general is unclear. However,
although the early MR imaging studies in depression were carried out on similar
clinical samples of subjects with severe depression, 2 recent large epidemiologic
MR imaging studies of community depression have shown that DWMHs are increased
in such depressed subjects too.32-33
This suggests that our findings may have a wider relevance to depression in
the elderly, not just to severe illness seen by specialists but also to milder
community forms of depression. Since our results do not appear to be due to
an excess of vascular disease in the depressed group, they imply, as has been
suggested previously,3, 11 that
depression may be more closely linked to vascular disease than clinical risk
factors show and may itself be regarded in the elderly as suggesting underlying
cerebral ischemic processes. Certainly, our results demonstrate that WMHs
should be regarded as evidence of cerebrovascular disease in elderly depressed
subjects.
Our results strongly support the vascular depression hypothesis of depression,
demonstrating that the majority of DWMHs in elderly subjects with severe depression
are probably due to ischemia, and this is especially the case when they are
located at the level of the DLPFC. Thus, not only are DWMHs more common in
depression,1-2 but we have now
shown that they are also much more likely to be due to ischemia in the cerebral
white matter. The suggestion that depression in the elderly be viewed "as
a potentially treatable variant of cerebrovascular disease"11
and treated accordingly is supported by our study.
AUTHOR INFORMATION
Submitted for publication May 1, 2001; final revision received August
9, 2001; accepted October 24, 2001.
This study was supported by the Stanley Foundation, Bethesda, Md.
We thank Edmund Juszczak, PhD, for his statistical advice.
Corresponding author and reprints: Alan J. Thomas, MRCPsych, Wolfson
Research Centre, Institute for Ageing and Health, Newcastle General Hospital,
Newcastle upon Tyne NE4 6BE, England (e-mail: a.j.thomas{at}ncl.ac.uk).
From the Department of Psychiatry (Drs Thomas, O'Brien, Davis, Ballard,
Barber, Kalaria, and Perry) and the Institute for Ageing and Health (Drs Thomas,
O'Brien, Davis, Ballard, Barber, Kalaria, and Perry), University of Newcastle
upon Tyne, Newcastle upon Tyne, England.
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