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Magnetic Resonance Imaging Correlates of Depression After Ischemic Stroke
Risto Vataja, MD;
Tarja Pohjasvaara, MD, PhD;
Antero Leppävuori, MD, PhD;
Riitta Mäntylä, MD;
Hannu Juhani Aronen, MD, PhD;
Oili Salonen, MD, PhD;
Markku Kaste, MD, PhD;
Timo Erkinjuntti, MD, PhD
Arch Gen Psychiatry. 2001;58:925-931.
ABSTRACT
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Background Depression affects up to 40% of patients with ischemic stroke. The relationship
between site and size of brain infarcts and poststroke depression is still
not well characterized. Further possible contribution and interaction of white
matter lesions and brain atrophy has not been studied previously. We conducted
a magnetic resonance image–based study of the radiologic correlates
of depression in a large, well-defined series of patients with ischemic stroke.
Methods Modified DSM-III-R and DSM-IV criteria were used to diagnose depressive disorders during a comprehensive
psychiatric evaluation in 275 of 486 consecutive patients aged 55 to 85 years
3 to 4 months after ischemic stroke. A standardized magnetic resonance imaging
protocol detailed side, site, type, and extent of brain infarcts and extent
of white matter lesions and brain atrophy.
Results Depressive disorders were diagnosed in 109 patients (40%). Patients
with depression had a higher number and larger volume of infarcts affecting
the prefrontosubcortical circuits, especially the caudate, pallidum, and genu
of internal capsule, with left-sided predominance. Extent of white matter
lesions and atrophy did not differ in patients with and without depression.
Independent correlates of poststroke depression in a logistic regression model
were mean frequency of infarcts in the genu of internal capsule on the left
side (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.0-10.1), mean
frequency of infarcts in the pallidum of any side (OR, 1.6; 95% CI, 1.1-2.3),
and mean volume of infarcts in the right occipital lobe (OR, 0.98; 95% CI,
0.96-0.99).
Conclusion Lesions affecting the prefrontosubcortical circuits, especially on the
left side, are correlates of depression after ischemic stroke.
INTRODUCTION
DEPRESSION is a common neuropsychiatric consequence of stroke, affecting
approximately 40% of the patients.1 In addition
to the psychosocial stress due to disability, loss of independence, and worsening
of quality of life, neurobiological factors such as site of infarcts2 and brain atrophy3
have also been proposed to be related to depression after stroke. In their
seminal works, Robinson4 and Lipsey5 and their collagues reported that ischemic lesions
located in the anterior parts of the brain were associated with more severe
depression. Since then, inconsistent results on relations between infarct
site and depression after stroke have been reported. Recent systematic reviews6, 7 of the many studies in this field have
not supported the hypothesis of the significance of stroke lesion location
and subsequent depression.
Silent infarcts,8 white matter lesions
(WMLs),9 and risk factors of cerebrovascular
disease (CVD)10 have also been associated with
depression. The concept of "vascular depression" has been introduced for a
syndrome of depression with onset late in life in patients with established
vascular risk factors or CVD.11, 12, 13
Previous studies on radiologic correlates of depression after stroke have
had a limited focus on infarct features, neglecting the simultaneous effect
of WMLs and atrophy. We hypothesized that brain infarcts and WMLs affecting
the structures constituting the prefrontosubcortical circuits14, 15
would contribute to the development of depression after stroke in a complex
way, analogously to that of poststroke dementia.16
The present study is the first, to our knowledge, to systematically use the
magnetic resonance imaging (MRI) technique and vigorous psychiatric methods
in a large cohort of patients with ischemic stroke 3 to 4 months after stroke
to investigate the radiologic correlates of depression after stroke.
PATIENTS AND METHODS
PATIENTS
The Helsinki Stroke Aging Memory Study was conducted at Helsinki University
Central Hospital in Helsinki, Finland, between December 1, 1993, and March
1, 1995. The detailed clinical,17 psychiatric,18 and radiologic19, 20
procedures have been published previously. Patients with suspected stroke,
defined as sudden or rapidly evolving transient or permanent symptoms or signs
indicating a global or focal neurological dysfunction of suspected vascular
origin,21 were identified by daily survey of
admissions to the emergency department at Helsinki University Central Hospital.
Included patients were aged 55 to 85 years at the onset of illness, resided
in Helsinki, and spoke Finnish. A total of 486 patients were initially evaluated
3 months after having a stroke. Recruitment of the consecutive patients for
the psychiatric study started 3 months after and ended 1 month before recruitment
for other procedures. Patient flow and reasons for nonenrollment are shown
in Figure 1. Of the 275 patients
included in the study, 233 were living at home, 12 were in nursing homes,
and 30 were hospitalized. Patients excluded from the psychiatric evaluation
were more often dependent in activities of daily living and had more severe
physical handicaps, more cognitive disturbances (as measured by the Mini-Mental
State Examination), and a more severe stroke (as measured by the Scandinavian
Stroke Scale) (Table 1).
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Patient flow in the Helsinki Stroke Aging Memory Study. SAH indicates
subarachnoid hemorrhage; ICH, intracerebral hemorrhage; and MRI, magnetic
resonance imaging.
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Table 1. Characteristics of Patients Excluded From and Included in
the Study*
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The study was approved by the ethics committee of the Department of
Clinical Neurosciences, Helsinki University Central Hospital.
PROCEDURES
The protocol included a detailed structured clinical interview with
the patient and a knowledgeable informant and a structured clinical and neurological
examination by board-certified neurologists (T.P. and R.V.). The cases were
also reviewed by a senior neurologist (T.E.). Cognitive function was assessed
using the Mini-Mental State Examination,22
stroke severity using the Scandinavian Stroke Scale,23
aphasia using the Acute Aphasia Screening Protocol,24
and impairment in activities of daily living using the Barthel Index.25
Magnetic resonance imaging was performed with a 1.0-T system 3 to 4
months after the stroke occurred. All images were reviewed by a single neuroradiologist
(R.M.) blinded to the clinical data. Reliability of the visual rating was
tested by review of 60 MRI scans independently by the same rater (R.M.), a
board-certified neuroradiologist (O.S.), and a general radiologist (H.J.A.).
For the reliability of rating WMLs, weighted  values for intraobserver
agreement were 0.72 to 0.95 and for interobserver reliability were 0.72 to
0.93. For the reliability of rating brain atrophy, intraobserver reliability
was 0.75 to 0.82 and the corresponding interobserver reliability was 0.61
to 0.74.
The number, type, side, site, and size of focal lesions were recorded.
Lesions equivalent to the signal characteristics of cerebrospinal fluid on
T1-weighted images and measuring more than 3 mm in diameter, as well as wedge-shaped
corticosubcortical lesions, were regarded as brain infarcts. We did not use
computer-based volumetric analysis. For estimation of lesion volumes, we grouped
the infarcts into 4 categories based on their largest diameter (3-9, 10-29,
30-59, and  60 mm), and the radii used for calculations were 3, 10, 20,
and 30 mm, respectively. The volume of the lesion was then estimated using
the formula for calculating the volume of a ball. The number and volumes of
infarcts affecting different anatomic sites were evaluated on both sides and
on the right and left sides separately. The sites included (1) brain lobes
(corticosubcortical lesions in the frontal, temporal, parietal, and occipital
lobes); (2) vascular territories (deep and superficial anterior cerebral arteries,
middle cerebral artery, posterior cerebral artery, internal cerebral artery,
and border-zone areas); and (3) specific locations, ie, the medulla, pons,
cerebellum, optic radiation, thalamus, caudate, putamen, pallidum, genu of
internal capsule, anterior and posterior capsules, anterior and posterior
corona radiata, anterior and posterior centrum semiovale, genu, body and splenium
of corpus callosum, angular gyrus, hypothalamus, hippocampus, and amygdala.
Prefrontosubcortical circuits14 include connections
among the frontal cortex, caudate, pallidum, thalamus, and thalamocortical
circuit. The thalamocortical circuit includes the genu of internal capsule,
anterior capsule, anterior corona radiata, and anterior centrum semiovale.
White matter lesions were rated on proton density–weighted images
in 6 areas: around the frontal and posterior horns; along the bodies of lateral
ventricles; and in subcortical, deep, and watershed areas.19, 20
Periventricular WMLs around the frontal and posterior horns were classified
based on size and shape into small cap ( 5 mm), large cap (6-10 mm), and
extending cap (>10 mm) and WMLs along the bodies of lateral ventricles into
thin lining (5 mm), smooth halo (6-10 mm), and irregular halo (>10 mm).
White matter lesions in the subcortical, deep, and watershed areas were classified
based on size (greatest diameter) and shape into small focal (5 mm), large
focal (6-10 mm), focal confluent (11-25 mm), diffusely confluent (>25 mm),
and extensive (diffuse hyperintensity without distinct focal lesions affecting
most of the white matter area). The number of each type of hyperintensity
was counted, and extensive WMLs were rated as absent or present. Moderate
and severe degrees of WMLs included large and extending caps at the periventricular
area; smooth halo and irregular halo along the bodies of lateral ventricles;
and focal confluent, diffusely confluent, and extensive WMLs in the subcortical,
deep, and watershed areas. In addition, the extent of WMLs was graded using
the 4-point scale of Fazekas et al.26
Brain atrophy was first rated as none, mild, moderate, or severe by
comparison to standard images according to the methods of Scheltens27 and Erkinjuntti28
and their coworkers. Cortical atrophy was rated in the frontal, parietal,
and occipital lobes; central atrophy in the temporal, frontal, and occipital
horns and bodies of the lateral ventricles; and mediotemporal lobe atrophy
in the entorhinal cortex and hippocampus. Cortical atrophy and central atrophy
were expressed as the mean of the rating in all the bilateral areas rated
and were divided into 2 groups: none to mild vs moderate to severe.
The clinical psychiatric examination was carried out after the MRI examination,
12 to 20 weeks (mean ± SD, 15.5 ± 1.7 weeks) after the index
stroke. The examination included the computer-assisted structured interview
Schedules for Clinical Assessment in Neuropsychiatry.29
The main content of the schedules is the 10th version of the Present State
Examination,30 whose earlier version (ninth
version) has been widely used in research concerning the elderly and physically
ill patients. Most patients (n = 220) were examined by a senior psychiatrist
(A.L.). The senior psychiatrist also supervised the afterwards data entry
concerning patients examined by a resident psychiatrist (n = 55). Both were
blinded to the radiologic data. The data from the interviews were entered
directly into a computer. Finally, the program evaluated a prediagnosis profile
for the DSM-III-R31
and ICD-1032 categories.
Severity of depression was measured using the Montgomery-Åsberg Depression
Rating Scale. For the final diagnoses of depressive disorders, all psychiatric
data from the clinical psychiatric examination, interviews with the close
informants of patients when possible, psychiatric rating scales, and the Schedules
for Clinical Assessment in Neuropsychiatry protocol were combined.
We included all patients with any DSM-IV33 depressive disorders 3 to 4 months after stroke (Table 2). Also, the 54 patients (20%) who
had had depressive episodes before the index stroke and the 83 (30%) with
previous stroke episodes were included.
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Table 2. Depressive Disorders by DSM-IV Categories
in 109 Patients With Depression in the Helsinki Stroke Aging Memory Study
(N = 275)
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STATISTICAL ANALYSIS
In the statistical analysis we compared patients with and without depression
after stroke. According to our hypothesis, we expected to find more damage
in the anatomic structures constituting the prefrontosubcortical circuits
in depressed patients. First, we created a sum variable model of these circuits
(see the "Procedures" subsection) and compared the number and volume of infarcts
affecting the circuits and their substructures between the 2 groups.
After testing this hypothesis we analyzed all other areas covered by
the MRI protocol to find other possible independent radiologic correlates
for the poststroke depression. The Fisher exact test (2-tailed) was applied
for categorical data and the Mann-Whitney nonparametric test was applied for
continuous data throughout. No adjustments were made for multiple comparisons
in statistical approaches. The  level of significance was P<.05. There were no missing data in any of the analyses described.
The radiologic variables that significantly differentiated patients in the
2 groups (Table 3 and Table 4) were set to an adding multiple
logistic regression analysis to find the independent MRI correlates of depression
after stroke. The statistics were analyzed using the BMDP34
and SAS35 computer programs. Data are given
as mean ± SD.
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Table 3. Frequency of Brain Infarcts in Patients With and Without Depression
After Stroke in the Helsinki Stroke Aging Memory Study
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Table 4. Brain Infarct Volumes in Patients With and Without Depression
After Stroke in the Helsinki Stroke Aging Memory Study
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RESULTS
Any depressive disorder was diagnosed in 109 (40%) of the 275 patients.
Major depression was present in 71 patients (26%) and minor depression was
present in 38 (14%) (Table 2).
Patients with depression after stroke more often had a history of previous
depressive episodes, had more severe stroke (a lower score on the Scandinavian
Stroke Scale), and were more impaired in activities of daily living (lower
score on the Barthel Index, more often dependent in activities of daily living)
(Table 5).
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Table 5. Characteristics of Patients With and Without Depression After
Stroke in the Helsinki Stroke Aging Memory Study*
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Of the 275 patients, 63 (23%) used antidepressive medications at 3-month
follow-up. For 57 of these patients, the antidepressant was prescribed first
after the index stroke, and 42 of these patients belonged to the depressed
group of 109 patients.
We counted the frequency and volumes of all infarcts affecting different
brain regions in the 2 patient groups (Table 3 and Table 4,
respectively). Patients had 3.2 ± 2.5 brain infarcts, of which 1.7
± 1.6 were located on the right hemisphere and 1.6 ± 1.4 on
the left hemisphere. Twelve patients fulfilling the clinical criteria for
ischemic stroke and thus included in our study had no lesions fulfilling the
radiologic criteria (ie, diameter <3 mm) for brain infarct. There was no
difference in the total number of infarcts, the number of infarcts in the
right or left hemisphere, or the number of infarcts in different lobes of
the brain in patients with and without depression after stroke. However, patients
with depression after stroke more frequently had lesions affecting the prefrontosubcortical
circuits or some of its substructures (the caudate, pallidum, genu of internal
capsule, and anterior capsule), especially in the left hemisphere (Table 3). Five of 6 patients with infarcts
affecting the amygdala had depression (0.6% vs 4.6%; P
= .04, 2-tailed Fisher exact test). On the right side, patients with depression
had significantly more lesions affecting the right pallidum and significantly
fewer lesions affecting the right occipital lobe. (Data concerning the frequency
and volume of brain infarcts and WMLs in patients with minor vs major depression
and in patients with first ever vs recurrent depressive episodes, as well
as data concerning the frequency and volume of brain infarcts at sites that
did not differ significantly between depressed and nondepressed patients,
are available from the author on request.)
The total volume of all brain infarcts was 33.7 ± 47.7 cm3. In patients with vs without depression after stroke, total infarct
volume (35.9 ± 52.4 vs 27.6 ± 39.2 cm3; df = 273; P = .64, Mann-Whitney test) and
volumes of infarcts in the right (21.6 ± 41.0 vs 13.2 ± 30.3
cm3; P = .40) and left (14.2 ±
31.3 vs 14.4 ± 30.2 cm3; P = .43)
hemispheres did not differ significantly. Depressed patients had significantly
larger lesions affecting the deep middle cerebral artery territory; caudate;
pallidum; genu and anterior part of internal capsule; posterior corona radiata;
and the amygdala, with a left-sided predominance (Table 4). Larger lesions in the right occipital lobes, however,
were found in patients without depression.
No differences between the depressed and nondepressed groups were found
in the percentage of moderate to severe WMLs; in mean Fazekas WML score; or
in the extent of central, cortical, or mediotemporal lobe atrophy (Table 6).
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Table 6. Moderate to Severe White Matter Hyperintensity and Cerebral
Atrophy in Patients With and Without Depression After Stroke*
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We also compared the lesion site and size in patients with major (n
= 71) and minor (n = 38) depression. Patients with major depression had more
infarcts affecting the prefrontosubcortical circuit area on any side (1.8
± 1.7 vs 1.2 ± 1.4; df = 107; P = .03, Mann-Whitney test) or on the right side (0.83
± 0.95 vs 0.45 ± 0.86; P = .02). No
significant differences in the size of the infarcts, the severity of WMLs,
and the extent of brain atrophy were found between these patient groups (data
not shown).
Of the 109 depressed patients, 77 had no depressive episodes before
the index stroke and 32 had had 1 or more depressive episodes. The total number
of brain infarcts was significantly smaller in patients with first-ever depression
after the index stroke compared with patients with previous episodes of depression
(2.8 ± 2.4 vs 4.1 ± 2.6; P = .01, df = 107, Mann-Whitney test), as was the number of right-sided
infarcts (1.3 ± 1.5 vs 2.3 ± 1.8; P
= .005). Furthermore, patients with first-ever depression had significantly
fewer infarcts in the superficial medial cerebral artery area (0.9 ±
1.1 vs 1.2 ± 1.1; P = .02). There were no
differences in the volumes of infarcts, severity of white matter changes,
or extent of atrophy between these groups.
The independent MRI correlates of depression after stroke determined
using logistic regression analysis were mean frequency of infarcts in the
genu of internal capsule on the left side (odds ratio [OR], 3.2; 95% confidence
interval [CI], 1.0-10.1), mean frequency of infarcts in the pallidum of any
side (OR, 1.6; 95% CI, 1.1-2.3), and mean volume of infarcts in the right
occipital lobe (OR, 0.98; 95% CI, 0.96-0.99).
COMMENT
To our knowledge, this is the first large MRI-based study that explores
the radiologic correlates of depression after stroke. We systematically assessed
the interaction among infarct side, site, number, and extent; WMLs; and atrophy.
Depression after stroke is related to ischemic lesions affecting the prefrontosubcortical
circuit, namely, the caudate, pallidum, and thalamocortical projection, including
the genu of internal capsule and anterior capsule, especially in the left
hemisphere. In a multivariate analysis, the independent correlates of depression
after stroke were number of infarcts in the genu of internal capsule on the
left side (OR, 3.2) and number of lesions in the pallidum of any side (OR,
1.6). Our results support the idea that lesions affecting the prefrontosubcortical
circuits relate to a higher risk of depression after stroke.37, 38
Evidence for the importance of pallidum in mood regulation is emerging
from neuropathologic studies.39 Furthermore,
lesions in the pallidum have been related to reduced glutamatergic input to
the dorsolateral prefrontal cortex and to depression.40
The distinct prefrontosubcortical circuits, ie, orbitofrontal, dorsolateral,
and anterior cingulate circuits,14 run closely
adjacent to each other in the genu of internal capsule38
and are likely to be damaged together in case of an infarct in that area.
In their seminal publication, Tatemichi et al41
showed that an infarct affecting the genu of internal capsule was related
to dementia and "frontal lobe symptoms." We hypothesize that anatomic closeness
of the 3 frontosubcortical circuits at the capsular genu and the thalamocortical
connection relate lesions in this area to depression after stroke.
The amygdala has multiple connections to the frontosubcortical circuit,
namely, the prefrontal cortex, striatum, and thalamus. Infarcts affecting
the amygdala are rare (2% of patients in the present series). The overrepresentation
of depression in patients with infarcts affecting the amygdala is an interesting
finding that awaits confirmation in future MRI studies.
Depression after stroke was statistically significantly less common
in patients with a higher frequency and larger volume of infarcts in the right
occipital lobe. This eventual "protective effect" against depression is difficult
to explain. Although right-sided lesions have been related to bipolar affective
disorders42 and mania,43
this association has not been reported earlier. However, in a study by Sinyor
et al,44 2 patients with large right-sided
posterior infarcts had to be excluded from the analysis before the association
between poststroke depression and proximity of the left-sided lesion location
from the anterior pole of the brain could be demonstrated.
Patients with previous depressive episodes had more brain infarcts—reflecting
more severe CVD—than patients with first-ever depression after stroke,
consistent with the vascular depression hypothesis11, 12, 13
of the relationship between chronic vascular disease and vulnerability to
depression.
In accordance with our core result, anterior lesions and lesions affecting
the prefrontosubcortical circuit have been previously related to depression
in many studies4, 45, 46, 47
but not in all.48, 49, 50
Factors related to these inconsistent findings include selection of patients,
distinction between major and minor depression, timing of evaluation, and,
brain imaging techniques.2, 7 Differentiation
between major and minor depression bears some difficulty after stroke,48 and in the major analyses of the present series we
did not make this distinction. However, in a subanalysis, infarcts affecting
prefrontosubcortical circuits on any side or on the right side seemed to be
more common in patients with major depression. Thus, minor and major depression
might be pathoanatomically different entities, as suggested by some authors.51 However, no specific location within these circuits
(eg, the pallidum or caudate) was more common in individuals with major depression.
Left hemispheric lesion prominence in patients with depression after
stroke has mostly been shown in studies 3 or more months after stroke, such
as in our series. The anatomic correlates of depression after stroke might
change over time: the left anterior lesion location might relate to a recent
stroke, and this association might be weaker or nonexistent in longer follow-up.45, 52
A critical issue in studies of pathoanatomic correlates of depression
after stroke is the brain imaging techniques used. Compared with computed
tomography (CT), MRI is superior in detecting the site, type, and extent of
infarcts, especially in deep gray matter structures. In addition, small infarcts,
WMLs, and mediotemporal lobe atrophy can also be more reliably estimated with
MRI than with CT. Most previous CT-based studies used simple descriptions
of lesion locations, eg, distance from frontal pole,4
and only recently more detailed atlas-based lesion analyses have been applied.53 Sensitivity to detect small deep lesions is likely
a factor explaining some of the difference between previous studies and the
present study. For example, in the present study, depressed patients did not
have more infarcts in the basal ganglia area as a whole than nondepressed
patients. However, when areas such as the caudate, putamen, and genu of internal
capsule were studied, differences emerged, as described.
White matter lesions related to age, clinical CVD, and vascular risk
factors have been associated with depression.54
Suggested critical locations of WMLs related to depression include the left
frontal deep white matter area.55 We applied
detailed reliable assessment of WMLs20 but
could not confirm a correlation between site or extent of WMLs and depression
after stroke. This does not necessarily contradict previous studies55 reporting a correlation with depression and WMLs,
as these studies have included older patients with and without established
CVD.
Atrophy relates to cumulative neuronal loss, and it has been suggested
to be an independent correlate of late-life depression56
and a risk factor for depression after stroke in a study matching patients
with and without depression for the size and location of their lesion and
for age and sex.3 In our study, with no such
matching procedures, we did not find a correlation between extent of atrophy
(evaluated by comparison to standard images) and depression after stroke.
Our study has several limitations. First, the patient sample is hospital
based and might be biased in patient age, stroke type, and stroke severity.
Second, we included patients with any number of infarcts on MRI to mimic a
realistic clinical situation. This makes comparison with results of older
CT-based studies that include patients with only one infarct difficult. Third,
simple ratings of atrophy and WMLs, as well as volume estimates of infarcts,
are less precise than using volumetric methods.
In conclusion, lesions affecting the frontosubcortical circuit, especially
the caudate, pallidum, and genu of internal capsule, and in particular on
the left side, are correlates of depression after stroke. This finding might
be important in understanding the pathophysiology of depressive disorders.
Furthermore, an infarct located in these critical locations should make the
clinician alert in diagnosis and treatment of eventual depression after stroke,
an independent correlate of stroke-related independence.
AUTHOR INFORMATION
Accepted for publication April 19, 2001.
This study was supported in part by grants from the Medical Council
of the Academy of Finland, Helsinki (Drs Mäntylä, Aronen, and Erkinjuntti);
the Clinical Research Institute, Helsinki University Central Hospital (Drs
Vataja, Pohjasvaara, and Mäntylä); The Finnish Alzheimer Foundation
for Research, Helsinki (Drs Vataja, Pohjasvaara, and Erkinjuntti); and the
University of Helsinki (Drs Erkinjuntti and Pohjasvaara).
We thank Vesa Kuusela, senior research officer, Statistics Finland,
Helsinki, for statistical support and review.
From the Department of Clinical Neurosciences, Memory Research Unit
(Drs Vataja, Pohjasvaara, and Erkinjuntti), the Department of Psychiatry,
Psychiatric Consultation Unit (Dr Leppävuori), the Department of Radiology
(Drs Mäntylä, Aronen, and Salonen), and the Stroke Unit (Dr Kaste),
Helsinki University Central Hospital, Helsinki, Finland; and the Department
of Clinical Radiology, University of Kuopio, Kuopio, Finland (Dr Aronen).
Corresponding author and reprints: Timo Erkinjuntti, MD, PhD, Department
of Clinical Neurosciences, Memory Research Unit, Helsinki University Central
Hospital, PO Box 300, FIN-00029 HUS, Finland (e-mail: timo.erkinjuntti{at}hus.fi).
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