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Psychiatry Research: Neuroimaging 221 (2014) 8691

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Psychiatry Research: Neuroimaging


journal homepage: www.elsevier.com/locate/psychresns

Depressive symptoms and regional cerebral blood ow in


Alzheimer's disease
Seishi Terada a,n, Etsuko Oshima a, Shuhei Sato b, Chikako Ikeda a, Shigeto Nagao a,
Satoshi Hayashi a, Chinatsu Hayashibara a, Osamu Yokota a, Yosuke Uchitomi a
a
Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
b
Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

art ic l e i nf o

a b s t r a c t

Article history:
Received 31 December 2012
Received in revised form
23 October 2013
Accepted 9 November 2013
Available online 15 November 2013

Depressive symptoms are common in patients with Alzheimer's disease (AD) and increase the caregiver
burden, although the etiology and pathologic mechanism of depressive symptoms in AD patients remain
unclear. In this study, we tried to clarify the cerebral blood ow (CBF) correlates of depressive symptoms
in AD, excluding the effect of apathy and anxiety. Seventy-nine consecutive patients with AD were
recruited from outpatient units of the Memory Clinic of Okayama University Hospital. The level of
depressive symptoms was evaluated using the depression domain of the Neuropsychiatric Inventory
(NPI). The patients underwent brain SPECT with 99mTc-ethylcysteinate dimer. After removing the effects
of age, anxiety and apathy scores of NPI, and ve subscales of Addenbrooke's Cognitive Examinationrevised (ACE-R), correlation analysis of NPI depression scores showed a signicant cluster of voxels in the
left middle frontal gyrus (Brodmann area 9), similar to the areas in the simple correlation analysis. The
dorsolateral prefrontal area is signicantly involved in the pathogenesis of depressive symptoms in AD,
and the area on the left side especially may be closely related to the depressive symptoms revealed
by NPI.
& 2013 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Alzheimer's disease (AD)
Depression
Depressive symptom
Regional cerebral blood ow (rCBF)

1. Introduction
Alzheimer's disease (AD) is the leading cause of late-onset
dementia worldwide. Depressive symptoms are common in
patients with AD and increase the caregiver burden (Akiyama
et al., 2008; Kataoka et al., 2010). Although the etiology and
pathologic mechanism of depressive symptoms in AD patients
remain unclear, a biological marker that objectively evaluates
depressive symptoms might be useful (Kataoka et al., 2010).
There have been several studies on the relationship of depressive
symptoms to regional cerebral blood ow (rCBF) or regional cerebral
glucose metabolism in AD (Hirono et al., 1998; Liao et al., 2003;
Holthoff et al., 2005; Lee et al., 2006; Levy-Cooperman et al., 2008;
Akiyama et al., 2008). Data from previous functional imaging studies
have mainly supported the role of the dorsolateral prefrontal region
(Hirono et al., 1998; Holthoff et al., 2005; Lee et al., 2006; LevyCooperman et al., 2008; Akiyama et al., 2008). Associations with the
anterior cingulate have been described inconsistently (Hirono et al.,

1998; Liao et al., 2003). However, most of these studies did not
exclude AD patients with apathy or anxiety, although depression
commonly coexists with apathy and anxiety (Kataoka et al., 2010).
The presence of apathy is particularly germane as anterior cingulate
and prefrontal hypoperfusion has been associated with apathy
symptoms in AD patients (Lanctt et al., 2007). Moreover, almost
all studies were performed in a cross-sectional setting (Hirono et al.,
1998; Holthoff et al., 2005; Lee et al., 2006; Levy-Cooperman et al.,
2008; Akiyama et al., 2008).
In this study, we tried to identify the cerebral blood ow
correlates of depressive symptoms in AD without the effect of apathy
and anxiety by correlation analysis. We predicted a signicant
relationship between depressive symptoms and rCBF in the dorsolateral prefrontal regions of AD patients.

2. Methods
2.1. Subjects

n
Correspondence to: Department of Neuropsychiatry, Okayama University Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences. Tel.: 81 86 235 7242;
fax: 81 86 235 7246.
E-mail address: terada@cc.okayama-u.ac.jp (S. Terada).

0925-4927/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.pscychresns.2013.11.002

Seventy-nine consecutive patients with Alzheimer's disease were recruited


from the outpatient units of the Memory Clinic of Okayama University Hospital
between September 2008 and April 2012 according to the following criteria. They
all (i) underwent general physical and neurological examinations and extensive

S. Terada et al. / Psychiatry Research: Neuroimaging 221 (2014) 8691

87

laboratory testing, including thyroid function tests, serum vitamin B12, and syphilis
serology; (ii) took the revised Addenbrooke's Cognitive Examination (ACE-R)
(Yoshida et al., 2012), the Mini Mental State Examination (MMSE) (Folstein et al.,
1975), the Frontal Assessment Battery (FAB) (Kugo et al., 2007); (iii) underwent
single photon emission computed tomography (SPECT) with 99mTc-ethylcysteinate
dimer of the brain as well as magnetic resonance imaging (MRI) of the head; and
(iv) were diagnosed with probable AD according to the criteria formulated by
the NINCDS-ADRDA (McKhann et al., 1984). The exclusion criteria were
(i) complications from other neurological diseases or illnesses; (ii) history of
mental illness or substance abuse prior to the onset of dementia; (iii) evidence of
focal brain lesions on head MRI; (iv) treatment with cholinesterase inhibitors,
memantine, antipsychotics, antidepressants, or anxiolytic drugs; and (v) left
handedness or ambidexterity.
The prole of each subject (age, sex, months of disease duration, and years of
education) was obtained. Scores on three subscales (depression, anxiety, and
apathy) of the Neuropsychiatric Inventory (NPI), Barthel Index, and Functional
Assessment Questionnaire (FAQ) were rated by a trained clinical psychologist,
based on the information from family caregivers. The Clinical Dementia Rating
(CDR) (Hughes et al., 1982) score was rated by the chief clinician.

images were then smoothed with an isotropic Gaussian kernel lter (12 mm fullwidth at half-maximum).
We applied a simple regression method using SPM8 to obtain the correlation
between NPI-dep scores and rCBF imaging data from SPECT among 79 AD subjects. The
analysis used a threshold of po0.001 (uncorrected) at the voxel level, and results were
considered signicant at 100 voxels at the cluster level (simple correlation analysis).
Thereafter, to remove the effect of other factors, age, ve subscale scores of ACE-R and
two subscale scores (anxiety, apathy) of NPI were entered into the model as nuisance
covariates, and we performed a simple regression method using SPM8 to obtain the
correlation between NPI-dep and rCBF imaging data from SPECT. The specic effects of
depressive symptoms were tested using [ 1] t-contrast with an additional zero for the
scores of other factors, assuming that the presence of the symptoms would be uniquely
associated with decreased rCBF. In the latter analysis, a threshold of po0.001
(uncorrected) was used at the voxel level, and results were considered signicant at
100 voxels at the cluster level. In both analyses, global normalization was performed by
proportional scaling with the mean voxel value. Masking was applied using the
threshold method (0.8 times the global value). In both analyses, global normalization
was performed by proportional scaling with the mean voxel value. Masking was applied
using the threshold method (0.8 times the global value).

2.2. Instruments

2.6. Statistical analysis

NPI is a valid and reliable instrument for measuring non-cognitive symptoms in


dementia (Cummings et al., 1994; Hirono et al., 1997). It is a caregiver-based tool
that assesses ten different domains in dementia. The NPI gives a composite score
for each domain, which is the product of frequency multiplied by severity
subscores: scores from 1 to 4 (with 4 being the most severe) for the frequency
and from 1 to 3 (with 3 being the most severe) for the severity of each behavior
(Akiyama et al., 2008). The maximum attainable score was 12. In this study, three
subscales (depression, anxiety, and apathy) were used.
ACE-R was developed to provide a brief test sensitive to early stage dementia,
and is capable of differentiating between dementia subtypes including AD,
frontotemporal dementia, progressive supranuclear palsy, and other parkinsonian
syndromes (Mioshi et al., 2006). ACE-R includes MMSE, but extends it to
encompass important areas not covered by MMSE, such as frontal-executive
function and visuospatial skills. For this study, we used the Japanese version of
ACE-R described by Yoshida et al. (2012).
The Barthel Index consists of 10 items that measure a person's daily functioning, specically the activities of daily living and mobility (Wade and Collin, 1988).
The total Barthel Index score ranges from 0 to 100. A higher score indicates a better
performance. The Functional Assessment Questionnaire (FAQ) measures functional
activities of older adults using the patient's partner as an informant (Pfeffer et al.,
1982). The FAQ consists of ten items, and the score on each item ranges from 0 to 3.
A higher score indicates more severe impairment.

Statistical analysis was performed using the SPSS 14.0J software program (SPSS
Inc., Chicago, IL). The correlation analysis of NPI-dep scores to other clinical
characteristics was done by Pearson's correlation coefciency. A value of po 0.05
was accepted as signicant.

2.3. Ethics
This study was approved by the Internal Ethical Committee of Okayama
University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences.
After a complete description of the study to the subjects and their relatives, written
informed consent was obtained.

2.4. Brain perfusion SPECT imaging


All subjects were examined by brain perfusion SPECT. Patients were examined
in a comfortable supine position with their eyes closed in quiet surroundings. Ten
minutes after intravenous administration of 99mTc-ethylcysteinate dimer (ECD,
600MBq, Daiichi Radioisotope Laboratories Ltd., Tokyo, Japan), SPECT images were
obtained using a triple-head, rotating gamma camera interfaced to a minicomputer
(GCA9300A/ DI; Toshiba, Tokyo, Japan) equipped with a fanbeam, low-energy,
high-resolution collimator. Sixty projection images over a 3601 angle in a 128  128
matrix were acquired. All images were reconstructed using ramp-ltered backprojection and then three-dimensionally smoothed with a Butterworth lter (order
8, cutoff 0.12 cycles/cm). The reconstructed images were corrected for gamma ray
attenuation using the Chang method (0.09).

2.5. Data analysis


Spatial reprocessing and statistical analysis of images was performed on a voxelby-voxel basis using Statistical Parametric Mapping 8 (SPM8, Wellcome Department
of Imaging Neuroscience, UK) running on MATLAB (The Mathworks, Inc., Natick, MA,
USA). All SPECT images of each subject were normalized to the standard brain of the
Montreal Neurological Institute (MNI), and spatial normalization was performed with
12-parameter afne and non-linear transformations (Friston et al., 1995). The voxel
sizes of the reslice option were 2 mm  2 mm  2 mm. The non-linear parameters
were set at 25 mm cut-off basis functions and 16 iterations. All the normalized SPECT

3. Results
3.1. Demographic characteristics
Demographic characteristics are shown in Table 1. Among 79
AD patients, 45 were women and 34 were men. For dementia
severity, 47 patients had CDR scores 0.5, 31 had CDR 1, and one
patient had CDR 2. On the NPI depression score, 51 patients had a
score of 0, seven patients scored 1, ten patients scored 2, ten
patients scored 3, and one patient had a score of 6.
Table 1
Clinical characteristics (n 79).

Age (years)
Duration
Education
NPI-dep
NPI-anxiety
NPI-apathy
MMSE
ACE-R
Attention
Memory
Fluency
Language
Visuospatial
FAB
Barthel
FAQ

Mean

S.D.

Range

76.2
28.3
11.0
0.8
0.2
2.0
21.4
65.4
13.7
10.3
6.4
22.0
12.9
10.3
96.9
12.0

7.6
16.6
2.5
1.3
0.7
2.8
4.2
13.3
3.2
5.0
2.9
3.3
3.0
2.8
5.4
7.2

4989
479
416
06
04
012
827
3291
318
123
013
1026
416
316
80100
027

Duration, disease duration (months);


Education, years of education;
NPI-Dep, depression scores of neuropsychiatric inventory;
Duration, duration of disease;
Education, years of education;
MMSE, mini mental state examination;
ACE-R, revised Addenbrook's cognitive examination;
Attention, attention and orientation scores of ACE-R;
Memory, memory scores of ACE-R;
Fluency, word uency scores of ACE-R;
Language, language scores of ACE-R;
Visuospatial, visuospatial scores of ACE-R;
FAB, frontal assessment battery;
Barthel. Barthel index;
FAQ, functinal assessment questionnaire.

88

S. Terada et al. / Psychiatry Research: Neuroimaging 221 (2014) 8691

Table 2
Correlation analysis of NPI-Dep.
NPI-Dep
Age
Duration
Education
NPI-anxiety
NPI-apathy
MMSE
ACE-R
Attention
Memory
Fluency
Language
Visuospatial
FAB
Barthel
FAQ

 0.166
0.001
 0.015
0.487nnn
0.340nn
 0.045
 0.026
0.023
 0.132
0.189
 0.142
0.050
0.121
 0.018
0.063

NPI-Dep, depression scores of neuropsychiatric inventory;


Duration, duration of disease;
Education, years of education;
MMSE, mini mental state examination;
ACE-R, revised Addenbrook's cognitive examination;
Attention, attention and orientation scores of ACE-R;
Memory, memory scores of ACE-R;
Fluency, word uency scores of ACE-R;
Language, language scores of ACE-R;
Visuospatial, visuospatial scores of ACE-R;
FAB, frontal assessment battery;
Barthel. Barthel index;
FAQ, functinal assessment questionnaire;
n
p o0.05.
nn

po 0.01.
p o 0.001.

nnn

Correlation analyses revealed that the NPI-dep score had no


signicant correlation to demographic characteristics, cognitive
functions, or activities of daily living, except for NPI-anxiety, and
NPI-apathy scores (Table 2).
3.2. rCBF
Fig. 1a and Table 3 show the SPM (z) map of signicant
correlation between rCBF and NPI-dep scores among AD patients.
Simple correlation analysis showed a signicant cluster of voxels
in the left middle frontal gyrus (Brodmann area 9). Table 3 shows
the probability results of the SPM analysis and the location of peak
z scores in terms of MNI coordinates.
After removing the effects of age, anxiety and apathy scores on
NPI, and ve subscales of ACE-R, correlation analysis showed a
signicant cluster of voxels in the left middle frontal gyrus
(Brodmann area 9), similar to the areas in the simple correlation
analysis (Fig. 1b).

bilateral precuneus different in AD patients with and without


depression. Their study included more severely impaired AD
patients (mean MMSE score was 12.9) compared to those in other
studies (Table 4). In their study, the severity of cognitive impairment was measured by MMSE scores. MMSE is useful, but too
simple to validate the similarity of cognitive impairment between
two groups. The difference between cognitive impairments in AD
patients with and without depression might indicate the difference of rCBF in the bilateral anterior cingulate, left posterior
cingulate and bilateral precuneus. Based on the above, we suppose
that the dorsolateral prefrontal area is signicantly related to
depressive symptoms in AD and that depressive symptoms in AD
are due to a specic pathogenesis rather than a reactive phenomenon (Liao et al., 2003).
The published ndings on brain lateralization of decreased
rCBF related to depressive symptoms in AD patients are conicting. Lee et al. (2006) reported a signicant decrease of rCBF in the
right superior frontal region, and Levy-Cooperman et al. (2008)
showed a decrease of rCBF in the right dominant dorsolateral and
superior prefrontal regions . In both studies, apathy and anxiety
coexisting with depression were not considered, and the NPI-dep
score was not used to divide positive and negative groups. In the
other four studies, signicantly related regions related to depressive symptoms were the bilateral superior frontal region (Hirono
et al., 1998), left dorsolateral region (Holthoff et al., 2005), left
prefrontal region (Akiyama et al., 2008), and left middle frontal
gyrus (our study). In the latter four studies, the NPI-dep score was
used to evaluate depressive symptoms (Table 4). Additionally,
Holthoff et al. (2005) tried to decrease the effect of coexisting
apathy statistically. In the study of Akiyama et al. (2008), the two
groups (depressive and not depressive) showed similar scores on
apathy and anxiety scales. In our study, correlation analyses after
removing the effects of apathy and anxiety scores revealed a
similar result. Laterality might be caused by several factors, such
as the inuence of other lesions or the severity of the disease, or it
might reect sample size, statistical threshold, or criteria used to
score depressive symptoms (Kataoka et al., 2010). Although not
conclusively, we can say that the left dorsolateral prefrontal region
is closely related to the depressive symptoms evaluated by NPI.
Many studies have reported that abnormalities in cortical-limbic
or cortical-subcortical circuits related to emotional regulation are
implicated in the mechanisms underlying emotional dysfunction
(Peng et al., 2012). The middle frontal gyrus is located in the
dorsolateral prefrontal cortex (DLPFC), and the DLPFC circuit is one
of the prefrontal-subcortical circuits, some of which are involved
in regulation of affect (Peng et al., 2012).
Several studies have found that depression is generally associated with less left frontal activity and/or more right frontal
activity (Bell et al., 1998; Minnix et al., 2004). It has been
hypothesized that relative left frontal activity is related to positive
emotion and approach motivation, whereas relative right frontal
activity is related to negative emotion and withdrawal motivation
(Davidson et al., 2000; Minnix et al., 2004). In AD, the left frontal
region might induce relative right frontal activity and negative
emotion.

4. Discussion
There have been seven published studies, including this one, on
rCBF or regional cerebral glucose metabolism among AD patients
with depressive symptoms (Table 4) (Hirono et al., 1998; Liao et al.,
2003; Holthoff et al., 2005; Lee et al., 2006; Levy-Cooperman et al.,
2008; Akiyama et al., 2008).
Among the seven studies, all except one (Liao et al., 2003),
showed that dorsolateral frontal regions are signicantly related to
depressive symptoms in AD. In only the study of Liao et al. is rCBF
in the bilateral anterior cingulate, left posterior cingulate, and

5. Limitations
The results in this study should be interpreted with some
caution. Firstly, domain scores lower than 4 points of NPI-dep
reect behavioral symptoms of mild severity referred to as a
subclinical disturbance (Holthoff et al., 2005). In this study, almost
all patients had scores less than 4 in the NPI-dep domain.
However, the degree of hypoperfusion in the middle frontal gyrus
was correlated with the severity of depressive symptoms in our

S. Terada et al. / Psychiatry Research: Neuroimaging 221 (2014) 8691

89

Fig. 1. (a) Correlation. The SPM (z) map of signicant correlation between rCBF and NPI-dep scores among AD patients. Upper line, three-way glass view of the area of
signicant correlation. Lower line, three-way section of the area of signicant hypoperfusion. Left, transverse, z 30; central, sagittal, x  30; right, coronal, y24.
(b) Correlation after removing effects of other factors. The SPM (z) map of signicant correlation between rCBF and NPI-dep scores among AD patients after removing the
effects of age, ve subscale scores of ACE-R, and two subscale scores (anxiety, apathy) of NPI. Upper line, three-way glass view of the area of signicant correlation. Lower
line, three-way section of the area of signicant hypoperfusion. Left, transverse, z 34; central, sagittal, x  30; right, coronal, y 24.

Table 3
Regions signicantly related with NPI-dep scores.
Number of voxels

Region where rCBF signicantly correlate with NPI-dep scores (Fig. 1a)

107

Region where rCBF signicantly correlate with NPI-dep scores after


removing the effect of other factorsn (Fig. 1b)

151

rCBF, regional cerebral blood ow; NPI-Dep, depression scores of neuropsychiatric inventory.
Voxels, number of voxels; Z scores, peak Z scores; MNI, Montreal Neurological Institute.
n

Other factors are age, ve subscales scores of ACE-R, anxiety and apathy subscale scores of NPI.

Peak z scores

3.90
3.77
4.15

o 0.001
o 0.001
o 0.001

Coordinates (MNI)
x

 30
 28
 30

24
22
24

30
34
34

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S. Terada et al. / Psychiatry Research: Neuroimaging 221 (2014) 8691

Table 4
Studies on the cerebral regions related with depressive symptoms in Alzheimer's disease.

Imaging
Software
Statistics
Number
Two
groups
Criteria
mean
MMSE
Regions

Hirono et al. (1998)

Liao et al. (2003)

Holthoff et al.
(2005)

Lee et al.
(2006)

Levy-Cooperman et al.
(2008)

Akiyama et al.
(2008)

this study
(2013)

PET
ROI
Comparison
53
1934

SPECT
SPM99
Correlation comparison
43
835

PET
SPM99
Comparison
20
1010

PET
SPM99
Comparison
24
1212

SPECT
SPM2
Comparison
56
2729

SPECT
eZIS
Comparison
44
1826

SPECT
SPM8
Correlation
79

NPI-dep o or 121.2

SCID
12.9

NPI-dep o or 422.2

NIMH criteria
nm

CSDD 0-7 or 823.6

NPI-dep o or 1(16.5)n

NPI-dep
21.4

bil superior Fr, lt anterior


Cin

bil anterior Cin, lt


posterior
Cin, bil precuneus

lt dorsolateral
(preFr)

rt superior Fr

dorsolateral &
superior preFr (rt Z lt)

lt preFr

lt preFr

ROI, manually placed range of interest; SPM, statistical parametric mapping;


eZIS, after eZIS analysis, semiquantitatively scored from 0 to 2;
Number, number of patients with Alzheimer's disease;
Two groups, number of two groups depression positive and negative;
Criteria, criteria for grouping;
Regions, areas showing signicant decrease of regional cerebral blood ow among patients with depression or areas showing signicant correlation to depressive symptoms;
NPI-dep, depression score of neuropsychiatric inventory;
SCID, structured clinical interview for the Diagnostic Statistical Manual of mental disorders ed 3 revised;
CSDD, Cornell scale for depression in dementia; MMSE, mini-mental state examination
n, mean score of the revised Hasegawa Dementia Scale (full score 30);
NIMH, NIMH criteria for depression in Alzheimer's disease;
nm, Not mentioned; bil, bilateral; r, right; lt, left; Fr, frontal; Cin, cingulate; AchE inhibitors, acetylcholine.

analysis. Therefore, we suppose that hypoperfusion in the middle


frontal gyrus was involved in the expression of clinically depressive symptoms in patients with AD. Secondly, although the
threshold of 0.001 (uncorrected) may be regarded as the standard
threshold currently, we did not nd any signicant area under the
strict threshold of 0.01 (corrected).

Acknowledgments
We sincerely thank Ms. Ido, Ms. Horiuchi, Ms. Imai, and Ms.
Yabe for their skillful assistance. This work was supported by
Grants from the Japanese Ministry of Education, Culture, Sports,
Science and Technology (21591517), and the Zikei Institute of
Psychiatry.
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