Psychiatry Research: Neuroimaging 221 (2014) 86–91
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Depressive symptoms and regional cerebral blood flow 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 flow (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 five subscales of Addenbrooke's Cognitive Examinationrevised (ACE-R), correlation analysis of NPI depression scores showed a significant 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 significantly 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 flow (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 flow (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 (Lanctôt 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 flow correlates of depressive symptoms in AD without the effect of apathy and anxiety by correlation analysis. We predicted a significant 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.: þ81 86 235 7242; fax: þ81 86 235 7246. E-mail address: [email protected] (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
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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 profile 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 filter (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 significant at 100 voxels at the cluster level (simple correlation analysis). Thereafter, to remove the effect of other factors, age, five 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 specific 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 significant 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, specifically 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 coefficiency. A value of po 0.05 was accepted as significant.
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-filtered backprojection and then three-dimensionally smoothed with a Butterworth filter (order 8, cutoff 0.12 cycles/cm). The reconstructed images were corrected for gamma ray attenuation using the Chang method (μ¼0.09).
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 affine 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 (n¼ 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
49–89 4–79 4–16 0–6 0–4 0–12 8–27 32–91 3–18 1–23 0–13 10–26 4–16 3–16 80–100 0–27
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 fluency 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.
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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 fluency 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 significant 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 significant correlation between rCBF and NPI-dep scores among AD patients. Simple correlation analysis showed a significant 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 five subscales of ACE-R, correlation analysis showed a significant 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 significantly related to depressive symptoms in AD and that depressive symptoms in AD are due to a specific pathogenesis rather than a reactive phenomenon (Liao et al., 2003). The published findings on brain lateralization of decreased rCBF related to depressive symptoms in AD patients are conflicting. Lee et al. (2006) reported a significant 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, significantly 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 influence of other lesions or the severity of the disease, or it might reflect 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 significantly 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 reflect 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
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Fig. 1. (a) Correlation. The SPM (z) map of significant correlation between rCBF and NPI-dep scores among AD patients. Upper line, three-way glass view of the area of significant correlation. Lower line, three-way section of the area of significant hypoperfusion. Left, transverse, z¼ 30; central, sagittal, x ¼ 30; right, coronal, y¼24. (b) Correlation after removing effects of other factors. The SPM (z) map of significant correlation between rCBF and NPI-dep scores among AD patients after removing the effects of age, five subscale scores of ACE-R, and two subscale scores (anxiety, apathy) of NPI. Upper line, three-way glass view of the area of significant correlation. Lower line, three-way section of the area of significant hypoperfusion. Left, transverse, z¼ 34; central, sagittal, x¼ 30; right, coronal, y¼ 24.
Table 3 Regions significantly related with NPI-dep scores. Number of voxels
Region where rCBF significantly correlate with NPI-dep scores (Fig. 1a)
107
Region where rCBF significantly correlate with NPI-dep scores after removing the effect of other factorsn (Fig. 1b)
151
rCBF, regional cerebral blood flow; 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, five subscales scores of ACE-R, anxiety and apathy subscale scores of NPI.
Peak z scores
3.90 3.77 4.15
p
o 0.001 o 0.001 o 0.001
Coordinates (MNI) x
y
z
30 28 30
24 22 24
30 34 34
90
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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 19–34
SPECT SPM99 Correlation comparison 43 8–35
PET SPM99 Comparison 20 10–10
PET SPM99 Comparison 24 12–12
SPECT SPM2 Comparison 56 27–29
SPECT eZIS Comparison 44 18–26
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 significant decrease of regional cerebral blood flow among patients with depression or areas showing significant 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 find any significant area under the strict threshold of 0.01 (corrected).
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Depressive symptoms and regional cerebral blood flow 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 flow (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 five subscales of Addenbrooke's Cognitive Examinationrevised (ACE-R), correlation analysis of NPI depression scores showed a significant 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 significantly 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 flow (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 flow (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 (Lanctôt 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 flow correlates of depressive symptoms in AD without the effect of apathy and anxiety by correlation analysis. We predicted a significant 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.: þ81 86 235 7242; fax: þ81 86 235 7246. E-mail address: [email protected] (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
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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 profile 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 filter (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 significant at 100 voxels at the cluster level (simple correlation analysis). Thereafter, to remove the effect of other factors, age, five 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 specific 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 significant 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, specifically 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 coefficiency. A value of po 0.05 was accepted as significant.
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-filtered backprojection and then three-dimensionally smoothed with a Butterworth filter (order 8, cutoff 0.12 cycles/cm). The reconstructed images were corrected for gamma ray attenuation using the Chang method (μ¼0.09).
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 affine 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 (n¼ 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
49–89 4–79 4–16 0–6 0–4 0–12 8–27 32–91 3–18 1–23 0–13 10–26 4–16 3–16 80–100 0–27
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 fluency 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.
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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 fluency 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 significant 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 significant correlation between rCBF and NPI-dep scores among AD patients. Simple correlation analysis showed a significant 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 five subscales of ACE-R, correlation analysis showed a significant 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 significantly related to depressive symptoms in AD and that depressive symptoms in AD are due to a specific pathogenesis rather than a reactive phenomenon (Liao et al., 2003). The published findings on brain lateralization of decreased rCBF related to depressive symptoms in AD patients are conflicting. Lee et al. (2006) reported a significant 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, significantly 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 influence of other lesions or the severity of the disease, or it might reflect 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 significantly 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 reflect 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
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Fig. 1. (a) Correlation. The SPM (z) map of significant correlation between rCBF and NPI-dep scores among AD patients. Upper line, three-way glass view of the area of significant correlation. Lower line, three-way section of the area of significant hypoperfusion. Left, transverse, z¼ 30; central, sagittal, x ¼ 30; right, coronal, y¼24. (b) Correlation after removing effects of other factors. The SPM (z) map of significant correlation between rCBF and NPI-dep scores among AD patients after removing the effects of age, five subscale scores of ACE-R, and two subscale scores (anxiety, apathy) of NPI. Upper line, three-way glass view of the area of significant correlation. Lower line, three-way section of the area of significant hypoperfusion. Left, transverse, z¼ 34; central, sagittal, x¼ 30; right, coronal, y¼ 24.
Table 3 Regions significantly related with NPI-dep scores. Number of voxels
Region where rCBF significantly correlate with NPI-dep scores (Fig. 1a)
107
Region where rCBF significantly correlate with NPI-dep scores after removing the effect of other factorsn (Fig. 1b)
151
rCBF, regional cerebral blood flow; 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, five subscales scores of ACE-R, anxiety and apathy subscale scores of NPI.
Peak z scores
3.90 3.77 4.15
p
o 0.001 o 0.001 o 0.001
Coordinates (MNI) x
y
z
30 28 30
24 22 24
30 34 34
90
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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 19–34
SPECT SPM99 Correlation comparison 43 8–35
PET SPM99 Comparison 20 10–10
PET SPM99 Comparison 24 12–12
SPECT SPM2 Comparison 56 27–29
SPECT eZIS Comparison 44 18–26
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 significant decrease of regional cerebral blood flow among patients with depression or areas showing significant 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.
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