Regional Cerebral Blood Flow Abnormalities Associated With Apathy and Depression in Alzheimer Disease

Transcription

1 ORIGINAL ARTICLE Regional Cerebral Blood Flow Abnormalities Associated With Apathy and Depression in Alzheimer Disease Ji Yeon Kang, MD,* Jae Sung Lee, PhD,*wz Hyejin Kang, PhD,* Hae-Woo Lee, MD,y Yu Kyeong Kim, MD, PhD,* Hong Jin Jeon, MD, PhD,8 June-Key Chung, MD, PhD,* Myung Chul Lee, MD, PhD,* Maeng Je Cho, MD, PhD,y and Dong Soo Lee, MD, PhD*z Abstract: The aim of this study was to identify brain areas related to apathy or depression in patients with Alzheimer disease (AD). Eighty-one AD patients were enrolled in this prospective study. 99m Tc-HMPAO single photon emission computed tomography was performed to evaluate regional cerebral blood flow (rcbf). According to the Neuropsychiatric Inventory subscores of apathy and depression, 9 patients were classified as clinically significant (cs) depressed and non-cs-apathetic (D+) groups and 9 were classified as cs-apathetic and non-cs-depressed (A+) groups. In addition, 18 patients were classified as age-matched and Mini-Mental State Examination-matched disease control groups (D, A ). The significance of rcbf differences between groups and the correlation between rcbf and subscores in 81 AD patients were estimated by SPM (uncorrected P<0.005) analysis. D+ patients had significantly lower perfusion in the right orbitofrontal and inferior frontal gyri than D patients, whereas A+ patients had this in the right amygdala, temporal, posterior cingulate, right superior frontal, postcentral, and left superior temporal gyri than A patients. The negatively correlated areas with depression subscores included the left inferior frontal and the right middle frontal gyri and those with apathy subscores included the right temporal and right medial frontal gyri. We suggest that this finding may indicate that apathy and depression in AD patients involve distinct functional circuits. Key Words: Alzheimer disease, brain SPECT, apathy, depression, regional cerebral blood flow, HMPAO (Alzheimer Dis Assoc Disord 2012;26: ) Alzheimer disease (AD) is the most frequent type of dementia and is likely to account for two-thirds of all dementia cases. 1 Behavioral disturbances in AD have received considerably less attention than cognitive impairment, but they are a greater burden to caregivers than cognitive decline. 2 Apathy and depression are common symptoms of AD, 3 and in particular, depression increases the likelihood of institutionalization and hastens death 4 and apathy is associated with increasing parkinsonism, 5 which can be a poor prognostic factor of AD. Received for publication October 19, 2010; accepted May 20, From the *Departments of Nuclear Medicine; wbrain and Cognitive Sciences; zbiomedical Sciences; ypsychiatry; zmolecular Medicine and Biopharmaceutical Science, Seoul National University, Yungun- Dong, Chongno-Gu; and 8Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea. Supported by grants from the Korean Research Foundation funded by the Korean Government (KRF E00443), and the World Class University Program (R ) of the Korean Science and Engineering Foundation (KOSEF). The authors declare no conflicts of interest. Reprints: Jae Sung Lee, PhD, Departments of Nuclear Medicine, Brain and Cognitive Sciences, and Biomedical Sciences, Seoul National University, 28 Yungun-Dong, Chongno-Gu, Seoul , Korea, ( jaes@snu.ac.kr). Copyright r 2012 by Lippincott Williams & Wilkins Apathy is defined as a lack of motivation, whereas depression concerns sadness and other related emotions and behaviors. Despite their quite different characteristics, apathy and depression frequently manifest simultaneously and share manifestations, such as a lack of interest, anergia, psychomotor slowing, and fatigue. 6 It is unclear whether these common manifestations reflect a common pathophysiology that depression and apathy share. These overlapping features and their frequent co-occurrence may impede the differential diagnosis of apathy and depression, which is of importance because they require different treatment approaches 7,8 and some medication for depression can worsen apathy. 9 Identifying and excluding the overlap between apathy and depression in AD patients and characterizing them objectively are necessary to understand the functional circuits involved in each of these symptoms and to implicate the brain regions that are not related to the co-occurrences of apathy and depression, that is, uniquely related to the apathy or depression. However, previous single photon emission computed tomography (SPECT) studies have addressed apathy and depression independently and thus have identified brain regions with less consideration of the overlap between apathy and depression. In this study, we selected depressive patients without apathy and apathetic patients without depression to identify brain areas related to apathy or depression and less affected by their co-occurrence in patients with AD using 99m Tc-HMPAO SPECT. METHODS Patients A total of 81 patients diagnosed with AD participated in a prospective Neuroimaging Study of Behavioral and Psychological Symptoms of Dementia at our institute. AD was diagnosed using the clinical criteria of the National Institute of Neurological and Communicative Disorders Association. The clinical and imaging evaluations performed in this study included complete medical history taking, a physical and a neurological examination, the applications of the CERAD-K battery, the Neuropsychiatric Inventory (NPI), and the Korean version of the Montgomery Asberg Depression Rating Scale (MADRS), magnetic resonance imaging and 99m Tc-HMPAO SPECT scans, and routine blood tests (including liver function tests, vitamin B12 level, folate level, BUN/Cr, and thyroid hormones). Exclusion criteria included a previous or a current neurologic disorder, alcohol or substance abuse, and a major systemic disease with disturbance in brain function. Patients and families provided informed consent before enrollment in this study. Alzheimer Dis Assoc Disord Volume 26, Number 3, July September

2 Kang et al Alzheimer Dis Assoc Disord Volume 26, Number 3, July September 2012 Nine patients with clinically significant depression and without clinically significant apathy were classified as the D+ group (NPI subscore for depression Z4 and NPI subscore for apathy r2). Age-matched and Mini-Mental State Examination (MMSE)-matched disease controls (9 patients, D group) were selected among the 32 patients without depression and apathy (NPI subscore for depression = 0 and subscore for apathy = 0). The A+ group (9 patients, NPI subscore for apathy Z4 and NPI subscore for apathy r2) was determined in the same way as the D+ group. The A group, as agematched and MMSE-matched disease controls, included 9 patients without depression and apathy (NPI subscore for depression = 0 and subscore for apathy = 0) and 1 patient with a subscore of 1 for depression (NPI subscore for depression = 1 and subscore for apathy = 0). In the D and A groups, patients with the remaining NPI subscores >9 were not selected to reduce the effects of other behavioral symptoms, except depression and apathy. In the D+, D, A+, and A groups, patients with an MMSE score <10 were not selected. Image Acquisition and Analysis With a patient in the supine position, with the eyes closed, in a quiet room with dimmed lights, 99m Tc-HMPAO of 555 MBq was administered and a SPECT image was acquired using a triple-head gamma camera (Prism 3000; Picker International, Cleveland, OH) equipped with a lowenergy, high-resolution fan beam collimator. The energy window was set at 140 kev with a 15% width. One hundred and twenty projections were acquired, in the step-and-shoot mode, and filtered using a 2D Metz filter (x = 1.5B2.0). Transaxial images were reconstructed as matrices using a filtered back projection algorithm and corrected for gamma ray attenuation using Chang s method. 10 SPECT data were analyzed with statistical parametric mapping (SPM5, Wellcome Department of Cognitive Neurology, London, UK). All images were spatially normalized onto the 99m Tc-HMPAO SPECT standard template provided by SPM software to remove inter-patient anatomic variability. 13,14 Spatially normalized images were smoothed by convolution using an isotropic Gaussian kernel with 16-mm full-width at half-maximum. Voxel counts were normalized to the global mean cerebral blood flow (proportional scaling in the SPM global normalization option). Statistical Analysis The Mann-Whitney test and t-test were performed to compare differences between groups using the SPSS version 16.0 (SPSS, Inc, Chicago, IL). Regional cerebral blood flows (rcbfs) in the D+ and D groups, and those in the A+ and A groups were compared using a 2-sample t- test. In addition, the correlation between rcbfs and the subscores for apathy and depression was examined in the entire group of 81 AD patients. Both in the SPM intergroup and in the correlation analyses, we used age, sex, and MMSE scores as the nuisance variables. The statistical threshold was set to an uncorrected P value = at the voxel level and the extent threshold was set at >30 voxels. RESULTS Patient Characteristics Demographic data are provided in Table 1. The mean age, MMSE score, and duration of education were not significantly different between the D+ and D groups and the A+ and A groups. In the D+ group, the mean value of the depression subscores was 5.3 and in the A+ group the mean value of the apathy subscores was 5.9. In disease controls (D and A groups), the mean values of subscores for depression and apathy were <1 and of the sum of the remaining subscores (ie, total subscores) were <4. The difference in the MADRS among D+, A+, and disease control groups represented that group selection according to NPI items showed a stepwise depressive symptomatology. Group Comparison The results of comparisons between the D+ and D groups using SPM are shown in Figure 1. The coordinates of areas showing significantly lower perfusion in D+ patients are listed in Table 2. rcbf in the right inferior frontal and orbitofrontal gyri was significantly lower in D+ patients than in D patients. The significant hypoperfusion areas in the A+ group compared with the A group involved a wider range of cerebral cortices than indicated by the comparison between the D+ and D groups (Table 3; Figure 2). The largest cluster included the right amygdala and the middle temporal gyri. The posterior cingulate, right superior frontal, postcentral, and left superior temporal gyri were TABLE 1. Demographic Data of D+, A+, and Control Groups D+ (n = 9) D (n = 9) P A+ (n = 9) A (n = 9) P Sex (M/F) 0/9 0/9 3/6 4/5 Age 74.5 ± ± ± ± MMSE 16.3 ± ± ± ± Education (y) 2.3 ± ± ± ± Duration of disease (code)* 3.4 ± ± ± ± MADRS 19.3 ± ± 5.3 < ± ± Depression subscore 5.3 ± < ± ± Apathy subscore 0.8 ± ± <0.001 Total subscores 19.1 ± ± 1.9 < ± ± *The durations of disease (estimated) were recorded as a code, not as months; 1: <6 months, 2: 6 to 12 months, 3: 12 to 24 months, 4: >24 months. In 3 patients (2 in D+ and 1 in D ), the information about duration was not obtained. D+, AD patients with clinically significant depression and without clinically significant apathy; D, AD patients without apathy and depression, matched disease controls; A+, AD patients with clinically significant apathy and without clinically significant depression; A, AD patients without apathy and depression, matched disease controls; MADRS, Montgomery-Asberg Depression Rating Scale. Data are the mean ± SD r 2012 Lippincott Williams & Wilkins

3 Alzheimer Dis Assoc Disord Volume 26, Number 3, July September 2012 Apathy and Depression in Alzheimer Disease clusters >190 voxels. The small clusters (<100 voxels) were the right inferior frontal, bilateral precentral gyri, and anterior cingulate gyri. Reduced cerebral perfusion was observed in the right medial frontal, parahippocampal, fusiform gyri, and paracentral lobule (Fig. 3) in the A+ group than the D+ group. There was no significant difference in rcbf in the D+ group compared with the A+ group. Correlation Analysis Correlation analysis was performed between rcbfs and the subscores for depression and apathy in 81 AD patients (M:F = 15:66; age, 72.4 ± 7.4 y; MMSE, 16.4 ± 6.4). There were 39 patients (48%) with depression subscores Z1 (age, 72.5 ± 7.2; MMSE, 16.7 ± 6.2; subscores 3.9 ± 2.7; disease duration (code) 3.5 ± 0.9) and 36 patients (44%) with apathy subscorez1 (age, 71.5 ± 7.7; MMSE, 15.8 ± 5.7; subscores, 4.7 ± 3.1; disease duration (code), 3.5 ± 0.9). The negatively correlated areas with the depression subscores were small clusters in the left inferior frontal, right middle frontal gyri, and right superior temporal area (Table 4; Fig. 4). The negatively correlated regions with the apathy subscores involved large clusters in the right temporal and medial frontal gyri. The other clusters included the bilateral precentral, superior frontal, right middle frontal, parahippocampal gyri, and left insula (Table 5; Fig. 5). FIGURE 1. Brain areas with lower rcbf in the D+ group than the D group (uncorrected P<0.005). D+, AD patients with clinically significant depression and without clinically significant apathy; D, AD patients without apathy and depression, matched disease controls. AD indicates Alzheimer disease; rcbf, regional cerebral blood flow. DISCUSSION In this study, to achieve a better discrimination of the scores between the groups and to obtain a larger sample size, the selection criteria included NPI scores Z4 for the symptom domain and NPI scores r2 for the other symptom domains. Despite the fact that the mean values of subscores for apathy and depression were <1 in the D and A groups, these criteria are imperfect to exclude the co-occurrence of depression and apathy completely. This is the first comparative study of rcbf related to apathy and depression with respect to their co-occurrence. The results of this study will help to identify the regions that are related to clinically significant depression and apathy, and are less affected by their co-occurrence. Previous SPECT studies have reported that AD patients with depression have reduced rcbfs in the prefrontal cortex, cingulate cortex, precuneus, and left temporal cortex. 14 Furthermore, reduced glucose metabolism in the bilateral superior frontal and left anterior cingulate cortices, 15 in the left superior and inferior frontal cortices, 16,17 and in parietal lobes 18 has been reported in AD patients with depression. TABLE 2. Brain Areas With Lower Perfusion in the D+ Group Than in the D group (Uncorrected P < 0.005) Regions Voxels x y z Z Score P Inferior frontal gyrus, Rt Inferior frontal gyrus, Rt Orbitofrontal gyrus, Rt D+, AD patients with clinically significant depression and without clinically significant apathy; D, AD patients without apathy and depression, matched disease controls. r 2012 Lippincott Williams & Wilkins 219

4 Kang et al Alzheimer Dis Assoc Disord Volume 26, Number 3, July September 2012 TABLE 3. Brain Areas With Lower Perfusion in the A+ Group Than in the A Group (Uncorrected P < 0.005) Regions Voxels x y z Z Score P Amygdala, Rt Middle temporal gyrus, Rt Superior temporal gyrus, Lt Inferior temporal gyrus, Lt Posterior cingulate, Rt Parahippocampal gyrus, Rt Precentral gyrus, Lt Inferior frontal gyrus, Lt Inferior parietal lobule, Rt Superior frontal gyrus, Rt Medial frontal gyrus, Lt Postcentral gyrus, Rt Paracentral lobule, Rt Paracentral lobule, Rt Precentral gyrus, Rt A+, AD patients with clinically significant apathy and without clinically significant depression; A, AD patients without apathy and depression, matched disease controls. Disruptions of the frontostriatal and limbic pathways have been proposed as a model of depression in various neurologic diseases Many studies on primary depression have reported frontal and cingulate abnormalities, which is in general agreement with the pattern observed in neurological depression In this study, the left inferior and orbitofrontal gyri were the regions related to depression that were less affected by apathy. The correlation analysis for depression subscores showed that the negatively correlated areas were the left inferior frontal and right middle frontal regions, which are in agreement with previous studies. Previous studies demonstrated that apathetic patients with AD had abnormal rcbfs in the orbitofrontal FIGURE 2. Brain areas with lower rcbf in the A+ group than the A group (uncorrected P < 0.005). A+, AD patients with clinically significant apathy and without clinically significant depression; A, AD patients without apathy and depression, matched disease controls. AD indicates Alzheimer disease; rcbf, regional cerebral blood flow r 2012 Lippincott Williams & Wilkins

5 Alzheimer Dis Assoc Disord Volume 26, Number 3, July September 2012 Apathy and Depression in Alzheimer Disease FIGURE 3. Brain areas with lower rcbf in the A+ group than the D+ group (uncorrected P<0.005). A+, AD patients with clinically significant apathy and without clinically significant depression; D+, AD patients with clinically significant depression and without clinically significant apathy. AD indicates Alzheimer disease; rcbf, regional cerebral blood flow. cortex A previous correlation study revealed that an apathy inventory representing lack of interest was negatively correlated with rcbf in the right orbitofrontal gyrus. 32 Furthermore, Wallis proposed that the orbitofrontal cortex integrates sensory, affective, and motivational information to derive potential reward outcome values in a model study of neuronal mechanisms underlying decision-making in the prefrontal cortex. 33 A correlation between apathy and the anterior cingulate cortex has been observed in several SPECT studies. 29,31,32,34,35 Furthermore, the anterior cingulate cortex is known to function as an interface for emotion, cognition, drive, and motor control. 36 However, in our study, abnormal rcbf in the anterior cingulate cortex was observed in a very small cluster in the A+ group than in the A group. Also, in the correlation analysis for the apathy subscore, the anterior cingulate cortex was not found. A previous FDG-PET study also demonstrated that metabolic abnormalities of the anterior cingulate cortex TABLE 4. Negative Correlation With NPI Subscores for Depression (Uncorrected P < 0.005) Regions Voxels x y z Z Score Inferior frontal gyrus, Lt Superior temporal, Rt Medial frontal gyrus, Rt P were not relevant to apathy in patients with early AD. 16 The authors presumed that the pathway related to orbitofrontal regions was involved first, and that functional deficits in additional pathways become apparent as the disease progresses in apathetic patients. Although in this study, the A+ patients did not have early disease, they seemed to be at a disease stage between the involvements of the orbitofrontal and anterior cingulate cortices. The current study showed that in apathetic patients, large clusters in the right temporal gyri were observed in comparison and correlation studies. The temporal cortex has been reported less frequently than the anterior cingulate or the orbitofrontal area in previous studies of apathy in AD. 30,31,37 This region, together with the right amygdala, is suggested to be part of the orbitofrontal circuit. It is one of the major 3 circuits linking the basal ganglia and the frontal cortex, which is closely involved in human behaviors including apathy. 38,39 The orbitofrontal subcortical circuits receives afferents from the superior temporal cortex, substantia nigra, dorsal raphe, and midbrain tegmentum. Moreover, the medial part of the orbitofrontal circuit also has the association with amygdala. 40 In the comparison study, the left inferior, medial frontal, and right superior frontal gyri were observed more often in the A+ group than the A group. Also, the negatively correlated area with the apathy subscore included the right orbitofrontal and medial frontal cortices. The other regions showing decreased perfusion in the A+ group compared with the A group were precentral and postcentral cortices. Postcentral activations have been reported to be relevant to emotional processes in a few functional magnetic resonance imaging r 2012 Lippincott Williams & Wilkins 221

6 Kang et al Alzheimer Dis Assoc Disord Volume 26, Number 3, July September 2012 FIGURE 4. Brain areas negatively correlated with NPI subscores for depression in the entire group of 81 AD patients (uncorrected P<0.005). AD indicates Alzheimer disease; NPI, Neuropsychiatric Inventory. studies. Postcentral dysfunction is related to sadness in schizophrenia patients, 41 emotional judgment in healthy patients, 42 and emotional prosody. 43 The right somatosensory and supramarginal gyri are involved in the representation of bodily feelings associated with emotion, according to a simulation model of emotion recognition. In this respect, the correlation between apathy and the right somatosensory gyrus might be caused by emotional blunting, which apathetic patients enrolled in this study manifested. In both comparison and correlation studies, apathetic patients showed more extensive deficit than depressive patients. Considering no significant difference in age, MMSE, subscores for each item, and disease duration between 2 groups, this finding could be explained by higher degeneration with apathy. Tagariello et al 9 suggested that apathy may be a behavioral marker of a more severe type of AD, by characterizing more severe behavioral problems than their cognitive status would suggest. These impairments could be based on the larger deficit observed in apathetic patients in the current study. There have been some reports that have demonstrated that apathy is not depression, that is, apathy and depression have a different neuroanatomical basis in AD 16 and dissociating clinical features in Huntington 44 and Parkinson disease. 45 We suggest that the current study is in agreement with these reports, specifically, excluding the co-occurrence, the regions related to depression (Fig. 1) and apathy (Fig. 2) occupied different brain areas. Some limitations of this study require consideration. First, the proposed conclusion is mainly sustained by the correlation analysis. However, only the small brain regions were identified in the direct comparison between A+ and D+ patients. This is probably due to the small sample size of the patients (9 vs. 9). Further studies with a larger sample size are needed to statistically confirm our results. Second, the influence of anti-psychotic drugs being taken by the patients was not considered, which can be a confounding factor. Third, among the 81 enrolled patients, we could not record the duration of AD in 6 patients because they denied having AD or the caregivers could not answer the duration of AD. Among the 18 patients in the D+ and D groups, we could not obtain information about the duration of AD in 3 patients (1 in D+ and 2 in D ). Finally, a normal control group would be required to investigate brain areas showing abnormal rcbf in AD patients, which is valuable to discriminate the regions in the AD from that in the behavioral disturbances. TABLE 5. Negative Correlation with NPI Subscores for Apathy (Uncorrected P < 0.005) Regions Voxels x y z Z Score P Superior temporal gyrus, Rt Middle temporal gyrus, Rt Middle temporal gyrus, Rt Medial frontal gyrus, Rt Superior frontal gyrus, Rt Medial frontal gyrus, Rt Superior frontal gyrus, Rt Precentral gyrus, Rt Insula, Lt Parahippocampal gyrus, Rt Middle frontal gyrus, Rt Precentral gyrus, Lt Superior frontal gyrus, Lt r 2012 Lippincott Williams & Wilkins

7 Alzheimer Dis Assoc Disord Volume 26, Number 3, July September 2012 Apathy and Depression in Alzheimer Disease FIGURE 5. Brain areas negatively correlated with NPI subscores for apathy in the entire group of 81 AD patients (uncorrected P < 0.005). AD indicates Alzheimer disease; NPI, Neuropsychiatric Inventory. REFERENCES 1. Small G, Rabins P, Barry P, et al. Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer s Association, and the American Geriatrics Society. JAMA. 1997;278: Thomas P, Clement JP, Hazif-Thomas C, et al. Family, Alzheimer s disease and negative symptoms. Int J Geriatr Psychiatry. 2001;16: Frisoni G, Rozzini L, Gozzetti A, et al. Behavioral syndromes in Alzheimer s disease: description and correlates. Dement Geriatr Cogn Disord. 1999;10: Olin JT, Katz IR, Meyers BS, et al. Provisional diagnostic criteria for depression of Alzheimer disease: rationale and background. Am J Geriatr Psychiatry. 2002;10: Starkstein SE, Merello M, Brockman S, et al. Apathy predicts more severe parkinsonism in Alzheimer s disease. Am J Geriatr Psychiatry. 2009;17: Boyle P, Malloy P. Treating apathy in Alzheimer s disease. Dement Geriatr Cogn Disord. 2004;17: Levy ML, Cummings JL, Fairbanks LA, et al. Apathy is not depression. J Neuropsychiatry Clin Neurosci. 1998;10: Marin RS, Firinciogullari S, Biedrzycki RC. Group differences in the relationship between apathy and depression. J Nerv Ment Dis. 1994;182: Tagariello P, Girardi P, Amore M. Depression and apathy in dementia: same syndrome or different constructs? A critical review. Arch Gerontol Geriatr. 2009;49: Chang L. A method for attenuation correction in radionuclide computed tomography. IEEE Transactions on Nuclear Science. 1978;25: Akiyama H, Hashimoto H, Kawabe J, et al. The relationship between depressive symptoms and prefrontal hypoperfusion demonstrated by ezis in patients with DAT. Neurosci Lett. 2008;441: Levy-Cooperman N, Burhan AM, Rafi-Tari S, et al. Frontal lobe hypoperfusion and depressive symptoms in Alzheimer disease. J Psychiatry Neurosci. 2008;33: Liao YC, Liu RS, Lee YC, et al. Selective hypoperfusion of anterior cingulate gyrus in depressed AD patients: a brain SPECT finding by statistical parametric mapping. Dement Geriatr Cogn Disord. 2003;16: Ritchie K, Gilham C, Ledesert B, et al. Depressive illness, depressive symptomatology and regional cerebral blood flow in elderly people with sub-clinical cognitive impairment. Age Ageing. 1999;28: Hirono N. Frontal lobe hypometabolism and depression in Alzheimer s disease. Neurology. 1998;50: Holthoff VA, Beuthien-Baumann B, Kalbe E, et al. Regional cerebral metabolism in early Alzheimer s disease with clinically significant apathy or depression. Biol Psychiatry. 2005;57: Lee DY, Choo IH, Jhoo JH, et al. Frontal dysfunction underlies depressive syndrome in Alzheimer disease: a FDG- PET study. Am J Geriatr Psychiatry. 2006;14: Sultzer D. The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer s disease. Am Neuropsych Assoc. 1995;7: Mayberg H. Paralimbic frontal lobe hypometabolism in depression associated with Huntington s disease. Neurology. 1992;42: Mayberg H. Frontal lobe dysfunction in secondary depression. Am Neuropsych Assoc. 1994;6: Ring HA, Bench CJ, Trimble MR, et al. Depression in Parkinson s disease. A positron emission study. Br J Psychiatry. 1994;165: r 2012 Lippincott Williams & Wilkins 223

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