Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson's disease patients

Parkinsonism and Related Disorders 21 (2015) 489e493

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Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson's disease patients* Gabriella Santangelo a, b, Carmine Vitale b, c, Marina Picillo d, Sofia Cuoco a, Marcello Moccia e, Domenica Pezzella a, Roberto Erro f, Katia Longo b, Caterina Vicidomini g, Maria Teresa Pellecchia d, Marianna Amboni b, Arturo Brunetti h,  g, * Marco Salvatore h, Paolo Barone e, **, Sabina Pappata a

Department of Psychology, Second University of Naples, Caserta, Italy IDC-Hermitage-Capodimonte, Naples, Italy c University Parthenope, Naples, Italy d Neurodegenerative Diseases Center, Department of Medicine and Surgery, University of Salerno, Salerno, Italy e Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy f Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom g Institute of Biostructure and Bioimaging, CNR, Naples, Italy h Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 November 2014 Received in revised form 6 February 2015 Accepted 17 February 2015

Introduction: Apathy is a neuropsychiatric symptom in Parkinson's Disease (PD) which has a negative impact on quality of life and might be related in part to damage of presynaptic dopaminergic system. Little is known about relationship between striatal dopamine levels and apathy in PD patients without dementia and/or depression. The aim of the present study was to investigate the relationship between “pure apathy” and striatal dopamine uptake in untreated, drug-naïve PD patients without clinically significant dementia and/or depression. Methods: Fourteen PD patients with pure apathy and 14 PD patients without apathy, matched for age, side of motor symptoms at onset, motor disability and disease duration, underwent both neuropsychological and behavioral examination including self-rated version of the Apathy Evaluation Scale (AESS). All patients underwent 123 I-FP-CIT (DaT-SCAN) SPECT to assess dopamine transporter (DAT) striatal uptake. Results: PD patients with apathy showed lower DAT levels in the striatum than non-apathetic patients. After Bonferroni correction the difference between groups was significant in the right caudate. Conclusions: Apathy is associated with reduced striatal dopamine transporter levels, independent of motor disability and depression in non-demented PD patients. These findings suggest that dysfunction of dopaminergic innervation in the striatum and particularly in the right caudate may contribute to development of apathy in early PD. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Parkinson's disease Non-motor symptoms Behavioral disorders [123] FP-CIT SPECT Dopamine Apathy

1. Introduction * The statistical analysis was performed by Santangelo Gabriella. PhD, Department of Psychology, Second University of Naples, Caserta, Italy. * Corresponding author. Institute of Biostructure and Bioimaging, CNR, Naples Via T. De Amicis 95, 80145 Naples, Italy. Tel.: þ39 081 2203187x214. ** Corresponding author. Neurodegenerative Diseases Center, Department of Medicine and Surgery, University of Salerno, Salerno, Italy. E-mail addresses: [email protected] (P. Barone), [email protected] (S. Pappat a).

http://dx.doi.org/10.1016/j.parkreldis.2015.02.015 1353-8020/© 2015 Elsevier Ltd. All rights reserved.

Apathy refers to a lack of motivation not attributable to reduced level of consciousness, cognitive impairment or emotional distress [1]. Recently, apathy has been considered as pathology of goaldirected behavior characterized by reduced self-generated voluntary and purposeful behaviors. It is associated with severe cognitive decline, mainly with executive/frontal dysfunctions mediated by

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altered prefrontal-subcortical circuitries in several neurodegenerative diseases such as Parkinson's Disease (PD) in which the dysfunction of dopaminergic system is a common pathological characteristic (see review, [2,3]). In PD apathy is a behavioral disturbance occurring alone or in concomitance with depression at early and advanced stages of disease; its prevalence ranges from 13.9% to 70%, whereas the prevalence of “pure apathy” (i.e. without depression and/or dementia) ranges from 3 to 47.9% [3]. Although it is associated with severe difficulties in social cognition [4] and reduced quality of life in PD [5], until now only limited functional studies have investigated neural correlates of apathy in PD patients [6]. Apathy seems to be related to a dysfunction in a large meso-cortico-limbic circuit including striatum, anterior and posterior cingulate, and inferior prefrontal gyrus [3]. To our knowledge, all previous studies about pathophysiological mechanisms of apathy were performed on PD patients under dopaminergic treatment and with depression and/ or dementia, which are the most frequent comorbid conditions of apathy in PD [3] (see Supplementary Table 1; A summary of neuroimaging studies on apathy in PD). Since some recent studies and case reports described an effect of dopaminergic treatment on cognitive and behavioral symptoms in PD patients [7], it could be interesting to explore the role of dopaminergic damage on the occurrence of “pure apathy” in untreated PD patients. The present study was designed to investigate the presynaptic nigrostriatal dopaminergic dysfunctions in newly diagnosed, drug-naive PD patients with and without pure apathy using SPECT imaging with the 123I-labeled ligand N-d-(fluoropropyl)- 2b-carbomethoxy-3b-(4-iodophenyl)tropene (123IFPCIT), a DAT-specific radiotracer. Moreover, we investigated the possible relationship between apathy and striatal dopamine transporter availability. 2. Material and methods In the present study, 28 PD patients were included: 14 with clinically significant apathy and 14 without apathy matched for age, disease duration, motor disability and side of PD onset, were included. They were retrospectively selected from a cohort of 70 consecutive drug-naïve patients with newly diagnosed PD referred to the Department of Neurological Sciences of the University “Federico II” of Naples. The patients were included in the present study if they satisfied the following inclusion criteria: 1) the presence of parkinsonian syndrome according to United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria, 2) a disease duration of less than 2 years; 3) no history of present or past therapy with prodopaminergic agents; 4) lack of significant cerebrovascular lesions on MRI or CT or severe concomitant disease which might explain the presence of cognitive or psychiatric disturbances; 5) without depression diagnosed by DSM-IV criteria; 6) without dementia diagnosed according to clinical diagnostic criteria. Moreover, patients who intook anti-cholinergic agents, choline esterase inhibitors, antidepressants were excluded.

2.1. Clinical and neuropsychological evaluation To identify clinically significant apathy, a clinical interview based on diagnostic criteria for apathy [8] and the self-rated version of Apathy Evaluation Scale (AES-S), validated in PD [9], were administrated. AES-S consists of 18 items; all items are scored on 4-point Likert scale with the following descriptors: not at all true, slightly true, somewhat true, very true. Some items (6, 7, 11) must be reverse scored because of the way they are written. Total score ranges from 18 to 72 points (higher score indicates more severe apathy). The cut-off score 37 was used to divide apathetic from non-apathetic patients. In the present study, we considered to be apathetic PD patients who showed a total AES-S score 37 and who satisfied clinical diagnostic criteria. Motor disability was measured by part III of Unified Parkinson's Disease Rating Scale (UPDRS-III). All PD patients underwent a comprehensive neuropsychological battery assessing memory (immediate and delayed recall of Rey's Auditory Verbal Test), executive functions (Clock Drawing Test, Phonological fluency test, interference task of Stroop Test, Trail Making Test: part B, Verbal span), visuospatial functions (Constructional Apraxia Test, Benton Judgment Orientation Line Test). Raw scores for each cognitive test were transformed to z-scores using the Italian normative data, matched for each participant by demographic parameters. An index score for each cognitive domain was calculated for each patient by averaging his/her

z-scores across the tests within that domain. References of cognitive tests was reported in Supplementary Table 2. 2.2. SPECT with 123I-FP-CIT PD patients received an intravenous injection of 185 MBq of [123I]FP-CIT (DaTSCAN, GE Healthcare) after thyroid block with oral administration of Lugol solution. SPECT studies were performed using a dual-head system equipped with low-energy high-resolution collimators (E.CAM, Siemens Medical systems, USA). The acquisition started between 3.45 and 4.15 h after the radiotracer injection and lasted 40 min. The time for SPECT imaging after tracer injection was selected based on results from previous reports demonstrating that the time window between 3 and 6 h allows stable measurement of specific-to non-displaceable ratio of [123I] FPCIT [10]. Images were acquired with a 128  128 matrix (zoom: 1.23; pixel size: 3.90  3.90 mm), reconstructed using a Butterworth filter (cut-off 0.5, order 10) and corrected for attenuation using Chang's algorithm (m ¼ 0.06 cm1). For data analysis, images were normalized with Statistical Parametric Mapping version 2000 (SPM2, Welcome Department of Imaging Neuroscience, London, UK) to the Montreal Neurological Institute (MNI) space using a [123I]FP-CIT SPECT template (voxel size of 4  4  4 mm) generated as a mean image of healthy control studies as previously reported. Normalized images were processed for region of interest (ROI) analysis with the software ImageJ (rsb.info.nih.gov/ij/, NIH, Bethesda, MD). A template, including four circular ROIs for caudate and putamen of both hemispheres and a poligonal ROI for the occipital cortex, was applied on each normalized scan on six consecutive transaxial slices. Estimates of specific binding in different striatal regions were made by subtracting occipital [123I]FP-CIT uptake (non-specific binding) from total [123I]FP-CIT uptake. Then the ratio of specific to non-specific [123I]FP-CIT binding, called V300 , was calculated by dividing the specific striatal binding by the occipital binding [11,12] The specific-to-nonspecific equilibrium partition coefficient V300 is defined as the equilibrium volume of distribution of specific relative to non specific tissue compartments [12] and is considered an index of DAT availability. V300 values were calculated for the right and left caudate and putamen. As at the enrollment all patients had a clinical diagnosis of parkinsonism, 1 year after enrollment a clinical re-evaluation was performed in all patients in order to assess the diagnosis of PD according to response to the dopaminergic therapy and exclusion of atypical symptoms/signs. 2.3. Standard protocol approvals, registration, and patient consent Written informed consent is obtained from each participant and the study meets the ethical standards of the responsible committee on human experimentation. 2.4. Statistical analysis Demographic, clinical, cognitive domains z-scores and DAT values in the right and left caudate and putamen were compared between apathetic and non-apathetic patients by means of ManneWhitney U Test. Linear regression model with stepwise method, in which left and right caudate and putamen DAT V300 values were included as covariates and cognitive domains and AES scores as dependent variables, were performed to assess possible relationship between striatal DAT availability, cognitive domains and apathy. A Bonferroni correction for multiple comparisons was applied to minimize the chance of false-positive findings. Statistical analysis was performed by the Statistical Package for Social Sciences (SPSS), version 20.

3. Results The demographic and clinical aspects of apathetic and nonapathetic de novo PD patients were shown in Table 1. ManneWhitney showed no significant difference between the two groups on memory, frontal functions and visuospatial domains after Bonferroni correction (0.05/5 ¼ 0.010, AES total score, MMSE total score, memory, frontal and visuospatial domains). In the apathetic group the V300 values were lower than in the non-apathetic group in both caudates and putamen (Table 2). After Bonferroni correction (0.05/4 ¼ 0.0125), ManneWhitney U test revealed significantly lower 123I-FP-CIT V300 values in the right caudate (p ¼ 0.006) but not in the left caudate, right putamen and left putamen of apathetic patients compared to non-apathetic patients (Table 2). Linear regression models revealed that right caudate V300 value (standardized beta ¼ 0.544, p ¼ 0.003) was significantly associated with total AES score (adjusted R2 ¼ 0.269), whereas it was not associated with visuospatial (adjusted R2 ¼ 0.015; standardized beta ¼ 0.122, p ¼ 0.535), memory (adjusted R2 ¼ 0.107; standardized

G. Santangelo et al. / Parkinsonism and Related Disorders 21 (2015) 489e493 Table 1 Demographic, clinical and apathetic features of PD patients with and without apathy. Patients with Patients without U apathy (n ¼ 14) apathy (n ¼ 14) Gender (F/M) Side onset of PD (R/L) Disease duration UPDRS-III score Age (years) MMSE Total AES-S score Cognitive domains mean Memory mean z-scores Frontal functions mean z-scores Visuospatial functions mean z-scores Memory domain: Immediate verbal recall (z-scores) Delayed verbal recall (z-scores) Frontal functions domain Verbal span (z-scores) Interference task of Stroop Test (z-scores) Trail Making Test-part B (z-scores) Phonological fluency (z-scores) Clock Drawing Test (z-scores) Visuospatial domain BJLOT (z-scores) Constructional apraxia test (z-scores)

P

e e e e 93.0 0.839 92.5 0.804 82.0 0.482 70.5 0.318 0.000 <0.001a

4/10 7/7 13.5 ± 6.1 14.2 ± 7.4 60.4 ± 7.7 26.5 ± 1.3 42.8 ± 7.4 z-scores 0.6 ± 0.8 0.7 ± 0.5

4/10 7/7 12.8 ± 14.1 ± 58.7 ± 27.1 ± 31.7 ±

0.2 ± 0.6 0.4 ± 0.4

61.0 61.0

0.094 0.094

1.6 ± 1

0.6 ± 0.7

39.0

0.012

0.6 ± 0.8

0.1 ± 0.7

61.0

0.089

0.5 ± 0.8

0.2 ± 0.5

89.0

0.679

0.7 ± 0.5 1.2 ± 0.9

0.5 ± 0.7 0.5 ± 0.5

72.5 46.0

0.229 0.017

0.2 ± 0.7

0 ± 0.9

77.5

0.346

0.4 ± 0.9

0.4 ± 0.6

93.0

0.818

1.1 ± 1.9

0.4 ± 1.7

71.0

0.213

1.9 ± 1.8 1.4 ± 0.8

0.8 ± 1.2 0.6 ± 0.8

51.5 42.5

0.055 0.010

5.8 8.9 7.4 1.9 4.1

PD ¼ Parkinson's Disease; F ¼ females; M ¼ males; R ¼ right; L ¼ left; UPDRS ¼ Unified Parkinson's Disease Rating Scale; MMSE ¼ Mini Mental State Examination; AES-S ¼ self-rated version of the Apathy Evaluation Scale; BJLOT ¼ Benton Judgment Orientation Line Test. a Indicates significant difference after Bonferroni correction (0.050/5 ¼ 0.010).

beta ¼ 0.327, p ¼ 0.090) and frontal functions (adjusted R2 ¼ 0.135; standardized beta ¼ 0.367, p ¼ 0.055) scores. 4. Discussion The present study explored the relationship between “pure” apathy and striatal DAT availability in untreated, non-demented and non-depressed de novo PD patients. We observed that patients with clinically significant “pure” apathy had lower dopaminergic levels in the striatum, particularly in the right caudate, than non-apathetic patients; this association can not be attributable to difference on age, duration of disease, side of PD onset and motor disability since apathetic and non-apathetic patients were selected to be matched for all abovementioned factors, which can influence striatal DAT availability in PD. Dopamine (DA) plays a pivotal role in brain mood regulation and is also involved in reward, goal directed behavior and motivation Table 2 Dopamine transporter (DAT) striatal V300 values in patients with and without apathy. Patients with apathy (n ¼ 14) Right Caudate Left Caudate Right Putamen Left Putamen

1.91 1.94 0.94 0.88

± ± ± ±

0.38 0.58 0.32 0.37

Patients without apathy (n ¼ 14) 2.27 2.23 1.22 1.11

Significant difference was indicated in bold.

± ± ± ±

0.31 0.36 0.34 0.35

U

P

39.0 60.0 46.0 52.0

0.006 0.081 0.017 0.035

491

circuits [2,13]. The contribution of dopaminergic deficit in parkinsonian apathy is in part supported by pharmacological studies showing improvement of apathy with dopaminergic agonists therapy [13]. The mechanisms implicated are still debated. Disruption of “emotional affective” meso-cortico-limbic dopaminergic pathways and/or of “cognitive” nigrostriatal dopaminergic caudate-prefrontal cortex circuits may play a role [2,13]. This latter might be more implicated in the occurrence of apathy at early stages of PD when the mesocortical systems are expected to be relatively spared [2,13]. Our findings of significantly reduced DAT availability in the right caudate of early, untreated PD with “pure apathy” might support in part this hypothesis. To our knowledge no SPECT/PET study has investigated the relationships between striatal DAT availability and “pure apathy” in PD. Roselli et al., using 123I-FP-CIT SPECT showed a significant association between severity of apathy and reduced caudate uptake in patients with Dementia with Lewy Body (DLB) [14]. In AD patients lack of interest was correlated with reduced DAT binding potential values in the left caudate, even after partial volume correction [15]. There are several morphological and functional studies supporting the concept that the alteration of the corticosubcortical circuitries, which connected dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) with caudate, may be involved in apathy in several neurological diseases such as Fronto-Temporal dementia (FTD [16], in AD patients [17], in nondemented and nondepressed PD patients [18,19]. Several studies evidenced that ACC plays a role in motivation, error detection and conflict monitoring [20]. In line with the abovementioned roles of ACC, a recent neuropsychological study showed that the development of apathy in de novo PD patients can be predicted by reduced performance on interference task of Stroop Test, which taps inhibitory control and actives medial prefrontal areas [21]. Overall these studies suggest that apathy may result at least in part from disruption/dysfunction of “cognitive” dopaminergic caudate-frontal cortex circuits. In more advanced depressed PD patients reduced 11C-RTI-32 binding in ventral striatum was inversely correlated with the degree of apathy [22]. It is noteworthy, however, that 11C-RTI-32 is a marker of both dopamine and noradrenaline transporters and thus it does not provide information on the specific contribution of DA loss in the occurrence of apathy. Moreover the presence of major depression limits the interpretation of these results on the role of reduction of catecholaminergic innervation in apathy. Interestingly the involvement of ventral striatum suggests that “emotional affective” mesocortico-limbic dopaminergic system might in part contribute to parkinsonian apathy in more advanced stages of non-demented depressed PD. The results of this study also suggest that loss of noradrenergic cortico-subcortical innervation of limbic system might be also implicated in mood disorders in PD including apathy. Our PD patients with clinically significant apathy showed more reduced DAT availability than non-apathetic PD patients in putamen, but the difference between two groups did not reach statistical significance. However, increased severity of apathy correlates with DAT loss in the right putamen after Bonferroni correction. While some studies by non-invasive measures of anatomical and functional connectivity in humans demonstrated a relationship between the caudate and executive frontal areas, the putamen has been reported to have associations to more basic sensorimotor regions (see review, [23]). However, the putamen was described as a subcortical structure sub-serving also cognitive functions more limited to stimulus-response, or habit, learning [23]; moreover, a recent SPECT study showed that bilateral reduction of DAT uptake in the putamen is associated with lack of initiative, a behavioral dimension of apathy, in AD and DLB patients [15]. Further studies are required to address this issue.

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In our study, we found that increase of apathy is associated with DAT loss in the right striatum. It is known that PD patients with the onset of PD in right side of the body have greater inferred left hemisphere pathology whereas PD patients with left-side onset of PD have greater inferred right hemisphere pathology [24]. Therefore, an asymmetrical depletion of dopamine in the substantia nigra lead to asymmetrical dysregulation of the striatum, which may in turn lead to asymmetrical dysfunction of cortical-subcortical circuits. Specific cognitive and neuropsychiatric problems are reported as consequence of side of initial motor onset [25]. Two previous studies showed that PD patients with right onset had higher odds of developing apathy and showed more severe apathy than PD patients with left onset [26,27]. The association between apathy and right onset of PD suggested that damage of left hemisphere might be a contributor to onset of the apathy. On the other hand, apathy is reported as more common behavioral disturbance in patients with right hemisphere damage than in patients with left hemisphere damage [28]. Recently, Robert et al. described a strong association between apathy and metabolism in the specific cerebral areas (inferior frontal gyrus, middle frontal gyrus, cuneus, and anterior insula) of right hemisphere in treated PD patients [18] and found a significant association between increased apathy after Subtalamic Nucleus Deep Brain Stimulation and reduced preoperative metabolism within the right ventral striatum [29] Taken together, these findings evidenced that damage in right hemisphere may be involved in the development of apathy. Our results seem to support a possible role of right nigrostriatal dopaminergic deficit as a possible contributor to onset of apathy. Our finding was not ascribable to enrollment bias: in fact in our sample there was a similar frequency distribution between patients with right and left side of onset of disease. It is noteworthy, however, that negative correlation was also found at a lesser significant thresholds, in the left striatum. Thus the potential role of left striatum in the apathetic symptoms in PD should be evaluated in a larger number of patients. The limitations of the study include the relatively small sample size. This is also related to the stringent selection criteria used in this study. In fact our groups of PD patients with and without apathy were matched for age, sex, disease duration and UPDRS in order to avoid the effects of confounding variables. Moreover, our patients were non-depressed and never treated with dopaminergic drugs. Another limitation is the relatively low spatial resolution of SPECT. We cannot exclude that part of anterior putamen and of the ventral striatum might have been included in the caudate and putamen ROIs due to partial volume effects. Neuroimaging studies showed altered function and volume of the caudate nucleus in depressed patients. In the present study we did not measure depressive symptomatology in our patients and we did not investigate its correlates with striatal DAT availability. This could be limitation of this study since neuroimaging studies showed altered function and volume of the caudate nucleus in depressed patients. Finally, we cannot exclude that other neurotransmitter systems might be implicated in apathy, as previously suggested [30]. Further studies are required to explore potential changes of acetylcholine, serotonin, and noradrenalin in early de novo PD. In conclusion, our results on a small sample of untreated, drug-naïve PD patient suggest that loss of presynaptic dopaminergic innervation in the striatum and in particular with right caudate might be associated with the presence of “pure apathy”. These findings need to be confirmed in a large sample. Longitudinal studies should be of interest to investigate whether dopaminergic dysfunctions in striatum might predict onset of apathy in early PD.

Individual contribution Gabriella Santangelo: study concept and design, acquisition of data, analysis of data, statistical analysis, interpretation of data, study supervision and coordination, drafting and revising. Carmine Vitale: recruitment of patients, acquisition of clinical data, interpretation of data and revising. Marina Picillo: recruitment of patients, acquisition of clinical data, revising. Sofia Cuoco: acquisition of behavioral data. Marcello Moccia: acquisition of clinical data, revising. Domenica Pezzella: acquisition of behavioral data. Roberto Erro: acquisition of clinical data, revising. Katia Longo: recruitment of patients, acquisition of clinical data, revising. Caterina Vicidomini: acquisition of data, revising. Maria Teresa Pellecchia: recruitment of patients, acquisition of clinical data, revising. Marianna Amboni: recruitment of patients, acquisition of clinical data, revising. Arturo Brunetti: study supervision and coordination, and revising. Marco Salvatore: study supervision and coordination, and revising. Paolo Barone: study concept and design, acquisition of data, interpretation of data, study supervision and coordination, drafting and revising. : study concept and design, acquisition of data, Sabina Pappata analysis of data, interpretation of data, study supervision and coordination, drafting and revising. Acknowledgment The present work was partly supported by MEdical Research in ITaly (MERIT) project n_ RBNE08LN4P. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n HEALTH. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2015.02.015. References [1] Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatr Clin Neurosci 1991;3:243e54. [2] Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortexbasal ganglia circuits. Cereb Cortex 2006;16:916e28. [3] Santangelo G, Trojano L, Barone P, Errico D, Grossi D, Vitale C. Apathy in Parkinson's disease: diagnosis, neuropsychological correlates, pathophysiology and treatment. Behav Neurol 2013;27:501e13. [4] Santangelo G, Vitale C, Trojano L, Errico D, Amboni M, Barbarulo AM, et al. Neuropsychological correlates of theory of mind in patients with early Parkinson's disease. Mov Disord 2012;27:98e105.  n J, Cubo E, Coronell C, ANIMO Study Group. Impact of apathy on [5] Benito-Leo health-related quality of life in recently diagnosed Parkinson's disease: the ANIMO study. Mov Disord 2012;27:211e8. [6] Benoit M, Robert PH. Imaging correlates of apathy and depression in Parkinson's disease. J Neurol Sci 2011;310:58e60. [7] Poletti M, Bonuccelli U. Acute and chronic cognitive effects of levodopa and dopamine agonists on patients with Parkinson's disease: a review. Ther Adv Psychopharmacol 2013;3:101e13. [8] Robert P, Onyike CU, Leentjens AF, Dujardin K, Aalten P, Starkstein S, et al. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry 2009;24:98e104. [9] Santangelo G, Barone P, Cuoco S, Raimo S, Pezzella D, Picillo M, et al. Apathy in untreated, de novo patients with Parkinson's disease: validation study of apathy evaluation scale. J Neurol 2014;261:2319e28.

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