REVIEW

Apathy in Parkinson’s Disease: A Systematic Review and Meta-analysis Melina G.H.E. den Brok, BSc,1† Jan Willem van Dalen, MSc,1†* Willem A. van Gool, MD, PhD,1 Eric P. Moll van Charante, MD, PhD,2 Rob M.A. de Bie, MD, PhD,1 and Edo Richard, MD, PhD1,3 1 Department of Neurology, Academic Medical Center Amsterdam, The Netherlands Department of General Practise, Academic Medical Center Amsterdam, The Netherlands 3 Department of Neurology, Radboud University Medical Center Nijmegen, The Netherlands 2

ABSTRACT:

Apathy is a frequently reported neuropsychiatric symptom in Parkinson’s disease (PD), but its prevalence and clinical correlates are debated. We aimed to address these issues by conducting a systematic review and meta-analysis. Embase, Medline/PubMed, and PsychINFO databases were searched for relevant studies. Data were extracted by two independent observers, using predefined extraction forms tailored specifically to the research question. From 1,702 titles and abstracts, 23 studies were selected. Meta-analysis showed a prevalence of apathy in PD of 39.8% (n 5 5,388, 905% CI 34.6-45.0%). Apathy was associated with higher age (3.3 years, 95% CI 5 1.7-4.9), lower mean Mini-Mental State Evaluation (MMSE) score (21.4 points, 95% CI 5 22.1 to 20.8), an increased risk of co-morbid depression (relative risk [RR] 5 2.3, 95% CI 5 1.9-2.8), higher Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (6.5 points, 95% CI 5 2.6-10.3), and more severe disability (Hedges-G 5 0.5, 95% CI 5 0.3-0.6). Half of the patients with apathy had concomitant depression (57.2%, 95%

Parkinson’s disease (PD) is characterized by the cardinal motor symptoms of bradykinesia, tremor, and rigidity.1 Many PD patients also experience nonmotor

------------------------------------------------------------

*Correspondence to: Dr. Jan Willem van Dalen, Department of Neurology, Room H2-235, Academic Medical Center Amsterdam, Meibergdreef 14, 1115 AZ, The Netherlands, e-mail: [email protected] Funding agencies: This study was supported by the Academic Medical Center, Amsterdam, The Netherlands

Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. y

Shared first authorship.

Received: 23 July 2014; Revised: 5 February 2015; Accepted: 12 February 2015 Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26208

CI 5 49.4-64.9%), and this estimate was similar after exclusion of patients with cognitive impairment (52.5%, 95% CI 5 42.2%-62.8%). In conclusion, we found that apathy affects almost 40% of patients with PD. Several factors influence reported prevalence rates, contributing to the considerable heterogeneity in study results. Half of patients with apathy do not suffer from concomitant depression or cognitive impairment, confirming its status as a separate clinical syndrome in PD. The pervasiveness of apathy in PD warrants research into its treatment, although different underlying pathophysiological mechanisms may require different treatment strategies. Treatment of apathy could improve patient quality of life, reduce caregiver burden, alleviate disability by increasing motivation for self-care, and reduce cognitive impairment C 2015 International by improving executive functioning. V Parkinson and Movement Disorder Society

K e y W o r d s : Parkinson’s disease; apathy; epidemiology; behavior/neuropsychiatric disorders

symptoms. One of the most burdensome nonmotor symptoms may be apathy.2-4 Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and cognition, and reduced emotional expression.5 Apathy is known to contribute significantly to caregiver burden in other neurological disorders, and has negative implications for treatment and long-term outcome.6,7 Therefore, recognition of apathy in PD may be important for treatment and care.8 The significance of apathy in PD has been a subject of debate. Reported estimates of the prevalence differ greatly between studies, ranging from 17% to 60%.9 Reports concerning its clinical impact also vary.9,10 The diversity in population characteristics and diagnostic instruments used to assess apathy hampers

Movement Disorders, Vol. 00, No. 00, 2015

1

D E N

B R O K

E T

A L

comparison between study results.11,12 Its common co-occurrence with depression and cognitive impairment has led to concerns that the impact of apathy in PD is mostly secondary to these features.12 These large differences between study findings and interpretations hinder progress in research on apathy in PD. This systematic review and meta-analysis aims to give a reliable estimate of the prevalence of apathy and its clinical correlates in PD and to explore to what extent specific differences in patient and study characteristics are able to explain the variation in study results.

Methods Data Collection We searched the Embase (from 1980), Medline/ PubMed, and PsychINFO databases (last updated: November 2014). “Parkinson’s disease” and synonyms were cross-referenced with “apathy,” related terms (eg, “abulia”), and names and acronyms of commonly used scales to assess apathy in PD. The full search strategy is listed in Supplemental Data s-1. Search results were reviewed by two independent observers (M.B., J.W.D.). Discrepancies in selection were resolved by discussion. Inclusion criteria, based on recommendations by the Center for Reviews and Dissemination,13 were: (1) observational cohort or case-control studies, (2) of patients with clinically diagnosed PD, (3) concerning at least 50 patients, (4) written in English, (5) employing the Neuropsychiatric Inventory (NPI), Lille Apathy Rating Scale (LARS), Apathy Evaluation Scale (AES), or Apathy Scale (AS) to measure apathy. Only these specific scales were recommended for apathy in PD in a large review of the reliability and validity of available apathy measures.11 References of obtained reviews were examined for additional articles. Two independent observers (M.B., J.W.D.) performed data extraction using a predefined extraction form (Supplemental Data s-2). Only studies that reported apathy prevalence were included. If studies reported on the same cohort, data were obtained from the study describing the largest sample. Data not reported in the largest study were supplemented with data from studies on the same cohort when necessary for sub-analyses. The instrument used to measure apathy, the measurement source (ie, rated by patients, informants, or clinicians), inpatient or outpatient population, exclusion of cognitive impairment, age, sex, disease duration, dopaminergic medication in levodopa equivalent dose (LED), depression rate, Mini Mental State Examination (MMSE) score, Unified Parkinson’s Disease Rating Scale (UPDRS) motor score, Hoehn and Yahr (HY) stage, and disability, quality of life, and caregiver burden rating scale scores were considered as potential correlates of apathy prevalence.6,9,10

2

Movement Disorders, Vol. 00, No. 00, 2015

When prevalence rates were reported for two different cutoff points for the NPI (1 or 4), we used the 1 estimate for the overall analysis, because this cutoff was used by most other studies. Estimates for both reported cutoff points were included separately for the cutoff point subgroup analysis. If apathy prevalence was reported according to several recommended measurement scales, we used the mean of the estimates for the overall analysis of prevalence, and each estimate separately for subgroup analyses based on measurement instrument. When means and standard deviations (SD) could only be obtained by combining means and SDs in subgroups (eg, population age by combining age in apathy and nonapathy subgroups), we used Review Manager (version 5.2.5) to do so.14 To obtain a single HY staging estimate for each study, the mean stage was calculated. To identify overlapping cases of depression and apathy with the greatest sensitivity, the highest estimate of depression prevalence reported in each study was used.15-17 Study quality was assessed with a specifically designed assessment form (Supplemental Data s-3), based on the Newcastle-Ottawa quality assessment scale.18

Statistical Analysis Statistical analyses were performed using OpenMeta[Analyst] (built 3 December 2013).19 Pooled estimates were calculated using the Der-Simonian Laird random effects model, adjusted for the binomial distribution of proportions. To evaluate whether one single study greatly affected the overall estimate, we conducted Jack-knife analysis, in which each study is excluded once from the overall analysis, resulting in a range of pooled estimates.20 Prevalence rates were pooled separately in subgroups based on rating source, rating instrument, cutoff point, exclusion of cognitive impairment, and outpatient, inpatient, or mixed population type. To evaluate the impact of our quality criteria, a sensitivity analysis was performed excluding half of all studies based on risk of bias on our bias assessment form (Supplemental Data s-3).13 To evaluate the clinical correlates of apathy, the number of studies that reportedly assessed the relation between apathy and each correlate, and the number that found a significant relation were registered. The relative risk of depression and possible sex differences in patients with apathy was calculated by pooling relative risks within each study. Associations with age, disease duration, MMSE score, disability, UPDRS motor score, and MDS-UPDRS motor score were analyzed by pooling the mean differences between apathy and non-apathy groups within studies. The relation between apathy and disability was assessed using Hedges-G analysis to allow pooling of scores measured using different instruments.13 For correlates with persistent high heterogeneity in the pooled mean

A P A T H Y

difference estimate, subgroup analyses were performed based on tertiles of study mean scores (if available for 90% of study participants). Depression prevalence in patients with apathy was estimated by pooling depression rates in apathy subgroups of studies. We separately assessed depression rates based on a DSM diagnosis, a rating scale cutoff for moderate/major depression, and a rating scale cutoff for mild/minor depression. Apathy prevalence in patients without cognitive impairment was estimated by pooling apathy rates in studies excluding patients with cognitive impairment or reporting separate apathy rates for noncognitive impairment subgroups. We separately assessed cognitive impairment based on a Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis of dementia and on a minimum score on cognitive rating scales. Apathy prevalence in patients without depression and cognitive impairment was estimated by pooling apathy rates in the nondepression subgroups of the noncognitive impairment cohorts. Univariate Der-Simonean Laird random-effects meta-regression was performed with apathy prevalence as outcome and in-/out-/mixed patient population type, exclusion of cognitive impairment, apathy cutoff point validity, mean age, mean disease duration, mean depression rate, mean MMSE score, mean HY stage, and mean UPDRS-III score as predictors. These potential correlates were selected because they were obtainable for most studies. Multivariate meta-regression was subsequently performed, including all predictors associated with apathy in univariate meta-regression. Heterogeneity was assessed using I2 statistics. Pooled effect sizes were deemed uninterpretable if I2 exceeded 60%. In these cases stepwise efforts were made to reduce heterogeneity. First, analyses were inspected for potential outliers using funnel plots. If heterogeneity after exclusion of the main outlier remained too high, consecutive-exclusion analyses were performed. In these analyses, studies reporting the largest association congruent with the pooled estimate were consecutively excluded until heterogeneity was acceptable, resulting in a conservative estimate of the effect size.

Results Study Selection Our search yielded 1,702 articles after duplicate removal (Fig. 1). Based on titles and abstracts, 95 studies were selected. References of reviews yielded two additional results. After detailed evaluation, 74 studies were excluded for reasons listed in Figure 1. The remaining 23 studies underwent bias assessment (Supplemental Data s-3). Table 1 shows the main characteristics of included studies. In total, 5,388 patients were evaluated in 23 studies,4,10,15-17,21-38 one describing

I N

P A R K I N S O N ’ S

D I S E A S E

FIG. 1. Article selection.

two different cohorts.28 Eight publications were used to supplement data of included studies (Supplemental Data s-4).2,20,39-44 Study and population characteristics are listed in Table 1. Eleven studies employed the AS to measure apathy,4,10,23,24,27,30,32,34,35,37,38 10 studies the NPI apathy item,15-17,25,26,28,29,31,36 three studies the LARS,17,21,33 and one study the AES.22 Cutoff points validated against a clinical diagnosis were used for the AES, for the AS by all but one study,10 for the LARS (–16) by two studies,17,21 and for the NPI (4) by one study.17 More sensitive cutoff points were used in one study employing the LARS (–22),33 and five studies employing the NPI (1).16,28,29,31,36 Three studies reported prevalence rates for both the 1 and the 4 point cutoff points on the NPI.15,25,26 In one study, apathy prevalence was measured using the NPI (4), LARS (16), and a clinical diagnosis, but only the clinical diagnosis was available for subanalyses.17

Apathy Prevalence The pooled apathy prevalence was 39.8% (n 5 5,388, 95% confidence interval [CI] 5 34.6%45.0%) with high heterogeneity (I2 5 93%)(Fig. 2). Jack-knife analysis showed a minimum pooled rate of 38.9% (95% CI 5 33.6%-42.2%),37 and a maximum of 40.9% (95%CI 5 36.0%-45.8%).16 Sensitivity analysis excluding half of the studies with the highest risk of bias yielded similar results (39.0%, n 5 2,898, 95% CI 5 31.4%-46.7%, I2 5 95%). Results of subgroup analyses regarding measurement source, measurement instrument, cutoff used, exclusion of cognitive impairment, outpatient versus inpatient population, mean disease duration, MMSE score, and HY staging are

Movement Disorders, Vol. 00, No. 00, 2015

3

TABLE 1. Study characteristics

Cohort and Population

Author, year (#)

Starkstein et al., 199235 16

Aarsland et al., 1999 * Lieberman, 2006 -Cohort28 28

Lieberman, 2006 -Cohort 2 Kulisevsky et al., 200825 Kirsch-Darrow et al., 2008

24

Starkstein et al., 200910 Stella et al., 2009

36

Butterfield et al., 201022 Oguru et al., 2010

4

Drijgers et al., 201017* Leiknes et al., 201015* Morley et al., 201130 Ziropadja et al., 201238 Kay et al., 201223* Benito-Leon et al., 201221

Cross Cons Outpat Long Rand Mixed Cross Cons Outpat Cross Cons Outpat Cross Cons Outpat Cross Cons Mixed Cross Cons Outpat Cross Cons Outpat Cross Recr Outpat Cross Cons Outpat Cross Cons Outpat

Major Exclusion Criteria % Excluded

n (% fem)

Age m (SD)

Disease Duration m (SD)

HY m (SD)

x

50 (39)

66.5 (9.6)

10.2 (4.9)

x

x

139 (56)

74.4 (7.9)

12.6 (5.1)

3.2 (x)

x

25.2 (5.9)

x

106 (56)

71.0 (11.0)

6.2 (5.9)

2.6 (0.8)

x

x

x

100 (38)

68.2 (11.2)

6.3 (6.5)

2.5 (1.0)

x

x

CI, RD, 25%

1351 (44)

70.6 (9.0)

5.7 (4.9)

2.5 (x)

x

x

Age: 30-90, NST, 10% x

301 (37)

68.0 (10.6)

8.1 (5.9)

2.5 (0.7)

30 (12)

x

164 (-)

65.9 (10.0)

x

2.7 (x)

19 (10)

UPDRS-III m (SD)

10 (7.5)

Apathy %, Measure

Depression %, Measure

27.0 (3.7)

42.0%, AS 14 (s) 16.5%, NPI >0 (i) 52.8%, NPI >0 (i) 51.0%, NPI >0 (i) 48.3%, NPI >0 (i) 50.8%, AS 14 (s) 31.7%, AS (s) 38.0%, NPI >0 (i) 20.6%, AES38 (s) 60.0%, AS 16 (s) 19.3% G, LARS: -16 (c), NPI: 4 (i) 29.1%, NPI >0 (i) 37.0%, AS 14 (s) 60.3%, AS 14 (s) 34.5%, AS 14 (s) 52.2%, LARS-16 (c) 26.3%, AS14 (s) 24.7%, NPI >0 (i) 48.8%, NPI >0 (i) 28.9%, LARS-22 (c) 28.0%, NPI >0 (i) 62.3%, AS16 (s) 43.1%, AS14 (s) 47.0%, AS14 (s)

56.0%, DSM/PSE 38.1%, NPI 27.4%, Ham-D21 30.6%, Ham-D21 49.7%, HADS-D 21.9%, BDI 58.5%, DSM/HAM-D 34.0%, DSM/MADRS 13.3%, BDI-II 56.0%, BDI-II 17.3%, DSM/HAM-D

24.2 (5.5) c

x

50 (44)

68.0 (6.8)

10.4 (5.3) 2.9 (1.0)

CI, SEA, OND, SCD,PSY SEA, OND, 6%

68 (34)

70.0 (7.0)

7.1 (5.0)

2.1 (x)

x

x

150 (53)

69.7 (8.6)

6.3 (4.4)

2.9 (0.9)

29 (16)

26.6 (3.9)

CI, OND

122 (41)

64.6 (8.5)

8.5 (5.6)

x

19 (8)

28.2 (1.8)

Long Cons Mixed Cross Recr

x, 11%

189 (40)

67.8 (x)

1.9 (x)

23 (x)

x

x

248 (25)

64.0 (10.0)

6.6 (5.4)

2.2 (0.7)

22 (10)

28.5 (1.9)

Cross Cons Outpat Long Recr/Cons

x

360 (35)

63.5 (10.3)

7.2 (5.1)

2.4 (x)

51 (23)

26.1 (4.1)

CI, SEA, OND

226 (33)

65.0 (8.8)

x

x

x

29.1 (0.7)

CI, SEA, Age >30 CI

557 (40)

68.8 (9.7)

1.3 (0.6)

1.6 (x)

21 (11)

x

99 (30)

63.2 (10.7)

7.8 (5.5)

2.4 (x)

29 (12)

28.5 (1.8)

SEA

73 (38)

65.3 (9.6)

9.3 (5.5)

x

23 (12)

27.0 (3)

2.3 (x)

a

69 (29)

b

MMSE m (SD)

66.2 (13.1)

CI, SCD, PSY

410 (40)

68.2 (9.5)

x

x

22 (12)

27.4 (2.0)

CI, Age >18, SCD, PSY SCD, PSY

90 (33)

62.6 (9.7)

x

1.8 (0.6)

20 (6)

28.8 (1.1)

Ojagbemi et al., 201331

Cross Cons Outpat Cross Recr Outpat Cross Cons Inpat R Cross Cons Outpat Cross Cons Outpat Cross Cons

50 (44)

65.6 (9.4)

3.4 (2.6)

x

x

22.2 (5.8)

Tanaka et al., 201337

Cross Cons

x, 21%

93 (51)

69.3 (9.8)

9.6 (6.6)

2.6 (0.9)

x

x

Rodrıguez-Violante et al., 201432 Skorvanek et al., 201434

Cross Cons Outpat Cross Recr Outpat

x

241(47)

62.2 (13.1)

6.6 (5.6)

2.3 (0.8)

33 (17)

22.2 (5.1)

CI, SEA, 25%

151 (47)

69.7 (8.6)

6.9 (4.9)

2.4 (0.9)

Leroi et al., 201227* Laatu et al, 201326 Monastero et al., 201329 Saez-Francas et al., 201333

36 (15)

d

26.9 (1.9)

e

f

36.0%, NPI 52.0%, IDS 41.4%, HDRS-17 27.0%, BDI 44.9%, DSM 25.3%, HADS-D 46.6%, NPI 61.7%, NPI 25.6%, HAM-D 46.0%, NPI 64.5%, NPI 62.7%, MDS-UPDRS 57.6%, BDI-II

Data are given as m (SD), or mean (standard deviation). *Studies supplemented with additional data from studies listed in Appendix S4. Cohort and population: Cross, cross-section; Long, longitudinal cohort; Cons, consecutive; Outpat, outpatients; Pros, prospective; Rand, random sample; Mixed, mixed inpatients and outpatients; Recr, recruited; Inpat R, inpatient rehabilitation; n (% fem): number of included patients (% female). Major exclusion criteria: CI, cognitive impairment; SEA, secondary/early onset/atypical Parkinson’s disease (PD); OND, other neurological disorder; NST, neurosurgical treatment for PD; SCD, severe concomitant disease; MT, medicinal treatment for PD; RD, recent diagnosis; PSY, psychiatric disorder other than depression or anxiety; n%, % excluded. Disease duration: Duration from diagnosis in years; HY: Hoehn and Yahr scale (higher scores indicating more severe PD). UPDRS III: Unified Parkinson’s Disease Rating Scale motor section; MMSE: Mini-Mental State Examination. Apathy measure: NPI, Neuropsychiatric Inventory; AS, Apathy Scale; AES, Apathy Evaluation Scale; LARS, Lille Apathy Rating Scale; (s), self-assessment; (i), informant assessment; (c), clinician assessment, PD severity: GLARS: –16: 19%, NPI: 4: 20%. Depression measure: BDI, beck depression inventory; BDI-II: revised version of Beck Depression Inventory; HADS-D, Hospital Anxiety and Depression Scale; Ham-D21, Hamilton Depression Rating Scale 21-Item; PSE, Modified Present State Examination; DSM, clinical diagnosis Diagnostic and Statistical Manual of Mental Disorders; MADRS, Montgomery Asberg Depression Rating Scale; HAM-D, Hamilton Rating Scale for Depression; HDRS-17, Hamilton Rating Scale for Depression 17-item; IDS, Inventory of Depressive Symptomatology. a Time from motor symptom onset. HY, Hoehn and Yahr scale (higher scores indicating more severe PD). b NUDS, Northwestern University Disability Scale. c UPDRS, Unified Parkinson’s Disease Rating Scale full score. d Movement Disorders Society Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (in all scales, higher scores indicating greater disability). e CAMCOG, cognitive and self-contained part of the Cambridge Examination for Mental Disorders of the Elderly. f MoCA, Montreal Cognitive Assessment (in all three scales, higher scores indicate better cognitive function).

A P A T H Y

I N

P A R K I N S O N ’ S

D I S E A S E

FIG. 2. Apathy prevalence. n, number of patients in study; Apathy, number of patients with apathy, % of patients with apathy; the NPI was informant rated with a cutoff of 1 unless stated otherwise; the LARS was clinician rated with a cutoff of –16 unless stated otherwise; the AES was selfrated with a cutoff 38; the AS was self-rated with a cutoff 14 unless stated otherwise; (A) NPI cutoff 1; (B) LARS cutoff –22; (C) AS score >0 for loss of motivation and for 2 of the 3 subdomains of cognition, emotion, and behavior; (D) AS cut-off 16. NPI, Neuropsychiatric Inventory; LARS, Lille Apathy Rating Scale; AES, Apathy Evaluation Scale; AS, Apathy Scale. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

depicted in Figure 3. None of the subgroup analyses substantially resolved heterogeneity. Meta-regression results are listed in Supplemental Data s-5. For every percentage point increase in depression rate, the apathy rate increased by 0.4 percentage point (P 5 0.02), and for every point increase in UPDRS-III score by 0.9 percentage point (P 5 0.01). Multivariate metaregression with both predictors gave similar results (Supplemental Data s-5).

Apathy and Patient Characteristics The relation between apathy and age was reported in 14 cohorts, six of which found an association between apathy and higher age.4,10,21,27,32,38 Separate meta-analysis for age was possible based on 11 cohorts,2,10,17,21,26,27,32,35,38,40,41 showing that patients with apathy were on average 3.3 years (95% CI 5 1.74.9, I2 5 68%, Fig. 4) older than those without. Exclusion of one outlier slightly attenuated the difference to 2.7 years (I2 5 44%, Supplemental Data s-6).27 Male sex was associated with apathy in 2 of 12 cohorts reporting on the subject.26,41 Separate meta-analysis on the association between apathy and sex was possible based on 10 cohorts.2,17,21,26,27,32,35,38,40,41 No association with sex was found (Fig. 4).

Disease Duration and Medication Apathy was associated with longer disease duration in 2 of 11 cohorts reporting on the subject.27,38 Separate meta-analysis on disease duration was possible based on eight cohorts.2,17,26,27,35,38,40,41 No significant difference in disease duration was found between patients with and without apathy (Fig. 4). Consecutive-exclusion analysis results were similar (Supplemental Data s-6). Paradoxically, subgroup analysis showed a trend of decreasing apathy rates with increasing disease duration (Fig. 3). Four studies reported that higher levodopa (L-dopa) equivalent dosage (LED), particularly of dopamine agonists, was associated with lower apathy scores in regression analysis.2,27,32,42 In contrast, L-dopa use was significantly higher in patients with apathy compared with those without in two studies,21,32 and higher L-dopa dosage was associated worse apathy scores in another.38

Cognition and Depression Apathy was associated with lower MMSE scores in 7 of 10 cohorts reporting on the subject,4,10,17,28,38,40 and with a worse Montreal Cognitive Assessment

Movement Disorders, Vol. 00, No. 00, 2015

5

D E N

B R O K

E T

A L

FIG. 3. Subgroup analyses. n, number of patients; s, number of cohorts; AS, apathy scale with validated cutoff; AS*, apathy scale with cutoff > 0 for loss of motivation and for 2 of the 3 subdomains of cognition, emotion, and behavior; NPI, Neuropsychiatric Inventory; LARS, Lille Apathy Rating Scale; AES, Apathy Evaluation Scale with validated cutoff. Exclusion of CI, exclusion of patients with cognitive impairment; DSM, based on a diagnosis of dementia according to the Diagnostic and Statistical Manual of Psychiatric Diseases; Screening cutoff, based on a minimum score on cognitive screening instruments (supplement S-7). Subgroups of disease duration, MMSE score, and HY stage based on tertiles of study averages; MMSE, Mini Mental State Examination; HY, Hoehn & Yahr stage. [Color figure can be viewed in the online issue, which is available at wileyonline library.com.]

FIG. 4. Pooled within-study differences between apathy and non-apathy subgroups. Included studies are listed in the text. The x-axis denotes the size the effect in units denoted under Measure. The vertical line represents the point of no significant difference between apathy and no-apathy groups. Apathy ES, effect size in the apathy group; CI, confidence intervals; MMSE, Mini Mental State Examination; UPDRS III, Unified Parkinson’s Disease Rating. Scale motor section: MDS-UPDRS, movement disorders society adaptation of the UPDRS; MD, mean difference; RR, relative risk.

6

Movement Disorders, Vol. 00, No. 00, 2015

A P A T H Y

score in another.32 Separate meta-analysis regarding MMSE score was possible based on nine cohorts.2,10,17,26,27,35,38,40,41 Patients with apathy on average had a 1.4-point lower MMSE score (95% CI 5 22.1-0.8, I2 5 61%, Fig. 4). The difference was slightly smaller in consecutive-exclusion analysis (21.2 points, Supplemental Data s-6). Pooled apathy rates were similar to the overall estimate in studies excluding patients based on a DSM-IV diagnosis of dementia (39.3%, 95% CI 5 30.3-48.3, I 5 94%),10,21,25,29,36,41 but lower (28.1%, 95% CI 5 15.7-40.4, I 5 96%, Fig. 4) when based on a minimum score in cognitive screening tests (Supplemental Data s-7).4,17,22,23,27,32-34 Depression was significantly associated with apathy in 14 of 22 studies reporting on the subject.2,4,10,16,17,22,25-28,32,38,40,43 Separate meta-analysis regarding depression was possible based on 17 cohorts.2,4,10,16,17,21-24,26-28,32,35,36,38,40 Patients with apathy had a higher risk of depression (relative risk [RR] 5 2.3, 95% CI 5 1.9-2.8, I2 5 74%, Fig. 4). The difference was slightly smaller in consecutiveexclusion analysis (2.0 y, Supplemental Data s-6). The relative risk was lower for patients diagnosed using DSM criteria for depression (n 5 1,415, RR 5 1.9, 95% CI 5 1.5-2.4, I2 5 50%), compared with those diagnosed using a rating scale cutoff for mild/minor (n 5 1,042, RR 5 2.4, 95% CI 5 1.7-3.4, I2 5 85%), or moderate/ major (n 5 575, RR 5 3.3, 95% CI 5 2.4-4.5, I2 5 0%) depression. Prevalence of depression in patients with apathy was 57.2% (n 5 1,294, 95% CI 5 49.4%64.9%, I2 5 87%) compared with 25.6% in patients without apathy (n 5 1,738, 95% CI 5 18.6%-32.5%, I2 5 93%). The overlap was higher in studies using a rating scale cutoff for mild/minor depression (63.34%, I2 5 90%),4,16,23,24,26,32,38 compared with those using a cutoff for moderate/major depression (37.1%,I2 5 0%),22,28,40 or a DSM diagnosis (58.2%, I2 5 84%).10,17,21,27,35,36 The prevalence of apathy in patients without depression or cognitive impairment was 22.6% (n 5 1033, 95% CI 5 15.2%-29.9%, I2 5 88%).2,4,10,17,2123,27,36,41 This was similar when only including studies in which both conditions were diagnosed according to DSM criteria (n 5 372, 23.9%, 95% CI 5 0.03%44.9%, I2 5 93%).10,21,26 The prevalence of depression was 57.7% in patients with apathy without cognitive impairment (n 5 660, 95% CI 5 47.2%-64.2%, I2 5 83%) compared with 21.9% in patients without apathy (n 5 1,012, 95% CI 5 15.0%-30.9%, I2 5 90%).

Motor Symptoms, Disability, and Hoehn and Yahr Stage Higher UPDRS motor scores were associated with apathy in 8 of 11 cohorts reporting on the subject.2,4,17,21,27,32,38,41 Eight cohorts could be used for meta-analysis.10,17,21,26,27,38,40,41 On average, patients

I N

P A R K I N S O N ’ S

D I S E A S E

with apathy had a 6.5 points higher UPDRS motor score (95% CI 5 2.6-10.3, I2 5 88%, Fig. 4). The difference was no longer significant in consecutiveexclusion analysis, although only one study did not report a higher mean score in patients with apathy (Supplemental Data s-6).40 In the two studies that employed the MDS-UPDRS, patients with apathy on average scored 7.7 points higher (95% CI 5 3.6-11.8, I2 5 35%).2,32 More severe disability was associated with apathy in six cohorts.2,4,10,26,32,41 Separate meta-analysis for disability was possible based on five cohorts.2,10,26,32,41 Disability was measured using the Alzheimer’s Disease Co-operative Study ADL sum score26 and the UPDRS II.2,10,32,41 Hedges-G analysis showed a standardized effect size of 0.5 (95% CI 5 0.3-0.6, I2 5 0%, Fig. 4), indicating that, overall, patients with apathy scored half a standard deviation worse in ADL measures than those without apathy. In four of nine studies reporting on the subject, apathy was associated with higher HY stages,4,21,27,32 whereas in one study it was associated with lower HY stages.38 In subgroup analysis, no association between apathy and HY staging was found.

Disease Burden In four of five studies reporting on the subject, patients with apathy had worse quality of life scores on the EuroQol-5D,4,21 the SF-36,39 or the 39-item Parkinson Disease Questionnaire,2,4 however, not when adjusted for concomitant depression,2 or combined motor and non-motor symptoms.39 Increased caregiver burden was associated with apathy in two cohorts.20,44 In another, caregivers of patients with apathy were found to suffer from distress particularly often compared with those of patients with other NPI symptoms, including depression, anxiety, and irritability.15

Discussion We found that up to 40% of individuals with PD suffer from apathy. In almost half of patients’ apathy occurs without concomitant depression or cognitive impairment. Apathy is associated with older age, worse cognitive function, depression, increased motor symptoms, more severe disability, and potentially with a lower quality of life and increased caregiver burden.

Prevalence and Clinical Correlates Reported apathy rates in community-dwelling populations of comparable age range from 0% to 20%.41,45-47 Based on these estimates, most cases of apathy in PD could be attributable to PD itself. As in the general population, apathy in PD is associated

Movement Disorders, Vol. 00, No. 00, 2015

7

D E N

B R O K

E T

A L

with older age.6,45 This relation, however, may be mediated by other factors, including cognitive impairment and disability. Next to age, the relation between apathy and MMSE scores is confounded by many factors, including depression and disease duration. Aside from cognitive impairment, executive inhibition and lack of effort also may lower MMSE scores.48,49 This fits the markedly lower apathy prevalence found in studies excluding patients based on cognitive screening tests, compared with those excluding patients based on a DSM diagnosis of dementia. Interestingly, the prevalence of apathy decreased with longer disease duration. This relation has not been identified within individual studies and contradicts the association of apathy with older age, worse ADL, and cognitive impairment. This finding may be an ecological fallacy, possibly explained by survival or selection bias. Because patients with apathy are less capable of selfcare and have a higher risk of rapid cognitive decline and mortality, they may be less likely to be included in studies of community-dwelling outpatients in later stages of PD.22,41 Although apathy can occur as a symptom of depression,50 42.8% of patients with apathy did not suffer from depression, confirming that apathy in PD also commonly occurs as a separate symptom. The similar percentage of depression in apathy patients without cognitive impairment suggests that these cases are not all attributable to cognitive decline.12 We found that apathy occurs in approximately 20% of PD patients without depression or cognitive impairment. Although apathy was related to a worse quality of life,2,4,21 some evidence exists that this is mainly attributable to its association with depression and other symptoms of PD.2,39,51 The reported associations of apathy with increased caregiver burden20,44 seem plausible and have been reported in other diseases as well.52,53 However, paucity of data prohibit any firm conclusions on these subjects.

Apathy Assessment The many different assessment instruments, sources, and cutoff points used may be an important source of heterogeneity. Studies employing the LARS and the NPI reported a nearly 10% lower rate compared with studies employing the AS. This is consistent with findings in stroke patients.54 In our study, each instrument was mostly confined to its own measurement source (NPI: informant-based, AS: self-reported, LARS: clinician-based), obstructing differentiation between whether the difference in estimates is caused by the instruments or the source. Discrepancy between selfand informant-based assessment,17,55,56 as well as between different assessment instruments,11 has been reported before. Most studies used clinically validated cutoff points for the diagnosis of apathy. Interestingly,

8

Movement Disorders, Vol. 00, No. 00, 2015

studies employing a more sensitive cutoff, mainly the NPI score of 1 or higher, did not find a much higher prevalence. Supposedly, this could suggest the NPI of 1 or higher cutoff corresponds relatively well with the validated cutoff points for the other scales. However, the NPI of 4 or higher point cutoff has been validated against a clinical diagnosis,17 and studies employing both cutoff points reported 3 times higher prevalence rates using the 1 or higher cutoff, implying they are not interchangeable.15,25,26 The diagnostic criteria for the diagnosis of apathy also may be a source of heterogeneity. This definition requires the presence of the cardinal symptom of loss of motivation in addition to symptoms in at least two of the three domains of cognition, behavior, and emotion.57 Some studies adapted the interpretation of the Apathy Scale questionnaire to correspond with this definition.10,58 Although these adaptations may approximate the diagnostic criteria, they have not been widely implemented nor validated. Data regarding the validity of the available measurement instruments in their normal form against the diagnostic criteria is, however, also limited.11,17,46 The diagnostic criteria may necessitate structured clinical interviews or development of rating instruments specifically designed to implement the impaired motivation and three-domain structure of the definition.57 Although the instruments have been validated separately, a direct comparison between the AS, AES, LARS, and NPI using different cutoff points may provide valuable data regarding their convergent validity, discriminant validity (especially from depression and physical constraints),59,60 and the factors influencing both self- and informant-based rating scores.55,56,60 This could aid comparison between study results and promote consensus on which instruments are best suited to measure apathy in different circumstances.

Treatment The relation between apathy and dopaminergic treatment is currently unclear. Findings that apathy is lower in patients with higher LED,2,27,42 particularly of dopamine agonists, are in line with theories that apathy in PD results from dopaminergic depletion.61 Research in patients before and after deep brain stimulation (DBS) also suggests that apathy in patients postsurgery is related to dopamine withdrawal.62,63 Mood and behavioral symptoms in DBS are a debated issue not discussed in detail here. However, a recent comprehensive evaluation of the available evidence suggests that the reduction in anti-parkinsonian drugs allowed by motor improvement can unveil hypodopaminergic behavior, including apathy.64 The contradictory findings of higher L-dopa dosage in patients with apathy21,38 may be explained by differentiation between L-dopa and dopamine agonists.21,27,42 If dopamine agonists are effective against apathy rather

A P A T H Y

than L-dopa, findings of higher L-dopa dosage in patients with apathy could be attributable to the association between apathy and worse motor symptoms. Although specifically designed randomized controlled trials (RCT) are lacking, RCT post hoc analysis has provided some suggestions that apathy in PD may benefit from dopamine agonist use.65 Decisive data on the benefit of dopamine agonists in PD-related apathy is unavailable, however, and any benefits will always have to be balanced against the side effects. Next to dopamine replacement, other treatment options have been suggested, including anticholinergic drugs, antidepressants, and nonpharmacological treatment strategies such as exercise and cognitive training.50,66-69 Recently, a small RCT showed that rivastigmine improved apathy in patients without depression and cognitive impairment.66 Improvement of apathy coincided with improvement in instrumental activities of daily living and caregiver burden, although not in quality of life.66 Successful treatment of apathy (ADL) after DBS also coincided with improved ADL scores.62 These results suggest that successful treatment of apathy also may alleviate these clinical correlates, although improvement in ADL may be partly attributable to improvement in depression ratings.70 Research into the pathophysiology and treatment of apathy may be hampered by clinical correlates with overlapping symptoms.71 Depression, cognitive impairment, fatigue.31,34,72 and physical constraint,59 may all lead to higher apathy ratings. Loss of motivation also can occur as a normal psychological response to the loss of ADL73 Even in isolated apathy, pathophysiological mechanisms and brain regions involved may differ. For instance, apathy may result from an isolated loss of anticipatory pleasure but also from an isolated loss of sense of reward.73-76 The different underlying mechanisms may be decisive in determining which treatment is successful, and perhaps multiple strategies should be attempted.

Strengths and Limitations We employed a comprehensive literature search and thoroughly explored our data through various subgroup analyses and meta-regression. Although, arguably, we disregarded potentially relevant information by leaving out studies that measured apathy with the UPDRS, studies comparing the UPDRS apathy item with the AS showed no cutoff value with an adequate balance between sensitivity and specificity for apathy assessment.24,58 Bias seems relatively limited according to the bias assessment, but our results may suffer from unidentified sources of bias. Heterogeneity was considerable, and exploration of the factors causing heterogeneity was hampered by differences in apathy definitions, depression definitions, and report of cognitive function. We have tried to explore these factors

I N

P A R K I N S O N ’ S

D I S E A S E

more extensively by separately analyzing the apathy prevalence and heterogeneity in subgroups based on the different definitions of these factors. None of these subgroups, however, substantially resolved the identified heterogeneity. Other, less easily identifiable factors also may have impacted heterogeneity, including differences in apathy scale translations, culture, settings, and unreported comorbidities (eg, cardiovascular disease). Because we were unable to identify a single main source of heterogeneity, most likely the interplay between several factors is decisive. This interplay may have distorted the identified relations between apathy and the clinical correlates examined in our study. The relation between apathy and age, disease duration, depression, MMSE scores, and UPDRS-III scores seems especially intricate. Only six studies reported all of these correlates, leaving too little information for reliable multivariate meta-regression with all of these predictors. The high heterogeneity limits the interpretation of our findings. We tried to take this into account by using a random effects model, excluding outliers, and performing consecutive-exclusion analyses. Consecutive-exclusion analyses provided a conservative estimate when no main outlier could be identified and heterogeneity was mostly caused by differences in size of the association rather than its direction. This approach does not identify the causes of heterogeneity but did allow us to more confidently identify clinical correlates of apathy. The interpretation of these clinical correlates is, however, limited by the cross-sectional design of almost all of the studies included in our review, impeding causal inferences. Finally, a true prevalence of psychiatric disorders cannot be estimated using cutoff points on neuropsychiatric rating scales. Therefore, the estimates provided in this paper should be considered pooled estimated frequencies rather than true prevalence rates.

Clinical Implications Because of their overlap in symptomatology, apathy may easily be misidentified as depression. Accurate identification of isolated apathy can prevent inefficacious prescription of antidepressant drugs, to which apathy does not respond or may even worsen.8 In patients considered for DBS, apathy has been identified as a significant predictor of negative patientperceived DBS treatment outcome, regardless of objective treatment effectiveness.77 The pervasiveness of apathy in PD warrants research into its treatment, although different underlying mechanisms may require different treatment regimens. Dopamine agonist treatment seems promising, but any benefit will have to be balanced against the side effects. Other treatment options include acetylcholinesterase inhibitors and nonpharmacological treatment strategies. Treatment of apathy could improve patient quality of life, reduce

Movement Disorders, Vol. 00, No. 00, 2015

9

D E N

B R O K

E T

A L

caregiver burden, alleviate disability by increasing motivation for self-care, and reduce cognitive impairment by improving executive functioning.

References

functioning in Parkinson’s disease. Neuropsychology 2010;24:721730. 23.

Kay DB, Kirsch-Darrow L, Zahodne LB, Okun MS, Bowers D. Dimensions of apathy in Parkinson’s disease: exploratory factor analysis of the apathy scale. J Parkinsons Dis 2012;2:161-166.

24.

Kirsch-Darrow L, Zahodne LB, Hass C, et al. How cautious should we be when assessing apathy with the Unified Parkinson’s Disease Rating Scale? Mov Disord 2009;24:684-688.

25.

Kulisevsky J, Pagonabarraga J, Pascual-Sedano B, Garcıa-S anchez C, Gironell A. Prevalence and correlates of neuropsychiatric symptoms in Parkinson’s disease without dementia. Mov Disord 2008; 23:1889-1896.

1.

Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368-376.

2.

Skorvanek M, Rosenberger J, Gdovinova Z, et al. Apathy in elderly nondemented patients with Parkinson’s disease: clinical determinants and relationship to quality of life. J Geriatr Psychiatry Neurol 2013;26:237-243.

26.

3.

Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Disord 2009;24:16411649.

Laatu S, Karrasch M, Martikainen K, Marttila R. Apathy is associated with activities of daily living ability in Parkinson’s disease. Dement Geriatr Cogn Disord 2013;35:249-255.

27.

Oguru M, Tachibana H, Toda K, Okuda B, Oka N. Apathy and depression in Parkinson disease. J Geriatr Psychiatry Neurol 2010; 23:35-41.

Leroi I, Andrews M, McDonald K, et al. Apathy and impulse control disorders in Parkinson’s disease: a direct comparison. Parkinsonism Relat Disord 2012;18:198-203.

28.

Lieberman A. Are dementia and depression in Parkinson’s disease related? J Neurol Sci 2006;248:138-142.

29.

Monastero R, Di Fiore P, Ventimiglia GD, Camarda R, Camarda C. The neuropsychiatric profile of Parkinson’s disease subjects with and without mild cognitive impairment. J Neural Transm 2013;120:607-611.

30.

Morley JF, Weintraub D, Mamikonyan E, Moberg PJ, Siderowf AD, Duda JE. Olfactory dysfunction is associated with neuropsychiatric manifestations in Parkinson’s disease. Mov Disord 2011;26:2051-2057.

31.

Ojagbemi AA, Akinyemi RO, Baiyewu O. Neuropsychiatric symptoms in Nigerian patients with Parkinson’s disease. Acta Neurol Scand 2013;128:9-16.

32.

Rodriguez-Violante M, Gonz alez-Latapi P, Cervantes-Arriaga A, Martınez-Ramırez D, Vel azquez-Osuna S, Camacho-Ordo~ nez A. Apathy and associated factors in Mexican patients with Parkinson’s Disease. Neurol Sci 2014;35:729-734.

33.

S aez-Franc as N, Hern andez-Vara J, Corominas Roso M, Alegre Martın J, Casas Brugue M. The association of apathy with central fatigue perception in patients with Parkinson’s disease. Behav Neurosci 2013;127:237-244.

4.

5.

Starkstein SE, Leentjens AF. The nosological position of apathy in clinical practice. J Neurol Neurosurg Psychiatry 2008;79:10881092.

6.

Van Reekum R, Stuss DT, Ostrander L. Apathy: why care? J Neuropsychiatry Clin Neurosci 2005;17:7-19.

7.

Chase TN. Apathy in neuropsychiatric disease: diagnosis, pathophysiology, and treatment. Neurotox Res 2011;19:266-278.

8.

Drijgers RL, Aalten P, Winogrodzka A, Verhey FR, Leentjens AF. Pharmacological treatment of apathy in neurodegenerative diseases: a systematic review. Dement Geriatr Cogn Disord 2009;28:13-22.

9.

Bogart KR. Is apathy a valid and meaningful symptom or syndrome in Parkinson’s disease? A critical review. Health Psychol 2011;30:386-400.

10.

Starkstein SE, Merello M, Jorge R, Brockman S, Bruce D, Power B. The syndromal validity and nosological position of apathy in Parkinson’s disease. Mov Disord 2009;24:1211-1216.

11.

Clarke DE, Ko JY, Kuhl E a, van Reekum R, Salvador R, Marin RS. Are the available apathy measures reliable and valid? A review of the psychometric evidence. J Psychosom Res 2011;70:73-97.

12.

Starkstein SE. Apathy in Parkinson’s disease: diagnostic and etiological dilemmas. Mov Disord 2012;27:174-178.

34.

13.

Center for Reviews and Dissemination, Univ of York. Systematic Reviews: CRD’s guidance for undertaking reviews in health care. Author, Univ York, UK, 2008.

Skorvanek M, Gdovinova Z, Rosenberger J, et al. The associations between fatigue, apathy and depression in Parkinson’s disease. Acta Neurol Scand. (Epub) 2014; DOI: 10.1111/ane.12282.

35.

Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1992;4:134-139.

36.

Stella F, Banzato CE, Quagliato EM, Viana MA, Christofoletti G. Psychopathological features in patients with Parkinson’s disease and related caregivers’ burden. Int J Geriatr Psychiatry 2009;24: 1158-1165.

37.

Tanaka K, Wada-Isoe K, Nakashita S, Yamamoto M, Nakashima K. Impulsive compulsive behaviors in Japanese Parkinson’s disease patients and utility of the Japanese version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease. J Neurol Sci 2013;15:76-80.

14.

Review Manager (RevMan) [Computer program]. Version 5.2. The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, 2012.

15.

Leiknes I, Tysnes O-B, Aarsland D, Larsen JP. Caregiver distress associated with neuropsychiatric problems in patients with early Parkinson’s disease: the Norwegian ParkWest study. Acta Neurol Scand 2010;122:418-424.

16.

Aarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;67:492-496.

17.

Drijgers RL, Dujardin K, Reijnders JS, Defebvre L, Leentjens AF. Validation of diagnostic criteria for apathy in Parkinson’s disease. Parkinsonism Relat Disord 2010;16:656-660.

38.

Wells G, Shae B, O’Connel D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalysis (online). [cited 2005 September 2]. Available from: http// www.ohri.ca/programs/clinical_epidemiology.

Ziropadja L, Stefanova E, Petrovic M, Stojkovic T, Kostic VS. Apathy and depression in Parkinson’s disease: the Belgrade PD study report. Parkinsonism Relat Disord 2012;18:339-342.

39.

Wallace B, Schmid C, Lau J, Trikalinos TA. Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodology 2009. [cited 2014 June 17]. Available from: http://www.biomedcentral.com/1471-2288/9/80/.

M€ uller B, Assmus J, Herlofson K, Larsen JP, Tysnes OB. Importance of motor vs. non-motor symptoms for health-related quality of life in early Parkinson’s disease. Parkinsonism Relat Disord 2013;19:1027-1032.

40.

Pedersen KF, Alves G, Brønnick K, Aarsland D, Tysnes OB, Larsen JP. Apathy in drug-na€ıve patients with incident Parkinson’s disease: the Norwegian ParkWest study. J Neurol 2010;257:217223.

41.

Pedersen KF, Alves G, Aarsland D, Larsen JP. Occurrence and risk factors for apathy in Parkinson disease: a 4-year prospective longitudinal study. J Neurol Neurosurg Psychiatry 2009;80:1279-1282.

42.

Zahodne LB, Bernal-Pancheco O, Bowers D, et al. Are serotonine reuptake inhibitors associated with apathy in Parkinson’s disease? J Neuropsychiatry Clin Neurosci 2012;24:326-330.

18.

19.

20.

Van Dalen JW, Moll van Charante EP, Nederkoorn PJ, van Gool WA, Richard E. Poststroke apathy. Stroke 2013;44:851-860.

21.

Benito-Le on J, Cubo E, Coronell C. Impact of apathy on healthrelated quality of life in recently diagnosed Parkinson’s disease: the ANIMO study. Mov Disord 2012;27:211-218.

22.

Butterfield LC, Cimino CR, Oelke LE, Hauser RA, Sanchez-Ramos J. The independent influence of apathy and depression on cognitive

10

Movement Disorders, Vol. 00, No. 00, 2015

A P A T H Y

43.

Zahodne LB, Marsiske M, Okun MS, Bowers D. Components of depression in Parkinson disease. J Geriatr Psychiatry Neurol 2012; 25:131-137.

44.

Leroi I, Harbishettar V, Andrews M, McDonald K, Byrne EJ, Burns A. Carer burden in apathy and impulse control disorders in Parkinson’s disease. Int J Geriatr Psychiatry 2012;27:160-166.

45.

Dujardin K, Sockeel P, Delliaux M, Destee A, Defebvre L. The Lille Apathy Rating Scale: validation of a caregiver-based version. Mov Disord 2008;23:845-849.

46.

Brodaty H, Altendorf A, Withall A, Sachdev P. Do people become more apathetic as they grow older? A longitudinal study in healthy individuals. Int Psychogeriatr 2010;22:426-436.

47.

Jordan LL, Zahodne LB, Okun MS, Bowers D. Hedonic and behavioral deficits associated with apathy in Parkinson’s disease: potential treatment implications. Mov Disord 2013;28:1301-1304.

48.

Ligthart SA, Richard E, Fransen NL, et al. Association of vascular factors with apathy in community-dwelling elderly individuals. Arch Gen Psychiatry 2012;69:636-642.

I N

P A R K I N S O N ’ S

D I S E A S E

tors and underlying mesolimbic denervation. Brain 2010;133:11111127. 63.

Czernecki V, Sch€ upbach M, Yalci S, et al. Apathy following subthalamic stimulation in Parkinson’s disease: a dopamine responsive syndrome. Mov Disord 2008;23:964-969.

64.

Castrioto A, Lhommee E, Moro E, Krack P. Mood and behavioural effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurol 2014;13:287-305.

65.

Ray Chaudhuri K, Martinez-Martin P, Antonini A, et al. Rotigotine and specific non-motor symptoms of Parkinson’s disease: post hoc analysis of RECOVER. Parkinsonism Relat Disord 2013;19: 660-665.

66.

Devos D, Moreau C, Malt^ete D, et al. Rivastigmine in apathetic but dementia and depression-free patients with Parkinson’s disease: a double-blind, placebo controlled, randomised clinical trial. J Neurol Neurosurg Psychiatry 2014;85:668-674.

67.

Abrantes AM, Friedman JH, Brown RA, et al. Physical activity and neuropsychiatric symptoms of Parkinson disease. J Geriatr Psychiatry Neurol 2012;25:138-145.

49.

Blonder LX, Slevin JT. Emotional dysfunction in Parkinson’s disease. Behav Neurol 2011;24:201-217.

68.

50.

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;27:501-513.

Van der Kolk NM, King LA. Effects of exercise on mobility in people with Parkinson’s disease. Mov Disord 2013;28: 1587-1596.

69.

51.

Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991;3:243-254.

Lane-Brown AT, Tate RL. Apathy after acquired brain impairment: a systematic review of non-pharmacological interventions. Neuropsychol Rehabil 2009;19:481-516.

52.

Opara JA, Brola W, Leonardi M, Błaszczyk B. Quality of life in Parkinson’s disease. J Med Life 2012;5:375-381.

70.

Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Effect of psychiatric and other nonmotor symptoms on disability in Parkinson’s disease. J Am Geriatr Soc 2004;52:784-788.

53.

Marsh NV, Kersel DA, Havill JH, Sleigh JW. Caregiver burden at 1 year following severe traumatic brain injury. Brain Inj 1998;12: 1045-1059.

71.

Vriend C, Pattij T, Van der Werf YD, et al. Depression and impulse control disorders in Parkinson’s disease: two sides of the same coin? Neurosci Biobehav Rev 2014;38:60-71.

54.

Thomas P, Clement JP, Hazif-Thomas C, Leger JM. Family, Alzheimer’s disease and negative symptoms. Int J Geriatr Psychiatry 2001;16:192-202.

72.

Dujardin K, Langlois C, Plomhause L, et al. Apathy in untreaded early-stage Parkinson disease: relationship with other non-motor symptoms. Mov Disord (Epub) 2014; DOI: 10.1002/mds.26058.

55.

Schiehser DM, Liu L, Lessig SL, et al. Predictors of discrepancies in Parkinson’s disease patient and caregiver ratings of apathy, disinhibition, and executive dysfunction before and after diagnosis. J Int Neuropsychol Soc 2013;19:295-304.

73.

Simpson J, McMillan H, Leroi I, Murray CD. Experiences of apathy in people with Parkinson’s disease: a qualitative exploration. Disabil Rehabil 2014;29:1-9.

56.

Pfeifer L, Drobetz R, Fankhauser S, Mortby ME, Maercker A, Forstmeier S. Caregiver rating bias in mild cognitive impairment and mild Alzheimer’s disease: impact of caregiver burden and depression on dyadic rating discrepancy across domains. Int Psychogeriatr 2013;25:1345-1355.

74.

Adam R, Leff A, Sinha N, et al. Dopamine reverses reward insensitivity in apathy following globus pallidus lesions. Cortex 2013;49: 1292-1303.

75.

Jordan LL, Zahodne LB, Okun MS, Bowers D. Hedonic and behavioral deficits associated with apathy in Parkinson’s disease: potential treatment implications. Mov Disord 2013;28:1301-1304.

76.

Lawrence AD, Goerendt IK, Brooks DJ. Apathy blunts neural response to money in Parkinsons’s disease. Soc Neurosci 2011;6: 653-662.

77.

Maier F, Lewis CJ, Horstkoetter N, et al. Patients’ expectations of deep brain stimulation, and subjective perceived outcome related to clinical measures in Parkinson’s disease: a mixed-method approach. J Neurol Neurosurg Psychiatry 2013;84:1273-1281.

57.

58.

Robert P, Onyike CU, Leentjens AF, et al. Proposed diagnostic criteria in Alzheimer’s disease and other neuropsychiatric disorders. Eur Psychiatry 2009;24:98-104. Pedersen KF, Larsen JP, Aarsland D. Validation of the Unified Parkinson’s Disease Rating Scale (UPDRS) section I as a screening and diagnostic instrument for apathy in patients with Parkinson’s disease. Parkinsonism Relat Disord 2008;14:183-186.

59.

Leentjens AFG, Dujardin K, Marsh L, et al. Apathy and anhedonia rating scales in Parkinson’s disease: critique and recommendations. Mov Disord 2008;23:2004-2014.

60.

Schrag A. Apathy and depression scales in Parkinson’s disease: are they good enough? J Nourol Sci 2011;310:216-219.

Supporting Data

61.

Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex 2006;16:916-928.

62.

Thobois S, Ardouin C, Lhommee E, et al. Non-motor dopamine withdrawal syndrome after surgery for Parkinson’s disease: predic-

Additional Supporting Information may be found in the online version of this article at the publisher’s web-site.

Movement Disorders, Vol. 00, No. 00, 2015

11