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
2
Department of General Practise, Academic Medical Center Amsterdam, The Netherlands
3
Department of Neurology, Radboud University Medical Center Nijmegen, The Netherlands

ABSTRACT: Apathy is a frequently reported neu- CI 5 49.4-64.9%), and this estimate was similar after
ropsychiatric symptom in Parkinson’s disease (PD), but its exclusion of patients with cognitive impairment (52.5%,
prevalence and clinical correlates are debated. We aimed 95% CI 5 42.2%-62.8%). In conclusion, we found that
to address these issues by conducting a systematic apathy affects almost 40% of patients with PD. Several
review and meta-analysis. Embase, Medline/PubMed, and factors influence reported prevalence rates, contributing
PsychINFO databases were searched for relevant studies. to the considerable heterogeneity in study results. Half of
Data were extracted by two independent observers, using patients with apathy do not suffer from concomitant
predefined extraction forms tailored specifically to the depression or cognitive impairment, confirming its status
research question. From 1,702 titles and abstracts, 23 as a separate clinical syndrome in PD. The pervasiveness
studies were selected. Meta-analysis showed a preva- of apathy in PD warrants research into its treatment,
lence of apathy in PD of 39.8% (n 5 5,388, 905% CI although different underlying pathophysiological mecha-
34.6-45.0%). Apathy was associated with higher age (3.3 nisms may require different treatment strategies. Treat-
years, 95% CI 5 1.7-4.9), lower mean Mini-Mental State ment of apathy could improve patient quality of life,
Evaluation (MMSE) score (21.4 points, 95% CI 5 22.1 to reduce caregiver burden, alleviate disability by increasing
20.8), an increased risk of co-morbid depression (relative motivation for self-care, and reduce cognitive impairment
risk [RR] 5 2.3, 95% CI 5 1.9-2.8), higher Unified Parkin- by improving executive functioning. V C 2015 International

son’s Disease Rating Scale (UPDRS) motor score (6.5 Parkinson and Movement Disorder Society
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 K e y W o r d s : Parkinson’s disease; apathy; epidemiol-
with apathy had concomitant depression (57.2%, 95% ogy; behavior/neuropsychiatric disorders

Parkinson’s disease (PD) is characterized by the car- symptoms. One of the most burdensome nonmotor
dinal motor symptoms of bradykinesia, tremor, and symptoms may be apathy.2-4
rigidity.1 Many PD patients also experience nonmotor Apathy is defined as a lack of motivation character-
------------------------------------------------------------ ized by diminished goal-oriented behavior and cogni-
*Correspondence to: Dr. Jan Willem van Dalen, Department of Neurol- tion, and reduced emotional expression.5 Apathy is
ogy, Room H2-235, Academic Medical Center Amsterdam, Meibergdreef
14, 1115 AZ, The Netherlands, e-mail: [email protected] known to contribute significantly to caregiver burden
Funding agencies: This study was supported by the Academic Medical
in other neurological disorders, and has negative
Center, Amsterdam, The Netherlands implications for treatment and long-term outcome.6,7
Relevant conflicts of interest/financial disclosures: Nothing to report. Therefore, recognition of apathy in PD may be impor-
Full financial disclosures and author roles may be found in the online ver- tant for treatment and care.8
sion of this article. The significance of apathy in PD has been a subject
y
Shared first authorship. of debate. Reported estimates of the prevalence differ
Received: 23 July 2014; Revised: 5 February 2015; Accepted: 12 greatly between studies, ranging from 17% to 60%.9
February 2015 Reports concerning its clinical impact also vary.9,10
Published online 00 Month 2015 in Wiley Online Library The diversity in population characteristics and diag-
(wileyonlinelibrary.com). DOI: 10.1002/mds.26208 nostic instruments used to assess apathy hampers

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D E N B R O K E T A L

comparison between study results.11,12 Its common When prevalence rates were reported for two differ-
co-occurrence with depression and cognitive impair- ent cutoff points for the NPI (1 or 4), we used the
ment has led to concerns that the impact of apathy in 1 estimate for the overall analysis, because this cut-
PD is mostly secondary to these features.12 off was used by most other studies. Estimates for both
These large differences between study findings and reported cutoff points were included separately for the
interpretations hinder progress in research on apathy cutoff point subgroup analysis. If apathy prevalence
in PD. This systematic review and meta-analysis aims was reported according to several recommended mea-
to give a reliable estimate of the prevalence of apathy surement scales, we used the mean of the estimates for
and its clinical correlates in PD and to explore to the overall analysis of prevalence, and each estimate
what extent specific differences in patient and study separately for subgroup analyses based on measure-
characteristics are able to explain the variation in ment instrument. When means and standard devia-
study results. tions (SD) could only be obtained by combining
means and SDs in subgroups (eg, population age by
Methods combining age in apathy and nonapathy subgroups),
we used Review Manager (version 5.2.5) to do so.14
Data Collection To obtain a single HY staging estimate for each study,
We searched the Embase (from 1980), Medline/ the mean stage was calculated. To identify overlapping
PubMed, and PsychINFO databases (last updated: cases of depression and apathy with the greatest sensi-
November 2014). “Parkinson’s disease” and synonyms tivity, the highest estimate of depression prevalence
were cross-referenced with “apathy,” related terms reported in each study was used.15-17 Study quality
(eg, “abulia”), and names and acronyms of commonly was assessed with a specifically designed assessment
used scales to assess apathy in PD. The full search form (Supplemental Data s-3), based on the
strategy is listed in Supplemental Data s-1. Newcastle-Ottawa quality assessment scale.18
Search results were reviewed by two independent
observers (M.B., J.W.D.). Discrepancies in selection
Statistical Analysis
were resolved by discussion. Inclusion criteria, based
on recommendations by the Center for Reviews and Statistical analyses were performed using OpenMe-
Dissemination,13 were: (1) observational cohort or ta[Analyst] (built 3 December 2013).19 Pooled esti-
case-control studies, (2) of patients with clinically mates were calculated using the Der-Simonian Laird
diagnosed PD, (3) concerning at least 50 patients, (4) random effects model, adjusted for the binomial distri-
written in English, (5) employing the Neuropsychiatric bution of proportions. To evaluate whether one single
Inventory (NPI), Lille Apathy Rating Scale (LARS), study greatly affected the overall estimate, we con-
Apathy Evaluation Scale (AES), or Apathy Scale (AS) ducted Jack-knife analysis, in which each study is
to measure apathy. Only these specific scales were rec- excluded once from the overall analysis, resulting in a
ommended for apathy in PD in a large review of the range of pooled estimates.20 Prevalence rates were
reliability and validity of available apathy measures.11 pooled separately in subgroups based on rating source,
References of obtained reviews were examined for rating instrument, cutoff point, exclusion of cognitive
additional articles. Two independent observers (M.B., impairment, and outpatient, inpatient, or mixed popu-
J.W.D.) performed data extraction using a predefined lation type. To evaluate the impact of our quality cri-
extraction form (Supplemental Data s-2). teria, a sensitivity analysis was performed excluding
Only studies that reported apathy prevalence were half of all studies based on risk of bias on our bias
included. If studies reported on the same cohort, data assessment form (Supplemental Data s-3).13
were obtained from the study describing the largest To evaluate the clinical correlates of apathy, the
sample. Data not reported in the largest study were number of studies that reportedly assessed the relation
supplemented with data from studies on the same between apathy and each correlate, and the number
cohort when necessary for sub-analyses. The instru- that found a significant relation were registered. The
ment used to measure apathy, the measurement source relative risk of depression and possible sex differences
(ie, rated by patients, informants, or clinicians), inpa- in patients with apathy was calculated by pooling rela-
tient or outpatient population, exclusion of cognitive tive risks within each study. Associations with age,
impairment, age, sex, disease duration, dopaminergic disease duration, MMSE score, disability, UPDRS
medication in levodopa equivalent dose (LED), depres- motor score, and MDS-UPDRS motor score were ana-
sion rate, Mini Mental State Examination (MMSE) lyzed by pooling the mean differences between apathy
score, Unified Parkinson’s Disease Rating Scale and non-apathy groups within studies. The relation
(UPDRS) motor score, Hoehn and Yahr (HY) stage, between apathy and disability was assessed using
and disability, quality of life, and caregiver burden Hedges-G analysis to allow pooling of scores meas-
rating scale scores were considered as potential corre- ured using different instruments.13 For correlates with
lates of apathy prevalence.6,9,10 persistent high heterogeneity in the pooled mean

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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 sub-
groups of studies. We separately assessed depression
rates based on a DSM diagnosis, a rating scale cutoff
for moderate/major depression, and a rating scale cut-
off 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 apa-
thy 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 nonde-
pression subgroups of the noncognitive impairment
cohorts.
Univariate Der-Simonean Laird random-effects FIG. 1. Article selection.
meta-regression was performed with apathy prevalence
as outcome and in-/out-/mixed patient population two different cohorts.28 Eight publications were used to
type, exclusion of cognitive impairment, apathy cutoff supplement data of included studies (Supplemental
point validity, mean age, mean disease duration, mean Data s-4).2,20,39-44 Study and population characteristics
depression rate, mean MMSE score, mean HY stage, are listed in Table 1. Eleven studies employed the AS to
and mean UPDRS-III score as predictors. These poten- measure apathy,4,10,23,24,27,30,32,34,35,37,38 10 studies the
tial correlates were selected because they were obtain- NPI apathy item,15-17,25,26,28,29,31,36 three studies the
able for most studies. Multivariate meta-regression LARS,17,21,33 and one study the AES.22 Cutoff points
was subsequently performed, including all predictors validated against a clinical diagnosis were used for the
associated with apathy in univariate meta-regression. AES, for the AS by all but one study,10 for the LARS
Heterogeneity was assessed using I2 statistics. Pooled (–16) by two studies,17,21 and for the NPI (4) by
effect sizes were deemed uninterpretable if I2 exceeded one study.17 More sensitive cutoff points were used in
60%. In these cases stepwise efforts were made to one study employing the LARS (–22),33 and five stud-
reduce heterogeneity. First, analyses were inspected ies employing the NPI (1).16,28,29,31,36 Three studies
for potential outliers using funnel plots. If heterogene- reported prevalence rates for both the 1 and the 4
ity after exclusion of the main outlier remained too point cutoff points on the NPI.15,25,26 In one study,
high, consecutive-exclusion analyses were performed. apathy prevalence was measured using the NPI (4),
In these analyses, studies reporting the largest associa- LARS (16), and a clinical diagnosis, but only the clin-
tion congruent with the pooled estimate were consecu- ical diagnosis was available for subanalyses.17
tively excluded until heterogeneity was acceptable,
resulting in a conservative estimate of the effect size.
Apathy Prevalence
The pooled apathy prevalence was 39.8%
Results (n 5 5,388, 95% confidence interval [CI] 5 34.6%-
45.0%) with high heterogeneity (I2 5 93%)(Fig. 2).
Study Selection Jack-knife analysis showed a minimum pooled rate of
Our search yielded 1,702 articles after duplicate 38.9% (95% CI 5 33.6%-42.2%),37 and a maximum
removal (Fig. 1). Based on titles and abstracts, 95 stud- of 40.9% (95%CI 5 36.0%-45.8%).16 Sensitivity anal-
ies were selected. References of reviews yielded two ysis excluding half of the studies with the highest risk
additional results. After detailed evaluation, 74 studies of bias yielded similar results (39.0%, n 5 2,898, 95%
were excluded for reasons listed in Figure 1. The CI 5 31.4%-46.7%, I2 5 95%). Results of subgroup
remaining 23 studies underwent bias assessment (Sup- analyses regarding measurement source, measurement
plemental Data s-3). Table 1 shows the main character- instrument, cutoff used, exclusion of cognitive impair-
istics of included studies. In total, 5,388 patients were ment, outpatient versus inpatient population, mean
evaluated in 23 studies,4,10,15-17,21-38 one describing disease duration, MMSE score, and HY staging are

Movement Disorders, Vol. 00, No. 00, 2015 3

 TABLE 1. Study characteristics

Major
Exclusion Disease
Cohort and Criteria % Age m Duration HY UPDRS-III MMSE Apathy %, Depression
Author, year (#) Population Excluded n (% fem) (SD) m (SD) m (SD) m (SD) m (SD) Measure %, Measure

Starkstein et al., 199235 Cross Cons x 50 (39) 66.5 (9.6) 10.2 (4.9) x 10 (7.5) b
27.0 (3.7) 42.0%, 56.0%,
Outpat AS 14 (s) DSM/PSE
16
Aarsland et al., 1999 * Long Rand x 139 (56) 74.4 (7.9) 12.6 (5.1) 3.2 (x) x 25.2 (5.9) 16.5%, 38.1%,
Mixed NPI >0 (i) NPI
Lieberman, 2006 -Cohort28 Cross Cons x 106 (56) 71.0 (11.0) 6.2 (5.9) 2.6 (0.8) x x 52.8%, 27.4%,
Outpat NPI >0 (i) Ham-D21
28
Lieberman, 2006 -Cohort 2 Cross Cons x 100 (38) 68.2 (11.2) 6.3 (6.5) 2.5 (1.0) x x 51.0%, 30.6%,
Outpat NPI >0 (i) Ham-D21
Kulisevsky et al., 200825 Cross Cons CI, RD, 25% 1351 (44) 70.6 (9.0) 5.7 (4.9) 2.5 (x) x x 48.3%, 49.7%,
Outpat NPI >0 (i) HADS-D
24
Kirsch-Darrow et al., 2008 Cross Cons Age: 30-90, 301 (37) 68.0 (10.6) 8.1 (5.9) 2.5 (0.7) 30 (12) x 50.8%, 21.9%,
Mixed NST, 10% AS 14 (s) BDI
Starkstein et al., 200910 Cross Cons x 164 (-) 65.9 (10.0) x 2.7 (x) 19 (10) 24.2 (5.5) 31.7%, 58.5%,
Outpat AS (s) DSM/HAM-D
36 c e
Stella et al., 2009 Cross Cons x 50 (44) 68.0 (6.8) 10.4 (5.3) 2.9 (1.0) 69 (29) 66.2 (13.1) 38.0%, 34.0%,
Outpat NPI >0 (i) DSM/MADRS
Butterfield et al., 201022 Cross Recr CI, SEA, OND, 68 (34) 70.0 (7.0) 7.1 (5.0) 2.1 (x) x x 20.6%, 13.3%,
Outpat SCD,PSY AES38 (s) BDI-II
4
Oguru et al., 2010 Cross Cons SEA, OND, 6% 150 (53) 69.7 (8.6) 6.3 (4.4) 2.9 (0.9) 29 (16) 26.6 (3.9) 60.0%, 56.0%,
Outpat AS 16 (s) BDI-II
Drijgers et al., 201017* Cross Cons CI, OND 122 (41) 64.6 (8.5) 8.5 (5.6) x 19 (8) 28.2 (1.8) 19.3% G, 17.3%,
Outpat LARS: -16 DSM/HAM-D
(c), NPI: 4 (i)
Leiknes et al., 201015* Long Cons x, 11% 189 (40) 67.8 (x) 2.3 (x) a
1.9 (x) 23 (x) x 29.1%, 36.0%,
Mixed NPI >0 (i) NPI
Morley et al., 201130 Cross Recr x 248 (25) 64.0 (10.0) 6.6 (5.4) 2.2 (0.7) 22 (10) 28.5 (1.9) 37.0%, 52.0%,
AS 14 (s) IDS
Ziropadja et al., 201238 Cross Cons x 360 (35) 63.5 (10.3) 7.2 (5.1) 2.4 (x) 51 (23) 26.1 (4.1) 60.3%, 41.4%,
Outpat AS 14 (s) HDRS-17
Kay et al., 201223* Long Recr/Cons CI, SEA, OND 226 (33) 65.0 (8.8) x x x 29.1 (0.7) 34.5%, 27.0%, BDI
AS 14 (s)
Benito-Leon et al., 201221 Cross Cons CI, SEA, 557 (40) 68.8 (9.7) 1.3 (0.6) 1.6 (x) 21 (11) x 52.2%, 44.9%, DSM
Outpat Age >30 LARS-16 (c)
Leroi et al., 201227* Cross Recr CI 99 (30) 63.2 (10.7) 7.8 (5.5) 2.4 (x) 29 (12) 28.5 (1.8) 26.3%, 25.3%,
Outpat AS14 (s) HADS-D
Laatu et al, 201326 Cross Cons SEA 73 (38) 65.3 (9.6) 9.3 (5.5) x 23 (12) 27.0 (3) 24.7%, 46.6%, NPI
Inpat R NPI >0 (i)
Monastero et al., 201329 Cross Cons CI, SCD, PSY 410 (40) 68.2 (9.5) x x 22 (12) 27.4 (2.0) 48.8%, 61.7%, NPI
Outpat NPI >0 (i)
Saez-Francas et al., 201333 Cross Cons CI, Age >18, 90 (33) 62.6 (9.7) x 1.8 (0.6) 20 (6) 28.8 (1.1) 28.9%, 25.6%,
Outpat SCD, PSY LARS-22 (c) HAM-D
Ojagbemi et al., 201331 Cross Cons SCD, PSY 50 (44) 65.6 (9.4) 3.4 (2.6) x x 22.2 (5.8) 28.0%, 46.0%, NPI
NPI >0 (i)
Tanaka et al., 201337 Cross Cons x, 21% 93 (51) 69.3 (9.8) 9.6 (6.6) 2.6 (0.9) x x 62.3%, 64.5%, NPI
AS16 (s)
f
Rodrıguez-Violante Cross Cons x 241(47) 62.2 (13.1) 6.6 (5.6) 2.3 (0.8) 33 (17) 22.2 (5.1) 43.1%, 62.7%,
et al., 201432 Outpat AS14 (s) MDS-UPDRS
Skorvanek et al., 201434 Cross Recr CI, SEA, 25% 151 (47) 69.7 (8.6) 6.9 (4.9) 2.4 (0.9) 36 (15) d
26.9 (1.9) 47.0%, 57.6%, BDI-II
Outpat AS14 (s)

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, neu-
rosurgical 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 self-
rated 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 Disease Duration and Medication
substantially resolved heterogeneity. Meta-regression Apathy was associated with longer disease duration
results are listed in Supplemental Data s-5. For every in 2 of 11 cohorts reporting on the subject.27,38 Sepa-
percentage point increase in depression rate, the apa- rate meta-analysis on disease duration was possible
thy rate increased by 0.4 percentage point (P 5 0.02), based on eight cohorts.2,17,26,27,35,38,40,41 No signifi-
and for every point increase in UPDRS-III score by 0.9 cant difference in disease duration was found between
percentage point (P 5 0.01). Multivariate meta- patients with and without apathy (Fig. 4).
regression with both predictors gave similar results Consecutive-exclusion analysis results were similar
(Supplemental Data s-5). (Supplemental Data s-6). Paradoxically, subgroup
analysis showed a trend of decreasing apathy rates
Apathy and Patient Characteristics with increasing disease duration (Fig. 3).
The relation between apathy and age was reported Four studies reported that higher levodopa (L-dopa)
in 14 cohorts, six of which found an association equivalent dosage (LED), particularly of dopamine
between apathy and higher age.4,10,21,27,32,38 Separate agonists, was associated with lower apathy scores in
meta-analysis for age was possible based on 11 regression analysis.2,27,32,42 In contrast, L-dopa use
cohorts,2,10,17,21,26,27,32,35,38,40,41 showing that patients was significantly higher in patients with apathy com-
with apathy were on average 3.3 years (95% CI 5 1.7- pared with those without in two studies,21,32 and
4.9, I2 5 68%, Fig. 4) older than those without. Exclu- higher L-dopa dosage was associated worse apathy
sion of one outlier slightly attenuated the difference to scores in another.38
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 Cognition and Depression
on the association between apathy and sex was possi- Apathy was associated with lower MMSE scores in
ble based on 10 cohorts.2,17,21,26,27,32,35,38,40,41 No 7 of 10 cohorts reporting on the subject,4,10,17,28,38,40
association with sex was found (Fig. 4). and with a worse Montreal Cognitive Assessment

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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 diag-
nosis of dementia according to the Diagnostic and Statistical Manual of Psychiatric Diseases; Screening cutoff, based on a minimum score on cog-
nitive 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.

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score in another.32 Separate meta-analysis regarding with apathy had a 6.5 points higher UPDRS motor
MMSE score was possible based on nine score (95% CI 5 2.6-10.3, I2 5 88%, Fig. 4). The dif-
cohorts.2,10,17,26,27,35,38,40,41 Patients with apathy on ference was no longer significant in consecutive-
average had a 1.4-point lower MMSE score (95% exclusion analysis, although only one study did not
CI 5 22.1-0.8, I2 5 61%, Fig. 4). The difference was report a higher mean score in patients with apathy
slightly smaller in consecutive-exclusion analysis (21.2 (Supplemental Data s-6).40 In the two studies that
points, Supplemental Data s-6). Pooled apathy rates employed the MDS-UPDRS, patients with apathy on
were similar to the overall estimate in studies excluding average scored 7.7 points higher (95% CI 5 3.6-11.8,
patients based on a DSM-IV diagnosis of dementia I2 5 35%).2,32
(39.3%, 95% CI 5 30.3-48.3, I 5 94%),10,21,25,29,36,41 More severe disability was associated with apathy in
but lower (28.1%, 95% CI 5 15.7-40.4, I 5 96%, Fig. 4) six cohorts.2,4,10,26,32,41 Separate meta-analysis for dis-
when based on a minimum score in cognitive screening ability was possible based on five cohorts.2,10,26,32,41
tests (Supplemental Data s-7).4,17,22,23,27,32-34 Depression Disability was measured using the Alzheimer’s Disease
was significantly associated with apathy in 14 of 22 stud- Co-operative Study ADL sum score26 and the UPDRS
ies reporting on the subject.2,4,10,16,17,22,25-28,32,38,40,43 Sep- II.2,10,32,41 Hedges-G analysis showed a standardized
arate meta-analysis regarding depression was possible effect size of 0.5 (95% CI 5 0.3-0.6, I2 5 0%, Fig. 4),
based on 17 cohorts.2,4,10,16,17,21-24,26-28,32,35,36,38,40 indicating that, overall, patients with apathy scored
Patients with apathy had a higher risk of depression (rela- half a standard deviation worse in ADL measures than
tive risk [RR] 5 2.3, 95% CI 5 1.9-2.8, I2 5 74%, Fig. those without apathy. In four of nine studies reporting
4). The difference was slightly smaller in consecutive- on the subject, apathy was associated with higher HY
exclusion analysis (2.0 y, Supplemental Data s-6). The rel- stages,4,21,27,32 whereas in one study it was associated
ative risk was lower for patients diagnosed using DSM with lower HY stages.38 In subgroup analysis, no
criteria for depression (n 5 1,415, RR 5 1.9, 95% association between apathy and HY staging was
CI 5 1.5-2.4, I2 5 50%), compared with those diagnosed found.
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/ Disease Burden
major (n 5 575, RR 5 3.3, 95% CI 5 2.4-4.5, I2 5 0%) In four of five studies reporting on the subject,
depression. Prevalence of depression in patients with patients with apathy had worse quality of life scores
apathy was 57.2% (n 5 1,294, 95% CI 5 49.4%- on the EuroQol-5D,4,21 the SF-36,39 or the 39-item
64.9%, I2 5 87%) compared with 25.6% in patients Parkinson Disease Questionnaire,2,4 however, not
without apathy (n 5 1,738, 95% CI 5 18.6%-32.5%, when adjusted for concomitant depression,2 or com-
I2 5 93%). The overlap was higher in studies using a bined motor and non-motor symptoms.39 Increased
rating scale cutoff for mild/minor depression (63.34%, caregiver burden was associated with apathy in two
I2 5 90%),4,16,23,24,26,32,38 compared with those cohorts.20,44 In another, caregivers of patients with
using a cutoff for moderate/major depression apathy were found to suffer from distress particularly
(37.1%,I2 5 0%),22,28,40 or a DSM diagnosis (58.2%, often compared with those of patients with other NPI
I2 5 84%).10,17,21,27,35,36 symptoms, including depression, anxiety, and
The prevalence of apathy in patients without depres- irritability.15
sion or cognitive impairment was 22.6% (n 5 1033,
95% CI 5 15.2%-29.9%, I2 5 88%).2,4,10,17,21-
23,27,36,41
This was similar when only including studies Discussion
in which both conditions were diagnosed according to
We found that up to 40% of individuals with PD
DSM criteria (n 5 372, 23.9%, 95% CI 5 0.03%-
suffer from apathy. In almost half of patients’ apathy
44.9%, I2 5 93%).10,21,26 The prevalence of depres-
occurs without concomitant depression or cognitive
sion was 57.7% in patients with apathy without cog-
impairment. Apathy is associated with older age,
nitive impairment (n 5 660, 95% CI 5 47.2%-64.2%,
worse cognitive function, depression, increased motor
I2 5 83%) compared with 21.9% in patients without
symptoms, more severe disability, and potentially
apathy (n 5 1,012, 95% CI 5 15.0%-30.9%,
with a lower quality of life and increased caregiver
I2 5 90%).
burden.

Motor Symptoms, Disability, and Hoehn Prevalence and Clinical Correlates

and Yahr Stage Reported apathy rates in community-dwelling popu-
Higher UPDRS motor scores were associated with lations of comparable age range from 0% to
apathy in 8 of 11 cohorts reporting on the sub- 20%.41,45-47 Based on these estimates, most cases of
ject.2,4,17,21,27,32,38,41 Eight cohorts could be used for apathy in PD could be attributable to PD itself. As in
meta-analysis.10,17,21,26,27,38,40,41 On average, patients the general population, apathy in PD is associated

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D E N B R O K E T A L

with older age.6,45 This relation, however, may be studies employing a more sensitive cutoff, mainly the
mediated by other factors, including cognitive impair- NPI score of 1 or higher, did not find a much higher
ment and disability. Next to age, the relation between prevalence. Supposedly, this could suggest the NPI of
apathy and MMSE scores is confounded by many fac- 1 or higher cutoff corresponds relatively well with the
tors, including depression and disease duration. Aside validated cutoff points for the other scales. However,
from cognitive impairment, executive inhibition and the NPI of 4 or higher point cutoff has been validated
lack of effort also may lower MMSE scores.48,49 This against a clinical diagnosis,17 and studies employing
fits the markedly lower apathy prevalence found in both cutoff points reported 3 times higher prevalence
studies excluding patients based on cognitive screening rates using the 1 or higher cutoff, implying they are
tests, compared with those excluding patients based not interchangeable.15,25,26 The diagnostic criteria for
on a DSM diagnosis of dementia. Interestingly, the the diagnosis of apathy also may be a source of heter-
prevalence of apathy decreased with longer disease ogeneity. This definition requires the presence of the
duration. This relation has not been identified within cardinal symptom of loss of motivation in addition to
individual studies and contradicts the association of symptoms in at least two of the three domains of cog-
apathy with older age, worse ADL, and cognitive nition, behavior, and emotion.57 Some studies adapted
impairment. This finding may be an ecological fallacy, the interpretation of the Apathy Scale questionnaire to
possibly explained by survival or selection bias. correspond with this definition.10,58 Although these
Because patients with apathy are less capable of self- adaptations may approximate the diagnostic criteria,
care and have a higher risk of rapid cognitive decline they have not been widely implemented nor validated.
and mortality, they may be less likely to be included Data regarding the validity of the available measure-
in studies of community-dwelling outpatients in later ment instruments in their normal form against the
stages of PD.22,41 Although apathy can occur as a diagnostic criteria is, however, also limited.11,17,46 The
symptom of depression,50 42.8% of patients with apa- diagnostic criteria may necessitate structured clinical
thy did not suffer from depression, confirming that interviews or development of rating instruments spe-
apathy in PD also commonly occurs as a separate cifically designed to implement the impaired motiva-
symptom. The similar percentage of depression in apa- tion and three-domain structure of the definition.57
thy patients without cognitive impairment suggests Although the instruments have been validated sepa-
that these cases are not all attributable to cognitive rately, a direct comparison between the AS, AES,
decline.12 We found that apathy occurs in approxi- LARS, and NPI using different cutoff points may pro-
mately 20% of PD patients without depression or cog- vide valuable data regarding their convergent validity,
nitive impairment. discriminant validity (especially from depression and
Although apathy was related to a worse quality of physical constraints),59,60 and the factors influencing
life,2,4,21 some evidence exists that this is mainly both self- and informant-based rating scores.55,56,60
attributable to its association with depression and This could aid comparison between study results and
other symptoms of PD.2,39,51 The reported associa- promote consensus on which instruments are best
tions of apathy with increased caregiver burden20,44 suited to measure apathy in different circumstances.
seem plausible and have been reported in other dis-
eases as well.52,53 However, paucity of data prohibit
Treatment
any firm conclusions on these subjects.
The relation between apathy and dopaminergic
treatment is currently unclear. Findings that apathy is
Apathy Assessment lower in patients with higher LED,2,27,42 particularly
The many different assessment instruments, sources, of dopamine agonists, are in line with theories that
and cutoff points used may be an important source of apathy in PD results from dopaminergic depletion.61
heterogeneity. Studies employing the LARS and the Research in patients before and after deep brain stimu-
NPI reported a nearly 10% lower rate compared with lation (DBS) also suggests that apathy in patients post-
studies employing the AS. This is consistent with find- surgery is related to dopamine withdrawal.62,63 Mood
ings in stroke patients.54 In our study, each instrument and behavioral symptoms in DBS are a debated issue
was mostly confined to its own measurement source not discussed in detail here. However, a recent com-
(NPI: informant-based, AS: self-reported, LARS: clini- prehensive evaluation of the available evidence sug-
cian-based), obstructing differentiation between gests that the reduction in anti-parkinsonian drugs
whether the difference in estimates is caused by the allowed by motor improvement can unveil hypodopa-
instruments or the source. Discrepancy between self- minergic behavior, including apathy.64 The contradic-
and informant-based assessment,17,55,56 as well as tory findings of higher L-dopa dosage in patients with
between different assessment instruments,11 has been apathy21,38 may be explained by differentiation
reported before. Most studies used clinically validated between L-dopa and dopamine agonists.21,27,42 If
cutoff points for the diagnosis of apathy. Interestingly, dopamine agonists are effective against apathy rather

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

 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

than L-dopa, findings of higher L-dopa dosage in more extensively by separately analyzing the apathy
patients with apathy could be attributable to the asso- prevalence and heterogeneity in subgroups based on the
ciation between apathy and worse motor symptoms. different definitions of these factors. None of these sub-
Although specifically designed randomized controlled groups, however, substantially resolved the identified
trials (RCT) are lacking, RCT post hoc analysis has heterogeneity. Other, less easily identifiable factors also
provided some suggestions that apathy in PD may may have impacted heterogeneity, including differences
benefit from dopamine agonist use.65 Decisive data on in apathy scale translations, culture, settings, and unre-
the benefit of dopamine agonists in PD-related apathy ported comorbidities (eg, cardiovascular disease).
is unavailable, however, and any benefits will always Because we were unable to identify a single main
have to be balanced against the side effects. Next to source of heterogeneity, most likely the interplay
dopamine replacement, other treatment options have between several factors is decisive. This interplay may
been suggested, including anticholinergic drugs, anti- have distorted the identified relations between apathy
depressants, and nonpharmacological treatment strat- and the clinical correlates examined in our study. The
egies such as exercise and cognitive training.50,66-69 relation between apathy and age, disease duration,
Recently, a small RCT showed that rivastigmine depression, MMSE scores, and UPDRS-III scores seems
improved apathy in patients without depression and especially intricate. Only six studies reported all of
cognitive impairment.66 Improvement of apathy coin- these correlates, leaving too little information for reli-
cided with improvement in instrumental activities of able multivariate meta-regression with all of these pre-
daily living and caregiver burden, although not in dictors. The high heterogeneity limits the interpretation
quality of life.66 Successful treatment of apathy (ADL) of our findings. We tried to take this into account by
after DBS also coincided with improved ADL scores.62 using a random effects model, excluding outliers, and
These results suggest that successful treatment of apa- performing consecutive-exclusion analyses.
thy also may alleviate these clinical correlates, Consecutive-exclusion analyses provided a conservative
although improvement in ADL may be partly attribut- estimate when no main outlier could be identified and
able to improvement in depression ratings.70 Research heterogeneity was mostly caused by differences in size
into the pathophysiology and treatment of apathy may of the association rather than its direction. This
be hampered by clinical correlates with overlapping approach does not identify the causes of heterogeneity
symptoms.71 Depression, cognitive impairment, but did allow us to more confidently identify clinical
fatigue.31,34,72 and physical constraint,59 may all lead correlates of apathy. The interpretation of these clinical
to higher apathy ratings. Loss of motivation also can correlates is, however, limited by the cross-sectional
occur as a normal psychological response to the loss design of almost all of the studies included in our
of ADL73 Even in isolated apathy, pathophysiological review, impeding causal inferences. Finally, a true prev-
mechanisms and brain regions involved may differ. alence of psychiatric disorders cannot be estimated
For instance, apathy may result from an isolated loss using cutoff points on neuropsychiatric rating scales.
of anticipatory pleasure but also from an isolated loss Therefore, the estimates provided in this paper should
of sense of reward.73-76 The different underlying be considered pooled estimated frequencies rather than
mechanisms may be decisive in determining which true prevalence rates.
treatment is successful, and perhaps multiple strategies
should be attempted.
Clinical Implications
Because of their overlap in symptomatology, apathy
Strengths and Limitations may easily be misidentified as depression. Accurate
We employed a comprehensive literature search and identification of isolated apathy can prevent ineffica-
thoroughly explored our data through various subgroup cious prescription of antidepressant drugs, to which
analyses and meta-regression. Although, arguably, we apathy does not respond or may even worsen.8 In
disregarded potentially relevant information by leaving patients considered for DBS, apathy has been identi-
out studies that measured apathy with the UPDRS, fied as a significant predictor of negative patient-
studies comparing the UPDRS apathy item with the AS perceived DBS treatment outcome, regardless of objec-
showed no cutoff value with an adequate balance tive treatment effectiveness.77 The pervasiveness of
between sensitivity and specificity for apathy assess- apathy in PD warrants research into its treatment,
ment.24,58 Bias seems relatively limited according to the although different underlying mechanisms may require
bias assessment, but our results may suffer from different treatment regimens. Dopamine agonist treat-
unidentified sources of bias. Heterogeneity was consid- ment seems promising, but any benefit will have to be
erable, and exploration of the factors causing heteroge- balanced against the side effects. Other treatment
neity was hampered by differences in apathy options include acetylcholinesterase inhibitors and
definitions, depression definitions, and report of cogni- nonpharmacological treatment strategies. Treatment of
tive function. We have tried to explore these factors 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 functioning in Parkinson’s disease. Neuropsychology 2010;24:721-
730.
motivation for self-care, and reduce cognitive impair-
23. Kay DB, Kirsch-Darrow L, Zahodne LB, Okun MS, Bowers D.
ment by improving executive functioning. Dimensions of apathy in Parkinson’s disease: exploratory factor
analysis of the apathy scale. J Parkinsons Dis 2012;2:161-166.

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the online version of this article at the publisher’s
withdrawal syndrome after surgery for Parkinson’s disease: predic- web-site.

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