RESEARCH ARTICLE

Neuropsychiatric symptoms and cognitive abilities over the

initial quinquennium of Parkinson disease
Daniel Weintraub1,2,3 , Chelsea Caspell-Garcia4, Tanya Simuni5, Hyunkeun R. Cho4, Christopher S.
Coffey4, Dag Aarsland6, Roy N. Alcalay7 , Matthew J. Barrett8, Lana M. Chahine9, Jamie Eberling10,
Alberto J. Espay11, Jamie Hamilton10, Keith A. Hawkins12, James Leverenz13, Irene Litvan14, Irene
Richard15, Liana S. Rosenthal16, Andrew Siderowf2, Michele York17 & Parkinson’s Progression
Markers Initiative*
1
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
2
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
3
Parkinson’s Disease Research, Education and Clinical Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania
4
Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa
5
Feinberg School of Medicine, Northwestern University, Chicago, Illinois
6
Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, England
7
Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
8
Department of Neurology, Virginia Commonwealth University, Richmond, Virginia
9
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
10
Michael J. Fox Foundation for Parkinson’s Research, New York, New York
11
Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, Ohio
12
Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut
13
Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio
14
UCSD Movement Disorder Center, Department of Neurosciences, University of California San Diego, San Diego, California
15
Departments of Neurology and Psychiatry, School of Medicine and Dentistry, University of Rochester, Rochester, New York
16
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
17
Departments of Neurology and Psychiatry & Behavioral Sciences, Baylor College of Medicine, Houston, Texas

Correspondence Abstract
Daniel Weintraub, Perelman School of
Medicine at the University of Pennsylvania, Objective: To determine the evolution of numerous neuropsychiatric symp-
3615 Chestnut St., #330, Philadelphia, PA toms and cognitive abilities in Parkinson disease from disease onset. Methods:
19014. Tel: +1 (215) 349-8207; Prospectively collected, longitudinal (untreated, disease onset to year 5), obser-
Fax: +1 (215) 349-8389; E-mail: vational data from Parkinson’s Progression Markers Initiative annual visits was
[email protected]
used to evaluate prevalence, correlates, and treatment of 10 neuropsychiatric
symptoms and cognitive impairment in Parkinson disease participants and
Funding Information matched healthy controls. Results: Of 423 Parkinson disease participants evalu-
PPMI, a public–private partnership, is funded ated at baseline, 315 (74.5%) were assessed at year 5. Eight neuropsychiatric
by the Michael J. Fox Foundation for symptoms studied increased in absolute prevalence by 6.2–20.9% at year 5 rela-
Parkinson’s Research and funding partners tive to baseline, and cognitive impairment increased by 2.7–6.2%. In compar-
(see www.ppmi-info.org/fundingpartners). ison, the frequency of neuropsychiatric symptoms in healthy controls remained
stable or declined over time. Antidepressant and anxiolytic/hypnotic use in
Received: 31 January 2020; Revised: 21
Parkinson disease were common at baseline and increased over time (18% to
February 2020; Accepted: 24 February 2020
27% for the former; 13% to 24% for the latter); antipsychotic and cognitive-en-
Annals of Clinical and Translational
hancing medication use was uncommon throughout (2% and 5% of patients at
Neurology 2020; 7(4): 449–461 year 5); and potentially harmful anticholinergic medication use was common
and increased over time. At year 5 the cross-sectional prevalence for having
doi: 10.1002/acn3.51022 three or more neuropsychiatric disorders/cognitive impairment was 56% for
Parkinson disease participants versus 13% for healthy controls, and by then
*See PPMI author list at http://www.ppmi-inf seven of the examined disorders had either occurred or been treated at some
o.org/authorslist/
time point in the majority of Parkinson disease patients. Principal component
analysis suggested an affective disorder subtype only. Interpretation:

ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 449
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
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Psychiatric Symptoms and Cognitive Abilities in Early PD D. Weintraub et al.

Neuropsychiatric features in Parkinson disease are common from the onset,

increase over time, are frequently comorbid, and fluctuate in severity.

(mean duration of PD diagnosis = 7 months); (3) be

Introduction
untreated; (4) have a dopamine transporter (DAT) deficit
Parkinson disease (PD) is diagnosed based on the pres- on neuroimaging; and (5) be non-demented. Healthy
ence of motor symptoms, but the high prevalence of controls were required to have: (1) no significant neuro-
numerous neuropsychiatric symptoms (NPS) and cogni- logic dysfunction; (2) no first-degree family member with
tive impairment suggests that it is more accurately con- PD; and (3) a Montreal Cognitive Assessment (MoCA)
ceptualized as a neuropsychiatric disorder.1 It has only score ≥27. The aims and methodology of the study have
been relatively recently, with the introduction of levodopa been published elsewhere15 (www.ppmi-info.org/study-
and other PD medications, the increasing life span of design). The study was approved by the institutional
patients, and through increased awareness and research, review board at each site, and participants provided writ-
that NPS and cognitive impairment have gained recogni- ten informed consent.
tion as being common, often disabling, and associated
with poor long-term outcomes and caregiver burden.2
In addition to cognitive impairment (both mild cogni- Assessments
tive impairment [MCI] and dementia), depression, and Cognitive abilities
psychosis, other relatively common psychiatric complica-
tions include impulse control disorders (ICDs), anxiety Global cognition was assessed with the MoCA.17 As no
symptoms, disorders of sleep and wakefulness, apathy, MoCA cutoff was applied for PD patients, a direct com-
and fatigue. parison of PD patients and HCs on cognitive assessments
Although cognitive impairment and decline in early PD was not conducted. The following cognitive tests were
has been studied,3-7 less is known8-11 about the evolution administered: memory: Hopkins Verbal Learning Test-
of a broader range of NPS in newly diagnosed patients Revised (HLVT-R);18 visuospatial function: Benton Judg-
and compared with healthy controls (HC), point preva- ment of Line Orientation (JOLO)19 15-item (split-half)
lence versus cumulative prevalence, comorbidity of symp- version; processing speed-attention: Symbol-Digit Modali-
toms, and their stability over time. In addition, the use or ties Test (SDMT);20 and executive function and working
introduction of psychiatric medications has not been well memory: Letter-Number Sequencing (LNS)21 and seman-
studied, nor the impact of medications with anticholiner- tic (animal) fluency.22 Published norms (referenced
gic properties on cognitive performance. Finally, there is above) were applied.
an interest in subtyping of non-motor symptoms in PD,12 Cognitive impairment (CI) was defined at two levels: (1)
but this has not been well studied in de novo and early at the screening level, the recommended MoCA cutoff of
PD.13,14 <26 was applied;17,23 and (2) using psychometric tests, CI
The Parkinson’s Progression Markers Initiative (PPMI) categorization was reached through a cognitive test-based
study is a large, multi-site, international, observational, classification, requiring impairment (>1.5 standard devia-
biomarker-discovery program of de novo, untreated (at tions below the standardized mean score, in the range rec-
baseline) PD patients and a matched group of HC.15 We ommended to establish a MCI diagnosis24) on any two
previously reported PPMI baseline NPS data7 and bio- cognitive test scores (using both total immediate recall and
marker predictors of the 3-year cognitive data.16 Now we recognition recall from the HVLT-R, and single scores from
report NPS outcomes over the initial lustrum (i.e. each of the other tests). Within 2 years of study initiation,
5 years) of PD. an additional cognitive determination was added, the site
investigator’s clinical diagnosis of normal cognition, MCI
or dementia at each annual visit based on clinical judgment
Methods and option to review any clinical data.

Participants
Neuropsychiatric symptoms
Parkinson disease patients (N = 423) and HC (N = 196)
were enrolled in PPMI. At baseline PD participants were The following instruments (cutoff scores to indicate clini-
required to: (1) have an asymmetric resting tremor or cally significant symptoms) were administered: 15-item
asymmetric bradykinesia, or two of bradykinesia, resting Geriatric Depression Scale (GDS-15),25 score ≥ 5 for
tremor, and rigidity; (2) have a recent PD diagnosis depression;26 State-Trait Anxiety Inventory (STAI),27 state

450 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
D. Weintraub et al. Psychiatric Symptoms and Cognitive Abilities in Early PD

subscale, score ≥ 40 for anxiety;28 short version of the (Bonferroni correction) was applied to account for multi-
Questionnaire for Impulsive-Compulsive Disorders in ple comparisons.
Parkinson’s Disease (QUIP) for ICDs (gambling, sexual,
buying, and eating), related behaviors (punding, hobbyism,
Predictors of neuropsychiatric symptoms in PD partici-
and walkabout), and compulsive medication use, hereafter pants
together called ICDs;29 REM Sleep Behavior Disorder
Screening Questionnaire (RBDSQ),30 score ≥ 6 for RBD Similarly, GEEs were also used to examine demographics
symptoms; Epworth Sleepiness Scale,31 score ≥ 10 indicat- and PD medication use as univariate predictors of each
ing daytime sleepiness; in addition, psychosis, apathy, NPS over time in PD patients. Age, sex, and education
insomnia and fatigue were assessed with single items from level were assessed as baseline predictors, while total levo-
the Movement Disorder Society Unified Parkinson’s Dis- dopa equivalent daily dose (LEDD), dopamine agonist
ease Rating Scale (MDS-UPDRS)32 Part I. A score ≥ 2 was (DA) use, and Anticholinergic Cognitive Burden (ACB)
considered presence of a given symptom for apathy, insom- Scale33 (an assessment of anticholinergic burden of pre-
nia, and fatigue, and a score ≥ 1 was considered presence scribed medications) score were assessed as time-varying
of psychosis, in order to capture mild psychosis. predictors. All models treated time as linearly associated
with the log odds and were fit under the AR1 correlation
structure. ORs were presented for the interaction effect
Analyses between the predictor and time. Again, a Bonferroni cor-
Statistical analyses were performed using SAS 9.4 (SAS rection was applied.
Institute Inc., Cary, NC) on data downloaded from the
PPMI data portal at the Laboratory of Neuroimaging Results
(LONI) on July 1, 2019. Summary statistics for demo-
graphics, clinical characteristics, and NPS were presented Participant characteristics
by year separately in PD and HC. Cumulative prevalence
and number of NPS were also presented by year and Baseline characteristics for PD patients and HC are pre-
group. Kaplan–Meier survival curves were generated for sented in Table 1; the groups were similar in age, race
each NPS in PD participants. Time was calculated from and sex distribution, and education level. Clinical charac-
the baseline visit date to the first visit date where NPS, or teristics of PD participants over the 5-year period are pre-
NPS treatment, was present. Participants who did not sented in Table 2. Antidepressants were prescribed in
experience NPS within 5 years from baseline were cen- 26.7% of patients at year 5 visit, and anxiolytics/sedative-
sored at their last completed visit date. Principal compo- hypnotic agents in 24.1%, while antipsychotic and cogni-
nent analysis (PCA) was performed to examine clustering tive-enhancing medication use was uncommon even after
(i.e. potential subtypes) among NPS at baseline and year
5 in PD participants. In addition, the difference in cogni- Table 1. Baseline participant characteristics.

tion was examined in PD patients who dropped out of PD Healthy

the study early compared to those who completed the Participants Controls
year 5 visit. At a significance level of 0.05, Mann–Whitney Variable (N = 423) (N = 196)
U tests or Fisher’s exact tests were used to compare the
Age
last observed MoCA scores in PD patients who dropped Mean (SD) 61.66 (9.7) 60.82 (11.2)
out versus MoCA scores in patients who completed the (Min, Max) (33.5, 84.9) (30.6, 83.7)
study, separately at year 2, 3, and 4. Gender
Male 277 (65.5%) 126 (64.3%)
Female 146 (34.5%) 70 (35.7%)
Neuropsychiatric symptoms over time in PD partici- Education
pants versus HC <13 Years 75 (17.7%) 29 (14.8%)
≥13 Years 348 (82.3%) 167 (85.2%)
Changes in NPS over time in PD patients compared to
Race
HC were assessed using Generalized Estimating Equations White 391 (92.4%) 182 (92.9%)
(GEEs) under the first order autoregressive correlation Black/African-American 6 (1.4%) 9 (4.6%)
(AR1) structure. Under the assumption that the log odds Asian 8 (1.9%) 1 (0.5%)
of a positive response is linear in time, each model was fit Other 18 (4.3%) 4 (2.0%)
with effects for group, time, and an interaction between Duration of disease (months)
Mean (SD) 6.65 (6.5) NA
group and time. Odds Ratios (ORs) were presented for
(Min, Max) (0.4, 35.8) NA
the time and interaction effects. A family wise error rate

ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 451
Psychiatric Symptoms and Cognitive Abilities in Early PD D. Weintraub et al.

Table 2. Clinical characteristics over time in PD participants.

Baseline Year 1 Year 2 Year 3 Year 4 Year 5

Variable (N = 423) (N = 395) (N = 378) (N = 366) (N = 346) (N = 315)

MDS-UPDRS Part III OFF1

N 423 335 285 257 250 230
Mean (SD) 20.89 (8.9) 25.16 (11.1) 27.19 (11.3) 29.23 (12.2) 31.46 (12.3) 31.31 (12.6)
(Min, Max) (4.0, 51.0) (2.0, 67.0) (3.0, 68.0) (4.0, 80.0) (6.0, 80.0) (6.0, 90.0)
MDS-UPDRS Part III ON1
N 423 380 358 342 326 299
Mean (SD) 20.89 (8.9) 23.37 (10.9) 23.16 (11.3) 24.15 (12.2) 24.31 (13.1) 24.67 (13.4)
(Min, Max) (4.0, 51.0) (1.0, 67.0) (0.0, 68.0) (0.0, 65.0) (1.0, 70.0) (0.0, 85.0)
TD/PIGD Classification ON1
N 422 380 358 342 326 299
TD 299 (70.9%) 241 (63.4%) 217 (60.6%) 207 (60.5%) 167 (51.2%) 134 (44.8%)
PIGD 76 (18.0%) 96 (25.3%) 102 (28.5%) 101 (29.5%) 117 (35.9%) 126 (42.1%)
Indeterminate 47 (11.1%) 43 (11.3%) 39 (10.9%) 34 (9.9%) 42 (12.9%) 39 (13.0%)
PD medication use
Any PD medication 0 (0.0%) 224 (56.7%) 299 (79.1%) 316 (86.3%) 306 (88.4%) 279 (88.6%)
Levodopa 0 (0.0%) 92 (23.3%) 157 (41.5%) 210 (57.4%) 235 (67.9%) 239 (75.9%)
Dopamine agonist 0 (0.0%) 90 (22.8%) 123 (32.5%) 138 (37.7%) 133 (38.4%) 117 (37.1%)
MAO-B inhibitor 0 (0.0%) 103 (26.1%) 138 (36.5%) 144 (39.3%) 136 (39.3%) 120 (38.1%)
Total LEDD
N 0 224 299 316 306 279
Mean (SD) NA 306.1 (235.3) 397.7 (311.4) 481.7 (338.2) 556.6 (343.3) 645.0 (345.7)
(Min, Max) NA (30.3, 1600.0) (50.0, 2268.0) (50.0, 2474.0) (50.0, 3020.0) (120.0, 3184.0)
DBS treatment
Yes 0 (0.0%) 0 (0.0%) 1 (0.3%) 2 (0.5%) 4 (1.2%) 12 (3.8%)
Other medication use
Antidepressants 77 (18.2%) 84 (21.3%) 94 (24.9%) 95 (26.0%) 98 (28.3%) 84 (26.7%)
Anxiolytics/Sed.-Hypnotics 55 (13.0%) 64 (16.2%) 67 (17.7%) 70 (19.1%) 80 (23.1%) 76 (24.1%)
Antipsychotics 0 (0.0%) 0 (0.0%) 2 (0.5%) 8 (2.2%) 7 (2.0%) 7 (2.2%)
Stimulants 3 (0.7%) 2 (0.5%) 2 (0.5%) 4 (1.1%) 4 (1.2%) 7 (2.2%)
Cognitive-enhancing 0 (0.0%) 2 (0.5%) 5 (1.3%) 10 (2.7%) 16 (4.6%) 16 (5.1%)
Anticholinergic cognitive burden scale
N2 142 (33.6%) 168 (42.5%) 170 (45.0%) 183 (50.0%) 178 (51.4%) 162 (51.4%)
Mean (SD)3 2.16 (1.4) 2.49 (1.5) 2.71 (1.7) 2.83 (1.7) 2.76 (1.8) 2.86 (1.8)
(Min, Max)3 (1.0, 7.0) (1.0, 8.0) (1.0, 9.0) (1.0, 11.0) (1.0, 11.0) (1.0, 11.0)

1
OFF scores include untreated + treated OFF scores; ON scores include untreated + treated ON scores.
2
Number of patients on a medication with anticholinergic properties.
3
Includes only those patients on a medication with anticholinergic properties at that visit.

5 years. The percentage of patients taking a medication 20.6% for fatigue, 15.2% for daytime sleepiness, 12.5%
with possible or definite anticholinergic properties (i.e. for RBD, 9.6% for psychosis, 9.5% for apathy, 6.6% for
ACB score ≥ 1) increased from 33.6% at baseline to ICDs, and 6.2% for depression. In contrast, the anxiety
51.4% at year 5, and the mean ACB scale score for rate decreased by 3.1% over this time period. Individual
patients taking an anticholinergic medication increased by primary ICD rates at year 5 were 11.2% (eating), 7.1%
32.4% from baseline to year 5. (sexual behaviors), 5.4% (buying), and 1.3% (gambling).
At year 5, cross-sectional prevalence rates of >25%
occurred for insomnia, RBD, fatigue, daytime sleepiness,
Psychiatric and cognitive outcomes over time and ICDs; only RBD crossed this threshold at baseline.
For cognitive abilities, mean MoCA score declined by
Parkinson disease
only 2% over the 5-year period; applying MoCA cutoff
Baseline and year 5 neuropsychiatric outcome in PD scores, any cognitive impairment (i.e. MoCA score < 26)
patients is presented in Figure 1. Comparing year 5 with had an absolute increase of 6.2%, and significant cogni-
baseline, absolute prevalence rates increased by 6.2– tive impairment (i.e. MoCA score < 21) of 4.8%. Using
20.9%; specifically, they increased by 20.9% for insomnia, detailed cognitive testing the rate of impairment increased

452 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
D. Weintraub et al. Psychiatric Symptoms and Cognitive Abilities in Early PD

Figure 1. Neuropsychiatric symptoms and cognitive impairment in PD at year 5 compared with baseline.

by only 2.7%. By site investigator diagnosis the prevalence entry criteria no HC met criteria for cognitive impair-
of any cognitive impairment at the year 5 visit was 19.8% ment at baseline, and 18% did so by year 5.
(MCI = 16.2%, dementia = 3.6%).
Given the relatively low rates of cognitive impairment,
Comorbidity
we assessed whether study dropouts were more likely to
have cognitive impairment. By year 5, data were not avail- Accounting for psychiatric or cognitive treatment (i.e.
able for 25.3% (108/423) of PD participants with a baseline counting a disorder as present if treated, regardless of the
visit. Those PD participants who were not assessed starting assessment outcome), cross-sectional prevalence of ≥3
with the year 3 visit had evidence for lower MoCA scores at psychiatric/cognitive disorders increased in PD partici-
their last observed visit compared with PD patients who pants from 29% at baseline to 56% by year 5, whereas in
completed the year 5 visit (Table 3). HC the rates went from 12% to just 13% over this time
period (Fig. 2). Examining psychiatric symptoms only
(i.e. excluding cognition), rates increased from 24% to
Healthy controls
50% over time in PD patients, compared with decreasing
Unlike in PD, cross-sectional prevalence rates for HC from 12% to 10% in HC. Thus, rates of multimorbid
decreased, or remained the same or negligible, for depres- psychiatric disorders approximately doubled in PD
sion, anxiety, psychosis, daytime sleepiness, RBD, and patients over the 5-year period, and by year 5 were
ICDs. For cognition, mean MoCA score declined only 2% approximately five times more common in PD patients
over the 5-year period; applying MoCA cutoff scores, by than HC.

ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 453
Psychiatric Symptoms and Cognitive Abilities in Early PD D. Weintraub et al.

Table 3. MoCA scores in PD participants who completed year 5 visit

versus those who discontinued study participation. Cumulative prevalence

2 3 4 Again accounting for symptomatic treatment in addition

PD subjects to presence of symptoms, the Kaplan–Meier estimates for
cumulative prevalence of NPS/cognitive impairment in
MOCA Score Completed Discontinued study P-value
PD participants is presented in Figure 3. By year 5, seven
Year 2 of the 10 disorders studied had either been present or
N 302 14 treated at some time point in >50% of patients, with the
Mean (SD) 26.49 (2.7) 24.07 (6.0) 0.2187
highest frequency for insomnia and RBD. All 10 symp-
MoCA < 26 91 (30.1%) 8 (57.1%) 0.0416
toms had occurred or been treated in at least 25% of
MoCA < 21 10 (3.3%) 3 (21.4%) 0.0153
Year 3 patients.
N 305 15
Mean (SD) 26.60 (2.8) 25.07 (3.6) 0.0876
Persistence of symptoms
MoCA < 26 93 (30.5%) 7 (46.7%) 0.2519
MoCA < 21 8 (2.6%) 2 (13.3%) 0.0743 Persistence of NPS in PD participants is presented in
Year 4
Table 4. For psychiatric symptoms, the highest likelihood
N 302 18
of still having a symptom 1 year later was for depression
Mean (SD) 26.59 (3.4) 23.06 (6.0) 0.0148
MoCA < 26 87 (28.8%) 10 (55.6%) 0.0309 (60–79%), insomnia (60–78%) and RBD (64–81%). Less
MoCA < 21 15 (5.0%) 6 (33.3%) 0.0004 persistent were anxiety (55–60%), psychosis (33–58%), apa-
thy (25–54%), and ICDs and related disorders (33–68%).
Column definitions: 2, MoCA scores at each visit in PD subjects who Of those participants who had cognitive impairment at any
completed the year 5 visit; 3, Last observed MoCA scores in PD sub-
time point based on a MoCA score < 26, the percentage
jects who later discontinued study participation; 4, P-values from
Mann–Whitney U test or Fisher’s exact test.
still meeting this criterion 1 year later was 62–70%.

Figure 2. Psychiatric symptoms and cognitive disorder comorbidity over time in PD participants.

454 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
D. Weintraub et al. Psychiatric Symptoms and Cognitive Abilities in Early PD

Figure 3. Kaplan–Meier estimates for cumulative prevalence of neuropsychiatric disorders and cognitive impairment in PD at year 5.

ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 455
Psychiatric Symptoms and Cognitive Abilities in Early PD D. Weintraub et al.

Table 4. Persistence of neuropsychiatric symptoms-cognitive impairment in PD participants.

2 3 4 5 6 7 8 9 10 11
Variable Baseline Year 1 Year 1 Year 2 Year 2 Year 3 Year 3 Year 4 Year 4 Year 5

GDS-15
≥5 57 34 (59.6%) 59 37 (62.7%) 61 37 (60.7%) 56 35 (62.5%) 47 37 (78.7%)
STAI state
≥40 97 54 (55.7%) 85 48 (56.5%) 75 45 (60.0%) 63 37 (58.7%) 61 35 (57.4%)
MDS-UPDRS psychosis
≥1 9 3 (33.3%) 17 8 (47.1%) 24 13 (54.2%) 36 21 (58.3%) 36 15 (41.7%)
MDS-UPDRS apathy
≥2 11 5 (45.5%) 27 7 (25.9%) 32 11 (34.4%) 24 10 (41.7%) 28 15 (53.6%)
MDS-UPDRS fatigue
≥2 42 26 (61.9%) 63 37 (58.7%) 69 35 (50.7%) 68 48 (70.6%) 71 57 (80.3%)
MDS-UPDRS insomnia
≥2 92 55 (59.8%) 114 76 (66.7%) 112 73 (65.2%) 119 90 (75.6%) 127 99 (78.0%)
Epworth sleepiness scale
≥10 57 23 (40.4%) 65 45 (69.2%) 78 58 (74.4%) 94 67 (71.3%) 86 65 (75.6%)
RBDSQ
≥6 100 64 (64.0%) 95 77 (81.1%) 116 86 (74.1%) 117 88 (75.2%) 105 83 (79.0%)
QUIP
≥1 disorders1 84 28 (33.3%) 52 24 (46.2%) 73 44 (60.3%) 76 52 (68.4%) 83 49 (59.0%)
MOCA
<26 89 55 (61.8%) 126 88 (69.8%) 110 74 (67.3%) 103 72 (69.9%) 85 58 (68.2%)
<21 4 3 (75.0%) 13 8 (61.5%) 17 8 (47.1%) 12 8 (66.7%) 14 8 (57.1%)

Column definitions: 2,4,6,8,10, Number of subjects with symptoms at the visit (only includes subjects with data available 1 year later); 3,5,7,9,11,
Number (percentage) of subjects with symptoms at previous visit who remained symptomatic 1 year later, out of subjects with data available at
both years.
1
Defined as any of four main ICDs OR other behaviors OR compulsive medication use.

data. At both baseline and year 5, seven principal compo-

Models comparing NPS over time in PD
nents were needed to explain at least 80% of total vari-
participants versus HC
ance. The first component explained only 21% and 26%
Nearly all (except anxiety) of the nine assessed psychiatric of the total variance at baseline and year 5 and had high-
symptoms increased significantly in prevalence in the PD est and positively associated loadings for depression and
group over time. Comparing PD patients with HC, anxiety at baseline, and depression, anxiety, and fatigue at
insomnia, EDS, RBD, and ICD and related symptoms all year 5. Examining the Pearson correlation matrix for all
increased significantly in prevalence over time in PD 10 variables, only depression-anxiety (0.49) and fatigue-
patients relative to HC (Table 5). apathy (0.37) had an r value >0.30.

Models assessing predictors of NPS over time in Discussion

PD participants
In this analysis of the 5-year course in de novo PD
There were no significant effects of demographic vari- patients enrolled in the PPMI study, of the nine non-cog-
ables on change in symptoms in PD participants over nitive NPS we examined, cross-sectional prevalence rates
time. Regarding impact of PD treatments, lower total increased by 6.2–20.9% over the 5-year period for eight
LEDD was associated with cognitive impairment. There of the disorders, with only anxiety decreasing in preva-
were no significant impacts of DA use or ACB scale lence over time. This is consistent with previous research
score on symptoms over time, including cognitive done in smaller samples, and with different assessments,
impairment. that a range of non-motor symptoms are common in
early PD8 and increase over time.10 Although we can only
speculate based on the data presented herein, possible
Principal component analysis in PD
explanations for the increase in NPS over time in early
A PCA was conducted in PD patients for the 10 NPS/cog- PD include the spread of disease pathology, impact of PD
nitive impairment, using first baseline and then year 5 treatments on some symptoms, and psychological factors.

456 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
D. Weintraub et al. Psychiatric Symptoms and Cognitive Abilities in Early PD

Table 5. Psychiatric symptoms in PD participants versus HC over or a longer lag time after initiation of PD medications for
time. ICD development.36 The greatest increase in and highest
Year*Group1 prevalence of symptoms at year 5 occurred for disorders
Year Interaction of sleep and wakefulness, as well as fatigue.
In contrast, cognition in PD patients was relatively
OR2 OR4
Outcome (95% CI) P-value 3
(95% CI) P-value3
unimpaired at baseline and declined less over time than
reported in other longitudinal studies in early PD (3, 5,
GDS-15 1.10 (1.03, 0.0021 0.83 (0.70, 0.0318 6). Factors contributing to this may include a cohort that
1.17) 0.98) was relatively younger at baseline, highly educated, and
STAI state 0.96 (0.91, 0.1106 0.99 (0.86, 0.8926
highly motivated given the demands of study participa-
1.01) 1.14)
MDS-UPDRS 1.33 (1.23, <0.0001 0.50 (0.27, 0.0247
tion. Another possible factor, not typically examined, was
psychosis 1.44) 0.92) evidence that study discontinuation was associated with
MDS-UPDRS 1.26 (1.16, <0.0001 0.96 (0.71, 0.8139 worse cognitive performance, thus eliminating these par-
apathy 1.37) 1.30) ticipants from subsequent analyses. Variability in cogni-
MDS-UPDRS 1.27 (1.20, <0.0001 0.89 (0.74, 0.2184 tive performance around the MoCA cutoff score of 26
fatigue 1.35) 1.07) may have to do as much with instrument reliability as
MDS-UPDRS 1.22 (1.15, <0.0001 0.87 (0.80, 0.0006
with true variation in patient performance.
insomnia 1.28) 0.94)
Epworth 1.20 (1.14, <0.0001 0.86 (0.78, 0.0027
To put the results in context, cross-sectional preva-
sleepiness scale 1.27) 0.95) lence rates increased over time for nearly every NPS/cog-
RBDSQ 1.13 (1.08, <0.0001 0.81 (0.73, 0.0003 nitive impairment in PD patients, while they changed
1.19) 0.91) little in HC over time. This helps confirm that disease or
QUIP5 1.11 (1.05, 0.0003 0.84 (0.76, 0.0011 PD treatment effects, not increasing age, is the primary
1.18) 0.93) driving force to NPS in PD, although the fact that the
1
PD is the reference group. healthy control cohort all had normal cognition at base-
2
Year effect OR indicates the change in odds of the symptom in PD line may also have made them less likely to have NPS as
participants for every year increase. OR >1 indicates an increase in well.
odds of the symptom over time. When examining prevalence of NPS in PD, studies typ-
3
Bonferroni-corrected significant P value is < 0.005. ically don’t account for initiation of symptomatic therapy
4
Year*Group Interaction OR indicates the change in estimated OR
for the studied disorders. In additional analyses we
between HC relative to PD for every year increase. OR < 1 indicates
decided to include initiation of psychopharmacology as
the odds of the symptom increase faster in PD over time compared to
the change in odds in HC over time. indicating the presence of a disorder (ICDs excepted,
5
Defined as any of four main ICDs OR other behaviors OR compulsive given lack of approved treatments), regardless of the
medication use. assessment score, as a clinical decision had been made to
initiate symptomatic therapy. Then again examining
cross-sectional, as well as cumulative prevalence, the bur-
At baseline, we found that only one disorder (RBD) den of NPS was even higher. For instance, the cumulative
occurred in >25% of patients, while by year 5 this thresh- prevalence of all 10 NPS/cognitive impairment in PD was
old was crossed by five of the disorders. Within this over- >25% by year 5, and seven of the NPS/cognitive impair-
all increase in NPS over time, there are subtle differences. ment had a cumulative prevalence of >50%.
For instance, depression and anxiety, both considered fea- Given the high cumulative prevalence of nearly all the
tures of prodromal PD,34 were common at disease onset examined NPS, high disorder comorbidity is expected.
but did not increase markedly over the next 5 years. Anx- Considering the presence of three or more NPS/cognitive
iety actually decreased over time; possible explanations impairment at any time point as significant comorbidity,
for this include that some anxiety at baseline may be this prevalence doubled over the 5-year period, going
related to the recent PD diagnosis, anxiety that occurs in from approximately one-quarter to over one-half of
the context of non-motor fluctuations is not common in patients.
early disease, and that the nearly doubling in frequency of Fluctuations in cognitive performance and diagnosis
anxiolytic/sedative-hypnotic medication use over 5 years over time have been reported in PD, and we extend the
may have effectively treated anxiety symptoms in some findings to include other NPS too. Given that not all
patients. Psychosis and ICDs are both known to be asso- patients who screened positive for a neuropsychiatric
ciated with PD medication use, but only psychosis symptom were receiving treatment for that disorder, this
increased significantly over the 5-year period, perhaps indicates some natural variability in NPS from year to
suggesting a greater disease contribution for psychosis35 year, and also highlight the limitation in using a screening

ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 457
Psychiatric Symptoms and Cognitive Abilities in Early PD D. Weintraub et al.

instrument with a single cutoff point to indicate possible Longitudinal studies have demonstrated that the cumu-
presence of a disorder. lative prevalence of most psychiatric and cognitive com-
Regarding treatment of NPS/cognitive impairment, use plications are far higher than earlier cross-sectional
of antidepressants and anxiolytics/sedative-hypnotic studies suggested, and the results reported herein extend
agents were common even at disease onset, and rose to many of these findings to even early PD. From a research
approximately one-quarter of patients by year 5 for each standpoint, this indicates that NPS are a potential out-
medication class. In contrast, antipsychotic and cognitive- come measure for disease progression clinical trials. Clini-
enhancing medications were uncommon throughout this cally, under-recognition of NPS remains,37 and
period. The latter finding could represent either that psy- management options for most NPS remain quite lim-
chosis or cognitive deficits are often not determined to be ited.40 From disease onset, the common, accumulating,
clinically significant early in the disease course, or that and frequently comorbid occurrence of numerous NPS
NPS symptoms may be under-recognized and under- makes imperative investments into improving their recog-
treated in PD.37 nition and treatment. Parkinson disease is not only a
Medications can also have an adverse impact on NPS/ motor disorder, but also a neuropsychiatric disease from
cognitive abilities in PD. A range of PD medications are the beginning, and needs to be treated as such.
associated with both psychosis and ICDs, but neither total
LEDD nor DA use predicted the presence of either symp-
Conflict of Interest
tom in this study. This may in part be due to the low
overall prevalence or increase in the symptoms in the first Weintraub reports receiving salary support from the
5 years of the illness, or the lower doses of DAs and levo- Michael J Fox Foundation during the conduct of the
dopa used when initiated in early disease. In addition, the study (Weintraub serves on the Steering Committee of
use of medications with anticholinergic properties the PPMI Study). Ms. Caspell-Garcia has nothing to dis-
increased over time, and although there was no impact of close. Simuni reports receiving grant funding from
ACB score on meeting a MoCA cutoff score in these anal- NINDS, MJFF, as well as the Parkinson’s Foundation.
yses, it is possible that with more long-term ACB expo- Additionally, Simuni receives grants from Biogen, Roche,
sure and examination of other cognitive outcomes, an Neuroderm, Sanofi, Sun Pharma, Abbvie, IMPAX, as well
effect may be detected, as previously reported in PD.38 as other funding from Acadia, Abbvie, Accorda, Adamas,
There is increasing interest in subtyping non-motor Allergan, Amneal, Anavex, Aptinyx, Denali, General Elec-
symptoms in PD, which can be done at the symptom or tric (GE), Neuroderm, Neurocrine, Sanofi, Sinopia, Suno-
patient level, with some previous research showing broad vion, TEVA, Takeda, Voyager, and US WorldMeds. Cho
clusters including non-motor symptoms in early PD,13,39 has nothing to disclose. Coffey received grant funding
with subtypes also predicting long-term course.14,39 from the Michael J. Fox Foundation, NHLBI, and NINDS
Examining clustering of only NPS symptoms using PCA as well as consulting fees from the Michael J. Fox Foun-
in our PD cohort, only the first component (depression dation. Aarsland reports research support or honoraria
and anxiety symptoms) accounted for >20% of the vari- from AstraZeneca, H. Lundbeck, Novartis Pharmaceuti-
ance in NPS at either baseline or year 5, indicating lim- cals and GE Health; served as paid consultant for H.
ited clustering of symptoms in this cohort. Lundbeck, Biogen, Eisai, Heptares, Sanofi and Mentis
Limitations of the study include different inclusion cri- Cura; is partly funded by the National Institute for Health
terion for PD patients and HC related to cognitive perfor- Research (NIHR) Biomedical Research Centre at South
mance (i.e. HC were required to have normal cognition London and Maudsley NHS Foundation Trust and King’s
at baseline), which precluded comparison of the two College London; the views expressed are those of the
cohorts over time, and may also have impacted the fre- author and do not necessarily those of the NHR or the
quency of NPS in the two cohorts. In addition, approxi- Department of Health and Social Care. Alcalay reports
mately 25% of patients seen at baseline did not have a 5- receiving personal fees from Sanofi, Roche, Restorbio,
year visit, with evidence for differential dropout based on Uanssen, and Biogen. Barrett has nothing to disclose.
worse cognitive performance. All instruments were self- Chahine has nothing to disclose. Eberling has nothing to
rated, and detailed questionnaires or rating scales were disclose. Espay reports receiving grants from NIH, Great
not available for some of the NPS examined. Regarding Lakes Neurotechnologies, the Michael J Fox Foundation,
use of psychiatric medications, we were not able to deter- as well as personal fees from Abbvie, TEVA, lmpax, Aca-
mine the specific indication for medication use. Finally, dia, Acorda, Cynapsus/Sunovion, Lundbeck, US World-
the cohort is relatively young (at baseline), overwhelm- Meds, UCB, Lippincott Williams & Wilkins, Cambridge
ingly white, and highly educated, which limits generaliz- University Press, Springer, and lnTrance. Hamilton has
ability. nothing to disclose. Hawkins has nothing to disclose.

458 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
D. Weintraub et al. Psychiatric Symptoms and Cognitive Abilities in Early PD

Leverenz reports receiving grants from the Michael J. Fox it critically for important intellectual content. Roy N.
Foundation, National Institute of Health, as well as other Alcalay: Drafting the work or revising it critically for
funding from the Veterans Affairs (VA) during the con- important intellectual content. Matthew J. Barrett: Draft-
duct of the study. Additionally, Dr. Leverenz receives ing the work or revising it critically for important intellec-
grants from the Lewy Body Dementia Association, grants tual content. Lana M. Chahine: Substantial contributions
and personal fees from GE ’Healthcare, grants from Gen- to the conception or design of the work; the acquisition,
zyme, grants from Alzheimer’s Drug Discovery Founda- analysis, or interpretation of data for the work; and draft-
tion, personal fees from Eisai, grants and personal fees ing the work or revising it critically for important intellec-
from Biogen, personal fees from Acadia, personal fees tual content. Jamie Eberling: Substantial contributions to
from Aptinyx, grants and personal fees from Sanofi, per- the conception or design of the work; and drafting the
sonal fees from Takeda, and grants from Avid Biophar- work or revising it critically for important intellectual con-
maceuticals. Litvan reports receiving grants from the tent. Alberto J. Espay: Substantial contributions to the
Michael J Fox Foundation during the conduct of the conception or design of the work; or the acquisition, anal-
study; grants from the National Institutes of Health, ysis, or interpretation of data for the work; drafting the
grants from the Parkinson Study Group, grants from the work or revising it critically for important intellectual con-
Lewy Body Association, as well as Abbvie, Biogen, Roche, tent. Jamie Hamilton: Drafting the work or revising it crit-
and other funding from the Lundbeck Advisory Board ically for important intellectual content. Keith A.
and Sunovion. Richard has nothing to disclose. Rosenthal Hawkins: Substantial contributions to the conception or
received support from NIH/NINOS P50NS038377, the design of the work; the acquisition, analysis, or interpreta-
Marilyn and Edward Macklin Foundation, and the tion of data for the work; drafting the work or revising it
Michael J. Fox Foundation. She also received an honorar- critically for important intellectual content. James Lev-
ium from the Edmond J. Safra Foundation and from erenz: Drafting the work or revising it critically for impor-
Functional Neuromodulation. Siderowf has nothing to tant intellectual content. Irene Litvan: Drafting the work
disclose. York has nothing to disclose. or revising it critically for important intellectual content.
Irene Richard: Drafting the work or revising it critically
for important intellectual content. Liana Rosenthal: Draft-
Author Contributions
ing the work or revising it critically for important intellec-
Daniel Weintraub (corresponding author): Substantial tual content. Andrew Siderowf: Substantial contributions
contributions to the conception or design of the work; the to the conception or design of the work; the acquisition,
acquisition, analysis, or interpretation of data for the analysis, or interpretation of data for the work; drafting
work; drafting the work or revising it critically for impor- the work or revising it critically for important intellectual
tant intellectual content; final approval of the version to content. Michele York: Drafting the work or revising it
be published; and agreement to be accountable for all critically for important intellectual content.
aspects of the work in ensuring that questions related to
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ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 461