ORIGINAL CONTRIBUTION

ONLINE FIRST

Prognosis of Mild Cognitive Impairment

in Early Parkinson Disease
The Norwegian ParkWest Study
Kenn Freddy Pedersen, MD, PhD; Jan Petter Larsen, MD, PhD; Ole-Bjorn Tysnes, MD, PhD; Guido Alves, MD, PhD

Importance: Mild cognitive impairment (MCI) is common in Parkinson disease (PD), but the prognostic value
of MCI in early PD is unknown.
Objective: To examine the course of MCI and its pro-

gression to dementia in an incident PD cohort.

Design: Prospective longitudinal cohort study.
Setting: The Norwegian ParkWest study, an ongoing
population-based study of the incidence, neurobiology,
and prognosis of PD in western and southern Norway.
Participants: A population-based cohort of 182 patients with incident PD monitored for 3 years.
Main Outcomes and Measures: Serial neuropsychological tests of attention, executive function, verbal
memory, and visuospatial skills were administered at baseline, 1 year, and 3 years. Patients were classified as having MCI and received a diagnosis of dementia according
to published consensus criteria.

Author Affiliations: The

Norwegian Centre for
Movement Disorders
(Drs Pedersen, Larsen, and
Alves) and Department of
Neurology (Drs Pedersen and
Alves), Stavanger University
Hospital, Stavanger, Norway;
and Department of Neurology,
Haukeland University Hospital,
Bergen, Norway (Dr Tysnes).

Results: Significantly more patients with MCI than with-

out MCI at baseline (10 of 37 [27.0%] vs 1 of 145 [0.7%];

relative risk, 39.2 [95% CI, 5.2-296.5]; P .001) progressed to dementia during follow-up. Of those with MCI
at baseline, 8 of 37 (21.6%) had MCI that reverted to normal cognition during follow-up. Mild cognitive impairment at the 1-year visit was associated with a similar progression rate to dementia (10 of 36 patients [27.8%]) and
reversion rate to normal cognition (7 of 36 [19.4%]). However, among the 22 patients with persistent MCI at baseline and the 1-year visit, 10 (45.5%) developed dementia and only 2 (9.1%) had MCI that reverted to normal
cognition by the end of study.
Conclusions and Relevance: Mild cognitive impairment at PD diagnosis predicts a highly increased risk for
early dementia. Repeated neuropsychological testing increases the prognostic accuracy of MCI with respect to
early dementia development in PD.

JAMA Neurol. Published online March 25, 2013.

doi:10.1001/jamaneurol.2013.2110

ATIENTS WITH PARKINSON DIS-

ease (PD) experience a highly

increased risk for dementia
(PDD) compared with the
healthy population.1,2 Parkinson disease dementia has a substantial negative effect on patients wellbeing, caregivers burden, and health care
costs.3-6 Hence, early detection of those
who are at risk to develop PDD is important for clinical trials of preventive drugs
and for management of patients care.
Mild cognitive impairment (MCI) refers
to cognitive decline that is not normal for age
but with essentially preserved basic activities of daily living, thus not severe enough
to meet diagnostic criteria of dementia. Mild
cognitive impairment initially was conceptualized as a prodrome of Alzheimer disease
(AD)7 but has subsequently been extended
tootherneurodegenerativedisordersthatmay
lead to cognitive impairment and dementia,
including PD.8

JAMA NEUROL

PUBLISHED ONLINE MARCH 25, 2013

E1

Recent evidence suggests that MCI is frequent in PD (PD-MCI), even in the earliest
disease stages,9 although various definitions of PD-MCI have been used. Uniform
criteria of PD-MCI have recently been proposed to improve comparability between
studies10 but have not been validated. Because longitudinal studies in this field are
scarce, little is known about the usefulness
of the construct of PD-MCI, particularly in
patients with early disease. To study the
prognosis and course of PD-MCI, as defined by recently proposed consensus criteria, we prospectively monitored a large,
well-characterized population-based incident PD cohort for 3 years from diagnosis.
METHODS

PARTICIPANTS
All patients participate in the Norwegian ParkWest project, a population-based study of the
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Author Aff
Norwegian
Movement
(Drs Peders
Alves) and
Neurology
Alves), Stav
Hospital, St
and Depart
Haukeland
Bergen, No

incidence, neurobiology, and prognosis of PD. A detailed description of the multiple case finding strategies and the diagnostic procedures has been published.11 The initial study cohort was recruited between November 1, 2004, and August, 31,
2006, and comprised 212 patients with incident PD, of whom
196 were drug-naive, nondepressed and nondemented, and eligible for follow-up.12 After baseline, therapy with dopaminergic medication was started, and the patients came to clinical
visits at 6-month intervals, with standardized motor, neuropsychiatric, and cognitive assessments conducted at study entry and after a mean (SD) time of 1.0 (0.1) and 3.0 (0.2) years
of follow-up. During follow-up, diagnosis changed or became
uncertain in 14 participants. The remaining 182 patients met
the National Institute of Neurological Disorders and Stroke13
and the UK PD Society Brain Bank14 diagnostic criteria for PD
at their final visit. None fulfilled the diagnostic criteria of dementia with Lewy bodies,15 AD,16 or other dementia syndromes.17 All patients were white.
The study was approved by the Regional Committee for Medical Research Ethics, Western Norway. Signed written informed consent was obtained from all participants.

CLINICAL ASSESSMENT
All patients were interviewed and examined by trained members of the ParkWest study group. A semistructured interview was performed to obtain information on clinical history
and demographic variables at baseline, 1 year, and 3 years of
follow-up. At each visit, the severity of parkinsonism was
assessed by the Unified Parkinsons Disease Rating Scale18
motor section (part III). Disease stage was determined by the
Hoehn and Yahr scale.19 Severity of depressive symptoms
was assessed using the Montgomery-A sberg Depression Rating Scale,20 which has been validated and recommended for
use in patients with PD, with a score above 17 indicating
major depression with high specificity.21

NEUROPSYCHOLOGICAL ASSESSMENT
Patients underwent a standardized program of cognitive tests
at baseline12 and follow-up visits after 1 and 3 years. Global cognitive functioning was measured using the Mini-Mental State
Examination,22 and a neuropsychological test battery minimally affected by motor performance was administered by trained
study nurses who, at reassessments, were unaware of the patients previous MCI status, to assess cognitive domains known
to be affected in PD. Attention was examined using the wordreading and color-naming parts of the Stroop test.23 Executive
functions were assessed with the Semantic Verbal Fluency Test24
and the interference condition of the Stroop test. Verbal memory
was examined using the California Verbal Learning Test II
(CVLT-II),25 from which total immediate recall (sum of trials
1-5), short-delay, and long-delay free recall scores were included. Visuospatial abilities were assessed with the Silhouettes and Cube subtest from the Visual Object and Space Perception battery.26

DIAGNOSIS OF MCI
A diagnosis of MCI in patients with PD was made according to
recently proposed consensus criteria.10 In the present study, patients were required to meet the following criteria: (1) objective cognitive deficits as defined by at least 2 neuropsychological test scores falling 1.5 SDs or more below the mean value of
appropriate norms, (2) subjective cognitive problems reported by patients or family members as defined by a score
greater than 3.0 on the Informant Questionnaire on Cognitive
JAMA NEUROL

Decline in the Elderly,27 or a score of 1 or more on item 1 (intellectual impairment) of the Unified Parkinsons Disease Rating Scale part I (mentation, behavior, and mood section), (3)
no functional impairment in basic activities of living caused by
cognitive dysfunction (see the Diagnosis of Dementia subsection), and (4) not demented. Published normative data for all
neuropsychological tests were applied, correcting for age, as
well as sex and educational level, if possible.25,28-30 Because neuropsychological testing did not include measures of language
function, subclassification of PD-MCI was not performed (level
I criteria).10

DIAGNOSIS OF DEMENTIA
A diagnosis of possible or probable PDD was made by consensus between 2 of the authors (K.F.P. and G.A.) according to
published criteria31 on the basis of all available information, including neuropsychological testing, evidence of temporal cognitive decline as assessed by neuropsychological test scores and
Mini-Mental State Examination scores, and a standardized interview to assess functional impairment caused by cognitive dysfunction (including information about impaired occupational
functioning leading to disability benefit or the new appearance of problems with self-administration of medication and/or
car driving but not associated with motor impairment). Presence of apathy, hallucinations, or delusions was considered supportive but not mandatory for the diagnosis of PDD.31 Exclusion criteria for PDD included features suggesting other
comorbid conditions or diseases as the cause of mental impairment, such as acute confusion due to systemic diseases or drug
intoxication, major depression, and abrupt deterioration or stepwise progression of cognitive deficits indicating cerebrovascular disease.

FOLLOW-UP
The flow of patients through the study period is summarized
in the Figure. Of the 182 patients who met the criteria for PD
at diagnostic reevaluation, we could account for dementia status in all by the studys end, including 8 who withdrew consent from study participation (none with PDD after 3 years of
routine clinical follow-up). In addition, 8 patients died during
follow-up. Of these, 7 had not developed dementia, whereas 1
patient developed PDD 2 years after diagnosis, 6 months before death.

STATISTICAL ANALYSIS
Dementia incidence was estimated as the number of cases with
dementia divided by the total number of person-years at risk
during follow-up. Person-years at risk were estimated as the
total follow-up time until dementia, death, or study end for those
who remained nondemented. For cases of incident dementia,
the time of dementia onset was assumed to be the midpoint of
the interval between assessments at which dementia was diagnosed.1 Proportions and relative risks (RRs) with 95% CIs were
calculated. Group differences in demographic, clinical, and neuropsychological variables were analyzed with the independentsample unpaired t test, Mann-Whitney test, 2 test, and Fisher
exact test where appropriate. The paired Wilcoxon signed rank
test was used to compare differences in neuropsychological variables over time (baseline and follow-up surveys) and to calculate effect sizes. The effect size, r, was considered small if 0.1,
medium for 0.3, and large when 0.5 or greater.32 Analyses were
performed using commercial software (PASW, version 18.0;
SPSS/IBM). Two-tailed analysis was conducted, with P.05 considered significant.

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RESULTS

BASELINE CHARACTERISTICS
Of the 182 patients with incident PD included in this
3-year follow-up study, 37 patients (20.3%) met the cri-

212 In original ParkWest cohort

5 Not drug-naive at baseline

7 Had PDD at baseline
4 Had major depression at
baseline

Alves et al11

Aarsland et al12

196 In PD cohort assessed for

MCI at baseline

14 With diagnosis changed or

uncertain

182 Available for longitudinal

MCI study at baseline study
visit

4 Withdrew from study

follow-up

178 Had MCI and PDD status

available at 1-y study visit
Present study
4 Withdrew from study
follow-up

7 Died without PDD

8 Had PDD status

available at clinical
follow-up after 3 y

167 Had MCI and PDD

status available at 3-y
study visit

Figure. Flowchart summarizing the number and outcome of follow-up

assessments in the original ParkWest cohort. MCI indicates mild cognitive
impairment; PD, Parkinson disease; and PDD, PD with dementia.

teria of MCI at baseline, whereas 145 patients (79.7%)

did not (Table 1). Patients with MCI at baseline were
older and had less education, longer disease duration,
more severe parkinsonism, and lower Mini-Mental State
Examination scores than did those without MCI. There
were no significant differences regarding sex, severity of
depressive symptoms, or drug use.
MCI STATUS AND RISK OF DEMENTIA
Ten of 37 patients (27.0%) with MCI vs only 1 of 145
patients (0.7%) without MCI at baseline developed incident dementia within 3 years of follow-up, all meeting
the criteria of probable PDD. Hence, the sensitivity was
90.9% and the specificity was 84.2% for MCI at baseline
to detect patients with dementia development during the
first 3 years after PD was diagnosed. The corresponding
positive predictive value was 27.0% and the negative predictive value was 99.3%.
The RR for dementia in patients with MCI vs non-MCI
at baseline was 39.2 (95% CI, 5.2-296.5; P .001). The
incidence rate of dementia per 1000 person-years of observation was 2.3 (95% CI, 0.1-12.8) in patients without
MCI at baseline, 98.9 (95% CI, 47.4-181.9) in patients with
MCI at baseline, and 20.5 (95% CI, 10.2-36.7) overall.
At the 1-year follow-up, MCI status was available in
178 patients, with 36 patients (20.2%) classified as MCI
and 142 patients (79.8%) as non-MCI (Table 2). Mild
cognitive impairment at 1 year was equally predictive of
incident dementia during follow-up as MCI at PD diagnosis (27.8% vs 27.0%), and the reversion rate to normal cognition at the final visit was also similar (19.4%
for MCI at the 1-year visit compared with 21.6% for MCI
at baseline). However, the combination of MCI status at
baseline and 1 year of follow-up demonstrated that, among
patients with MCI on both occasions, 45.5% converted
to dementia and only 9.1% reverted to normal cognition. Thus, the sensitivity was 90.9% and the specificity
was 92.8%, whereas the positive predictive value was

Table 1. Baseline Demographic and Clinical Characteristics of Incident Parkinson Disease Patients With and Without
Mild Cognitive Impairment
Patients, Mean (SD)
Characteristic
yb

Age,
Female sex, No. (%)
Educational level, y
Disease duration, y
UPDRS motor score
Hoehn and Yahr stage
Test score
MMSE
MADRS
Antidepressants, No. (%) c
Sedatives, No. (%) c

All
(N = 182)

PDNo MCI
(n = 145)

PD-MCI
(n = 37)

P Value a

67.5 (9.3)
73 (40.1)
11.1 (3.3)
2.3 (1.8)
22.9 (11.0)
1.9 (0.6)

66.6 (9.6)
58 (40.0)
11.5 (3.4)
2.1 (1.6)
21.3 (10.3)
1.8 (0.6)

70.9 (7.1)
15 (40.5)
9.8 (2.5)
2.9 (2.4)
29.1 (11.7)
2.2 (0.7)

.003
.95
.01
.04
.001
.001

27.9 (2.3)
4.2 (4.3)
23 (12.6)
18 (9.9)

28.2 (1.9)
4.2 (4.3)
19 (13.1)
12 (8.3)

26.8 (3.2)
3.8 (4.7)
4 (10.8)
6 (16.2)

.002
.47
.79
.21

Abbreviations: MADRS, Montgomery-A sberg Depression Rating Scale; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; PD, Parkinson
disease; UPDRS, Unified Parkinsons Disease Rating Scale.
a For PDno MCI vs PD-MCI.
b Independent-sample t test.
c Fisher exact test.

JAMA NEUROL

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Table 2. Evolution of MCI in Early PD

Status at 3-y Follow-up, No. (%)
Time (No. of Patients)

Cognitively Normal

PD-MCI

PDD

Dead

Withdrew

8 (21.6)
7 (19.4)
2 (9.1)

12 (32.4)
15 (41.7)
7 (31.8)

10 (27.0)
10 (27.8)
10 (45.5)

3 (8.1)
3 (8.3)
2 (9.1)

4 (10.8)
1 (2.8)
1 (4.5)

PD-MCI
Baseline (n = 37)
1-y Follow-up (n = 36)
Baseline and 1-y follow-up (n = 22)

Abbreviations: MCI, mild cognitive impairment; PD, Parkinson disease; PDD, Parkinson disease with dementia.

Table 3. Baseline Demographic and Clinical Characteristics

in Patients With PD-MCI According to Dementia Status
at Final Visit a

Table 4. Baseline Neuropsychological Test Performance

in Patients With PD-MCI According to Dementia Status
at Final Visit a

PD-MCI, Mean (SD)

Characteristic
Age, y b
Female, sex, No. (%) c
Educational level, y
Disease duration, y
UPDRS motor score b
Hoehn and Yahr stage
Test score
MMSE
MADRS
Antidepressants, No. (%) c
Sedatives, No. (%) c

PD-MCI, Mean (SD)

Nonconverters
(n = 27)

Converters
(n = 10)

P Value

69.4 (7.3)
10 (37.0)
9.7 (2.6)
2.7 (2.2)
27.6 (11.1)
2.1 (0.6)

74.9 (4.7)
5 (50.0)
10.1 (2.5)
3.4 (2.9)
33.2 (13.0)
2.4 (0.7)

.03
.71
.64
.52
.20
.15

27.3 (2.7)
3.8 (4.9)
4 (14.8)
4 (14.8)

25.3 (4.0)
3.9 (4.2)
0
2 (20.0)

.09
.93
.56
.65

Abbreviations: MADRS, Montgomery-A sberg Depression Rating Scale;

MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination;
PD, Parkinson disease; UPDRS, Unified Parkinsons Disease Rating Scale.
a All baseline characteristics were obtained in off-medication
(dopaminergic drugnaive) state.
b Independent-sample t test.
c Fisher exact test.

45.5% and the negative predictive value was 99.4% for

persistent MCI at 1 year to detect incident dementia within
3 years of PD diagnosis.
PREDICTORS OF MCI CONVERSION
TO DEMENTIA
Patients with MCI that converted to dementia were older
and showed more deficits on measures of attention (Stroop
color) and verbal memory (CVLT-II total immediate and
total delayed free recall) at baseline than MCI nonconverters but did not differ significantly in other demographic, clinical, or neuropsychological variables (Table 3
and Table 4). There were no significant differences in
the use of levodopa, dopamine agonists, or entacapone
between MCI converters and nonconverters at their final visit. None of the MCI converters were receiving
monoamine oxidase inhibitors (Table 5).
REVERSAL OF MCI
Eight patients with MCI at baseline reverted to normal
cognition at the end of follow-up. Among these, 6 patients had less than 2 impaired neuropsychological tests,
and 2 failed to meet both objective and subjective cogJAMA NEUROL

Characteristic

Nonconverters
(n = 27)

Converters
(n = 10)

P Value

63.6 (16.5)
43.2 (14.3)
13.9 (4.2)
18.0 (7.2)

54.7 (15.0)
30.3 (10.7)
10.7 (4.6)
13.0 (8.4)

.15
.01
.06
.08

27.3 (9.8)
11.3 (6.2)

19.1 (6.3) e
6.4 (3.0) e

.02
.04

15.4 (3.3)
8.7 (1.8)

15.6 (3.3)
8.2 (2.0)

.97
.49

Stroop
Word b
Color b
Semantic fluency b
Stroop interference b
CVLT-II total, recall
Immediate c
Delayed free b,d
VOSP
Silhouettes
Cube

Abbreviations: CVLT-II, California Verbal Learning Test II; MCI, mild

cognitive impairment; PD, Parkinson disease; VOSP, Visual Object and Space
Perception battery.
a All neuropsychological baseline data were obtained in off-medication
(dopaminergic drug-naive) state, and are given as raw scores.
b Independent-sample t test.
c The CVLT-II total immediate recall score is the sum of scores from trials
1 through 5.
d The CVLT-II total delayed free recall score is the sum of the short-delay
and long-delay free recall scores.
e Data were available for 8 patients.

Table 5. Dopaminergic Drug Treatment in PD-MCI

Converters and MCI Nonconverters at Final Visit
PD-MCI, No. (%)
Drug or Drug Class

Nonconverters
(n = 27)

Converters
(n = 10)

P Value a

Levodopa
Entacapone
Dopamine agonist
MAOI-B

16 (59.3)
0
10 (37.0)
10 (37.0)

8 (80.0)
2 (20.0)
1 (10.0)
0

.44
.07
.22
.04

Abbreviations: MAOI-B, monoamine oxidase inhibitor type B; MCI, mild

cognitive impairment; PD, Parkinson disease.
a Fisher exact test.

nitive criteria of MCI at follow-up. Patients with MCI that

reverted to normal cognition during follow-up were significantly younger (P = .003) and had shorter disease duration (P = .03), less severe parkinsonism (P = .04), and
better test performance on the Stroop word (P = .002),
Stroop color (P = .001), semantic fluency (P = .02), and
CVLT-II total immediate recall (P = .045) at baseline than

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did MCI converters. Please refer to eTables 1 and 2 (http:

//www.jamaneuro.com) for more details. The MCI reverters also showed significant improvement in Stroop
interference and CVLT-II total immediate recall scores
between baseline and 3-year follow-up (median, 20.0 vs
25.0, P = .01; and median, 23.5 vs 33.0, P = .03), with
large effect sizes (r = 0.63 and 0.56, respectively) but exhibited no significant differences in other neuropsychological variables over time (data not shown). Neither MCI
reverters nor patients with stable MCI were using cholinesterase inhibitors at their final visit compared with
20% of the MCI converters.
COMMENT

This prospective population-based study of an incident

PD cohort demonstrates that MCI within the first year
of PD diagnosis signals a highly increased risk for early
incident dementia. More than 25% of patients with MCI
at diagnosis of PD developed dementia within 3 years of
follow-up compared with less than 1% of patients without MCI at PD diagnosis. Among patients with MCI at
baseline and 1 year of follow-up, almost half progressed
to dementia. These findings support the validity of the
MCI concept in patients with early PD.
Although long-term studies in PD demonstrate that
most patients will eventually develop dementia,33,34 the
time of onset of dementia and less severe cognitive deficits is highly variable.35,36 Future interventions are likely
to yield the most benefit if initiated early, when cognitive deficits are mild. The construct of MCI in PD has
received increased attention during the past 5 years37 but
prospective longitudinal studies using formal MCI criteria have not been published, except one study of advanced PD.38 Only recently, a task force of the Movement Disorder Society has proposed specific guidelines
and uniform diagnostic criteria for MCI in PD.10 These
criteria allow diagnosing PD-MCI based on comprehensive (level II) or abbreviated (level I) cognitive assessment, with the latter being more suitable for clinical
practice as well as for large-scale studies such as ours.
Our prospective study demonstrates that MCI, meeting
level I criteria, in the first year of PD diagnosis is highly
sensitive (91% sensitivity) in detecting patients who will
develop early PDD. Equally important, our data show that
patients without MCI at PD diagnosis are likely to remain free of dementia for at least 3 years, with a negative predictive value of more than 99%. The low positive predictive value (27%) was not unexpected given the
relatively short follow-up period. Whether more extensive neuropsychological testing and follow-up may further improve these figures remains to be clarified.
The pattern of cognitive impairment in PD is heterogeneous, both in cognitive profile, 3 7 pathologic
changes,39,40 and genetic contributions.41 In our cohort,
impairment in verbal memory and attention was associated with conversion from MCI to PDD. This is consistent with previous studies that have shown frontal/
executive and verbal memory deficits to be associated with
the development of PDD,42,43 although others have also
found visuospatial dysfunction44 to predict incident deJAMA NEUROL

mentia in PD. These inconsistencies deserve further investigations but may reflect different definitions of cognitive impairment and PDD, differences in sample
characteristics, or biological heterogeneity. In addition,
individual differences in cognitive reserve could account for some of these inconsistencies. Educational level
is frequently used as a proxy of cognitive reserve, and
there is some evidence to suggest that higher educational level may protect against cognitive decline in PD.45
Although patients with MCI in our study had lower educational levels than did those with MCI at baseline, we
found no significant differences between MCI converters and those who did not convert to dementia. However, the small sample size in each MCI subgroup, combined with the short follow-up, does not allow firm
conclusions. Studies with larger MCI cohorts, longer follow-up, and more detailed assessment of cognitive reserve are needed to clarify this issue.
The overall incidence of PDD in our study was 20.5
per 1000 person-years of observation but with substantial differences between patients with (98.9) and without (2.3) MCI. Hence, the incidence of PDD was largely
driven by participants with PD-MCI. The proportion of
patients with and without MCI may vary between studies depending on recruitment strategies and clinical characteristics, such as age, disease severity, and duration of
PD. Calculating the incidence of PDD among patients with
PD-MCI (separately from patients without PD-MCI) may
provide more stable estimates across different populations (ie, clinic vs population-based) and disease stages
and thus increase comparability between studies.46
Among patients with MCI at PD diagnosis, 27% developed incident dementia within 3 years, corresponding to an
annual progression rate of MCI to dementia of 9% in early
PD. One previous longitudinal study38 of advanced PD reported that 62% of patients with MCI developed dementia
during 4 years of follow-up, equivalent to an annual rate of
MCI conversion to dementia of 15.5%. These figures are consistent with studies47 in non-PD populations, reporting annual progression rates from MCI to dementia (mainly of Alzheimer disease type) of 6% to 10% in population-based cohorts and 10% to 15% in clinic-based samples.
However, longitudinal studies of MCI in non-PD populations also show that MCI in a considerable proportion
of patients remains stable over time or even reverts to
normal cognition; in large and well-designed communitybased cohorts, reversion rates of 14% to 41% have been
reported,48-50 even when MCI was based on comprehensive cognitive test batteries. In our population-based PD
cohort, we found that less than 25% of the patients with
MCI at PD diagnosis were determined to have normal
cognition at 3-year follow-up. However, among patients with persistent MCI during the first year of PD diagnosis, the reversion rate was considerably lower (9.1%),
and in almost half, MCI progressed to dementia within
the subsequent 2 years of follow-up. Hence, our study
demonstrates that repeated neuropsychological testing
during the first year of PD diagnosis increases the prognostic value of MCI in early PD, which has implications
for clinical practice and future research.
Potential explanations for the observed reversal of PDMCI in some of our patients include disease-related or

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unrelated comorbidities, measurement errors, learning

effects due to repeated neuropsychological testing, or improved cognition after initiation of symptomatic treatment.51 Although our study does not allow direct conclusions in this respect, we observed a significant
improvement in Stroop interference and CVLT-II total
immediate recall test performance over time in patients
in whom MCI reverted to normal cognition. The former
may indicate a cognition-enhancing effect of dopaminergic drugs resulting from increased response inhibition, which is partly mediated by frontostriatal dopamine pathways.51 Given the progressive nature of PD,
dopaminergic drug effects on cognition are likely to be
transient. Longer follow-up of our cohort will clarify
whether early PD-MCI reverters are prone to reconvert
to having MCI that may progress to dementia in a longterm perspective.
Strengths of this study include the (1) populationbased incident PD cohort, (2) comprehensive and prospective procedures to diagnose PD and to exclude individuals with alternative diagnoses, (3) repeated
neuropsychological assessments, and (4) diagnosis of PDMCI and PDD according to recently published diagnostic criteria. Our study also has limitations, such as the
(1) limited battery of cognitive tests because of the population-based design, (2) relatively few participants with
PDD, as expected in early PD, and (3) rather short follow-up period. These limitations, however, do not bias
our observation that MCI during the first year after PD
diagnosis predicts a highly increased risk for early dementia development in PD. Longitudinal studies with longer follow-up periods are needed to further examine the
cognitive trajectories of MCI in PD, their biological correlates, and their effect on dementia risk in a long-term
perspective.
Accepted for Publication: December 10, 2012.
Published Online: March 25, 2013. doi:10.1001
/jamaneurol.2013.2110
Correspondence: Kenn Freddy Pedersen, MD, PhD, The
Norwegian Centre for Movement Disorders, Stavanger
University Hospital, PO Box 8100, N-4068 Stavanger, Norway (kenfrp@online.no).
Author Contributions: Drs Pedersen and Alves had full
access to all the data in the study and take responsibility
for the integrity of the data and the accuracy of the data
analysis. Study concept and design: All authors. Acquisition of data: Pedersen, Tysnes, and Alves. Analysis and
interpretation of data: Pedersen, Larsen, and Alves. Drafting of the manuscript: Pedersen and Alves. Critical revision of the manuscript for important intellectual content: All
authors. Statistical analysis: Pedersen and Alves. Obtained funding: Larsen, Tysnes. Study supervision: Larsen
and Alves.
Conflict of Interest Disclosures: Dr Pedersen has received speaker honoraria from H. Lundbeck A/S. Dr Larsen
has served on scientific advisory boards for H. Lundbeck A/S and GlaxoSmithKline, has received speaker
honoraria from GlaxoSmithKline and Orion Pharma,
serves as associate editor of the Journal of Parkinsons Disease, and has received research support from the Western Norway Health Trust, the Norwegian Research CounJAMA NEUROL

sel, and the Norwegian Parkinson Disease Association.

Dr Tysnes has served on scientific advisory boards for
H. Lundbeck A/S and GlaxoSmithKline, has received
speaker honoraria from GlaxoSmithKline and Orion
Pharma, and serves on the editorial board of Acta Neurologica Scandinavica. Dr Alves has received speaker honoraria from H. Lundbeck A/S and Orion Pharma.
Funding/Support: The Norwegian ParkWest study was
supported by grant 911218 from the Western Norway
Regional Health Authority, grant 177966 from the Research Council of Norway, and the Norwegian Parkinson Disease Association.
Role of the Sponsors: The sponsors of the study had no
role in the study design, data collection, data analysis,
data interpretation, or writing of the report.
Online-Only Material: The eTables are available at http:
//www.jamaneuro.com.
Additional Contributions: The authors are grateful to
all patients for their willingness to participate in this study
and thank all personnel involved in planning and conducting the Norwegian ParkWest study.
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